Kinesin KIF18a inhibitor, and application thereof
By developing compounds that can inhibit KIF18A, the problem of difficulty in effectively inhibiting KIF18A in the prior art has been solved, and the inhibition of cancer cell proliferation and division has been achieved, providing new possibilities for cancer treatment.
Patent Information
- Application Number
- PCT/CN2024/121098
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2024-03-28
- Filing Date
- 2024-09-25
- Publication Date
- 2025-04-03
AI Technical Summary
The prior art is difficult to effectively inhibit kinesin KIF18A, resulting in challenges in cancer treatment.
A new class of compounds has been developed that have inhibitory activity against KIF18A and can bind alone or with microtubules to regulate the function of the KIF18A protein.
By inhibiting KIF18A, compounds can inhibit the proliferation and division of cancer cells, providing a new anti-cancer treatment.
Smart Images
Figure PCTCN2024121098-FTAPPB-I100001 
Figure PCTCN2024121098-FTAPPB-I100002 
Figure PCTCN2024121098-FTAPPB-I100003
Abstract
Description
Kinesin KIF18A inhibitors and their applications Technical Field
[0001] The present disclosure belongs to the field of medicine and relates to a class of kinesin KIF18A inhibitors and their use in inhibiting cancer cell proliferation and treating cancer. Background Art
[0002] KIF18A, a member of the kinesin-8 family of kinesins, uses the energy released by ATP hydrolysis to propel it along microtubules toward the positive pole within the cell. KIF18A is localized at the positive end of microtubules, where it regulates their dynamic instability, exerting an activity similar to that of a microtubule depolymerase. During mitosis, KIF18A regulates spindle microtubule dynamics and chromosome amplitude, playing a key role in ensuring the timely alignment of chromosomes during mitosis, maintaining genomic stability, and enabling the successful completion of mitosis.
[0003] The KIF18A gene belongs to the kinesin-8 subfamily of kinesins and is a plus-end-directed motor. KIF18A is thought to affect the dynamics of the plus ends of centromere microtubules to control correct chromosome positioning and spindle tension. Depletion of human KIF18A in HeLa cervical cancer cells leads to longer spindles, increased chromosome oscillation in metaphase, and activation of the mitotic spindle assembly checkpoint (MI Mayr et al., Current Biology 17, 488–98, 2007). KIF18A appears to be a viable target for cancer therapy. KIF18A is overexpressed in many types of cancer, including but not limited to colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, and ovarian cancer. In addition, in cancer cell lines, gene deletion or knockout or KIF18A inhibition affects the mitotic spindle apparatus. In particular, inhibition of KIF18A has been found to induce mitotic cell arrest, a known vulnerability that can promote mitotic cell death by apoptosis, mitotic catastrophe, or multiphase-driven lethality or death following mitotic slippage in interphase. Consequently, there is intense interest in finding inhibitors of the KIF18A protein. Therefore, inhibition of KIF18A ATPase activity is a promising approach for developing new anticancer agents.
[0004] Summary of the Invention
[0005] The present disclosure belongs to the field of medicine and relates to a class of kinesin KIF18A inhibitors, specifically to the compounds or their stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof or their pharmaceutically acceptable salts, cocrystals, metabolites, solvates, prodrugs or isotope-labeled forms, methods for preparing the compounds, and pharmaceutical compositions containing the compounds and their use as therapeutic agents, in particular, as agents for inhibiting cancer cell proliferation and treating cancer.
[0006] The present disclosure provides a novel class of compounds for use in regulating KIF18A protein, alone or in a binding complex with microtubules, for treating KIF18A-mediated conditions and / or diseases, including cancer, inflammation, or ciliary pathology.
[0007] The present disclosure provides compounds having MT-based KIF18A modulatory activity, particularly KIF18A inhibitory activity. To this end, the present disclosure also provides the use of these compounds and pharmaceutically acceptable salts thereof in the preparation and manufacture of pharmaceutical compositions or medicaments for the therapeutic, prophylactic, acute or chronic treatment of KIF18A-mediated diseases and disorders (including but not limited to cancer).
[0008] The present disclosure provides a technical solution:
[0009] Compounds having the following formula (I), and pharmaceutically acceptable salts, stereoisomers, isotopic isomers, and tautomers thereof:
[0010] Among them, Cy2 represents
[0011] Among them, * indicates the site connected to Y, and the wavy line indicates the site connected to L1;
[0012] in, Indicates a single bond or a double bond;
[0013] Among them, X1 represents CR W1 or N;
[0014] Among them, X2 represents CR W2 or N;
[0015] Among them, X3 represents CR W3 or N;
[0016] Among them, X4 represents CR W4 or N;
[0017] Among them, X5 represents CR W5 or N;
[0018] Among them, X6 represents CR W6 or N;
[0019] Among them, X7 represents CR W7 or N;
[0020] Among them, R W1 、R W2 、R W3 、R W4 、R W5 、R W6 、R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3Ra 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0021] Alternatively, the chemical bond between X2 and X3 may also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which may arbitrarily contain 0, 1, 2, or 3 heteroatoms selected from O, S, N, and Se; and the ring may also be selected from 0 to 3 of the following substituents: each independently representing hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0022] Alternatively, the chemical bond between X5, X6 or X6, X7 may be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which may contain 0, 1, 2, or 3 heteroatoms selected from O, S, N, and Se; and the ring may be further selected from 0-3 of the following substituents: each independently representing hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a Rb 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R bsubstituted by a substituent;
[0023] Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring;
[0024] Wherein, Y represents absence, -CH2-, -O-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups:
[0025] or Cy3;
[0026] Wherein, * indicates the site of connection with ring A; the wavy line indicates the site of connection with Y2;
[0027] wherein Cy1 and Cy3 each independently represent a substituted or unsubstituted 3-10 membered saturated or unsaturated cycloalkyl, 6-10 membered saturated or unsaturated spirocycloalkyl, 6-10 membered saturated or unsaturated bridged cycloalkyl, 6-10 membered saturated or unsaturated condensed cycloalkyl, 3-10 membered saturated or unsaturated heterocycloalkyl, 6-10 membered saturated or unsaturated spiroheterocycloalkyl, 6-10 membered saturated or unsaturated bridged heterocycloalkyl, 6-10 membered condensed heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NRa R b substituted by a substituent;
[0028] Wherein, Y1 represents -(CR a R b ) m -; Y2 represents -(CR a R b ) n -;
[0029] Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、PO(R a R b ),-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、—C≡C—、 5-6 membered heteroaryl, replaced by;
[0030] Among them, R L Indicates L2-R M ;
[0031] Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2、-NR a P(O)(OR a )2 or -NRa P(O)(R a )2-;
[0032] Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted C1-C6 alkyl or C3-C6 cycloalkyl;
[0033] Alternatively, L2-R M express
[0034] Wherein, m and n each independently represent an integer from 0 to 10;
[0035] Among them, R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a 、R b Together with the atoms to which they are connected, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S, N and Se.
[0036] In addition, the present disclosure provides a compound having the structure of the following formula (I-1), and pharmaceutically acceptable salts, stereoisomers, isotopic isomers, and tautomers thereof:
[0037] in, Indicates a single bond or a double bond;
[0038] Among them, X1 represents CR W1 or N;
[0039] Among them, X2 represents CR W2 or N;
[0040] Among them, X3 represents CR W3 or N;
[0041] Among them, X4 represents CR W4 or N;
[0042] Among them, X5 represents CR W5 or N;
[0043] Among them, X6 represents CR W6or N;
[0044] Among them, X7 represents CR W7 or N;
[0045] Among them, R W1 、R W2 、R W3 、R W4 、R W5 、R W6 、R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0046] Alternatively, the chemical bond between X2 and X3 may also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which may arbitrarily contain 0, 1, 2, or 3 heteroatoms selected from O, S, N, and Se; and the ring may also be selected from 0 to 3 of the following substituents: each independently representing hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0047] Alternatively, the chemical bond between X5, X6 or X6, X7 may be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which may contain 0, 1, 2, or 3 heteroatoms selected from O, S, N, and Se; and the ring may be further selected from 0-3 of the following substituents: each independently representing hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)ORb 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent;
[0048] Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring;
[0049] Wherein, Y represents absence, -CH2-, -O-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups:
[0050] or Cy3;
[0051] Wherein, * indicates the site of connection with ring A; the wavy line indicates the site of connection with Y2;
[0052] wherein Cy1 and Cy3 each independently represent a substituted or unsubstituted 3-10 membered saturated or unsaturated cycloalkyl, 6-10 membered saturated or unsaturated spirocycloalkyl, 6-10 membered saturated or unsaturated bridged cycloalkyl, 6-10 membered saturated or unsaturated condensed cycloalkyl, 3-10 membered saturated or unsaturated heterocycloalkyl, 6-10 membered saturated or unsaturated spiroheterocycloalkyl, 6-10 membered saturated or unsaturated bridged heterocycloalkyl, 6-10 membered condensed heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent;
[0053] Wherein, Y1 represents -(CR a R b ) m -; Y2 represents -(CR a R b ) n -;
[0054] Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、—C≡C—、 5-6 membered heteroaryl, replaced by;
[0055] Among them, R L Indicates L2-R M ;
[0056] Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2、-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-;
[0057] Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted C1-C6 alkyl or C3-C6 cycloalkyl;
[0058] Alternatively, L2-R M express
[0059] Wherein, m and n each independently represent an integer from 0 to 10;
[0060] Among them, R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a 、R b Together with the atoms to which they are connected, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S, N and Se.
[0061] Wherein, X1 represents CH or N, preferably CH.
[0062] In a preferred embodiment of formula (I) or formula (I-1), X2 represents CH or N, preferably CH.
[0063] In a preferred embodiment of formula (I) or formula (I-1), X3 represents CH or N, preferably CH.
[0064] In the preferred embodiment of formula (I) or formula (I-1), the chemical bond between X2 and X3 is fused with ring B to form a group of the following structure:
[0065] In a preferred embodiment of formula (I) or formula (I-1), X4 represents CH or N, preferably N.
[0066] In the preferred embodiment of formula (I) or formula (I-1), wherein X5 represents CR W5 or N, where R W5 It represents hydrogen, halogen, CH3O, CF3, CHF2, CH2F, NH2, -N(CH3)2, CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
[0067] In the preferred embodiment of formula (I) or formula (I-1), wherein X6 represents CR W6 or N, where R W6 It represents hydrogen, halogen, -CH3O, -CF3, -CHF2, -CH2F, -NH2, -N(CH3)2, -CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
[0068] In a preferred embodiment of formula (I) or formula (I-1), X7 represents CH or N, preferably N.
[0069] In the preferred embodiment of formula (I) or formula (I-1), the chemical bond between X5 and X6 is fused with ring A to form a group of the following structure:
[0070] In the preferred embodiment of formula (I) or formula (I-1), the chemical bond between X6 and X7 is fused with ring A to form a group of the following structure:
[0071] In the preferred embodiment of formula (I) or formula (I-1), wherein Cy1 represents the following group:
[0072] Among them, when When it represents a double bond, R means it does not exist; When it represents a single bond, R represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3;
[0073] wherein R1, R1', R2, R2', R3, R3', R4, and R4' each independently represent hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl;
[0074] Or R1, R1' pair, R2, R2' pair, R3, R3' pair, R4, R4' pair together with the carbon atom to which they are connected form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and further, the ring may also be selected from 0, 1, 2, or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -OR a or substituted with an oxo substituent;
[0075] Where W1 represents -(CR s R t ) o -;
[0076] Among them, R s 、R t Each independently represents hydrogen or C1-C6 alkyl;
[0077] Among them, o represents 1 or 2;
[0078] Among them, X8 represents CR W8 or N;
[0079] Among them, X9 represents CR W9 or N;
[0080] Among them, X 10 Indicates CR W10 or N;
[0081] Among them, X 11 Indicates CR W11 or N;
[0082] Among them, R W8 、R W9 、R W10 、R W11 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NRa R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b .
[0083] In a preferred embodiment of formula (I) or formula (I-1), X8 represents CH or N.
[0084] In a preferred embodiment of formula (I) or formula (I-1), X9 represents CH or N.
[0085] In the preferred embodiment of formula (I) or formula (I-1), wherein X 10 Indicates CH or N.
[0086] In the preferred embodiment of formula (I) or formula (I-1), wherein X 11 Indicates CH or N.
[0087] In a preferred embodiment of formula (I) or formula (I-1), R1, R1', R2, R2', R3, R3', R4, and R4' each independently represent hydrogen.
[0088] In a preferred embodiment of formula (I) or formula (I-1), W1 represents -CH2 or -CH2CH2.
[0089] In the preferred embodiment of formula (I) or formula (I-1), wherein Y represents the following groups: absent, -CH2-, -O-, -Se-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups:
[0090] In a preferred embodiment of formula (I) or formula (I-1), Y represents -O- or -NH-.
[0091] In the preferred embodiment of formula (I) or formula (I-1), wherein Y represents
[0092] In the preferred embodiment of formula (I) or formula (I-1), wherein Y represents
[0093] In a preferred embodiment of formula (I) or formula (I-1), wherein Y represents Cy3, wherein Cy3 represents the following group:
[0094] Among them, when When it represents a double bond, G means it does not exist; When it represents a single bond, G represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3;
[0095] wherein G1, G1', G2, G2', G3, G3', G4, and G4' each independently represent hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl;
[0096] Or G1, G1' pair, G2, G2' pair, G3, G3' pair, G4, G4' pair together with the carbon atom connected thereto form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and further, the ring may also be selected from 0, 1, 2, or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, OR a or substituted with an oxo substituent;
[0097] Wherein, W2 represents -(CR i R j ) p -;
[0098] Among them, R i 、R j Each independently represents hydrogen or C1-C6 alkyl;
[0099] Where p represents 1 or 2;
[0100] Among them, X 12 Indicates CR W12 or N;
[0101] Among them, X 13 Indicates CR W13 or N;
[0102] Among them, X 14 Indicates CR W14 or N;
[0103] Among them, X 15 Indicates CR W15 or N;
[0104] Among them, R W12 、R W13 、R W14 、R W15 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NRa C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b .
[0105] In the preferred embodiment of formula (I) or formula (I-1), wherein X 12 Indicates CH or N.
[0106] In the preferred embodiment of formula (I) or formula (I-1), wherein X 13 Indicates CH or N.
[0107] In the preferred embodiment of formula (I) or formula (I-1), wherein X 14 Indicates CH or N.
[0108] In the preferred embodiment of formula (I) or formula (I-1), wherein X 15 Indicates CH or N.
[0109] In a preferred embodiment of formula (I) or formula (I-1), G1, G1', G2, G2', G3, G3', G4, and G4' each independently represent hydrogen.
[0110] In a preferred embodiment of formula (I) or formula (I-1), W2 represents -CH2 or -CH2CH2.
[0111] In a preferred embodiment of formula (I) or formula (I-1), wherein,
[0112] L1 represents -C(O)NR a -、-NR a C(O)-、
[0113] In a preferred embodiment of formula (I) or formula (I-1), L1 represents -C(O)NH-.
[0114] In the preferred embodiment of formula (I) or formula (I-1), L1 represents
[0115] In the preferred embodiment of formula (I) or formula (I-1), wherein Y1 represents -(CR a R b ) m -.
[0116] In a preferred embodiment of formula (I) or formula (I-1), Y1 represents -NR-C(=O)-, -OC(=O)-, or -C(=O)O-.
[0117] In the preferred embodiment of formula (I) or formula (I-1), wherein Y1 represents -O(CR a R b ) m -or-(CR a R b ) m O-.
[0118] In a preferred embodiment of formula (I) or formula (I-1), wherein Y1 represents -CR a =CR a -or-CR a R b -CR a =CR b -.
[0119] In the preferred embodiment of formula (I) or formula (I-1), wherein Y2 represents -(CR a R b ) n -.
[0120] In a preferred embodiment of formula (I) or formula (I-1), wherein Y2 represents -NR a -C(=O)-.
[0121] In the preferred embodiment of formula (I) or formula (I-1), wherein Y2 represents -O(CR a R b ) n -or-(CR a R b ) n O-.
[0122] In a preferred embodiment of formula (I) or formula (I-1), wherein Y2 represents -CR a =CR a -、-CR a =CR b -CR a R b -or-CR a R b-CR a =CR b -.
[0123] In the preferred embodiment of formula (I) or formula (I-1), wherein Y 2 represents pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or triazolyl.
[0124] In a preferred embodiment of formula (I) or formula (I-1), wherein -Y1-Y2- represents -CR a =CR a -、-CR a R b CR a =CR b -.
[0125] In a preferred embodiment of formula (I) or formula (I-1), wherein -Y1-Y2- represents -CR a R b -NR a C(O)-.
[0126] In the preferred embodiment of formula (I) or formula (I-1), wherein -Y1-Y2- represents -
[0127] In the preferred embodiment of formula (I) or formula (I-1), wherein R L represents -NHS(O)2CH2CH2OH, -NHS(O)2CH2CH3, -NHS(O)2CH3.
[0128] In addition, the present disclosure also provides a compound having a structure of formula (II) or (III), a pharmaceutically acceptable salt thereof, stereoisomers, isotope isomers, tautomers,
[0129] Among them, Cy2 represents
[0130] Among them, * indicates the site connected to Y, and the wavy line indicates the site connected to L1;
[0131] in, Indicates a single bond or a double bond;
[0132] Among them, X 1 Indicates CR W1 or N;
[0133] Among them, X 2 Indicates CR W2 or N;
[0134] Among them, X 3 Indicates CR W3 or N;
[0135] Among them, X 4 Indicates CR W4 or N;
[0136] Among them, X 5 Indicates CR W5 or N;
[0137] Among them, X 6 Indicates CR W6 or N;
[0138] Among them, X 7 Indicates CR W7 or N;
[0139] Among them, R W1 、R W2 、R W3 、R W4 、R W5 、R W6 、R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0140] Alternatively, the chemical bond between X2 and X3 may also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring may also be selected from 0 to 3 of the following substituents: each independently representing hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;- C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0141] Or the chemical bond between X5, X6 or X6, X7 can be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0-3 of the following substituents: deuterium, halogen, cyano, oxo, nitro, oxo, hydroxy C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C3-C6 cycloalkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b, -SF5 or -NR a R b substituted by a substituent;
[0142] Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring;
[0143] Wherein, Y represents absence, -CH2-, -O-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups:
[0144] or Cy3;
[0145] Wherein, * indicates the site of connection with ring A; the wavy line indicates the site of connection with Y2;
[0146] Among them, when When it represents a double bond, R means it does not exist; When it represents a single bond, R represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3;
[0147] wherein R1, R1', R2, R2', R3, R3', R4, and R4' each independently represent hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl;
[0148] Or R1, R1' pair, R2, R2' pair, R3, R3' pair, R4, R4' pair together with the carbon atom to which they are connected form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and further, the ring may also be selected from 0, 1, 2, or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -OR a or substituted with an oxo substituent;
[0149] wherein Cy3 each independently represents a substituted or unsubstituted 3-10 membered saturated or unsaturated cycloalkyl, 6-10 membered saturated or unsaturated spirocycloalkyl, 6-10 membered saturated or unsaturated bridged cycloalkyl, 6-10 membered saturated or unsaturated condensed cycloalkyl, 3-10 membered saturated or unsaturated heterocycloalkyl, 6-10 membered saturated or unsaturated spiroheterocycloalkyl, 6-10 membered saturated or unsaturated bridged heterocycloalkyl, 6-10 membered condensed heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein the substituents are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2Ra 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0150] Among them, Y 1 Indicates -(CR a R b ) m -;Y 2 Indicates -(CR a R b ) n -;
[0151] Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NRa -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、PO(R a R b ),-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、—C≡C—、 5-6 membered heteroaryl, replaced by;
[0152] Among them, R L Indicates L2-R M ;
[0153] Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2、-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-;
[0154] Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted C1-C6 alkyl or C3-C6 cycloalkyl;
[0155] Alternatively, L2-R M express
[0156] Wherein, m and n each independently represent an integer from 0 to 10;
[0157] Among them, R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a 、R b Together with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may optionally contain 0-2 heteroatoms selected from O, S, Se and N.
[0158] In addition, the present disclosure also provides a compound having a structure of formula (II-1) / (III-1), and pharmaceutically acceptable salts, stereoisomers, isotope isomers, and tautomers thereof:
[0159] in, Indicates a single bond or a double bond;
[0160] Among them, X 1 Indicates CR W1 or N;
[0161] Among them, X 2 Indicates CR W2 or N;
[0162] Among them, X 3 Indicates CR W3 or N;
[0163] Among them, X 4 Indicates CR W4 or N;
[0164] Among them, X 5 Indicates CR W5 or N;
[0165] Among them, X 6 Indicates CR W6 or N;
[0166] Among them, X 7 Indicates CR W7 or N;
[0167] Among them, R W1 、R W2 、R W3 、R W4 、R W5 、R W6 、R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0168] Alternatively, the chemical bond between X2 and X3 may also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring may also be selected from 0 to 3 of the following substituents: each independently representing hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a Rb ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0169] Or the chemical bond between X5, X6 or X6, X7 can be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0-3 of the following substituents: deuterium, halogen, cyano, nitro, oxo, hydroxy C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, halo C1-C6 alkyl, halo C2-C6 alkenyl, halo C2-C6 alkynyl, halo C3-C6 cycloalkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b , -SF5 or -NR a R b substituted by a substituent;
[0170] Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring;
[0171] Wherein, Y represents absence, -CH2-, -O-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups:
[0172] or Cy3;
[0173] Wherein, * indicates the site of connection with ring A; the wavy line indicates the site of connection with Y2;
[0174] Among them, when When it represents a double bond, R means it does not exist; When it represents a single bond, R represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3;
[0175] wherein R1, R1', R2, R2', R3, R3', R4, and R4' each independently represent hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl;
[0176] Or R1, R1' pair, R2, R2' pair, R3, R3' pair, R4, R4' pair together with the carbon atom to which they are connected form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and further, the ring may also be selected from 0, 1, 2, or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -OR a or substituted with an oxo substituent;
[0177] wherein Cy3 each independently represents a substituted or unsubstituted 3-10 membered saturated or unsaturated cycloalkyl, 6-10 membered saturated or unsaturated spirocycloalkyl, 6-10 membered saturated or unsaturated bridged cycloalkyl, 6-10 membered saturated or unsaturated condensed cycloalkyl, 3-10 membered saturated or unsaturated heterocycloalkyl, 6-10 membered saturated or unsaturated spiroheterocycloalkyl, 6-10 membered saturated or unsaturated bridged heterocycloalkyl, 6-10 membered condensed heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein the substituents are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NRa R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、 -C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a Rb ;
[0178] Among them, Y 1 Indicates -(CR a R b ) m -;Y 2 Indicates -(CR a R b ) n -;
[0179] Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、PO(R a R b ),-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、—C≡C—、 5-6 membered heteroaryl, replaced by;
[0180] Among them, R L Indicates L2-R M ;
[0181] Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2、-NR a P(O)(OR a )2 or -NRa P(O)(R a )2-;
[0182] Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted C1-C6 alkyl or C3-C6 cycloalkyl;
[0183] Alternatively, L2-R M express
[0184] Wherein, m and n each independently represent an integer from 0 to 10;
[0185] Among them, R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a 、R b Together with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may optionally contain 0-2 heteroatoms selected from O, S and N.
[0186] In a preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein X1 represents CH or N, preferably CH.
[0187] In a preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein X2 represents CH or N, preferably CH.
[0188] In a preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein X3 represents CH or N, preferably CH.
[0189] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), the chemical bond between X2 and X3 is fused with ring B to form a group of the following structure:
[0190] In a preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein X4 represents CH or N, preferably N.
[0191] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein X5 represents CR W5 or N, where R W5 It represents hydrogen, halogen, CH3O, CF3, CHF2, CH2F, NH2, -N(CH3)2, CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
[0192] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein X6 represents CR W6 or N, where R W6 It represents hydrogen, halogen, -CH3O, -CF3, -CHF2, -CH2F, -NH2, -N(CH3)2, -CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
[0193] In a preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein X7 represents CH or N, preferably N.
[0194] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), the chemical bond between X5 and X6 is fused with ring A to form a group of the following structure:
[0195] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), the chemical bond between X6 and X7 is fused with ring A to form a group of the following structure:
[0196] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y represents the following groups: absent, -CH2-, -O-, -Se-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups:
[0197] In a preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y represents -O-, -Se- or -NH-.
[0198] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y represents
[0199] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y represents
[0200] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y represents Cy3, wherein Cy3 represents the following group:
[0201] Among them, when When it represents a double bond, G means it does not exist; When it represents a single bond, G represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3;
[0202] wherein G1, G1', G2, G2', G3, G3', G4, and G4' each independently represent hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl;
[0203] Or G1, G1' pair, G2, G2' pair, G3, G3' pair, G4, G4' pair together with the carbon atom connected thereto form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and further, the ring may also be selected from 0, 1, 2, or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, OR a or substituted with an oxo substituent;
[0204] Wherein, W2 represents -(CR i R j ) p -;
[0205] Among them, R i 、R j Each independently represents hydrogen or C1-C6 alkyl;
[0206] Where p represents 1 or 2;
[0207] Among them, X 12 Indicates CR W12 or N;
[0208] Among them, X 13 Indicates CR W13 or N;
[0209] Among them, X 14 Indicates CR W14 or N;
[0210] Among them, X 15 Indicates CR W15 or N;
[0211] Among them, R W12 、R W13 、R W14 、R W15 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b .
[0212] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein X 12 Indicates CH or N.
[0213] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein X 13 Indicates CH or N.
[0214] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein X 14 Indicates CH or N.
[0215] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein X 15Indicates CH or N.
[0216] In a preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), G1, G1', G2, G2', G3, G3', G4, and G4' each independently represent hydrogen.
[0217] In a preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), W2 represents -CH2 or -CH2CH2.
[0218] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein,
[0219] L1 represents -C(O)NR a -、-NR a C(O)-、
[0220] In a preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), L1 represents -C(O)NH-.
[0221] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), L1 represents
[0222] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y1 represents -(CR a R b ) m -.
[0223] In a preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y1 represents -NR-C(=O)-, -OC(=O)-, or -C(=O)O-.
[0224] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y1 represents -O(CR a R b ) m -or-(CR a R b ) m O-.
[0225] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y1 represents -CR a=CR a -or-CR a R b -CR a =CR b -.
[0226] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y2 represents -(CR a R b ) n -.
[0227] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y2 represents -NR a -C(=O)-.
[0228] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y2 represents -O(CR a R b ) n -or-(CR a R b ) n O-.
[0229] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y2 represents -CR a =CR a -、-CR a =CR b -CR a R b -or-CR a R b -CR a =CR b -.
[0230] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein Y 2 represents pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or triazolyl.
[0231] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein -Y1-Y2- represents -CR a =CR a -、-CR a R b CR a =CR b -.
[0232] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein -Y1-Y2- represents -CR a R b -NR a C(O)-.
[0233] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein -Y1-Y2- represents -
[0234] In the preferred embodiment of formula (II) or formula (II-1) or formula (III) or formula (III-1), wherein R L represents -NHS(O)2CH2CH2OH, -NHS(O)2CH2CH3, -NHS(O)2CH3.
[0235] In addition, the present disclosure provides a compound having the structure of the following formula (I-3), its pharmaceutically acceptable salts, stereoisomers, isotope isomers, tautomers,
[0236] Among them, X 1 Indicates CR W1 or N;
[0237] Among them, X 2 Indicates CR W2 or N;
[0238] Among them, X 3 Indicates CR W3 or N;
[0239] Among them, X 4 Indicates CR W4 or N;
[0240] Among them, X 5 Indicates CR W5 or N;
[0241] Among them, X 6 Indicates CR W6 or N;
[0242] Among them, X 7 Indicates CR W7 or N;
[0243] Among them, R W1 、R W2 、R W3 、R W4 、R W5 、R W6、R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)ORa 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0244] Alternatively, the chemical bond between X2 and X3 may also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring may also be selected from 0 to 3 of the following substituents: each independently representing hydrogen, deuterium, halogen, cyano, nitro, oxo (oxo), azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent;
[0245] Alternatively, the chemical bond between X5, X6 or X6, X7 may be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which may contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring may be further selected from 0-3 substituents, each independently representing hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a Rb ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent;
[0246] Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring;
[0247] wherein R represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, or -C(O)CH3;
[0248] Wherein, X represents CR9R9', O, NR a ;
[0249] wherein R1, R1', R2, R2', R3, R3', R4, R4', R5, R5', R6, R6', R7, R7', R9, and R9' each independently represent hydrogen, C1-C6 alkyl, halogen, or C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, or halogenated C1-C6 alkyl;
[0250] Or R1, R1' pair, R2, R2' pair, R3, R3' pair, R4, R4' pair, R5, R5' pair, R6, R6' pair, R7, R7' pair, R9, R9' pair together with the carbon atom to which they are connected form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and further, the ring may also be selected from 0, 1, 2, or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -OR a or substituted with an oxo substituent;
[0251] Among them, Y 1 Indicates -(CR a R b ) m -;Y 2 Indicates -(CR a R b ) n -;
[0252] Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、PO(R a R b ),-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、—C≡C—、 5-6 membered heteroaryl, replaced by;
[0253] Among them, R L Indicates L2-R M ;
[0254] Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2、-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-;
[0255] Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted C1-C6 alkyl or C3-C6 cycloalkyl;
[0256] Alternatively, L2-R M express
[0257] Wherein, m and n each independently represent an integer from 0 to 10;
[0258] Among them, R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a 、R b Together with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may optionally contain 0-2 heteroatoms selected from O, S, Se and N.
[0259] In a preferred embodiment of formula (I-3), X1 represents CH or N, preferably CH.
[0260] In a preferred embodiment of formula (I-3), X2 represents CH or N, preferably CH.
[0261] In a preferred embodiment of formula (I-3), X3 represents CH or N, preferably CH.
[0262] In a preferred embodiment of formula (I-3), the chemical bond between X2 and X3 is fused with ring B to form a group of the following structure:
[0263] In a preferred embodiment of formula (I-3), X4 represents CH or N, preferably N.
[0264] In a preferred embodiment of formula (I-3), wherein X5 represents CR W5 or N, where R W5 It represents hydrogen, halogen, -CH3O, -CF3, -CHF2, CH2F, NH2, -N(CH3)2, -CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
[0265] In a preferred embodiment of formula (I-3), wherein X6 represents CR W6 or N, where R W6 It represents hydrogen, halogen, -CH3O, -CF3, -CHF2, -CH2F, -NH2, -N(CH3)2, -CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
[0266] In a preferred embodiment of formula (I-3), X7 represents CH or N, preferably N.
[0267] In a preferred embodiment of formula (I-3), the chemical bond between X5 and X6 is fused with ring A to form a group of the following structure:
[0268] In a preferred embodiment of formula (I-3), the chemical bond between X6 and X7 is fused with ring A to form a group of the following structure:
[0269] In a preferred embodiment of formula (I-3),
[0270] L1 represents -C(O)NR a -、-NR a C(O)-、
[0271] In a preferred embodiment of formula (I-3), L1 represents -C(O)NH-.
[0272] In the preferred embodiment of formula (I-3), L1 represents
[0273] In a preferred embodiment of formula (I-3), wherein Y1 represents -(CR a R b ) m -.
[0274] In a preferred embodiment of formula (I-3), Y1 represents -NR-C(=O)-, -OC(=O)-, or -C(=O)O-.
[0275] In a preferred embodiment of formula (I-3), wherein Y1 represents -O(CR a R b ) m -or-(CR a R b ) m O-.
[0276] In a preferred embodiment of formula (I-3), wherein Y1 represents -CR a =CR a -or-CR a R b -CR a =CR b -.
[0277] In a preferred embodiment of formula (I-3), wherein Y2 represents -(CR a R b ) n -.
[0278] In a preferred embodiment of formula (I-3), wherein Y2 represents -NR a -C(=O)-.
[0279] In a preferred embodiment of formula (I-3), wherein Y2 represents -O(CR a R b ) n -or-(CR a R b ) n O-.
[0280] In a preferred embodiment of formula (I-3), wherein Y2 represents -CR a =CR a -、-CR a =CR b -CR a Rb -or-CR a R b -CR a =CR b -.
[0281] In the preferred embodiment of formula (I-3), wherein Y 2 represents pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or triazolyl.
[0282] In a preferred embodiment of formula (I-3), wherein -Y1-Y2- represents -CR a =CR a -、-CR a R b CR a =CR b -.
[0283] In a preferred embodiment of formula (I-3), wherein -Y1-Y2- represents -CR a R b -NR a C(O)-.
[0284] In a preferred embodiment of formula (I-3), wherein -Y1-Y2- represents -
[0285] In the preferred embodiment of formula (I-3), wherein R L represents -NHS(O)2CH2CH2OH, -NHS(O)2CH2CH3, -NHS(O)2CH3.
[0286] A compound having the structure of formula (I-1-1) or formula (I-1-2), a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, a tautomer,
[0287] Among them, X 1 Indicates CR W1 or N;
[0288] Among them, X 2 Indicates CR W2 or N;
[0289] Among them, X 3 Indicates CR W3 or N;
[0290] Among them, X 4 Indicates CR W4 or N;
[0291] Among them, X 5 Indicates CRW5 or N;
[0292] Among them, X 6 Indicates CR W6 or N;
[0293] Among them, X 7 Indicates CR W7 or N;
[0294] Among them, R W1 、R W2 、R W3 、R W4 、R W5 、R W6 、R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、 -C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0295] Alternatively, the chemical bond between X2 and X3 may also be fused with ring B to form a 4-7 membered saturated or unsaturated (hetero) ring, which may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring may also be selected from 0 to 3 of the following substituents: each independently representing hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent;
[0296] Alternatively, the chemical bond between X5, X6 or X6, X7 may be fused with ring A to form a 4-7 membered saturated or unsaturated (hetero) ring, which may contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring may be further selected from 0-3 of the following substituents: each independently representing hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a Rb ) or -C0-C 10 Alkyl NR a R b substituted by a substituent;
[0297] wherein R represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, or -C(O)CH3;
[0298] Wherein, X represents CR9R9', O, NR a ;
[0299] wherein R1, R1', R2, R2', R3, R3', R4, R4', R5, R5', R6, R6', R7, R7', R9, and R9' each independently represent hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, or halogenated C1-C6 alkyl;
[0300] Or R1, R1' pair, R2, R2' pair, R3, R3' pair, R4, R4' pair, R5, R5' pair, R6, R6' pair, R7, R7' pair, R9, R9' pair together with the carbon atom to which they are connected form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and further, the ring may also be selected from 0, 1, 2, or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, OR a or substituted with an oxo substituent;
[0301] Among them, R L Indicates L2-R M ;
[0302] Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2、-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-;
[0303] Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted C1-C6 alkyl or C3-C6 (hetero)cycloalkyl;
[0304] Alternatively, L2-R M express
[0305] Wherein, m and n each independently represent an integer from 0 to 10;
[0306] Among them, R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a 、R b Together with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated (hetero) ring, which may optionally contain 0-2 heteroatoms selected from O, S, Se and N.
[0307] In a preferred embodiment of formula (I-1-1) or formula (I-1-2), X1 represents CH or N, preferably CH.
[0308] In a preferred embodiment of formula (I-1-1) or formula (I-1-2), X2 represents CH or N, preferably CH.
[0309] In a preferred embodiment of formula (I-1-1) or formula (I-1-2), X3 represents CH or N, preferably CH.
[0310] In the preferred embodiment of formula (I-1-1) or formula (I-1-2), the chemical bond between X2 and X3 is fused with ring B to form a group of the following structure:
[0311] In a preferred embodiment of formula (I-1-1) or formula (I-1-2), X4 represents CH or N, preferably N.
[0312] In the preferred embodiment of formula (I-1-1) or formula (I-1-2), wherein X5 represents CR W5 or N, where R W5It represents hydrogen, halogen, -CH3O, -CF3, -CHF2, -CH2F, -NH2, -N(CH3)2, -CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
[0313] In the preferred embodiment of formula (I-1-1) or formula (I-1-2), wherein X6 represents CR W6 or N, where R W6 It represents hydrogen, halogen, -CH3O, -CF3, -CHF2, -CH2F, -NH2, -N(CH3)2, -CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
[0314] In a preferred embodiment of formula (I-1-1) or formula (I-1-2), X7 represents CH or N, preferably N.
[0315] In the preferred embodiment of formula (I-1-1) or formula (I-1-2), the chemical bond between X5 and X6 is fused with ring A to form a group of the following structure:
[0316] In the preferred embodiment of formula (I-1-1) or formula (I-1-2), the chemical bond between X6 and X7 is fused with ring A to form a group of the following structure:
[0317] In a preferred embodiment of formula (I-1-1) or formula (I-1-2), wherein L1 represents -C(O)NR a -、-NR a C(O)-、
[0318] In the preferred embodiment of formula (I-1-1) or formula (I-1-2), wherein R L represents -NHS(O)2CH2CH2OH, -NHS(O)2CH2CH3, -NHS(O)2CH3.
[0319] In addition, the present disclosure provides a compound having the structure of formula (I-1-3), its pharmaceutically acceptable salts, stereoisomers, isotopic isomers, tautomers,
[0320] Among them, X 1 Indicates CR W1 or N;
[0321] Among them, X2 Indicates CR W2 or N;
[0322] Among them, X 3 Indicates CR W3 or N;
[0323] Among them, X 4 Indicates CR W4 or N;
[0324] Among them, X 5 Indicates CR W5 or N;
[0325] Among them, X 6 Indicates CR W6 or N;
[0326] Among them, X 7 Indicates CR W7 or N;
[0327] Among them, X8 represents CR W8 or N;
[0328] Among them, X9 represents CR W9 or N;
[0329] Among them, X 10 Indicates CR W10 or N;
[0330] Among them, X 11 Indicates CR W11 or N;
[0331] Among them, R W1 、R W2 、R W3 、R W4 、R W5 、R W6 、R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0332] Among them, R W8 、R W9 、R W10 、R W11 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0333] Alternatively, the chemical bond between X2 and X3 may also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring may also be selected from 0 to 3 of the following substituents: each independently representing hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent;
[0334] Alternatively, the chemical bond between X5, X6 or X6, X7 may be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which may contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring may be further selected from 0-3 substituents, each independently representing hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent;
[0335] Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring;
[0336] Wherein, Y represents absence, -CH2-, -O-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups:
[0337] or Cy3;
[0338] Wherein, * indicates the site of connection with ring A; the wavy line indicates the site of connection with Y2;
[0339] wherein Cy3 each independently represents a substituted or unsubstituted 3-10 membered saturated or unsaturated cycloalkyl, 6-10 membered saturated or unsaturated spirocycloalkyl, 6-10 membered saturated or unsaturated bridged cycloalkyl, 6-10 membered saturated or unsaturated condensed cycloalkyl, 3-10 membered saturated or unsaturated heterocycloalkyl, 6-10 membered saturated or unsaturated spiroheterocycloalkyl, 6-10 membered saturated or unsaturated bridged heterocycloalkyl, 6-10 membered condensed heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein the substituents are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a Rb ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0340] Among them, Y 1 Indicates -(CR a R b ) m -;Y 2 Indicates -(CR a R b ) n -;
[0341] Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、PO(R a R b ),-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、—C≡C—、 5-6 membered heteroaryl, replaced by;
[0342] Among them, R L Indicates L2-R M ;
[0343] Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a-、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2、-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-;
[0344] Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted C1-C6 alkyl or C3-C6 cycloalkyl;
[0345] Alternatively, L2-R M express
[0346] Wherein, m and n each independently represent an integer from 0 to 10;
[0347] Among them, R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a 、R b Together with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may optionally contain 0-2 heteroatoms selected from O, S and N.
[0348] In a preferred embodiment of formula (I-1-3), X1 represents CH or N, preferably CH.
[0349] In a preferred embodiment of formula (I-1-3), X2 represents CH or N, preferably CH.
[0350] In a preferred embodiment of formula (I-1-3), X3 represents CH or N, preferably CH.
[0351] In a preferred embodiment of formula (I-1-3), the chemical bond between X2 and X3 is fused with ring B to form a group of the following structure:
[0352] In a preferred embodiment of formula (I-1-3), X4 represents CH or N, preferably N.
[0353] In a preferred embodiment of formula (I-1-3), wherein X5 represents CR W5 or N, where R W5 It represents hydrogen, halogen, CH3O, CF3, CHF2, CH2F, NH2, -N(CH3)2, CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
[0354] In the preferred embodiment of formula (I-1-3), wherein X6 represents CR W6 or N, where R W6 It represents hydrogen, halogen, CH3O, CF3, CHF2, CH2F, NH2, -N(CH3)2, CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
[0355] In a preferred embodiment of formula (I-1-3), X7 represents CH or N, preferably N.
[0356] In a preferred embodiment of formula (I-1-3), the chemical bond between X5 and X6 is fused with ring A to form a group of the following structure:
[0357] In a preferred embodiment of formula (I-1-3), the chemical bond between X6 and X7 is fused with ring A to form a group of the following structure:
[0358] In the preferred embodiment of formula (I-1-3), wherein Y represents the following groups: absent, -CH2-, -O-, -Se-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups:
[0359] In a preferred embodiment of formula (I-1-3), Y represents -O- or -NH-.
[0360] In the preferred embodiment of formula (I-1-3), wherein Y represents
[0361] In the preferred embodiment of formula (I-1-3), wherein Y represents
[0362] In a preferred embodiment of formula (I-1-3), wherein Y represents Cy3, wherein Cy3 represents the following group:
[0363] Among them, when When it represents a double bond, G means it does not exist; When it represents a single bond, G represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3;
[0364] wherein G1, G1', G2, G2', G3, G3', G4, and G4' each independently represent hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, or halogenated C1-C6 alkyl;
[0365] Or G1, G1' pair, G2, G2' pair, G3, G3' pair, G4, G4' pair together with the carbon atom connected thereto form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and further, the ring may also be selected from 0, 1, 2, or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, OR a or substituted with an oxo substituent;
[0366] Wherein, W2 represents -(CR i R j ) p -;
[0367] Among them, R i 、R j Each independently represents hydrogen or C1-C6 alkyl;
[0368] Where p represents 1 or 2;
[0369] Among them, X 12 Indicates CR W12 or N;
[0370] Among them, X 13 Indicates CR W13 or N;
[0371] Among them, X 14 Indicates CR W14 or N;
[0372] Among them, X 15 Indicates CR W15 or N;
[0373] Among them, R W12 、R W13 、R W14 、R W15 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)Ra 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b .
[0374] In the preferred embodiment of formula (I-1-3), wherein X 12 Indicates CH or N.
[0375] In the preferred embodiment of formula (I-1-3), wherein X 13 Indicates CH or N.
[0376] In the preferred embodiment of formula (I-1-3), wherein X 14 Indicates CH or N.
[0377] In the preferred embodiment of formula (I-1-3), wherein X 15 Indicates CH or N.
[0378] In a preferred embodiment of formula (I-1-3), G1, G1', G2, G2', G3, G3', G4, and G4' each independently represent hydrogen.
[0379] In a preferred embodiment of formula (I-1-3), W2 represents CH2 or CH2CH2.
[0380] In a preferred embodiment of formula (I-1-3), wherein L1 represents -C(O)NR a -、-NR a C(O)-、
[0381] In a preferred embodiment of formula (I-1-3), L1 represents -C(O)NH-.
[0382] In the preferred embodiment of formula (I-1-3), L1 represents
[0383] In a preferred embodiment of formula (I-1-3), wherein Y1 represents -(CR a R b ) m -.
[0384] In a preferred embodiment of formula (I-1-3), Y1 represents -NR-C(=O)-, -OC(=O)-, or -C(=O)O-.
[0385] In a preferred embodiment of formula (I-1-3), wherein Y1 represents -O(CR a R b ) m -or-(CR a R b ) m O-.
[0386] In a preferred embodiment of formula (I-1-3), wherein Y1 represents -CR a =CR a -or-CR a R b -CR a =CR b -.
[0387] In a preferred embodiment of formula (I-1-3), wherein Y2 represents -(CR a R b ) n -.
[0388] In a preferred embodiment of formula (I-1-3), wherein Y2 represents -NR a -C(=O)-.
[0389] In a preferred embodiment of formula (I-1-3), wherein Y2 represents -O(CR a R b ) n -or-(CR a R b ) n O-.
[0390] In a preferred embodiment of formula (I-1-3), wherein Y2 represents -CR a =CR a -、-CR a =CR b-CR a R b -or-CR a R b -CR a =CR b -.
[0391] In the preferred embodiment of formula (I-1-3), wherein Y 2 represents pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or triazolyl.
[0392] In a preferred embodiment of formula (I-1-3), wherein -Y1-Y2- represents -CR a =CR a -、-CR a R b CR a =CR b -.
[0393] In a preferred embodiment of formula (I-1-3), wherein -Y1-Y2- represents -CR a R b -NR a C(O)-.
[0394] In a preferred embodiment of formula (I-1-3), wherein -Y1-Y2- represents -
[0395] In the preferred embodiment of formula (I-1-3), wherein R L represents -NHS(O)2CH2CH2OH, -NHS(O)2CH2CH3, -NHS(O)2CH3.
[0396] In addition, the present disclosure also provides a compound having the structure of formula (I-1-4), its pharmaceutically acceptable salts, stereoisomers, isotopic isomers, tautomers,
[0397] Among them, X 1 Indicates CR W1 or N;
[0398] Among them, X 2 Indicates CR W2 or N;
[0399] Among them, X 3 Indicates CR W3 or N;
[0400] Among them, R W1 、R W2 、R W3Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、 -SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0401] Alternatively, the chemical bond between X2 and X3 may also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring may also be selected from 0 to 3 of the following substituents: each independently representing hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent;
[0402] wherein Cy1 represents a substituted or unsubstituted 3-10 membered saturated or unsaturated cycloalkyl, a 6-10 membered saturated or unsaturated spirocycloalkyl, a 6-10 membered saturated or unsaturated bridged cycloalkyl, a 6-10 membered saturated or unsaturated condensed cycloalkyl, a 3-10 membered saturated or unsaturated heterocycloalkyl, a 6-10 membered saturated or unsaturated spiroheterocycloalkyl, a 6-10 membered saturated or unsaturated bridged heterocycloalkyl, a 6-10 membered condensed heterocycloalkyl, a 6-10 membered aryl, or a 5-10 membered heteroaryl, wherein each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, or hydroxyl. 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b)、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent;
[0403] Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring;
[0404] Among them, Y 1 Indicates -(CRa R b ) m -;Y 2 Indicates -(CR a R b ) n -;
[0405] Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、PO(R a R b ),-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、—C≡C—、 5-6 membered heteroaryl, replaced by;
[0406] Among them, R L Indicates L2-R M ;
[0407] Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2、-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-;
[0408] Among them, Cy2 represents
[0409] Among them, * indicates the site connected to Y2, and the wavy line indicates the site connected to L1;
[0410] Among them, X 5 Indicates CR W5 or N;
[0411] Among them, X 6 Indicates CR W6 or N;
[0412] Among them, X 7 Indicates CR W7 or N;
[0413] Among them, R W5 、R W6 、R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(Ra R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ;
[0414] Or the chemical bond between X5, X6 or X6, X7 can be fused with ring A to form a 4-8 membered saturated or unsaturated ring, a 4-8 membered saturated or unsaturated heterocyclic ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0-3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halogenated C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 Alkyl S(O)R a 、-C0-C 10Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 Alkyl OC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent;
[0415] wherein G1, G1', G2, G2', G3, and G3' each independently represent hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, or halogenated C1-C6 alkyl;
[0416] Or G1, G1' pair, G2, G2' pair, G3, G3' pair together with the carbon atom connected thereto form a 3-6 membered ring, or a 3-6 membered heterocyclic ring, wherein the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and further, the ring may also be selected from 0, 1, 2, or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, OR a or substituted with an oxo substituent;
[0417] Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR aR b , cyano and -O-halogenated C1-C6 alkyl groups substituted C1-C6 alkyl or C3-C6 (hetero)cycloalkyl;
[0418] Alternatively, L2-R M express
[0419] Wherein, m and n each independently represent an integer from 0 to 10;
[0420] Among them, R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a 、R b Together with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may optionally contain 0-2 heteroatoms selected from O, S, Se and N.
[0421] In a preferred embodiment of formula (I-1-4), X1 represents CH or N, preferably CH.
[0422] In a preferred embodiment of formula (I-1-4), X2 represents CH or N, preferably CH.
[0423] In a preferred embodiment of formula (I-1-4), X3 represents CH or N, preferably CH.
[0424] In a preferred embodiment of formula (I-1-4), the chemical bond between X2 and X3 is fused with ring B to form a group of the following structure:
[0425] In a preferred embodiment of formula (I-1-4), wherein X5 represents CR W5 or N, where R W5 It represents hydrogen, halogen, CH3O, CF3, CHF2, CH2F, NH2, -N(CH3)2, CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
[0426] In a preferred embodiment of formula (I-1-4), wherein X6 represents CR W6 or N, where R W6It represents hydrogen, halogen, CH3O, CF3, CHF2, CH2F, NH2, -N(CH3)2, CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
[0427] In a preferred embodiment of formula (I-1-4), X7 represents CH or N, preferably N.
[0428] In a preferred embodiment of formula (I-1-4), the chemical bond between X5 and X6 is fused with ring A to form a group of the following structure:
[0429] In a preferred embodiment of formula (I-1-4), the chemical bond between X6 and X7 is fused with ring A to form a group of the following structure:
[0430] In a preferred embodiment of formula (I-1-4), wherein L1 represents -C(O)NR a -、-NR a C(O)-、
[0431] In a preferred embodiment of formula (I-1-4), L1 represents -C(O)NH-.
[0432] In the preferred embodiment of formula (I-1-4), L1 represents
[0433] In a preferred embodiment of formula (I-1-4), wherein Y1 represents -(CR a R b ) m -.
[0434] In a preferred embodiment of formula (I-1-4), Y1 represents -NR-C(=O)-, -OC(=O)-, or -C(=O)O-.
[0435] In a preferred embodiment of formula (I-1-4), wherein Y1 represents -O(CR a R b ) m -or-(CR a R b ) m O-.
[0436] In a preferred embodiment of formula (I-1-4), wherein Y1 represents -CR a =CR a -or-CR a R b -CRa =CR b -.
[0437] In a preferred embodiment of formula (I-1-4), wherein Y2 represents -(CR a R b ) n -.
[0438] In a preferred embodiment of formula (I-1-4), wherein Y2 represents -NR a -C(=O)-.
[0439] In a preferred embodiment of formula (I-1-4), wherein Y2 represents -O(CR a R b ) n -or-(CR a R b ) n O-.
[0440] In a preferred embodiment of formula (I-1-4), wherein Y2 represents -CR a =CR a -、-CR a =CR b -CR a R b -or-CR a R b -CR a =CR b -.
[0441] In the preferred embodiment of formula (I-1-4), wherein Y 2 represents pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or triazolyl.
[0442] In a preferred embodiment of formula (I-1-4), wherein -Y1-Y2- represents -CR a =CR a -、-CR a R b CR a =CR b -.
[0443] In a preferred embodiment of formula (I-1-4), wherein -Y1-Y2- represents -CR a R b -NR a C(O)-.
[0444] In a preferred embodiment of formula (I-1-4), wherein -Y1-Y2- represents -
[0445] In the preferred embodiment of formula (I-1-4), R L represents -NHS(O)2CH2CH2OH, -NHS(O)2CH2CH3, -NHS(O)2CH3.
[0446] Specifically, the present disclosure provides compounds having the following structure:
[0447] In addition, the present disclosure provides a pharmaceutical composition comprising any one of the above compounds, pharmaceutically acceptable salts, stereoisomers, isotopic isomers, and tautomers thereof.
[0448] In addition, the present disclosure also provides a pharmaceutical composition containing any one of the compounds in the technical solutions of the present disclosure or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, and a pharmaceutically acceptable carrier thereof.
[0449] In addition, the present disclosure also provides a method for treating tumors by inhibiting KIF18A, comprising administering any one of the compounds of the present disclosure or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof to an individual in need thereof.
[0450] definition
[0451] Unless otherwise indicated, the compounds of the present disclosure may be interpreted to include, in addition to the specific structures of the compounds, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotopomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, and metabolites. In other words, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotopomers, solvates, hydrates, prodrugs, and metabolites also fall within the scope of protection of the compounds.
[0452] Unless otherwise indicated, the following terms used in this patent specification and claims have the meanings discussed below. Furthermore, many of the groups defined herein may be optionally substituted. The list of typical substituents in this definitions section is provided as an example and is not intended to limit the substituents defined elsewhere in this patent specification and claims.
[0453] Unless otherwise indicated, "R1", "R 1 ” and “R1” have the same meaning and can be replaced with each other. For other symbols such as R2, similar definitions have the same meaning.
[0454] The term "alkyl" refers to a saturated aliphatic hydrocarbon group or linker, comprising straight and branched chain groups of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. "Lower alkyl" particularly refers to an alkyl group having 1 to 4 carbon atoms. Examples of alkyl groups include -(CH2)3-, methyl, trifluoromethyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like. Alkyl groups may be substituted or unsubstituted. Typical substituents include cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, C-carboxyl, O-carboxyl, nitro, silyl, amino, and -NR x R y , where R x With R y Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and combined 5- or 6-membered heterocyclyl rings.
[0455] The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
[0456] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkynyl" group contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and the like.
[0457] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above having the specified number of carbon atoms attached via a sulfur bridge; for example, methyl-S- and ethyl-S-.
[0458] The term "cycloalkyl" refers to a 3- to 8-membered all-carbon monocyclic or bicyclic ring structure, an all-carbon 5-membered / 6-membered or 6-membered / 6-membered fused bicyclic ring, or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares at least one adjacent carbon atom with another ring in the system), wherein one or more rings may contain one or more double bonds, but none of such rings have a complete conjugated π-electron system, or the bicyclic rings may form a spirocycle by sharing a carbon atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, and cycloheptatriene. Bicyclic cycloalkyl groups include bridged, spiro, or fused cycloalkyl groups. Illustrative examples of cycloalkyl groups are derived from, but are not limited to, the following:
[0459] "Aryl" refers to an all-carbon monocyclic or fused-ring polycyclic group of 6 to 12 carbon atoms with a complete conjugated π-electron system. Examples of aryl groups are, but are not limited to, phenyl, naphthyl, and anthracenyl. Aryl groups may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, sulfinyl, sulfonyl, amino, and -NR a R b , where R a With R b Tie
[0460] As defined above. Aryl-fused saturated or unsaturated cycloalkyl / saturated or unsaturated heterocycloalkyl can be considered as special substituents for aryl, typical examples of which include but are not limited to:
[0461] "Heteroaryl" refers to a monocyclic or fused ring of 5 to 12 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O and S, the remaining ring atoms being C, and further, having a complete conjugated π-electron system.Examples of typical heteroaryl groups are, but are not limited to, acridinyl, azetidinyl, azcinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolenyl, dihydroindole , indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolidinyl, oxazolopyridinyl, oxazolidinyl, perylene, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiol, phenoxazinyl , phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-"; wherein the present disclosure also includes fused ring and spiro compounds containing, for example, the above-mentioned heterocycles.
[0462] Specifically, the term "5-6 membered heteroaryl" should be understood as an aromatic ring group having 5 or 6 ring atoms and containing 1, 2 or 3 heteroatoms independently selected from O, N or S. Specific examples include but are not limited to: thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl.
[0463] Pharmaceutically acceptable is sufficiently stable to be linked to the compounds of the present disclosure, formulated into a pharmaceutical composition, and subsequently administered to a patient in need thereof.
[0464] Unless otherwise defined, the definitions of substituents disclosed herein are independent of each other and not interrelated. For example, for a substituent R a (or R b ), they are independent of each other in the definitions of different substituents. Specifically, for R a (or R b ) When a definition is selected in a substituent, it does not mean that the R a (or R b ) has the same definition in other substituents. More specifically, for example (listing only non-exhaustive) for NR a R b In the case of R a (or R b ) is selected from hydrogen, it does not mean that in -C(O)-NR a R b Middle R a (or R b ) must be hydrogen.
[0465] "Halo" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl," which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms.
[0466] "Haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group as defined above with the specified number of carbon atoms attached via an oxygen bridge. For example, "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" refers to a haloalkyl group as defined above with the specified number of carbon atoms attached via a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-.
[0467] In the present disclosure, when referring to certain substituent groups, the expression Cx1-Cx2 is used, which means that the number of carbon atoms in the substituent group may be x1 to x2. For example, C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C1-C8 means that the group contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C2-C8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C3-C8 means that the group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C4-C8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6 means that the group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C1-C6 means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6 means that the group contains 2, 3, 4, 5 or 6 carbon atoms, and C3-C6 means that the group contains 3, 4, 5 or 6 carbon atoms.
[0468] In the present disclosure, when referring to a cyclic group (such as an aryl, heteroaryl, cycloalkyl and heterocycloalkyl), the expression "x1-x2 membered ring" is used, which means that the number of ring atoms of the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; the 3-6 membered ring means that the cyclic group can be a 3-, 4-, 5- or 6-membered ring, and the number of its ring atoms can be 3, 4, 5 or 6; the 3-8 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7- or 8-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7 or 8; the 3-9 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7, 8 or 9-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, The term "4-7 membered ring" refers to a 4-, 5-, 6-, or 7-membered ring having 4, 5, 6, or 7 ring atoms; a 5-, 8-, or 5-membered ring refers to a 5-, 6-, 7-, or 8-membered ring having 5, 6, 7, or 8 ring atoms; a 5-, 12-, or 5-membered ring refers to a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; and a 6-, 12-, or 6-membered ring refers to a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms may be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, such as heteroatoms selected from N, O and S.
[0469] In the present disclosure, one or more halogens may each be independently selected from fluorine, chlorine, bromine and iodine.
[0470] As used herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valence is maintained and the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).
[0471] Where nitrogen atoms (e.g., amines) are present on the compounds of the present disclosure, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the present disclosure. Thus, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxide to obtain the derivatives of the present disclosure.
[0472] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.
[0473] The term "patient" as used herein refers to an organism to be treated by the methods of the present disclosure. Such organisms preferably include, but are not limited to, mammals (e.g., mice, apes / monkeys, horses, cows, pigs, dogs, cats, etc.) and most preferably refer to humans.
[0474] The term "effective amount" as used herein means the amount of a drug or pharmaceutical agent (i.e., a compound of the present disclosure) that will cause a biological or medical response of a tissue, system, animal, or human being, such as that sought by a researcher or clinician. In addition, the term "therapeutically effective amount" means an amount that results in improved treatment, cure, prevention, or alleviation of a disease, condition, or side effect, or reduces the rate of progression of a disease or condition, compared to a corresponding subject that has not received the above amount. An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited by a specific formulation or route of administration. The term also includes within its scope an effective amount that enhances normal physiological function.
[0475] The term "treatment" as used herein includes its broad meaning, covering therapeutic treatment and / or prophylactic treatment of a subject. Specifically, the "treatment" includes any treatment that leads to the alleviation, suppression, elimination and improvement and / or prevention of a condition, disease, disorder, etc., such as alleviating, reducing, regulating, improving, eliminating, preventing, preventing or improving its symptoms. The therapeutic treatment includes alleviating, suppressing or improving the symptoms or conditions of the disease; suppressing the occurrence of complications; improving potential metabolic syndrome; suppressing the occurrence of the disease or symptoms, such as controlling the development of the disease or condition; alleviating the disease or symptoms; reducing the disease or symptoms; alleviating complications caused by the disease or symptoms, or treating signs caused by the disease or symptoms. The prophylactic treatment includes prior treatment to prevent, block or delay, slow down the occurrence or development of the disease or condition or reduce the severity of the disease or condition.
[0476] Likewise, "therapeutic agent" also includes agents or reagents that have therapeutic and / or prophylactic effects on a subject.
[0477] The terms "pharmaceutically acceptable" or "pharmaceutically acceptable" are used herein to refer to those compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response and / or other problems or complications, and commensurate with a reasonable benefit / risk ratio.
[0478] Specific pharmaceutical and medical terms
[0479] The term "cancer," as used herein, refers to an abnormal, uncontrolled growth of cells that can metastasize (spread) under certain conditions. This type of cancer includes, but is not limited to, solid tumors (such as those of the bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (such as the thyroid), prostate, skin (melanoma), or blood tumors (such as non-leukemic leukemias).
[0480] The term "combination administration" or its like, as used herein, refers to the administration of several selected therapeutic agents to a single patient, using the same or different administration routes at the same or different times.
[0481] The terms "enhance" or "enhancing," as used herein, refer to the ability to increase or prolong the potency or duration of a desired effect. Thus, in the context of enhancing the therapeutic effect of a drug, the term "enhancing" refers to the ability of the drug to increase or prolong the potency or duration of the drug in a system. "Potentiation," as used herein, refers to the ability of another therapeutic agent to maximize its potency in an ideal system.
[0482] The term "immune disease" refers to a disease or condition that results from an adverse or deleterious response to an endogenous or exogenous antigen. The result is usually cellular dysfunction, or the resulting damage and malfunction of, or destruction of, organs or tissues that may be responsible for the immune condition.
[0483] The terms "kit" and "product packaging" are synonymous.
[0484] The terms "subject," "subject," or "patient" include mammals and non-mammals. Mammals include, but are not limited to, mammals such as humans, non-human primates such as gorillas, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; livestock such as rabbits and dogs; and experimental animals including rodents such as rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds and fish. In a preferred embodiment, the mammal is a human.
[0485] As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration, regardless of whether the administration is fixed or temporary, continuous or intermittent, and can be attributed to or related to the administration.
[0486] Route of administration
[0487] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, auricular, nasal, and topical administration. In addition, parenteral administration, by way of example only, includes intramuscular, subcutaneous, intravenous, intramedullary, intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
[0488] The administration of the disclosed compounds can be local. In certain embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. In another embodiment, the drug is administered via a targeted drug delivery system. For example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are selectively directed to and absorbed by a specific organ.
[0489] Pharmaceutical composition and dosage
[0490] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutical substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., a lubricant, talc, magnesium stearate, calcium stearate, or zinc stearate, or stearic acid), or solvent encapsulating substance, which is involved in carrying or transporting the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
[0491] The term "pharmaceutical composition" means a composition comprising a compound of the present disclosure and optionally other pharmaceutically acceptable carriers. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals (particularly mammals), including (i.e.) adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the nature of the dosage form.
[0492] The pharmaceutical compositions of the present disclosure may include a therapeutically effective amount of one or more compounds of the present disclosure formulated with optional one or more pharmaceutically acceptable carriers (additives) and / or diluents, and optionally one or more other therapeutic agents. The compounds of the present disclosure may be administered in any suitable manner for any of the above-mentioned purposes, for example, orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion technology (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membrane, such as by inhalation spray; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories; or by intratumoral injection. They can be administered alone, but are typically administered using a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice.
[0493] Pharmaceutically acceptable carriers are formulated based on a variety of factors well within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media and various solid and semisolid dosage forms.
[0494] Such carriers may include many different ingredients and additives in addition to the active agent, and such other ingredients are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, binding agents, etc. Descriptions of suitable pharmaceutical carriers and factors involved in carrier selection can be found in a number of readily available sources, such as Allen LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.
[0495] Of course, the dosage regimen of the disclosed compounds varies depending on known factors, such as the pharmacodynamic properties of the specific agent and its mode and route of administration; the species, age, sex, health condition, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and hepatic function and the desired effect. As a general guide, when used for a specified effect, the daily oral dose of each active ingredient should be from about 0.001 mg / day to about 10-5000 mg / day, preferably from about 0.01 mg / day to about 1000 mg / day, and most preferably from about 0.1 mg / day to about 250 mg / day. During a constant rate infusion, the most preferred intravenous dose should be from about 0.01 mg / kg / minute to about 10 mg / kg / minute. The disclosed compounds can be administered in a single daily dose, or the total daily dose can be administered in divided doses twice, three times or four times a day.
[0496] The compounds are usually administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected according to the intended administration form (e.g., oral tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice.
[0497] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight based on the total weight of the composition.
[0498] The present disclosure includes pharmaceutical compositions comprising, alone or in combination with a pharmaceutically acceptable carrier, a therapeutically effective amount of at least one compound of the present disclosure as an active ingredient. Optionally, the compounds of the present disclosure may be used alone, in combination with other compounds of the present disclosure, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).
[0499] Regardless of the route of administration selected, the compounds of the present invention (which may be used in a suitable hydrated form) and / or the pharmaceutical compositions of the present disclosure are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.
[0500] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
[0501] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the present disclosure employed, or its ester, salt, or amide; the route of administration; the time of administration; the rate of excretion of the particular compound employed; the rate and extent of absorption; the duration of the treatment; other drugs, compounds, and / or substances used in combination with the particular compound employed; and the age, sex, weight, condition, general health and prior medical history of the patient being treated, and other factors well known in the medical art.
[0502] A doctor or veterinarian with ordinary skills in the art can easily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, in order to achieve the desired therapeutic effect, the physician or veterinarian can start the dosage of the disclosed compound used in the pharmaceutical composition at a level lower than the desired level, and gradually increase the dosage until the desired effect is achieved. Typically, a suitable daily dose of the disclosed compound will be the amount of the compound at the lowest dose that effectively produces a therapeutic effect. Such an effective dose generally depends on the above factors. Typically, oral, intravenous, intracerebroventricular and subcutaneous doses of the disclosed compound for patients range from about 0.01 to about 50 mg / kg body weight / day. If necessary, the effective daily dose of the active compound can be administered separately at appropriate intervals throughout the day in two, three, four, five, six or more subdoses, optionally in unit dosage form. In certain aspects of the present disclosure, medication is administered once a day. Although the disclosed compound can be administered alone, it is preferred that the compound be administered in the form of a pharmaceutical preparation (composition).
[0503] Kit / Product Packaging
[0504] Kits / product packaging are also described herein for use in treating the aforementioned indications. These kits can consist of a carrier, a pouch, or a container box, each of which can be divided into compartments to accommodate one or more containers, such as vials, test tubes, and the like, each containing a single component of the method. Suitable containers include bottles, vials, syringes, and test tubes. The containers can be made of acceptable materials such as glass or plastic.
[0505] For example, a container may contain one or more compounds described herein, either as a pharmaceutical composition or in admixture with other ingredients described herein. The container may have a sterile delivery port (e.g., an IV bag or bottle with a stopper pierceable by a hypodermic needle). Such a kit may include a compound and instructions, labeling, or operating instructions for use as described herein.
[0506] A typical kit may include one or more containers, each containing one or more materials (e.g., reagents, concentrated stock solutions, and / or instruments) to suit the commercialization and user needs of the compound. These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, delivery devices, bags, containers, bottles, and / or test tubes, accompanied by a list of contents and / or instructions for use, including instructions for use within the packaging. The complete set of instructions should be included.
[0507] The label may be displayed on or closely associated with the container. Labeling on a container means that the label letters, numbers, or other features are affixed, molded, or engraved onto the container. Labels may also appear inside a container or shipping box containing multiple containers, such as in a product insert. A label may indicate a specific therapeutic use of the contents. A label may also indicate instructions for use of the contents, such as those described in the above methods.
[0508] All features described in this specification (including any claims, abstracts and figures), and / or all steps involved in any method or process, may exist in any combination, unless certain features or steps are mutually exclusive in the same combination.
[0509] The features described above, or the features described in the examples, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features.
[0510] The present disclosure will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present disclosure only and are not intended to limit the scope of the present disclosure. The experimental methods in the following examples, where specific conditions are not specified, were generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise indicated, all percentages, ratios, proportions, or parts are by weight.
[0511] The units used in this disclosure for weight-volume percentages are well known to those skilled in the art, for example, referring to the weight of solute in 100 ml of solution. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the disclosed methods. The preferred embodiments and materials described herein are for illustrative purposes only. DETAILED DESCRIPTION
[0512] The present disclosure is further illustrated by way of examples below, but the present disclosure is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.
[0513] NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the measurements are indicated in the spectral analysis.
[0514] MS was determined using an Agilent 1200-G1956A / 1200-6110A / 1200-6140A / 1260-6125B / Prime-6125B / 1260-6120 LC / MS, a SHIMADZU 20A-2010 / 20A-2020 LC / MS, and a Waters ACQ-QDA LC / MS.
[0515] HPLC analysis was performed using a SHIMADZU 20A high performance liquid chromatograph.
[0516] SFC analysis was performed using a Waters UPCC with PDA Detector and QDa Detector ultra-high performance convergence chromatograph, a Waters UPC 2 with PDA detector ultra high performance convergence chromatograph, Agilent 1260with DAD detector high performance liquid chromatograph, Shimadzu LC-20AB with PDA detector high performance liquid chromatograph, Shimadzu LC-20AD with PDA detector high performance liquid chromatograph.
[0517] Preparative HPLC separation was performed using a Shimadzu LC-20AP pump, Shimadzu LH-40 Liquid Handler, Shimadzu SPD-20A Detector, Gilson GX-281 Liquid Handler, Gilson 322 pump, and Gilson 156 UV Detector preparative chromatograph.
[0518] SFC separation uses The Berger MG II, MG III, Sepiatec's Prep SFC 100system, Waters Prep 80Q SFC SYSTEM, Prep 150AP SFC SYSTEM, Prep 200SFC SYSTEM, and Prep 350SFC SYSTEM.
[0519] Flash column chromatography separation was performed using a Biotage IsoleraOne flash preparative chromatograph.
[0520] The thin layer chromatography silica gel plate used was GF254 acrylic adhesive silica gel plate produced by Anhui Liangchen Silicon Source Material Co., Ltd. The specification of the silica gel plate used in thin layer chromatography (TLC) was 0.25 mm, and the specification of the thin layer chromatography separation and purification product was 0.5 mm.
[0521] Pressurized hydrogenation reaction hydride bottles and hydrogen gas cylinders.
[0522] Microwave reactions were performed using a Biotage Initiator+ microwave synthesizer.
[0523] The glove box is customized by DELLIX.
[0524] The present disclosure is described in detail below by way of examples, but is not intended to limit the present disclosure in any way. The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present disclosure. It will be apparent to those skilled in the art that various changes and improvements will be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.
[0525] Preparation of intermediate A
[0526] Step 1: Dissolve N-tert-butyloxycarbonyl-4-oxopiperidine (17.02 g, 85.41 mmol) in tetrahydrofuran (50.00 mL) at 25°C. This solution was slowly added to a 1.0 M solution of lithium bistrimethylsilylamide (85.41 mL, 85.41 mmol) in tetrahydrofuran (150.00 mL) at -78°C under a nitrogen atmosphere. The reaction mixture was stirred at -78°C for 1 hour, and (vinylsulfinyl)benzene (10.0 g, 65.7 mmol) was added. The reaction mixture was heated to 25°C and stirred for 1 hour. Aqueous sodium hydroxide solution was added and stirred at 25°C for 1 hour. The mixture was extracted with ethyl acetate (300 mL x 2), the organic layer was washed with water (200 mL), the organic phase was dried over sodium sulfate, filtered, the filtrate was spin-dried, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give a yellow oily compound tert-butyl 4-oxo-3-(2-(phenylsulfinyl)ethyl)piperidine-1-carboxylate (16.00 g, 45.58 mmol, yield 69.4%). LCMS (ESI): [M+H] +=352.20.
[0527] Step 2: Diethylaminosulfur trifluoride (15.45 g, 91.05 mmol) was added to a solution of tert-butyl 4-oxo-3-(2-(phenylsulfinyl)ethyl)piperidine-1-carboxylate (16.00 g, 45.58 mmol) in dichloromethane (200.00 mL) at -78°C under a nitrogen atmosphere. The yellow mixture was stirred at 25°C for 16 hours. The reaction was quenched with saturated sodium bicarbonate (200 mL), extracted with dichloromethane (200 mL x 3), and the organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give an orange oily compound tert-butyl 4,4-difluoro-3-(2-(phenylsulfinyl)ethyl)piperidine-1-carboxylate (6.90 g, 18.5 mmol, yield 40.6%). LCMS (ESI): [M-99] + =274.00.
[0528] Step 3: A suspension of calcium carbonate (40.20 g, 401.65 mmol) and tert-butyl 4,4-difluoro-3-(2-(phenylsulfinyl)ethyl)piperidine-1-carboxylate (15.00 g, 40.16 mmol) in xylene (300 mL) was stirred at 140°C for 16 hours. The suspension was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / petroleum ether) to give tert-butyl 4,4-difluoro-3-vinylpiperidine-1-carboxylate (8.04 g, 32.51 mmol, 81.0% yield) as a yellow oil. LCMS (ESI): [M-55] + =192.10.
[0529] Step 4: At 20°C, tert-butyl 4,4-difluoro-3-vinylpiperidine-1-carboxylate (10.73 g, 43.39 mmol) was added to a 2M solution of hydrogen chloride in dioxane (200.00 mL), and the reaction was stirred at 25°C for 16 hours. Thin layer chromatography (petroleum ether / ethyl acetate with a volume ratio of 5:1) showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a pale yellow solid crude compound 4,4-difluoro-3-vinylpiperidine hydrochloride (11.00 g, 42.57 mmol, yield 98.1%). LCMS (ESI): [M+H] + =148.10. 1H NMR(400MHz,DMSO-d6)δppm 9.60(br s,2H),5.90-5.65(m,1H),5.46-5.24(m,2H),3.47-3.36(m,2H),3.23-3.07(m,1H),3.05-2.91(m,2H),2.41-2.23(m,2H)
[0530] Preparation of intermediate B
[0531] At 20 ° C, 4,4-difluoro-3-vinylpiperidine hydrochloride (1.00 g, 5.44 mmol), 2-chloro-6-methylpyrimidin-4-amine (782 mg, 5.44 mmol) and N,N-diisopropylethylamine (7.17 mL, 39.56 mmol) were dissolved in dry dimethyl sulfoxide (10.00 mL) and the reaction was stirred at 120 ° C for 24 hours. After the reaction was completed, the mixture was cooled naturally and cold water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined and washed with sodium bicarbonate solution (100 mL). The organic phases were dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 0-50% ethyl acetate / petroleum ether) to give 2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-amine (1.30 g, 5.10 mmol, yield 93.9%) as a colorless liquid. LCMS (ESI): [M+H] + =255.10. 1 H NMR (400MHz, DMSO-d6) δppm6.50-6.17(m,2H),5.91-5.71(m,1H),5.65(s,1H),5.38-5.25(m,2H ),4.61-4.43(m,2H),3.19-3.01(m,2H),2.74-2.56(m,1H),2.15-1.97(m,4H),1.93-1.72(m,1H)
[0532] Preparation of intermediate C
[0533] Intermediate C was obtained by a similar method to that of intermediate A. 1 H NMR(400MHz,DMSO-d6)δppm 9.67(br s,2H),5.97-5.64(m,1H),5.32-4.97(m,2H),3.53-3.22(m,3H),3.06-2.90(m,1H),2.86-2.69(m,1H),2.49-2.21(m,3H),2.13-1.97(m,1H)
[0534] Preparation of intermediate D
[0535] Refer to the method of intermediate B to obtain intermediate D, 1 H NMR(400MHz,DMSO-d6)δppm 6.29(br s,2H),5.85(tdd,J=6.8,10.0,17.2Hz,1H),5.64(s,1H),5.25-5.02(m,2H),4.54-4.35(m,2H),3.23-3.11(m,1H),2.90(br dd,J=9.2,12.8Hz,1H),2.44-2.31(m,1H),2.06(s,3H),2.05-1.69(m,4H)
[0536] Synthesis of intermediate E
[0537] Step 1: Under a nitrogen atmosphere at 20°C, methyltriphenylphosphonium bromide (24.06 g, 66.00 mmol) was dissolved in dry tetrahydrofuran (350.00 mL). The solution was cooled to 0°C, followed by the slow addition of a 1.0 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (66.00 mL, 66.00 mmol) and stirring for 1 hour. A solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (10.00 g, 44.00 mmol) in tetrahydrofuran (20.00 mL) was added to the reaction system, and the temperature was raised to 20°C and stirred for 16 hours. After completion of the reaction, saturated sodium bicarbonate solution (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give tert-butyl 4-allylpiperidine-1-carboxylate (10.00 g, 66.00 mmol, 100.0% yield) as a colorless liquid.
[0538] Step 2: tert-Butyl 4-allylpiperidine-1-carboxylate (10.00 g, 66.00 mmol) was dissolved in dichloromethane (200.00 mL) at 20°C, and trifluoroacetic acid (10.02 mL, 131.81 mmol) was added. The mixture was stirred at 20°C for 16 hours. After the reaction was complete, the solvent and excess trifluoroacetic acid were removed to obtain crude 4-allylpiperidine trifluoroacetate (approximately 15.50 g). 1H NMR (400MHz, DMSO-d6) δ = 9.36-8.94 (m, 2H), 5.75 (tdd, J = 6.8, 10.0, 16.8Hz, 1H), 5.13-4.93 (m, 2H), 3.18 (br d,J=12.4Hz,2H),2.84-2.72(m,2H),1.97(t,J=6.8Hz,2H),1.73(br d,J=13.2Hz,2H),1.58(dtd,J=4.0,7.0,14.8Hz,1H),1.41-1.29(m,2H)
[0539] Synthesis of intermediate F
[0540] Step 1: Dissolve 2,4-dichloro-6-methoxypyrimidine (20.0 g, 111 mmol) in tert-butanol (400 mL), add N,N-diisopropylethylamine (57.7 g, 446.93 mmol) and 4,4-difluoro-3-vinylpiperidin-1-yl)-6-methoxypyrimidine (26.6 g, 145 mmol), and stir at 100°C for 16 hours. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (400 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-3% gradient of tetrahydrofuran / petroleum ether) to give 4-chloro-2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methoxypyrimidine (27.8 g, 47.7 mmol, 43.0% yield) as a yellow oil. LCMS (ESI): [M+H] + =289.8. 1 H NMR(400MHz,CHLOROFORM-d)δppm 6.09-6.02(m,1H),5.93-5.79(m,1H),5.39-5.32(m,2H),4.60-4.47(m,2H) ,3.95-3.89(m,3H),3.49-3.32(m,2H),2.74-2.57(m,1H),2.25-1.81(m,2H)
[0541] Step 2: 4-chloro-2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methoxypyrimidine (10.0 g, 34.5 mmol) and diphenylmethaneimine (9.57 g, 51.7 mmol) were dissolved in dioxane (100 mL), and cesium carbonate (33.7 g, 103 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylanthracene (3.99 g, 6.90 mmol) and tris(dibenzylideneacetone)dipalladium (3.16 g, 3.45 mmol) were added and stirred at 100 ° C for 16 hours under nitrogen atmosphere. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic phase was dried, filtered, and concentrated to obtain a brown oily N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methoxypyrimidin-4-yl)-1,1-diphenylmethanimine (15.0 g, crude product), which was used directly in the next step. LCMS (ESI): [M+H] + =435.1
[0542] Step 3: Dissolve N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methoxypyrimidin-4-yl)-1,1-diphenylcarbamidine (15.0 g, 34.5 mmol) in methanol (300 mL), add sodium acetate (8.50 g, 103 mmol) and hydroxylamine hydrochloride (4.80 g, 69.0 mmol), and stir at 25°C for 2 hours. Water (400 mL) was added to the reaction solution, which was extracted with ethyl acetate (400 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / petroleum ether) to afford 2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methoxypyrimidin-4-amine (7.90 g, 26.5 mmol, 77.0% yield) as a yellow oil. LCMS (ESI): [M+H] + =271.0. 1 H NMR(400MHz,CHLOROFORM-d)δppm 5.78(ddd,J=8.0,10.4,18.0Hz,1H),5.27-5.18(m,2H),5.11(s,1H),4.50-4.35(m,4H), 3.75(s,3H),3.26-3.07(m,2H),2.63-2.43(m,1H),2.06-1.89(m,1H),1.87-1.65(m,1H)
[0543] Synthesis of intermediate G
[0544] Refer to the method of intermediate F to obtain intermediate G, 1H NMR(400MHz,CHLOROFORM-d)δppm 5.86-5.69(m,1H),5.11(s,1H),5.10-4.98(m,2H),4.49-4.31(m,4H),3.77-3.73( m,3H),3.31-3.19(m,1H),3.03-2.89(m,1H),2.50-2.39(m,1H),2.00-1.75(m,4H)
[0545] Synthesis of intermediate H
[0546] Step 1: Dissolve 4-bromo-2-fluorobenzoic acid (5.00 g, 22.8 mmol) and N-iodosuccinimide (5.13 g, 22.8 mmol) in N,N-dimethylformamide (50 mL). Add palladium acetate (0.52 g, 2.28 mmol) and stir at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture is diluted with water (50.0 mL) and the pH is adjusted to 3 with dilute hydrochloric acid. The mixture is extracted with ethyl acetate (50 mL x 3). The organic phase is dried, filtered, and concentrated. The residue is purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to afford 4-bromo-2-fluoro-6-iodobenzoic acid (6.00 g, 17.4 mmol, 76.2% yield) as a yellow solid.
[0547] Step 2: Dissolve 4-bromo-2-fluoro-6-iodobenzoic acid (6.00 g, 17.4 mmol) in N,N-dimethylformamide (60 mL), add iodomethane (3.70 g, 26.1 mmol), and stir at 25°C for 16 hours. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / petroleum ether) to afford methyl 4-bromo-2-fluoro-6-iodobenzoate (4.00 g, 11.1 mmol, 64.0% yield) as a yellow solid. LCMS (ESI): no mass indicated.
[0548] Step 3: Dissolve methyl 4-bromo-2-fluoro-6-iodobenzoate (500 mg, 1.39 mmol), but-3-en-1-ol (150 mg, 2.09 mmol), sodium bicarbonate (350 mg, 4.18 mmol), and tetra-n-butylammonium bromide (460 mg, 1.39 mmol) in N,N-dimethylformamide (5.00 mL). Add palladium acetate (32.0 mg, 139 mmol). Under nitrogen, heat to 60°C and stir for 16 hours. Add ammonium bicarbonate (10 mL) to the reaction mixture, extract with ethyl acetate (50 mL x 3), and dry, filter, and concentrate the organic phase. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / petroleum ether) to give methyl 4-bromo-2-fluoro-6-(4-oxobutylidenebutyl)benzoate (150 mg, 0.49 mmol, 35.5% yield) as a yellow oil. LCMS (ESI): [M+H] + =302.9. 1 H NMR(400MHz,DMSO-d6)δppm 9.64(t,J=1.2Hz,1H),7.57(dd,J=1.6,9.2Hz,1H),7.50-7.43(m,1H),3.8 8(s,3H),2.62(dd,J=6.8,8.8Hz,2H),2.46-2.42(m,2H),1.80-1.72(m,2H)
[0549] Step 4: Dissolve methyl 4-bromo-2-fluoro-6-(4-oxydebutyl)benzoate (750 mg, 2.47 mmol) and sodium hydroxide (299 mg, 7.42 mmol) in methanol (5.00 mL) and water (5.00 mL). Add silver oxide (1.17 g, 4.94 mmol) to the reaction mixture. Heat to 60°C and stir for 16 hours under nitrogen. Adjust the pH of the reaction mixture to 3 with dilute hydrochloric acid and extract with ethyl acetate (10 mL x 3). The organic phase is dried, filtered, and concentrated to yield 4-bromo-2-(3-carboxypropyl)-6-fluorobenzoic acid (750 mg, 2.45 mmol, 99.3% yield) as a yellow oil. LCMS (ESI): [M+H] + =326.9.
[0550] Step 5: Dissolve 4-bromo-2-(3-carboxypropyl)-6-fluorobenzoic acid (750 mg, 2.46 mmol) in dichloromethane (15 mL). Add oxalyl chloride (0.96 g, 7.37 mmol) and a drop of N,N-dimethylformamide to the reaction mixture. Stir at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a crude yellow oil, 4-bromo-2-(4-chloro-4-oxydebutyl)-6-fluorobenzoyl chloride (0.80 g, 2.33 mmol, 95.1% yield), which was used directly in the next step. LCMS (ESI): [M+H] + =335.0 (methanol sample)
[0551] Step 6: Aluminum trichloride (0.88 g, 6.57 mmol) was dissolved in dichloromethane (15 mL), and then a solution of methyl 4-bromo-2-(4-chloro-4-oxyylidenebutyl)-6-fluorobenzoyl chloride (0.75 g, 2.19 mmol) in dichloromethane (2 mL) was added to the reaction solution, and the temperature was raised to 50 ° C and stirred for 16 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran / petroleum ether) to give 4-bromo-2-fluoro-5-oxyylidene-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (600 mg, 2.08 mmol, 95.3% yield) as a yellow solid. LCMS (ESI): [M+H] + =287.0.
[0552] Synthesis of intermediate I
[0553] Step 1: Dissolve 7-bromo-5-fluoro-1-oxyylidene-2,3-dihydro-1H-indene-4-carboxylic acid (3.00 g, 11.0 mmol) in dimethylformamide (30 mL) and cool to 0°C. Add potassium carbonate (3.80 g, 27.5 mmol) and iodomethane (2.34 g, 16.5 mmol), and stir the reaction at 25°C for 2 hours. The reaction mixture is quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases are dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated. The crude product is purified by flash column chromatography (silica gel, 0-10% tetrahydrofuran / petroleum ether gradient) to afford methyl 7-bromo-5-fluoro-1-oxyylidene-2,3-dihydro-1H-indene-4-carboxylate (2.50 g, 8.69 mmol, 79% yield) as a white solid. LCMS (ESI): [M+H]+=288.7
[0554] Step 2: To a solution of dichloromethane (20 mL) at 25°C, add methyl 7-bromo-5-fluoro-1-oxyylidene-2,3-dihydro-1H-indene-4-carboxylate (1.00 g, 3.48 mmol) and boron trifluoride etherate (2.97 g, 20.9 mmol). Ethanedithiol (0.98 g, 10.5 mmol) and acetic acid (0.50 mL) are then added. The reaction mixture is stirred at 50°C for 16 hours. The reaction mixture is quenched with saturated ammonium chloride (30 mL) and extracted with dichloromethane (30 mL x 3). The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate is evaporated to dryness to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give methyl 7'-bromo-5'-fluoro-2',3'-dihydrospiro[1,3-dithiolano-2,1'-indene]-4'-carboxylate (0.8 g, 2.20 mmol, yield 63.2%) as a white solid compound. 1 HNMR(400MHz,CHLOROFORM-d)δppm 7.30(d,J=10.0Hz,1H),3.92(s,3H),3.64-3.55(m,2H),3.47-3.39(m,2H),3.19(t,J=6.8Hz,2H),2.73(t,J=6.8Hz,2H)
[0555] Step 3: Under nitrogen, dibromohydantoin (4.10 g, 14.0 mmol) was added to a dichloromethane (80 mL) solution. The reaction mixture was cooled to -65°C, and a pyridine solution of hydrofluoric acid (8 mL) was added dropwise. Methyl 7'-bromo-5'-fluoro-2',3'-dihydrospiro[1,3-dithiolano-2,1'-indene]-4'-carboxylate (1.70 g, 4.68 mmol) was dissolved in dichloromethane (10 mL) and added dropwise to the system. The mixture was stirred at -65-25°C for 16 hours. The reaction system was quenched with 2N sodium hydroxide solution (50 mL) and sodium thiosulfate solution (5 mL), extracted with dichloromethane (50 mL x 3), and the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / petroleum ether) to give methyl 2,7-dibromo-1,1,5-trifluoro-2,3-dihydro-1H-indene-4-carboxylate (1.30 g, 3.37 mmol, yield 72%) as a yellow oily compound. 1 H NMR (400MHz, DMSO-d6) δppm 7.89 (d, J=10.4Hz, 1H), 5.20-4.99 (m, 1H), 3.96-3.88 (m, 1H), 3.87 (s, 3H), 3.33-3.28 (m, 1H)
[0556] Step 4: To a solution of methyl 2,7-dibromo-1,1,5-trifluoro-2,3-dihydro-1H-indene-4-carboxylate (1.30 g, 3.37 mmol) in dimethyl sulfoxide (20.0 mL) at 25°C was added potassium carbonate (1.16 g, 8.38 mmol). The reaction mixture was stirred at 120°C for 12 hours. The reaction system was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-8% gradient of tetrahydrofuran / petroleum ether) to obtain methyl 7-bromo-1,1,5-trifluoro-1H-indene-4-carboxylate (0.22 g, 0.66 mmol, 21% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δppm 7.63(d,J=10.4Hz,1H),7.29(d,J=6.0Hz,1H),6.76(d,J=6.0Hz,1H),3.88(s,3H)
[0557] Step 5: Dissolve methyl 7-bromo-1,1,5-trifluoro-1H-indene-4-carboxylate (200 mg, 0.65 mmol) and 2-nitrobenzene-1-sulfonyl chloride (289 mg, 1.30 mmol) in acetonitrile (5 mL). Cool the mixture to 0°C and add hydrazine hydrate (163 mg, 2.61 mmol). Stir at 25°C for 16 hours. Dilute the reaction mixture with water (10 mL) and extract with ethyl acetate (10 mL x 3). The organic phase is dried, filtered, and concentrated. The residue is purified by flash column chromatography (silica gel, 0-8% gradient of tetrahydrofuran / petroleum ether) to afford methyl 7-bromo-1,1,5-trifluoro-2,3-dihydro-1H-indene-4-carboxylate (0.1 g, 0.32 mmol, 50% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm 7.79 (d, J=10.4Hz, 1H), 3.86 (s, 3H), 3.26-3.20 (m, 2H), 2.73-2.61 (m, 2H)
[0558] Step 6: To a solution of methyl 7-bromo-1,1,5-trifluoro-2,3-dihydro-1H-indene-4-carboxylate (0.10 g, 0.32 mmol) in methanol (1.00 mL) and water (1.00 mL) was added sodium hydroxide (104 mg, 2.58 mmol) at 25°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction solution was diluted with water (5 mL) and the pH was adjusted to 2-3 with 1N dilute hydrochloric acid. The solution was extracted with ethyl acetate (10 mL x 2). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 7-bromo-1,1,5-trifluoro-2,3-dihydro-1H-indene-4-carboxylic acid (95 mg, 0.29 mmol, 92% yield) as a yellow solid.
[0559] Synthesis of intermediate J
[0560] Step 1: Dissolve methyl 7-bromo-5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carboxylate (3.00 g, 10.4 mmol) in methanol (20.0 mL), add sodium acetate (2.05 g, 20.9 mmol) and hydroxylamine hydrochloride (1.45 g, 20.9 mmol), and stir at 25°C for 16 hours. The reaction solution was filtered and concentrated. A yellow solid methyl (Z)-7-bromo-5-fluoro-1-(oximino)-2,3-dihydro-1H-indene-4-carboxylate (1.50 g, crude) was obtained and used directly in the next step. LCMS (ESI): [M+H] + =301.8
[0561] Step 2: Dissolve methyl (Z)-7-bromo-5-fluoro-1-(oximino)-2,3-dihydro-1H-indene-4-carboxylate (150 mg, 0.50 mmol) in dichloromethane (4.00 mL), add triethylamine (753 mg, 7.45 mmol) and 4-dimethylaminopyridine (6.07 mg, 0.05 mmol), add p-toluenesulfonyl chloride (189 mg, 0.99 mmol) at 0°C, raise the temperature to 25°C and stir for 3 hours. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of tetrahydrofuran / petroleum ether) to obtain methyl (Z)-7-bromo-5-fluoro-1-((tosyloxy)aminoylidene)-2,3-dihydro-1H-indene-4-carboxylate (140 mg, 0.31 mmol, 62.0% yield) as a white solid. LCMS (ESI): [M+H] + =455.9
[0562] Step 3: Dissolve methyl (Z)-7-bromo-5-fluoro-1-((tosyloxy)aminoylidene)-2,3-dihydro-1H-indene-4-carboxylate (20.0 mg, 0.04 mmol) in trifluoroacetic acid (0.50 mL) and stir at 25°C for 16 hours and at 60°C for 5 hours. The reaction mixture was monitored by LCMS (ESI): [M+H] + =303.7
[0563] Synthesis of intermediate K
[0564] Step 1: To a mixture of methyl 7-bromo-5-fluoro-1-oxyylidene-2,3-dihydro-1H-indene-4-carboxylate (2.50 g, 8.7 mmol) and difluoro(2-pyridylsulfonyl)methane (3.36 g, 17 mmol) in N,N-dimethylformamide (30.00 mL) was added dropwise a solution of potassium tert-butoxide (2.96 g, 26 mmol) in N,N-dimethylformamide (100.00 mL) at -40°C. The yellow mixture was stirred at -40°C for 0.5 hours. 12 mL of saturated ammonium chloride and 30 mL of 3M hydrochloric acid were added to the reaction solution. The reaction mixture was slowly warmed to room temperature. TLC (PE:EA = 10:1, Rf = 0.7) indicated the reaction was complete. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO) 80 grams Silica gel flash column, 0-8% tetrahydrofuran / petroleum ether gradient elution @ 60 mL / min). Methyl 7-bromo-1-(difluoromethylene)-5-fluoro-2,3-dihydro-1H-indene-4-carboxylate (1.70 g, 60%) was obtained. LCMS (ESI): [M+H]+=321.0
[0565] Step 2: To a solution of methyl 7-bromo-1-(difluoromethylene)-5-fluoro-2,3-dihydro-1H-indene-4-carboxylate (0.85 g, 2.66 mmol) in methanol (5.00 mL) and water (5.00 mL) was added sodium hydroxide (312 mg, 7.74 mmol) at 25°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (5 mL) and the pH was adjusted to 2-3 with 1N dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL x 2). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 7-bromo-1-(difluoromethylene)-5-fluoro-2,3-dihydro-1H-indene-4-carboxylic acid (0.77 g, 2.52 mmol, 93% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 307.0
[0566] Synthesis of intermediate L
[0567] Step 1: To a mixture of methyl 7-bromo-5-fluoro-1-oxyylidene-2,3-dihydro-1H-indene-4-carboxylate (2.50 g, 8.7 mmol) and 1-(tert-butyl)-5-((fluoromethyl)sulfonyl)-1H-tetrazole (3.77 g, 17 mmol) in tetrahydrofuran (30.00 mL) at 0°C was added hexamethylphosphoric triamide (1 mL) and lithium diisopropylamide (26 mL, 26 mmol) dropwise. The yellow mixture was stirred at 0°C for 2 hours. 12 mL of saturated ammonium chloride and 30 mL of 3M hydrochloric acid were added to the reaction solution. The reaction mixture was slowly warmed to room temperature. TLC (PE:EA = 10:1, Rf = 0.7) indicated the reaction was complete. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO) 40 grams Silica gel flash column, 0-10% tetrahydrofuran / petroleum ether gradient elution @ 60 mL / min). 7-bromo-1-(fluoromethylene)-5-fluoro-2,3-dihydro-1H-indene-4-carboxylic acid methyl ester (1.70 g, 60%) was obtained. LCMS (ESI): [M+H]+=303.0
[0568] Step 2: To a solution of methyl 7-bromo-1-(fluoromethylene)-5-fluoro-2,3-dihydro-1H-indene-4-carboxylate (0.85 g, 2.66 mmol) in methanol (5.00 mL) and water (5.00 mL) was added sodium hydroxide (312 mg, 7.74 mmol) at 25°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction solution was diluted with water (5 mL) and the pH was adjusted to 2-3 with 1N dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL x 2). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 7-bromo-1-(fluoromethylene)-5-fluoro-2,3-dihydro-1H-indene-4-carboxylic acid (0.70 g, 2.22 mmol, 89% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 289.0
[0569] Synthesis of intermediate M
[0570] The first step: At 0 ° C, potassium tert-butoxide (2.91 g, 26 mmol) was added to a mixture of methyl 7-bromo-5-fluoro-1-oxyylidene-2,3-dihydro-1H-indene-4-carboxylate (4.97 g, 17.4 mmol) and methyltriphenylphosphine bromide (12.39 g, 34.8 mmol) in tetrahydrofuran (100.00 mL). The mixture was stirred at 0 ° C for 1 hour. The reaction mixture was then slowly heated to 60 ° C and continued to stir for 10 hours. TLC (PE: EA = 10: 1, Rf = 0.7) showed that the reaction was complete. The reaction mixture was diluted with water 50 mL and extracted with ethyl acetate (50 mL * 2). The combined organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO) 100 grams Silica gel flash column, 0-10% tetrahydrofuran / petroleum ether gradient elution @ 60 mL / min). 7-bromo-5-fluoro-1-methylene-2,3-dihydro-1H-indene-4-carboxylic acid methyl ester (2.96 g, yield 60%) was obtained. LCMS (ESI): [M+H]+=285.0
[0571] Step 2: To a solution of 7-bromo-5-fluoro-1-methylene-2,3-dihydro-1H-indene-4-carboxylic acid methyl ester (1.48 g, 5.22 mmol) in tetrahydrofuran (5.00 mL) was added (trifluoromethyl)trimethylsilane (7.41 g, 52.2 mmol) and sodium iodide (77 mg, 0.522 mmol) at 25 ° C. The reaction mixture was stirred at 65 ° C for 12 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate solution (10 mL x 2). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO). 40 grams Silica gel flash column, 0-10% tetrahydrofuran / petroleum ether gradient elution @ 60 mL / min). 7'-bromo-2,2,5'-trifluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-4'-carboxylic acid methyl ester (871.8 mg, yield 50%) was obtained. LCMS (ESI): [M+H]+=335.0
[0572] Step 3: 7'-bromo-2,2,5'-trifluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-4'-carboxylic acid was obtained by referring to the method of Intermediate I. LCMS (ESI): [M+H]+=321.0
[0573] Synthesis of intermediate N
[0574] Step 1: At 0°C, diethylzinc solution (28.7 mL, 28.7 mmol) and trifluoroacetic acid (2.1 mL) were added to dichloromethane (5.00 mL), followed by diiodomethane (7.70 g, 28.7 mmol). The reaction mixture was stirred at 0°C for 0.5 hours. A solution of methyl 7-bromo-5-fluoro-1-methylene-2,3-dihydro-1H-indene-4-carboxylate (4.09 g, 14.3 mmol) in dichloromethane (50 mL) was then added. The mixture was then warmed to room temperature and stirred for 4 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate solution (50 mL x 2). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO). 80 grams Silica gel flash column, 0-10% tetrahydrofuran / petroleum ether gradient elution @ 60 mL / min). 7'-bromo-5'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-4'-carboxylic acid methyl ester (2.13 g, yield 50%) was obtained. LCMS (ESI): [M+H]+=299.0
[0575] Step 2: 7'-bromo-5'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-4'-carboxylic acid was obtained by referring to the method of Intermediate I. LCMS (ESI): [M+H]+=285.0
[0576] Example 1A to Example 1D: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(1,2)-naphthyl ring naphthalene-8-ene-5 4 Four isomers of 2-hydroxyethane-1-sulfonamide
[0577] Step 1: Dissolve 4-bromo-2-fluoronaphthalene-1-carboxylic acid (5.00 g, 18.6 mmol) in dimethyl sulfoxide (100 mL), add potassium carbonate (7.86 g, 55.7 mmol) and 4-(prop-2-en-1-yl)piperidin-1-yl]naphthalene-1-carboxylic acid (3.90 g, 1.30 mmol), and stir at 130°C for 60 hours. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give 4-bromo-2-[4-(prop-2-en-1-yl)piperidin-1-yl]naphthalene-1-carboxylic acid (3.20 g, 8.55 mmol, 46.0% yield) as a yellow oil. LCMS (ESI): [M+H]+ =374.0.
[0578] Step 2: Dissolve 2-(3-vinyl-4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (680 mg, 2.67 mmol) in tetrahydrofuran (20.0 mL), add N,N-diisopropylethylamine (1.04 g, 8.02 mmol), 4-bromo-2-[4-(prop-2-en-1-yl)piperidin-1-yl]naphthalene-1-carboxylic acid (1.00 g, 2.67 mmol), and 2-chloro-1-methylpyridinium iodide (1.04 g, 4.01 mmol), and stir at 60°C for 16 hours. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-11% gradient of tetrahydrofuran / petroleum ether) to afford 2-(4-allylpiperidin-1-yl)-4-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-1-naphthamide (0.50 g, 0.82 mmol, 31.0% yield) as a yellow oil. LCMS (ESI): [M+H] + =584.10. 1 H NMR (400MHz, DMSO-d6) δppm 10.68(br s,1H),8.22-8.05(m,1H),7.95-7.68(m,2H),7.68-7.54(m,2H),7.49(br s,1H),5.96-5.63(m,2H),5.36-5.08(m,2H),4.96(br d,J=12.4Hz,2H),4.69-4.26(m,2H),3.30(br d,J=2.0Hz,1H),3.26-3.07(m,2H),2.92-2.56(m,4H),2.42-2.28(m,3H),2.20-1.78(m,4H),1.64(br d,J=11.2Hz,2H),1.48-1.31(m,1H),1.28-1.00(m,2H)
[0579] Step 3: 2-(4-allylpiperidin-1-yl)-4-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-1-naphthamide (500 mg, 0.82 mmol) was dissolved in dichloromethane (200 mL), Grubbs second-generation catalyst (151 mg, 0.17 mmol) was added, and stirred at 50 ° C for 16 hours under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of tetrahydrofuran / petroleum ether) to obtain a yellow solid 5 4-Br-1 4 ,1 4 -Difluoro-2 6 -methyl-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-bipiperidin-5(1,2)-naphthocyclonon-8-en-4-one (400 mg, 0.69 mmol, 84.0% yield). LCMS (ESI): [M+H]+=584.1
[0580] Step 4: Place 5 4 -Br-1 4 ,1 4 -Difluoro-2 6 3-Methyl-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-bipiperidin-5(1,2)-naphthocyclonon-8-en-4-one (300 mg, 0.52 mmol) and 2-hydroxyethanesulfonamide (83.8 mg, 0.67 mmol) were dissolved in dioxane (10.0 mL), and potassium phosphate (437 mg, 2.06 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (43.7 mg, 0.10 mmol), and tris(dibenzylideneacetone)dipalladium (47.2 mg, 0.05 mmol) were added. The mixture was stirred at 60°C under a nitrogen atmosphere for 3 hours. The reaction mixture was filtered, diluted, and purified by preparative HPLC (C18, 25-56% gradient of water (hydrochloric acid) / acetonitrile) to obtain the cis- and trans-products.
[0581] Cis product: white solid ((cis)-N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(1,2)-naphthyl ring naphthalene-8-ene-5 4 1-Hydroxyethane-2-sulfonamide (86 mg). LCMS (ESI): [M+H] + =627.2 1H NMR(400MHz,DMSO-d6)δppm 11.02-10.34(m,1H),8.37-8.23(m,2H),7.59-7.37(m,3H),7.25(s,1H),5.84-5.65(m,1H),5.46(t,J=10.4Hz, 1H),5.19-4.84(m,1H),4.82-4.65(m,1H),4.63-4.48(m,1H),3.79(t,J=6.8Hz,2H),3.50-3.40(m,1H),3.24(br t,J=6.4Hz,2H),3.14(br t,J=12.0Hz,1H),3.06-2.71(m,5H),2.49-2.43(m,1H),2.38(s,3H),2.28-1.87(m,4H),1.84-1.62(m,4H),1.45-1.29(m,1H)
[0582] Trans product: white solid (trans)-N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(1,2)-naphthyl ring naphthalene-8-ene-5 4 1-Hydroxyethane-2-sulfonamide (27.7 mg). LCMS (ESI): [M+H] + =627.3 1 H NMR(400MHz,DMSO-d6)δppm 10.20(s,1H),10.09-9.49(m,1H),8.34-8.03(m,2H),7.59-7.45(m,2H),7.43-7.33(m,2H),5.9 2-5.68(m,1H),5.35(dd,J=8.4,15.6Hz,1H),5.11-4.87(m,3H),3.79(t,J=6.8Hz,2H),3.52-3.3 9(m,1H),3.30-3.24(m,2H),3.19-3.08(m,1H),3.00-2.80(m,3H),2.77-2.63(m,1H),2.35(s,2H ),2.45-2.33(m,1H),2.33-2.10(m,2H),2.09-1.84(m,3H),1.74-1.42(m,4H),1.20-1.09(m,1H)
[0583] The cis product was separated by SFC (chromatographic column type: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 um), mobile phase type: CO2-EtOH (0.1% NH3H2O), gradient: isocratic 50%, flow rate: 80 mL / min, column temperature: 40°C) to obtain Example 1A and Example 1B.
[0584] Example 1A: White solid (12.6 mg), SFC analysis (column: Chiralpak AS-3 50x4.6mm ID, 3um; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B maintained at 40%; flow rate: 4 ml / min). Chiral column peak position at 1.537 min; LCMS (ESI): [M+H]+ = 627.2 1 H NMR(400MHz,DMSO-d6)δppm 10.27(s,1H),10.05-9.74(m,1H),8.27(d,J=8.4Hz,1H),8.11(d,J=8.4Hz ,1H),7.6-7.4(m,3H),7.18(s,1H),5.74(dt,J=5.0,11.2Hz,1H),5.44(br t,J=10.4Hz,1H),5.19-4.90(m,1H),4.84-4.66(m,1H),4.59(br d,J=12.0Hz,1H),3.81(br t,J=6.4Hz,2H),3.51(br d,J=10.8Hz,1H),3.31(br s,2H),3.23-3.10(m,1H),3.07-2.96(m,2H),2.95-2.69(m,3H),2.39(s,3H),2.26-1.84(m,4H),1.82-1.57(m,4H),1.43-1.19(m,1H)
[0585] Example 1B: White solid (16.9 mg), SFC analysis (column: Chiralpak AS-3 50x4.6mm ID, 3um; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B maintained at 40%; flow rate: 4 ml / min). Chiral column peak position at 1.212 min; LCMS (ESI): [M+H]+ = 627.3 1H NMR(400MHz,DMSO-d6)δppm 10.30(s,1H),9.98(s,1H),8.33(d,J=8.4Hz,1H),8.16(d,J=8.4Hz,1H),7.75-7.53(m,3H),7.23(s,1H),5.80(dt,J=5.6,11.2Hz,1H),5.50(br t,J=10.4Hz,1H),4.78(br d,J=12.4Hz,1H),4.65(br d,J=12.4Hz,1H),3.87(t,J=6.4Hz,2H),3.57(br d,J=10.8Hz,1H),3.20(br t,J=12.4Hz,1H),3.13-3.02(m,2H),3.00-2.74(m,3H),2.45(s,3H),2.30-1.98(m,4H),1.91-1.60(m,5H),1.48-1.16(m,3H)
[0586] The trans product was separated by SFC (chromatographic column type: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um), mobile phase type: CO2-EtOH (0.1% NH3H2O), gradient: isocratic 35%, flow rate: 80 mL / min, column temperature: 35°C) to obtain Example 1C and Example 1D.
[0587] Example 1C: White solid (7.11 mg), SFC analysis (column: Chiralpakl IG-3 50x4.6mm ID, 3um; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: from 5% to 40% of B in 1.5 minutes and hold 40% for 1 minute, then 5% of B for 0.5 minutes; flow rate: 4 ml / min). Chiral column peak position at 0.572 minutes; LCMS (ESI): [M+H] + = 627.3 1H NMR (400MHz, DMSO-d6) δppm10.20(s,1H),8.22(d,J=8.4Hz,1H),8.15(d,J=8.4Hz,1H),7.55(s,1H),7.50(br t,J=7.6Hz,1H),7.43-7.32(m,2H),5.89-5.69(m,1H),5.36(br dd,J=8.4,15.6Hz,1H),5.02(br t,J=13.2Hz,2H),3.79(t,J=6.8Hz,2H),3.44(br d,J=9.6Hz,1H),3.31-3.24(m,4H),3.16(br d,J=12.4Hz,1H),3.00-2.80(m,3H),2.72(br t,J=11.6Hz,1H),2.36(s,3H),2.30-1.87(m,4H),1.79-1.43(m,4H),1.31-1.12(m,2H)
[0588] Example 1D: White solid (8.64 mg), SFC analysis (column: Chiralpakl IG-3 50x4.6mm ID, 3um; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: from 5% to 40% of B in 1.5 minutes and hold 40% for 1 minute, then 5% of B for 0.5 minutes; flow rate: 4 ml / min). Chiral column peak position at 1.134 minutes; LCMS (ESI): [M+H]+ = 627.4 1 H NMR (400MHz, DMSO-d6) δppm10.25(s,1H),8.28(dd,J=8.4,16.8Hz,2H),7.62(s,1H),7.51(br t,J=7.8Hz,1H),7.43-7.33(m,2H),5.87(td,J=7.8,15.2Hz,1H),5.43(br dd,J=8.4,15.2Hz,1H),5.17-4.97(m,2H),3.83(t,J=6.8Hz,2H),3.47(br d,J=10.0Hz,1H),3.32-3.16(m,4H),3.09-2.86(m,3H),2.74(br t,J=11.6Hz,1H),2.41(s,3H),2.37-2.26(m,1H),2.24-1.87(m,4H),1.75-1.52(m,4H),1.34-1.18(m,4H),0.99-0.85(m,1H)
[0589] Example 2A to Example 2D: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide four isomers
[0590] Step 1: A mixture containing methyl 4-bromo-2-fluoro-6-methylbenzoate (25.00 g, 101.19 mmol), N-bromosuccinimide (21.60 g, 121.43 mmol), azobisisobutyronitrile (8.50 g, 50.60 mmol), and acetonitrile (250.00 mL) was stirred at 70°C for 3 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether gradient) to obtain methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (26.20 g, crude) as a colorless oil. LCMS (ESI): [M+H] + =326.9
[0591] Step 2: A mixture containing methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (26 g, 79.76 mmol), tert-butyl propan-1,3-diolate (16.5 g, 87.74 mmol), cesium carbonate (53.0 g, 159.53 mmol), and N,N-dimethylformamide (200.00 mL) was stirred at 20°C for 2 hours. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether gradient) to afford 1-(tert-butyl)-3-ethyl-2-(5-bromo-3-fluoro-2-(methoxycarbonyl)benzyl)malonate (21.00 g, crude) as a colorless oil. LCMS (ESI): [M+Na] + =455.0
[0592] Step 3: A solution containing 1-(tert-butyl)-3-ethyl-2-(5-bromo-3-fluoro-2-(methoxycarbonyl)benzyl)malonate (21.00 g, 48.47 mmol) and trifluoroacetic acid (60.00 mL) was stirred at 20°C for 1 hour. The reaction solution was concentrated to remove the trifluoroacetic acid, and then toluene (60 mL) and triethylamine (50.0 g, 484.69 mmol) were added. Stirring was continued at 120°C for 3 hours. The reaction solution was concentrated, and the pH was adjusted to approximately 8 by adding aqueous sodium bicarbonate. The solution was then extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting mixture was then purified by column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether gradient) to afford methyl 4-bromo-2-(3-ethoxy-3-oxopropyl)-6-fluorobenzoate (11.20 g, crude product). LCMS (ESI): [M+H] + =333.0.
[0593] Step 4: A mixture containing methyl 4-bromo-2-(3-ethoxy-3-oxopropyl)-6-fluorobenzoate (11.20 g, 33.62 mmol), lithium hydroxide monohydrate (8.1 g, 336.18 mmol), tetrahydrofuran (40 mL), methanol (40 mL), and water (40 mL) was stirred at 20°C for 4 hours. The reaction mixture was concentrated to remove tetrahydrofuran and methanol, and the pH was adjusted to 5 by adding 4 M hydrochloric acid in ethyl acetate (100 mL). The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 4-bromo-2-(2-carboxyethyl)-6-fluorobenzoic acid (5.1 g, 17.52 mmol, yield: 52.1%) as a white solid. LCMS (ESI): [M+Na] + =313.0.
[0594] Step 5: Add oxalyl chloride (11.10 g, 85.89 mmol) to a mixed solution containing 4-bromo-2-(2-carboxyethyl)-6-fluorobenzoic acid (5.00 g, 17.18 mmol) and dichloromethane (50 mL). Stir the resulting mixture at 20°C for 1 hour. The reaction solution is concentrated to obtain the compound 4-bromo-2-(3-chloro-3-oxopropyl)-6-fluorobenzoyl chloride (5.7 g, crude product) as a yellow oil. LCMS (ESI): [M+H] + =319.0 (corresponding methyl ester).
[0595] Step 6: 4-Bromo-2-(3-chloro-3-oxopropyl)-6-fluorobenzoyl chloride (5.60 g, 17.08 mmol) was dissolved in dichloromethane (10.00 mL) and added dropwise to a solution containing aluminum chloride (9.10 g, 68.30 mmol) and dichloromethane (50.00 ml) at 0°C. The reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to give compound 7-bromo-5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (3.40 g, crude product) as a brown solid. LCMS (ESI): [M+H] + =273.0.
[0596] Step 7: A mixed solution containing 7-bromo-5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (3.40 g, 12.45 mmol), 4-allylpiperidine (1.90 g, 14.94 mmol), potassium carbonate (5.30 g, 37.35 mmol) and dimethyl sulfoxide (30 mL) was stirred at 100 ° C for 3 hours. The reaction solution was poured into water (30 mL), and hydrochloric acid / ethyl acetate solution (20 mL, 4 M) was added to adjust the pH to about 5, and ethyl acetate (30 mL x 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to obtain compound 5-(4-allylpiperidin-1-yl)-7-bromo-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (1.90 g, 5.02 mmol, yield: 40.3%) as a yellow solid, LCMS (ESI): [M+H] + = 378.0.
[0597] Step 8: A mixture containing 5-(4-allylpiperidin-1-yl)-7-bromo-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (1.40 g, 3.70 mmol), 2-(4,4-difluoro-3-vinylpiperidinyl)-6-methylpyrimidin-4-amine (1.10 g, 4.44 mmol), 2-chloro-1-methylpyridinium iodide (1.40 g, 5.55 mmol), N,N-diisopropylethylamine (1.50 g, 11.10 mmol) and dichloromethane (2 A mixed solution of 5-(4-allylpiperidin-1-yl)-7-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-indene-4-carboxamide (1.00 g, 1.63 mmol, yield: 44.0%) was stirred at 20°C for 12 hours. The reaction solution was concentrated and purified by column chromatography (silica gel, 0-70% ethyl acetate / petroleum ether gradient) to obtain 5-(4-allylpiperidin-1-yl)-7-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-indene-4-carboxamide (1.00 g, 1.63 mmol, yield: 44.0%) as a yellow solid. LCMS (ESI): [M+H]+ = 614.20.
[0598] Step 9: A solution containing 5-(4-allylpiperidin-1-yl)-7-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-indene-4-carboxamide (1.00 g, 1.63 mmol), Grubbs second-generation catalyst (141 mg, 0.16 mmol) and dichloromethane (200.00 mL) was stirred at 50° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to obtain compound 5 7 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 1 ,4-dione (700 mg, crude) as a yellow solid. LCMS (ESI): [M+H]+=586.20.
[0599] Step 10: Under nitrogen atmosphere, containing 5 7 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-5 2 ,5 3 -Dihydro-5 1H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 1 The reaction mixture of 4-dione (300 mg, 0.51 mmol), 2-hydroxyethanesulfonamide (131 mg, 1.02 mmol), potassium phosphate (332 mg, 1.53 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (22 mg, 0.051 mmol), tris(dibenzylideneacetone)dipalladium (48 mg, 0.051 mmol) and dioxane (5 mL) was stirred at 100 ° C for 2 hours, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) and C18 (0-100% gradient of acetonitrile / water) to obtain a mixture of the four isomers of Example 2 (38 mg, 0.060 mmol, yield: 11.8%) as a white solid. LCMS (ESI): [M+H]+=631.30. 1 H NMR (400MHz, DMSO) δppm 11.24–9.85(m,2H),7.47–7.27(m,1H),7.20–6.98(m,1H),5.84–5.69(m,1H),5.51 –5.29(m,1H),5.11–4.86(m,2H),4.71–4.38(m,1H),3.84–3.73(m,2H),3.59–3.51(m,2H),3.50–3.34(m,2H),3. 29–3.02(m,3H),2.99–2.60(m,6H),2.36–2.30(m,3H),2.29–2.21(m,1H),2.18–1.96(m,2H),1.93–1.38(m,6H).
[0600] The four isomer mixture of Example 2 was purified by preparative HPLC (C18, 26%-66% gradient of water (hydrochloric acid) / acetonitrile) to give a white solid trans isomer mixture (10.7 mg) and a cis isomer mixture (7.2 mg).
[0601] The trans isomer mixture (10.7 mg) was separated by SFC (chromatographic column type: REGIS (s, s) WHELK-O1 (250 mm*30 mm, 5 μm), mobile phase type: CO2-MeOH (0.1% NH3H2O), gradient: isocratic 45%, flow rate: 80 mL / min, column temperature: 40°C) to obtain Example 2A (1.0 mg) and Example 2B (1.0 mg).
[0602] Example 2A: White solid (1.00 mg), SFC analysis (column: Chiralpak AD-3 50x4.6 mm ID, 3 μm; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / methanol; gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; flow rate: 4 mL / min). Chiral column peak elution position at 0.824 min; LCMS (ESI): [M+H]+ = 631.2 1 H NMR(400MHz,DMSO-d6)δppm10.04(br s,1H),9.91(br s,1H),7.45(s,1H),7.01(br s,1H),5.89-5.67(m,1H),5.46-5.29(m,1H),5.16-4.79(m,3H),3.77(br d,J=4.4Hz,2H),3.61-3.37(m,4H),3.28-3.13(m,3H),2.99-2.77(m,5H),2.66-2.60(m,1H),2.32(s ,3H),2.29-2.23(m,1H),2.09-1.96(m,2H),1.94-1.83(m,1H),1.76-1.55(m,4H),1.21-1.13(m,1H)
[0603] Example 2B: White solid (1.00 mg), SFC analysis (column: Chiralpak AD-3 50x4.6mm ID, 3um; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / methanol; gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; flow rate: 4 ml / min). Chiral column peak position at 0.953 min; LCMS (ESI): [M+H]+ = 631.2 1H NMR(400MHz,DMSO-d6)δppm10.09(s,1H),9.97(s,1H),7.51(s,1H),7.07(s,1H),5.91-5 .76(m,1H),5.41(dd,J=8.8,15.6Hz,1H),5.15-4.86(m,3H),3.89-3.81(m,2H),3.60(br t,J=5.2Hz,2H),3.56-3.42(m,2H),3.30-3.18(m,2H),3.06-2.79(m,5H),2.74-2.64(m,2H),2.41-2.3 7(m,3H),2.36-2.27(m,1H),2.23-2.02(m,2H),1.99-1.88(m,1H),1.83-1.52(m,4H),1.27-1.19(m,1H)
[0604] The cis isomer mixture (7.2 mg) was further separated by SFC (chromatographic column type: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um), mobile phase type: CO2-MeOH (0.1% NH3H2O), gradient: isocratic 50%, flow rate: 80 mL / min, column temperature: 40°C) to obtain Example 2C and Example 2D.
[0605] Example 2C: White solid (1.00 mg). SFC analysis (column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / methanol; gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; flow rate: 4 mL / min). Chiral column peak elution position at 1.026 min; LCMS (ESI): [M+H]+ = 631.2 1H NMR (400MHz, DMSO-d6) δppm11.38-10.98(m,1H),10.21-9.72(m,1H),7.30(s,1H),7.23-7.04(m,1H),5.89-5.67(m,1H),5.47(br t,J=10.0Hz,1H),5.21-4.92(m,1H),4.75-4.58(m,1H),4.53-4.36(m,1H),3.89-3.71(m,2H),3.66-3.39(m,4H),3.24-3.0 4(m,4H),3.02-2.75(m,3H),2.66-2.61(m,1H),2.38-2.26(m,5H),2.17-2.02(m,2H),1.98-1.68(m,5H),1.63-1.50(m,1H)
[0606] Example 2D: White solid (1.00 mg). SFC analysis (column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / methanol; gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; flow rate: 4 mL / min). Chiral column peak elution position at 1.497 min; LCMS (ESI): [M+H]+ = 631.2 1 H NMR (400MHz, DMSO-d6) δppm11.58-11.08(m,1H),10.46-9.78(m,1H),7.36(s,1H),7.27-7.1 0(m,1H),5.98-5.77(m,1H),5.63-5.47(m,1H),5.27-5.02(m,1H),4.81-4.60(m,1H),4.58- 4.44(m,1H),3.96-3.77(m,2H),3.73-3.44(m,4H),3.27-3.08(m,4H),3.05-2.82(m,3H),2. 71-2.66(m,1H),2.43-2.30(m,5H),2.19-2.08(m,2H),1.98-1.75(m,5H),1.70-1.59(m,1H)
[0607] Example 3: N-(1 4 -Fluorine-2 6 -methyl-5 1 ,4-dioxo-1 1 ,1 2 ,13 ,1 6 ,5 2 ,5 3 -Hexahydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,5)-pyridin-6(1,4)-piperidin-5(4,5)-indenononan-8-ene-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide
[0608] Example 3 was prepared according to a similar synthetic route as Example 2. LCMS (ESI): [M+H]+=611.30.
[0609] Example 4: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-5- 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide
[0610] Step 1: Contains 5 7 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 1 ,4-diketone (400 mg, 0.68 mmol), triethylsilane (801 mg, 6.82 mmol) and trifluoroacetic acid (5.00 mL) were stirred at 80 ° C for 12 hours. The reaction solution was concentrated and sodium bicarbonate aqueous solution (500 mL) was added to adjust the pH to about 8. Then, it was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-30% gradient ethyl acetate / petroleum ether) to obtain compound 5 7 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-5 2 ,5 3 -Dihydro-5 1H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenocyclonon-8-en-4-one (120 mg, 0.21 mmol, yield: 30.7%) was obtained as a yellow solid. LCMS (ESI): [M+H]+ = 572.20.
[0611] Step 2: Under nitrogen atmosphere, containing 5 7 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-5 2 ,5 3 -Dihydro-5 1 The reaction mixture of H-3-aza-2(2,4)-pyrimidinyl-1(1,3),6(1,4)-dipiperidinyl-5(4,5)-indenylheterocyclonon-8-en-4-one (120 mg, 0.21 mmol), 2-hydroxyethanesulfonamide (54 mg, 0.42 mmol), potassium phosphate (136 mg, 0.63 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (9 mg, 0.021 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.021 mmol) and dioxane (5.00 mL) was stirred at 100° C. for 2 hours, poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain compound N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-5- 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide (51 mg, 0.08 mmol, yield: 39.5%), as a yellow solid. LCMS (ESI): [M+H]+=617.30. 1H NMR (400MHz, DMSO) δ12.75-12.65(m,1H),10.47-10.39(m,1H),9.34(s,1H),7.50-7.28(m,1H),7.26-7.01(m,1H),5.87-5.70(m,1H),5.55–5.36 (m,1H),5.07-4.78(m,2H),4.75-4.41(m,1H),3.85-3.70(m,2H),3.31– 2.67(m,10H),2.34-2.27(m,3H),2.23–1.43(m,11H),1.31–1.10(m,3H).
[0612] Example 5: N-(1 4 ,1 4 -Difluoro-2 6 -Methoxy-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclononane-8-ene-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide
[0613] Step 1: A mixture containing methyl 4-bromo-2-fluoro-6-methylbenzoate (25.00 g, 101.19 mmol), N-bromosuccinimide (21.60 g, 121.43 mmol), azobisisobutyronitrile (8.50 g, 50.60 mmol), and acetonitrile (250.00 mL) was stirred at 70°C for 3 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether gradient) to obtain methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (26.20 g, crude) as a colorless oil. LCMS (ESI): [M+H] + =326.90.
[0614] Step 2: A mixture containing methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (26.00 g, 79.76 mmol), tert-butyl propan-1,3-diolate (16.50 g, 87.74 mmol), cesium carbonate (53.00 g, 159.53 mmol), and N,N-dimethylformamide (200.00 mL) was stirred at 20°C for 2 hours. The reaction solution was poured into water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether gradient) to afford 1-(tert-butyl)-3-ethyl-2-(5-bromo-3-fluoro-2-(methoxycarbonyl)benzyl)malonate (21.00 g, crude) as a colorless oil. LCMS (ESI): [M+Na] + =455.00.
[0615] Step 3: A solution containing 1-(tert-butyl)-3-ethyl-2-(5-bromo-3-fluoro-2-(methoxycarbonyl)benzyl)malonate (21.00 g, 48.47 mmol) and trifluoroacetic acid (60.00 mL) was stirred at 20°C for 1 hour. The reaction solution was concentrated to remove the trifluoroacetic acid, and then toluene (60.00 mL) and triethylamine (50.00 g, 484.69 mmol) were added. Stirring was continued at 120°C for 3 hours. The reaction solution was concentrated, and the pH was adjusted to approximately 8 by adding aqueous sodium bicarbonate. The solution was then extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting mixture was then purified by column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether gradient) to afford methyl 4-bromo-2-(3-ethoxy-3-oxopropyl)-6-fluorobenzoate (11.20 g, crude product). LCMS (ESI): [M+H] + =333.00.
[0616] Step 4: A mixture containing methyl 4-bromo-2-(3-ethoxy-3-oxopropyl)-6-fluorobenzoate (11.20 g, 33.62 mmol), lithium hydroxide monohydrate (8.10 g, 336.18 mmol), tetrahydrofuran (40 mL), methanol (40 mL), and water (40 mL) was stirred at 20°C for 4 hours. The reaction mixture was concentrated to remove tetrahydrofuran and methanol, and the pH was adjusted to 5 by adding 4 M hydrochloric acid in ethyl acetate (100 mL). The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 4-bromo-2-(2-carboxyethyl)-6-fluorobenzoic acid (5.10 g, 17.52 mmol, 52.1% yield) as a white solid. LCMS (ESI): [M+Na] + =313.00.
[0617] Step 5: Add oxalyl chloride (11.10 g, 85.89 mmol) to a mixed solution containing 4-bromo-2-(2-carboxyethyl)-6-fluorobenzoic acid (5.00 g, 17.18 mmol) and dichloromethane (50 mL). Stir the resulting mixture at 20°C for 1 hour. The reaction solution was concentrated to obtain the compound 4-bromo-2-(3-chloro-3-oxopropyl)-6-fluorobenzoyl chloride (5.70 g, crude product) as a yellow oil. LCMS (ESI): [M+H] + =319.00 (corresponding methyl ester).
[0618] Step 6: 4-Bromo-2-(3-chloro-3-oxopropyl)-6-fluorobenzoyl chloride (5.60 g, 17.08 mmol) was dissolved in dichloromethane (10.00 mL) and added dropwise to a solution containing aluminum chloride (9.10 g, 68.30 mmol) and dichloromethane (50.00 ml) at 0°C. The reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to give compound 7-bromo-5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (3.40 g, crude product) as a brown solid. LCMS (ESI): [M+H] + =273.00.
[0619] Step 7: A solution of 7-bromo-5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (1.00 g, 3.66 mmol), 4-allylpiperidine (550 mg, 4.39 mmol) and potassium carbonate (2.60 g, 18.31 mmol) in dimethyl sulfoxide (10.00 mL) was stirred at 100 °C for 3 hours. The reaction solution was poured into water (30 mL), and hydrochloric acid / ethyl acetate solution (6 mL, 4 M) was added to adjust the pH to about 5. The mixture was then washed with ethyl acetate (30 mL x 10 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound 5-(4-allylpiperidin-1-yl)-7-bromo-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (1.00 g, 2.64 mmol, yield 72.2%) as a yellow solid, LCMS (ESI): [M+H] + =378.10.
[0620] Step 8: containing 5-(4-allylpiperidin-1-yl)-7-bromo-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (1.00 g, 2.64 mmol), 2-(4,4-difluoro-3-vinylpiperidinyl)-6-methoxypyrimidin-4-amine (857 mg, 3.17 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.10 g, 7.93 mmol) and 4-dimethylaminopyridine (1.60 g A solution of 5-(4-allylpiperidin-1-yl)-7-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methoxypyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-indene-4-carboxamide (1.00 g, crude) was stirred at 80°C for 12 hours. The reaction solution was concentrated and purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain the compound 5-(4-allylpiperidin-1-yl)-7-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methoxypyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-indene-4-carboxamide (crude product) as a yellow oil. LCMS (ESI): [M+H] + =630.20.
[0621] Step 9: A solution of 5-(4-allylpiperidin-1-yl)-7-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methoxypyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-indene-4-carboxamide (400 mg, 0.63 mmol) and Grubbs second-generation catalyst (55 mg, 0.063 mmol) in dichloromethane (100.00 mL) was stirred at 50° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain compound 5. 7 -Br-1 4 ,1 4 -Difluoro-2 6 -Methoxy-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 1 ,4-dione (200 mg, 0.33 mmol, yield 52.4%), as a gray solid. LCMS (ESI): [M+H] + =602.20.
[0622] Step 10: Contains 5 7 -Br-1 4 ,1 4 -Difluoro-2 6 -Methoxy-5 2 ,5 3-Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 1 ,4-dione (200 mg, 0.33 mmol), 2-hydroxyethanesulfonamide (84 mg, 0.66 mmol), potassium phosphate (216 mg, 1.00 mmol), cuprous iodide (65 mg, 0.337 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (48 mg, 0.33 mmol) in dioxane (5.00 mL) was stirred at 100 ° C for 2 hours under nitrogen. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain compound N-(1 4 ,1 4 -Difluoro-2 6 -Methoxy-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclononane-8-ene-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide (60 mg, 0.093 mmol, yield 27.9%), as a gray solid. LCMS (ESI): [M+H] + =647.30.
[0623] Example 6: N-((1 3 S)-1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclononane-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide
[0624] Step 1: N-((1 3 S, Z)-1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 7 1-Hydroxyethane-2-sulfonamide (40.0 mg, 0.06 mmol) was dissolved in methanol (10.00 mL) and wet palladium carbon (20.0 mg, 0.01 mmol) was added. The reaction mixture was replaced with argon three times and then replaced with hydrogen three times. The mixture was stirred at 25°C for 16 hours under a hydrogen (50 Psi) atmosphere. The reaction mixture was filtered under reduced pressure to remove palladium carbon and then concentrated under vacuum. The residue was purified by preparative HPLC (C18, 46%-86% gradient of water (formic acid) / acetonitrile) to give a white solid N-((1 3 S)-1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclononane-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide (15.0 mg, 0.02 mmol, 37.4% yield). LCMS (ESI): [M+H]+=633.2. 1 H NMR(400MHz,DMSO-d6)δppm 10.44-10.23(m,1H),10.07-9.53(m,1H),7.56-7.41(m,1H),6.94(br s,1H),5.33-4.88(m,1H),4.80-4.52(m,2H),3.77(br d,J=5.2Hz,2H),3.52(br s,3H),3.20-3.02(m,2H),2.96-2.78(m,3H),2.66-2.58(m,2H),2.36-2.22(m,3H),2.12-1.47(m,10H),1.39-0.95(m,6H)
[0625] Example 7: N-((1 3 R, Z)-1 4 ,1 4 -Difluoro-5- 1 -Hydroxy-2 6 -methyl-4-oxo-5- 2 ,5 3 -Dihydro-5 1H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 7 (2-Hydroxyethane-1-sulfonamide)
[0626] Step 1: N-((1 3 R, Z)-1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 7 1-Hydroxy-2-methyl-1-thiazolyl-1-ol (40.0 mg, 0.06 mmol) was dissolved in methanol (10.0 mL), sodium borohydride (7.32 mg, 0.19 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction solution was poured into water (5.00 mL) and extracted with ethyl acetate (5 mL*2). The organic phase was concentrated to obtain a crude product. The residue was purified by preparative HPLC (C18, 34%-74% gradient of water (formic acid) / acetonitrile) to obtain a white solid N-((1 3 R, Z)-1 4 ,1 4 -Difluoro-5- 1 -Hydroxy-2 6 -methyl-4-oxo-5- 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 7 1-Hydroxy-2-[4-(2-[4-(2-(2-hydroxyethane-1-sulfonamide)]-2-hydroxyethane-1-sulfonamide (14.0 mg, 0.02 mmol, 34.8% yield). LCMS (ESI): [M+H]+=591.2. 1H NMR (400MHz, DMSO-d6) δppm 12.60 (br d, J=10.4Hz, 1H), 9.37-8.66 (m, 1H), 7.30 (s, 2H), 5.87-5.71 (m, 1H), 5.50 (br t,J=9.6Hz,2H),5.39-5.20(m,1H),5.15-4.95(m,1H),4.71(br d,J=12.4Hz,1H),4.57-4.39(m,1H),3.78(br s,2H),3.41(br s,2H),3.17(br s,3H),3.08-2.66(m,6H),2.41-2.20(m,5H),2.17-2.03(m,2H),2.00-1.66(m,6H),1.53(br d,J=13.6Hz,1H)
[0627] Example 8: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 1 ,5 2 ,5 3 ,5 4 -Tetrahydro-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(5,6)-indenylheterocyclonon-8-ene-5 8 -yl)-2-hydroxyethane-1-sulfonamide
[0628] Example 8 was prepared by a similar synthetic route as Example 2.
[0629] Example 8A (trans isomer) LCMS (ESI): [M+H] + =645.8. 1H NMR(400MHz,DMSO-d6)δppm 12.25(s,1H),10.36(s,1H),7.40(s,1H),6.98(s,1H),5.83-5.63(m,1H),5.29(dd,J=8.4,15.6Hz,1H),4.99(br d,J=12.0Hz,2H),3.74(t,J=6.0Hz,2H),3.48(br s,2H),3.12-3.06(m,1H),3.03-2.79(m,4H),2.76-2.57(m,4H),2.34(s,3H),2.29-1. 94(m,5H),1.93-1.71(m,3H),1.67-1.52(m,3H),1.44-1.28(m,1H),1.18-1.00(m,1H).
[0630] Example 8B (cis isomer) LCMS (ESI): [M+H] + =645.7. 1 H NMR(400MHz,DMSO-d6)δppm 12.21(br s,1H),10.32(s,1H),7.02(s,1H),6.82(s,1H),5.71(dt,J=5.6,11.2Hz,1H),5.5 4-5.31(m,1H),5.07-4.85(m,1H),4.77-4.61(m,1H),4.59-4.46(m,1H),3.74(br d,J=2.4Hz,2H),3.64(br d,J=10.8Hz,1H),3.47(t,J=6.4Hz,2H),3.31-3.27(m,1H),3.24-3.12(m,1H),3.11-2.92(m,2H),2.91-2.72( m,4H),2.63-2.57(m,2H),2.34(s,3H),2.20(s,2H),2.02-1.77(m,4H),1.75-1.59(m,4H),1.43-1.27(m,1H).
[0631] Example 9: N-(11,11-difluoro-6-methyl-1,5,22-trioxo-1,5,6,9,10,11,12,15,16,17,18,22,23,24-tetradecahydro-2H-3,7-(nitrogenyl)-16,19-ethylidene-8,12-methyleneindeno[4,5-i][1,3,7,11]tetraazacyclohexenecan-21-yl)-2-hydroxyethane-1-sulfonamide
[0632] Step 1: Under nitrogen atmosphere, a solution of 6-amino-3-methylpyrimidine-2,4(1H,3H)-dione (1.00 g, 7.09 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.45 g, 35.43 mmol) and benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate (9.50 g, 21.26 mmol) in N,N-dimethylformamide (50.00 mL) was stirred for 15 minutes, and then 4,4-difluoro-3-vinylpiperidine hydrochloride (1.56 g, 8.50 mmol) was added and the reaction was stirred at 20°C for 2 hours. After the reaction was complete, cold water (40 mL) was added to quench the reaction, followed by extraction with ethyl acetate (50 mL x 3). The combined organic phases were washed with sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated to obtain the crude product. Purification by flash column chromatography (silica, 0-20% dichloromethane / methanol) afforded 6-amino-2-(4,4-difluoro-3-vinylpiperidin-1-yl)-3-methylpyrimidin-4(3H)-one (1.60 g, 5.92 mmol, 83.5% yield) as a yellow liquid. LCMS (ESI): [M+H] + =271.10.
[0633] Step 2: A solution of 6-amino-2-(4,4-difluoro-3-vinylpiperidin-1-yl)-3-methylpyrimidin-4(3H)-one (1.60 g, 5.92 mmol), 7-bromo-5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (1.62 g, 5.92 mmol), 2-chloro-1-methylpyridinium iodide (2.31 g, 8.88 mmol) and N,N-diisopropylethylamine (3.90 g, 29.60 mmol) in tetrahydrofuran (30.00 mL) was stirred in an oil bath at 50°C for 15 hours. After the reaction was complete, sodium bicarbonate solution (30 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product. This was then purified by flash column chromatography (silica, 50-100% ethyl acetate / petroleum ether) to afford 7-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carboxamide (370 mg, 0.70 mmol, 11.9% yield) as a yellow solid. LCMS (ESI): [M+H] + =525.10.
[0634] Step 3: A solution of 7-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carboxamide (370 mg, 0.70 mmol), 4-allylpiperidine hydrochloride (228 mg, 1.41 mmol) and N,N-diisopropylethylamine (464 mg, 3.52 mmol) in dimethyl sulfoxide (20.00 mL) was stirred in an oil bath at 80 ° C for 8 hours. After the reaction was complete, cold water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 50-100% ethyl acetate / petroleum ether) to give 5-(4-allylpiperidin-1-yl)-7-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-indene-4-carboxamide (300 mg, 0.48 mmol, 67.6% yield) as a yellow solid. LCMS (ESI): [M+H] + =630.20.
[0635] Step 4: Under nitrogen atmosphere, 5-(4-allylpiperidin-1-yl)-7-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-indene-4-carboxamide (300 mg, 0.48 mmol) was dissolved in dry dichloroethane (50.00 mL), Grubbs second-generation catalyst (21 mg, 0.02 mmol) was added, and the mixture was heated to 80 ° C for 16 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 30-70% ethyl acetate / petroleum ether) to afford 21-bromo-11,11-difluoro-6-methyl-9,10,11,12,15,16,17,18,23,24-decahydro-2H-3,7-(nitro)-16,19-ethylidene-8,12-methyleneindeno[4,5-i][1,3,7,11]tetraazacycloheneicosane-1,5,22(6H)-trione (60 mg, 0.10 mmol, 20.9% yield) as a white solid. LCMS (ESI): [M+H] + =602.20.
[0636] Step 5: Under nitrogen atmosphere, 21-bromo-11,11-difluoro-6-methyl-9,10,11,12,15,16,17,18,23,24-decahydro-2H-3,7-(nitro)-16,19-ethylidene-8,12-methyleneindeno[4,5-i][1,3,7,11]tetraazacycloheneicosane-1,5,22(6H)-trione (60 mg, 0.10 mmol) and 2 -Hydroxyethylsulfonamide (38 mg, 0.30 mmol), potassium phosphate (49 mg, 0.50 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (8 mg, 0.01 mmol) were dissolved in 1,4-dioxane (5.00 mL), and the resulting reaction mixture was stirred at 100 ° C for 6 hours. After the reaction was complete, cold water (20 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated to obtain the crude product, which was purified by flash column chromatography (silica, 60-90% ethyl acetate / petroleum ether) to obtain N-(11,11-difluoro-6-methyl-1,5,22-trioxo-1,5,6,9,10,11,12,15,16,17,18,22,23,24-tetradecahydro-2H-3,7-(nitrogenyl)-16,19-ethylidene-8,12-methyleneindeno[4,5-i][1,3,7,11]tetraazacycloheneicosane-21-yl)-2-hydroxyethane-1-sulfonamide (47 mg, 0.07 mmol, yield 73.0%) as a white solid. LCMS(ESI):[M+H] + =647.30. 1 H NMR(400MHz,DMSO-d6)δ11.23(s,0.6H),10.06(s,0.6H),9.98–9.68(m,0.8H),7.34–6.3 6(m,3H),5.93–4.79(m,4H),4.11–3.48(m,9H),3.13–2.62(m,8H),2.40–1.54(m,9H)ppm;
[0637] Example 10: N-((1 3 S)-1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1H-3-Aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenebicyclononane-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide
[0638] N-((1 3 S, Z)-1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenocyclononane-8-ene-5-ol 7 1-Hydroxy-2-methyl-1-thiazolinone (100 mg, 0.16 mmol) was dissolved in methanol (10.00 mL) and dry palladium on carbon (10.0 mg, 0.01 mmol) was added. The reaction mixture was replaced with argon three times and then replaced with hydrogen three times. The mixture was stirred at 25°C for 16 hours under a hydrogen (50 Psi) atmosphere. The reaction mixture was filtered under reduced pressure to remove palladium on carbon and then concentrated under vacuum. The residue was purified by preparative HPLC (C18, 58%-88% gradient of water (formic acid) / acetonitrile) to give a white solid N-((1 3 S)-1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenebicyclononane-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide (25.0 mg, 0.04 mmol, 25% yield). LCMS (ESI): [M+H]+=633.2. 1H NMR(400MHz,DMSO-d6)δppm 10.31(s,1H),9.86(s,1H),7.51(s,1H),6.93(s,1H),5.06(br t,J=4.4Hz,1H),4.84-4.51(m,2H),3.77(q,J=5.6Hz,2H),3.60-3.48(m,3H),3.25-3.01(m,3H),2.93-2.81(m,3H),2.62(br d,J=4.0Hz,2H),2.31(s,3H),2.09-1.56(m,9H),1.52(br d,J=12.4Hz,1H),1.39-1.30(m,1H),1.23-1.01(m,4H)
[0639] Example 11: (Z)-N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 Hydrogen-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenocyclophen-8-ene-5-ol 7 (4-amino-1-hydroxypropane-2-sulfonamide)
[0640] At 25°C, (Z)-5 7 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-5 2 ,5 3 -Dihydro-5 1 Hydrogen-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenocyclononane-8-ene-5-ol 1, 4-dione (300 mg, 0.51 mmol) in dioxane (6.00 mL) were added 1-hydroxypropane-2-sulfonamide (142 mg, 1.02 mmol), potassium phosphate (332 mg, 1.53 mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (21.7 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium (47.8 mg, 0.05 mmol), and the reaction mixture was heated to 100 ° C under the protection of nitrogen and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent and the residue was diluted with N,N-dimethylformamide (10 mL). The dilution solution was purified by preparative HPLC (C18, 46-86% gradient of water (formic acid) / acetonitrile) to give a white solid compound (Z)-N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 Hydrogen-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenocyclophen-8-ene-5-ol 7 1-Hydroxypropane-2-sulfonamide (15 mg, 0.02 mmol, yield 4.55%). LCMS (ESI): [M+H] + =645.3. 1 H NMR (400MHz, DMSO-d6) δppm 11.16 (br s, 1H), 10.02 (br s, 1H), 7.37-7.13 (m, 2H), 5.75 (dt, J=5.6, 11.2Hz, 1H), 5.45 (br t, J=10.4Hz, 1H), 5.20 (br s,1H),4.63(br d,J=12.8Hz,1H),4.51-4.37(m,1H),3.80-3.68(m,1H),3.68-3.48(m,2H),3.47-3.40(m,1H),3.30 -3.27(m,1H),3.25-3.16(m,2H),3.14-3.03(m,2H),2.99-2.85(m,2H),2.84-2.75(m,1H),2.67(br d,J=2.0Hz,2H),2.38-2.23(m,4H),2.16-2.01(m,2H),2.00-1.65(m,5H), 1.63-1.48(m,1H),1.29(br dd, J = 3.2, 6.8 Hz, 3H).
[0641] Example 12: (Z)-N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 Hydrogen-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenocyclophen-8-ene-5-ol 7 1-Hydroxy-2-methylpropane-2-sulfonamide
[0642] At 25°C, (Z)-5 7 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-5 2 ,5 3 -Dihydro-5 1 Hydrogen-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenocyclononane-8-ene-5-ol 1 , 4-dione (300 mg, 0.51 mmol) in dioxane (6.00 mL) were added 1-hydroxy-2-methylpropane-2-sulfonamide (157 mg, 1.02 mmol), potassium phosphate (332 mg, 1.53 mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (21.7 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium (47.8 mg, 0.05 mmol), and the reaction mixture was heated to 100 ° C under nitrogen and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was diluted with N,N-dimethylformamide (10 mL). The dilution solution was purified by preparative HPLC (C18, 50-90% gradient of water (formic acid) / acetonitrile) to obtain a white solid compound (Z)-N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 Hydrogen-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenocyclophen-8-ene-5-ol 7 1-Hydroxy-2-methylpropane-2-sulfonamide (13 mg, 0.02 mmol, yield 3.9%). LCMS (ESI): [M+H] + =659.3.1 H NMR(400MHz,DMSO-d6)δppm 11.36(br s,1H),10.15(br s,1H),7.43(s,1H),7.36(s,1H),5.86-5.78(m,1H),5.59-5.37(m,2H),4.70(br d,J=11.6Hz,1H),4.52(br d,J=13.2Hz,1H),3.66(br s,2H),3.58-3.45(m,2H),3.27(br d,J=14.0Hz,2H),3.20-3.08(m,2H),3.05-2.90(m,2H),2.85-2.78(m,1H),2.74(br s,2H),2.42-2.32(m,4H),2.21-2.07(m,2H),2.01-1.85(m,2H),1.84-1.74(m,3H),1.70-1.60(m,1H),1.36(s,6H).
[0643] Example 13: (cis)-N-(1 4 ,1 4 -Difluoro-5- 1 -Hydroxy-2 6 ,5 1 -Dimethyl-4-oxo-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylcyclononane-8-ene-5-ol 7 (2-Hydroxyethane-1-sulfonamide)
[0644] (cis)-N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 H-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenocyclophen-8-ene-5-ol 7A solution of tetrahydrofuran (12.0 mL) of methyl)-2-hydroxyethane-1-sulfonamide (300 mg, 0.48 mmol) was cooled to 0°C, and a mixed solution of methylmagnesium bromide (0.79 mL, 2.38 mmol) and tetrahydrofuran (4.00 mL) was slowly added dropwise. The reaction mixture was naturally heated to 25°C under the protection of nitrogen and stirred for 2 hours. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (10*3 mL). The organic phase was collected, dried, filtered, and dried, and the residue was diluted with N,N-dimethylformamide (10 mL). The dilution was purified by preparative HPLC (C18, 42-82% gradient of water (formic acid) / acetonitrile) to obtain a white solid compound (cis)-N-(1 4 ,1 4 -Difluoro-5- 1 -Hydroxy-2 6 ,5 1 -Dimethyl-4-oxo-5 2 ,5 3 -Dihydro-5 1 Hydrogen-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylcyclononane-8-ene-5-ol 7 1-Hydroxyethane-2-sulfonamide (70 mg, 0.11 mmol, yield 23%). LCMS (ESI): [M+H] + =647.3. 1 H NMR (400MHz, DMSO-d6) δppm 12.89-12.33(m,1H),8.95-8.80(m,1H),7.36-7.19(m,2H),6.23-6.08(m,1H),5.76(dt,J=5.2,11.2Hz,1H),5.49(br t,J=10.0Hz,1H),5.21-5.02(m,1H),4.83-4.57(m,1H),4.53-4.36(m,1H),3.86-3.72(m,2H),3.63-3.46(m,3H),3.27-2.89 (m,6H),2.87-2.65(m,3H),2.31(d,J=2.0Hz,4H),2.17-2.02(m,4H),1.98-1.64(m,5H),1.60-1.48(m,1H),1.47-1.25(m,3H)
[0645] Example 14: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 3 ,4-dioxo-5 2,5-dihydro-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(7,6)-benzofurancyclononane-8-ene-5 4 (2-Hydroxyethane-1-sulfonamide)
[0646] Step 1: Dissolve methyl 4-bromo-2-fluoro-6-hydroxybenzoate (9.50 g, 38.1 mmol) and tert-butyl glycolate (6.04 g, 45.7 mmol) in tetrahydrofuran (200 mL). Add triphenylphosphine (20.0 g, 76.3 mmol) and diisopropyl azodicarboxylate (11.6 g, 57.2 mmol). Stir at 25°C under a nitrogen atmosphere for 16 hours. The reaction mixture is diluted with water (200.0 mL) and extracted with ethyl acetate (200 mL x 3). The organic phase is dried, filtered, and concentrated. The residue is purified by flash column chromatography (silica gel, 0-9% gradient of tetrahydrofuran / petroleum ether) to afford methyl 4-bromo-2-(2-(tert-butyloxy)-2-oxyylideneethoxy)-6-fluorobenzoate (13.0 g, 35.8 mmol, 93.8% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δppm 7.32 (dd, J=1.2, 8.8Hz, 1H), 7.14 (s, 1H), 4.85 (s, 2H), 3.84 (s, 3H), 1.42 (s, 9H)
[0647] Step 2: Dissolve methyl 4-bromo-2-(2-(tert-butoxy)-2-oxyylideneethoxy)-6-fluorobenzoate (13.0 g, 38.1 mmol) in dichloromethane (130 mL), add trifluoroacetic acid (30 mL), and stir at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude yellow oil, 2-[5-bromo-3-fluoro-2-(carbomethoxy)phenoxy]acetic acid (10.9 g, 35.7 mmol, crude), which was used directly in the next step. LCMS (ESI): [M+H] + =308.7
[0648] Step 3: Dissolve 2-[5-bromo-3-fluoro-2-(carbomethoxy)phenoxy]acetic acid (10.9 g, 35.5 mmol) in dichloromethane (130 mL). Add oxalyl chloride (16.4 g, 127 mmol) and a drop of N,N-dimethylformamide to the reaction mixture. Stir at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude yellow oil, methyl 4-bromo-2-(2-chloro-2-oxyylideneethoxy)-6-fluorobenzoate (11.5 g, 35.5 mmol, crude), which was used directly in the next step. LCMS (ESI): [M+H] + =322.8 (methanol sample)
[0649] Step 4: Aluminum trichloride (16.4 g, 127 mmol) was dissolved in dichloromethane (110 mL), and then a solution of methyl 4-bromo-2-(2-chloro-2-oxyylideneethoxy)-6-fluorobenzoate (16.4 g, 127 mmol) in dichloromethane (200 mL) was added to the reaction solution, the temperature was raised to 60°C, and the mixture was stirred for 16 hours. The reaction solution was diluted with water (200 mL), extracted with ethyl acetate (200 mL x 3), and the organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give methyl 4-bromo-6-fluoro-3-oxyylidene-2,3-dihydro-1-benzofuran-7-carboxylate (5.50 g, 35.5 mmol, 56.8% yield) as a yellow solid. LCMS (ESI): [M+H] + =288.7
[0650] Step 5: To a solution of methyl 4-bromo-6-fluoro-3-oxyylidene-2,3-dihydro-1-benzofuran-7-carboxylate (3.00 g, 10.4 mmol) and ethylene glycol (6.57 g, 104 mmol) in toluene (200 mL) was added p-toluenesulfonic acid (201 mg, 1.03 mmol). The temperature was raised to 130°C and stirred for 16 hours while removing water using a water separator. The reaction mixture was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (200 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / petroleum ether) to give methyl 4-bromo-6-fluoro-2H-spiro[1-benzofuro-3,2'-[1,3]dioxolane]-7-carboxylate (0.70 g, 2.10 mmol, 20.2% yield) as a yellow solid. LCMS (ESI): [M+H] + =334.8
[0651] Step 6: To a solution of methyl 4-bromo-6-fluoro-2H-spiro[1-benzofuran-3,2'-[1,3]dioxolane]-7-carboxylate (700 mg, 2.10 mmol) in methanol (7 mL) and water (7 mL) was added lithium hydroxide (133 mg, 3.15 mmol) and stirred at 25 ° C for 16 hours. The reaction solution was adjusted to pH 3 with 1M hydrochloric acid and extracted with ethyl acetate (10 mL x 3). The organic phase was dried, filtered, and concentrated to obtain a yellow solid 4-bromo-6-fluoro-2H-spiro[1-benzofuran-3,2'-[1,3]dioxolane]-7-carboxylic acid (600 mg, 1.87 mmol, 89.4% yield). LCMS (ESI): [M+H] + =334.8. 1H NMR (400MHz, DMSO-d6) δppm 13.57 (br s, 1H), 7.26 (d, J = 10.0Hz, 1H), 4.57-4.44 (m, 2H), 4.32-4.19 (m, 2H), 4.13-3.97 (m, 3H)
[0652] Step 7: To a solution of 4-bromo-6-fluoro-2H-spiro[1-benzofuran-3,2'-[1,3]dioxolane]-7-carboxylic acid (600 mg, 1.88 mmol) and 2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-amine (478 mg, 1.88 mmol) in tetrahydrofuran (12 mL) was added N,N-diisopropylethylamine (1214 mg, 9.40 mmol) and 2-chloro-1-methylpyridinium iodide (1430 mg, 3.76 mmol). The temperature was raised to 60°C and stirred for 16 hours. The reaction solution was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / petroleum ether) to afford 4-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-fluoro-2H-spiro[benzofuro-3,2'-[1,3]dioxolane]-7-carboxamide (600 mg, 1.08 mmol, 57.4% yield) as a yellow solid. LCMS (ESI): [M+H] + =556.7
[0653] Step 8: A solution of 4-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-fluoro-2H-spiro[benzofurano-3,2'-[1,3]dioxolane]-7-carboxamide (500 mg, 1.88 mmol) in 2M hydrochloric acid (12 mL) was stirred at 25°C for 16 hours. The reaction solution was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL x 2). The organic phase was dried, filtered, and concentrated to give 4-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-fluoro-3-oxyylidene-2,3-dihydrobenzofuran-7-carboxamide (400 mg, 1.63 mmol, 86.9% yield). LCMS (ESI): [M+H] + =512.6
[0654] Step 9: To a solution of 4-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-fluoro-3-oxyylidene-2,3-dihydrobenzofuran-7-carboxamide (400 mg, 0.78 mmol) and 4-allylpiperidine hydrochloride (478 mg, 1.88 mmol) in dimethyl sulfoxide (12 mL) was added N,N-diisopropylethylamine (1214 mg, 9.40 mmol), and the temperature was raised to 50°C and stirred for 16 hours. The reaction solution was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-12% gradient of tetrahydrofuran / petroleum ether) to give 6-(4-allylpiperidin-1-yl)-4-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-3-oxylidene-2,3-dihydrobenzofuran-7-carboxamide (390 mg, crude) as a yellow solid. LCMS (ESI): [M+H] + =618.1.
[0655] Step 10: 6-(4-allylpiperidin-1-yl)-4-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-3-oxyylidene-2,3-dihydrobenzofuran-7-carboxamide (380 mg, 0.62 mmol) was dissolved in dichloromethane (190 mL), Grubbs second-generation catalyst (52.3 mg, 0.06 mmol) was added, and stirred at 50°C under nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-8% gradient of tetrahydrofuran / petroleum ether) to obtain a gray solid 5. 4 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-5 2 ,5-dihydro-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(7,6)-benzofuranocyclononane-8-ene-5 3 ,4-dione (300 mg, 0.51 mmol, 83.0% yield). LCMS (ESI): [M+H] + =590.0
[0656] Step 11: Put 5 4 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-5 2,5-dihydro-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(7,6)-benzofuranocyclononane-8-ene-5 3 ,4-dione (290 mg, 0.49 mmol) and 2-hydroxyethane-1-sulfonamide (185 mg, 1.48 mmol) were dissolved in dioxane (10.0 mL), potassium acetate (241 mg, 2.46 mmol) and t-BuXphos Pd G3 (117 mg, 0.15 mmol) were added, and stirred at 50 ° C for 2 hours under a nitrogen atmosphere. The reaction solution was diluted with water (50.0 mL), extracted with ethyl acetate (50.0 mL x 3), and the organic phase was dried, filtered, and concentrated. The crude product was purified by preparative HPLC (C18, 24%-64% gradient of water (formic acid) / acetonitrile) to give white solid Example 14A (33.57 mg, 11.0% yield) and Example 14B (15.19 mg, 5.00% yield)
[0657] Example 14A: LCMS (ESI): [M+H] + =633.7. 1 H NMR(400MHz,DMSO-d6)δppm 10.24(br s,1H),9.04(s,1H),7.42(s,1H),6.63(s,1H),5.82-5.70(m,1H),5.33(dd,J=8.4,15.2Hz,1H),4.96(br d,J=13.2Hz,2H),4.90-4.78(m,2H),3.82-3.78(m,2H),3.60-3.55(m,2H),3.53-3.49(m,1H),3.31(br d,J=13.2Hz,1H),3.19(br d,J=12.0Hz,1H),3.00(br t,J=12.0Hz,1H),2.94-2.80(m,3H),2.38-2.32(m,3H),2.28-2.20(m,1H),2.18-1.98(m,2H),1.89(br dd,J=9.2,12.8Hz,1H),1.72-1.55(m,3H),1.51-1.37(m,1H),1.13(br d,J=12.4Hz,1H)
[0658] Example 14B: LCMS (ESI): [M+H] + =633.7. 1H NMR(400MHz,DMSO-d6)δppm 10.52(br s,1H),9.09(s,1H),7.19(s,1H),6.69(s,1H),5.73(dt,J=5.2,11.2Hz,1 H),5.43(t,J=10.4Hz,1H),4.93-4.80(m,2H),4.64-4.54(m,1H),4.45(br d,J=12.8Hz,1H),3.80(t,J=6.0Hz,2H),3.61-3.54(m,2H),3.48(br d,J=11.2Hz,1H),3.39-3.25(m,2H),3.16(br t,J=12.0Hz,1H),3.04-2.81(m,3H),2.38(s,3H),2.26-2.18(m,1H),2.16-2.02( m,2H),2.00-1.78(m,2H),1.78-1.68(m,2H),1.66-1.55(m,1H),1.54-1.42(m,1H)
[0659] Example 15: 2-Hydroxy-N-(1 4 ,1 4 , 5 1 ,5 1 —Tetrafluoroethylene-2 6 -methyl-4-dioxo-5- 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-benzofurancyclononane-8-ene-5-ol 7 1-Methyl-1-thiazolyl)-ethane-1-sulfonamide
[0660] Example 15 was prepared by a similar synthetic route to Example 2. LCMS (ESI): [M+H]+=653.2
[0661] Example 16: N-(6 4 ,6 4 -Difluoro-5- 6 -methyl-2 1 ,3-dioxo-2 2 ,2 3 -Dihydro-2 1 H-4-Aza-2(5,4)-isoindole-5(4,2)-pyrimidinyl-1(1,4),6(1,3)-dipiperidinylheterocyclonon-7-ene-2-yl 7 -yl)-2-hydroxyethane-1-sulfonamide
[0662] Step 1: Under a nitrogen atmosphere, a mixture of 2-chloro-4-fluorobenzoic acid (25.00 g, 143.22 mmol), palladium acetate (3.22 g, 14.32 mmol), potassium dihydrogen phosphate (58.47 g, 429.66 mmol), and dibromomethane (100.00 mL) was stirred at 140°C for 36 hours in a Teflon-capped reaction tube, then filtered through celite. The filtrate was concentrated and purified by column chromatography (silica gel, 0-30% ethyl acetate / petroleum ether gradient) to afford 4-chloro-5-fluoroisobenzofuran-1(3H)-one (20.10 g, 107.74 mmol, 75.22% yield) as a yellow solid. LCMS (ESI): [M+H] + =187.10.
[0663] Step 2: Ammonia gas was passed through a solution of 4-chloro-5-fluoroisobenzofuran-1(3H)-one (20.10 g, 107.74 mmol) in methanol (500.00 mL) for 30 minutes. The mixture was heated to 120°C in an autoclave for 7 hours. The reaction mixture was concentrated and then purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain 7-chloro-5-fluoroisoindolin-1-one (12.40 g, 107.20 mmol, 62.3% yield) as a yellow solid. LCMS (ESI): [M+H] + =186.00.
[0664] Step 3: 7-Chloro-5-fluoroisoindolin-1-one (12.40 g, 107.20 mmol) was dissolved in concentrated sulfuric acid (100.00 mL) at 0°C. Subsequently, N-iodosuccinimide (26.53 g, 117.92 mmol) was added portionwise, and the reaction mixture was stirred at 0°C for 4 hours. The reaction mixture was warmed to room temperature and then poured into ice water (1.2 L). 1N sodium thiosulfate (400 mL) was added to the solution, and the mixture was extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (silica, 20-50% ethyl acetate / petroleum ether) to afford 7-chloro-5-fluoro-4-iodoisoindolin-1-one (17.20 g, 55.22 mmol, 82.6% yield) as a yellow solid. LCMS(ESI):[M+H] + =312.00.
[0665] Step 4: 7-Chloro-5-fluoro-4-iodoisoindolin-1-one (17.20 g, 55.22 mmol), palladium acetate (620 mg, 2.76 mmol), and potassium carbonate (22.88 g, 165.66 mmol) were dissolved in water (55.22 mL) and polyethylene glycol 400 (220.88 mL) at 20°C and reacted under a carbon monoxide atmosphere (15 psi) for 2 hours. After the reaction was complete, sodium chloride solution (1 L) was added to quench the reaction. 3M hydrochloric acid was added to adjust the pH to 5, and the mixture was extracted with ethyl acetate (200 mL x 3). The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification by flash column chromatography (silica, 50-100% ethyl acetate / petroleum ether) afforded the compound 7-chloro-5-fluoro-1-oxoisoindoline-4-carboxylic acid (7.60 g, 33.10 mmol, 59.9% yield) as a yellow solid. LCMS (ESI): [M+H] + =230.00.
[0666] Step 5: 2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-amine (2.22 g, 8.71 mmol), 7-chloro-5-fluoro-1-oxoisoindoline-4-carboxylic acid (2.00 g, 8.71 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (9.94 g, 26.13 mmol) and 4-dimethylaminopyridine (4.26 g, 34.84 mmol) were dissolved in dichloroethane (100.00 mL) at 20 ° C, heated to 80 ° C and stirred for 24 hours. After the reaction was complete, sodium bicarbonate solution (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-20% ethyl acetate / petroleum ether) to give 7-chloro-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-1-oxoisoindoline-4-carboxamide (2.01 g, 4.31 mmol, 49.5% yield) as a white solid. LCMS (ESI): [M+H] + =466.20.
[0667] Step 6: A solution of 7-chloro-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-1-oxoisoindoline-4-carboxamide (2.01 g, 4.31 mmol), 4-allylpiperidine hydrochloride (756 mg, 6.04 mmol) and N,N-diisopropylethylamine (1.67 g, 12.93 mmol) in dimethyl sulfoxide (30.00 mL) was stirred at 60°C for 10 hours and the reaction was complete. The reaction mixture was cooled naturally and quenched by adding cold water (100 mL). The mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (100 mL). The organic phases were dried, filtered, and concentrated to give the crude product, 5-(4-allylpiperidin-1-yl)-7-chloro-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-1-oxoisoindoline-4-carboxamide (2.10 g, 3.68 mmol, 85.2% yield), as a white solid. LCMS (ESI): [M+H] + =571.40.
[0668] Step 7: Under nitrogen atmosphere, 5-(4-allylpiperidin-1-yl)-7-chloro-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-1-oxoisoindoline-4-carboxamide (2.10 g, 3.68 mmol) was dissolved in dry dichloroethane (120.00 mL), Grubbs second-generation catalyst (156 mg, 0.18 mmol) was added, and the reaction was heated under reflux for 16 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 0-20% ethyl acetate / petroleum ether) to obtain 2 7 -6-chloro- 4 ,6 4 -Difluoro-5- 6 -methyl-2 2 ,2 3 -Dihydro-2 1 H-4-Aza-2(5,4)-isoindole-5(4,2)-pyrimidinyl-1(1,4),6(1,3)-dipiperidinylheterocyclonon-7-ene-2-yl 1 ,3-diketone (1.62 g, 2.98 mmol, yield 81.1%), as a white solid. LCMS (ESI): [M+H] + =543.20.
[0669] Step 8: Under nitrogen atmosphere, 7 -6-chloro- 4 ,6 4 -Difluoro-5- 6 -methyl-2 2 ,23 -Dihydro-2 1 H-4-Aza-2(5,4)-isoindole-5(4,2)-pyrimidinyl-1(1,4),6(1,3)-dipiperidinylheterocyclonon-7-ene-2-yl 1 ,3-diketone (1.62 g, 2.98 mmol), 2-hydroxyethylsulfonamide (1.13 g, 9.00 mmol), potassium acetate (1.18 g, 12.00 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (238 mg, 0.30 mmol) were dissolved in 1,4-dioxane (30.00 mL), and the resulting reaction mixture was stirred at 50 ° C for 6 hours. After the reaction was complete, sodium carbonate solution (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated to obtain the crude product, which was purified by flash column chromatography (silica, 70-90% ethyl acetate / petroleum ether) to obtain N-(6 4 ,6 4 -Difluoro-5- 6 -methyl-2 1 ,3-dioxo-2 2 ,2 3 -Dihydro-2 1 H-4-Aza-2(5,4)-isoindole-5(4,2)-pyrimidinyl-1(1,4),6(1,3)-dipiperidinylheterocyclonon-7-ene-2-yl 7 -yl)-2-hydroxyethane-1-sulfonamide (503 mg, 0.80 mmol, yield 26.7%), as a white solid. LCMS (ESI): [M+H] + =632.20.
[0670] Example 17: N-(6 4 ,6 4 -Difluoro-5- 6 -methyl-2 1 ,3-dioxo-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-4-aza-2(6,5)-isoquinolin-5(4,2)-pyrimidine-1(1,4),6(1,3)-dipiperidinylcyclononane-7-ene-2 8 -yl)-2-hydroxyethane-1-sulfonamide
[0671] Example 17 was prepared by a similar synthetic route to Example 16. LCMS (ESI): [M+H] +=646.3
[0672] Example 18: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 7 -yl)-ethylsulfonamide
[0673] Example 18 was prepared by a similar synthetic route as Example 2.
[0674] Example 18A (trans isomer) LCMS (ESI): [M+H] + =615.3. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.05(s,1H),9.90(s,1H),7.45(s,1H),6.96(s,1H),5.90-5.66(m,1H),5.3 4(dd,J=8.8,15.2Hz,1H),5.13-4.82(m,2H),3.52-3.44(m,2H),3.25-3.12( m,2H),3.02-2.76(m,5H),2.72-2.64(m,2H),2.33(s,3H),2.29-2.21(m,1H) ,2.19-1.97(m,2H),1.93-1.84(m,1H),1.75-1.46(m,4H),1.30-1.11(m,6H).
[0675] Example 18B (cis isomer) LCMS (ESI): [M+H] + =615.3. 1H NMR(400MHz,DMSO-d6)δppm 11.19(s,1H),9.99(s,1H),7.31(s,1H),7.12(s,1H),5.76(dt,J=5.6,11.2Hz,1H),5.46 (t,J=10.4Hz,1H),4.69-4.56(m,1H),4.49-4.39(m,1H),3.51-3.46(m,2H),3.28-3.18(m ,2H),3.16-3.05(m,2H),3.01-2.80(m,3H),2.76-2.64(m,2H),2.41-2.35(m,3H),2.34- 2.25(m,1H),2.18-2.03(m,2H),2.00-1.65(m,5H),1.62-1.51(m,1H),1.29-1.12(m,5H).
[0676] Example 19: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-dioxo-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 7 -yl)-methanesulfonamide
[0677] Example 19 was prepared by a similar synthetic route to Example 2. LCMS (ESI): [M+H] + =601.3
[0678] Example 20: N-(1 4 ,1 4 , 5 1 ,5 1 —Tetrafluoroethylene-2 6 -methyl-4-dioxo-5- 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-benzofurancyclononane-8-ene-5-ol 7 1-Methyl-1-(2-Methyl-2-amino)-ethylsulfonamide
[0679] Example 20 was prepared by a similar synthetic route as Example 2. LCMS (ESI): [M+H] + =637.3
[0680] Example 21: 2-Hydroxy-N-(1 4 ,1 4 , 5 1 ,5 1 —Tetrafluoroethylene-2 6 -methyl-4-dioxo-5- 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-benzofurancyclononane-8-ene-5-ol 7 methylsulfonamide
[0681] Example 21 was prepared by a similar synthetic route to Example 2. LCMS (ESI): [M+H] + =623.3
[0682] Example 22: N-(5 1 -(difluoromethylene)-1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-5- 2 ,5 3 -Dihydro-5 1 H-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indanedionenaphthalene-8-ene-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide
[0683] Example 22 was prepared by a similar synthetic route as Example 2. LCMS (ESI): [M+H] + =665.3
[0684] Example 23: N-((5 1 ,8)-1 4 ,1 4 -Difluoro-5- 1 -(fluoromethylene)-2 6 -methyl-4-oxo-5- 2 ,5 3 -Dihydro-5 1 H-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenonaphth-8-ene-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide
[0685] Example 23 was prepared by a similar synthetic route to Example 2. LCMS (ESI): [M+H] + =647.3
[0686] Example 24: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,4-diketone-5 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indanedion-8-ene-5-ol 7 -yl)-1-hydroxypropane-2-sulfonamide
[0687] Example 24 was prepared by a similar synthetic route to Example 2. LCMS (ESI): [M+H] + =645.3
[0688] Example 25: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,3-dioxo-5 2 ,5 3 -Dihydro-5 1 H-4-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide
[0689] Step 1: Under nitrogen atmosphere, a solution of 1-fluoro-3-iodo-2-nitrobenzene (25.00 g, 93.63 mmol), prop-2-en-1-ol (8.16 g, 140.45 mmol), palladium acetate (1.05 g, 4.68 mmol), tetrabutylammonium chloride (26.02 g, 93.63 mmol) and sodium bicarbonate (39.32 g, 498.50 mmol) in N,N-dimethylformamide (200.00 mL) was stirred at 40 ° C for 8 hours. After the reaction was complete, sodium chloride solution (300 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (250 mL x 3). The mixture was washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to obtain 3-(3-fluoro-2-nitrophenyl)propanal (15.92 g, 80.74 mmol, 86.2% yield) as a yellow solid. LCMS (ESI): [M+H]+ =198.30.
[0690] Step 2: To a solution of 3-(3-fluoro-2-nitrophenyl)propanal (15.92 g, 80.74 mmol) and 2-methyl-2-butene (100.00 mL) in tetrahydrofuran (300.00 mL) and tert-butanol (300.00 mL) at 0°C, a solution of sodium chlorite (21.91 g, 242.22 mmol) and sodium dihydrogen phosphate (29.06 g, 242.22 mmol) in water (100.0 mL) was slowly added. After the reaction was complete, sodium sulfite solution (300 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (250 mL x 3). The mixture was washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to obtain 3-(3-fluoro-2-nitrophenyl)propanoic acid (14.20 g, 66.62 mmol, 82.5% yield) as a yellow solid. LCMS (ESI): [M+H] + =214.30.
[0691] Step 3: To a solution of 3-(3-fluoro-2-nitrophenyl)propanoic acid (14.20 g, 66.62 mmol) in dichloromethane (120.00 mL) was added oxalyl chloride (34.04 g, 17.60 mmol). After stirring for 2 hours, the mixture was concentrated under reduced pressure to remove the solvent and excess oxalyl chloride. The crude product was dissolved in dichloromethane (250.00 mL), and aluminum chloride (17.77 g, 133.24 mmol) was added. The reaction was stirred for 6 hours. The reaction mixture was quenched by pouring into ice water (500 mL), extracted with dichloromethane (3 x 100 mL), filtered, concentrated, and purified by column chromatography (silica gel, 0-20% ethyl acetate / petroleum ether gradient) to afford 5-fluoro-4-nitro-2,3-dihydro-1H-inden-1-one (6.20 g, 31.77 mmol, 47.7% yield) as a yellow solid. LCMS(ESI):[M+H] + =196.30.
[0692] Step 4: A mixture of 5-fluoro-4-nitro-2,3-dihydro-1H-inden-1-one (6.20 g, 31.77 mmol), ammonium chloride (17.00 g, 317.70 mmol), and iron powder (8.90 g, 158.85 mmol) in ethanol (160.00 mL) and water (40.00 mL) was stirred at 80°C for 4 hours. After the reaction was complete, the mixture was filtered, concentrated, and extracted with ethyl acetate (100 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether gradient) to afford 4-amino-5-fluoro-2,3-dihydro-1H-inden-1-one (4.57 g, 27.67 mmol, 87.1% yield) as a yellow solid. LCMS (ESI): [M+H] + =166.30.
[0693] Step 5: To a solution of 4-amino-5-fluoro-2,3-dihydro-1H-inden-1-one (4.57 g, 27.67 mmol) in dichloromethane (180.00 mL) was added N-bromosuccinimide (9.61 g, 54.00 mmol). The reaction was stirred for 3 hours until complete. Sodium sulfite solution (200 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (150 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-20% ethyl acetate / petroleum ether gradient) to afford 4-amino-7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-one (4.30 g, 17.62 mmol, 63.7% yield) as a yellow solid. LCMS (ESI): [M+H] + =244.10.
[0694] Step 6: A solution of 4,4-difluoro-3-vinylpiperidine hydrochloride (4.00 g, 21.78 mmol), ethyl 2-chloro-6-methylpyrimidine-4-carboxylate (4.37 g, 21.78 mmol), and potassium carbonate (6.02 g, 43.56 mmol) in N,N-dimethylformamide (100.00 mL) was stirred at 100°C for 16 hours. After completion of the reaction, ice water (100 mL) was added to quench the reaction, followed by extraction with ethyl acetate (150 mL x 3), washing with sodium chloride solution, drying over anhydrous sodium sulfate, filtration, concentration, and purification by column chromatography (silica gel, 30-50% ethyl acetate / petroleum ether gradient) to afford ethyl 2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (4.25 g, 13.65 mmol, 62.7% yield) as a yellow solid. LCMS(ESI):[M+H] + =312.30.
[0695] Step 7: To a solution of ethyl 2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (4.25 g, 13.65 mmol) in tetrahydrofuran (30.00 mL) and methanol (30.00 mL) was added 2M sodium hydroxide solution (15.00 mL, 30.00 mmol) and stirred at 50°C for 6 hours. After the reaction was complete, 2M hydrochloric acid (15 mL) was added and the pH was adjusted to 7. The mixture was extracted with ethyl acetate (150 mL x 3), washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 30-100% gradient of ethyl acetate / petroleum ether) to afford 2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidine-4-carboxylic acid (2.70 g, 9.53 mmol, 69.8% yield) as a yellow solid. LCMS(ESI):[M+H] + =384.30.
[0696] Step 8: A solution of 2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidine-4-carboxylic acid (2.00 g, 7.06 mmol), 4-amino-7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-one (1.72 g, 7.06 mmol), 2-chloro-1-methylpyridinium iodide (3.82 g, 14.12 mmol) and N,N-diisopropylethylamine (4.83 g, 37.40 mmol) in tetrahydrofuran (100.00 mL) was stirred at 50°C for 16 hours. The mixture was quenched with sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The mixture was washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to afford N-(7-bromo-5-fluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)-2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidine-4-carboxamide (2.53 g, 4.97 mmol, 70.4% yield) as a yellow solid. LCMS (ESI): [M+H] + =509.20.
[0697] Step 9: A solution of N-(7-bromo-5-fluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)-2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidine-4-carboxamide (2.53 g, 4.97 mmol), 4-allylpiperidine hydrochloride (1.21 g, 7.50 mmol) and potassium carbonate (13.83 g, 10.00 mmol) in dimethyl sulfoxide (30.00 mL) was stirred at 100 °C for 16 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The mixture was washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to afford N-(5-(4-allylpiperidin-1-yl)-7-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)-2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidine-4-carboxamide (2.62 g, 4.26 mmol, 85.8% yield) as a yellow solid. LCMS (ESI): [M+H] + =614.30.
[0698] Step 10: A solution of N-(5-(4-allylpiperidin-1-yl)-7-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)-2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidine-4-carboxamide (2.62 g, 4.26 mmol) and Grubbs second-generation catalyst (366 mg, 0.43 mmol) in dichloromethane (200.00 mL) was stirred at 50° C. for 16 hours. The reaction solution was concentrated and purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain compound 5. 7 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-5 2 ,5 3 -Dihydro-5 1 H-4-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 1 ,3-diketone (2.03 g, 3.46 mmol, yield 81.2%), as a yellow solid. LCMS (ESI): [M+H] + =586.30.
[0699] Step 11: Under nitrogen atmosphere, 5 7 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-5 2 ,53 -Dihydro-5 1 H-4-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 1 ,3-diketone (1.96 g, 3.33 mmol), 2-hydroxyethylsulfonamide (1.25 g, 10.00 mmol), potassium acetate (1.30 g, 13.33 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (265 mg, 0.33 mmol) were dissolved in 1,4-dioxane (15.00 mL), and the resulting reaction mixture was stirred at 60 ° C for 8 hours. After the reaction was complete, cold water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated to obtain the crude product, which was purified by flash column chromatography (silica, 60-90% ethyl acetate / petroleum ether) to obtain N-(1 4 ,1 4 -Difluoro-2 6 -methyl-5 1 ,3-dioxo-5 2 ,5 3 -Dihydro-5 1 H-4-Aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenylheterocyclonon-8-ene-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide (1.31 g, 2.08 mmol, yield 62.2%), as a white solid. LCMS (ESI): [M+H] + =631.30.
[0700] Example 26: N-((5 1 Z, 8E)-5 1 -(Cyanofluoromethylene)-1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-5- 2 ,5 3 -Dihydro-5 1 H-3-Aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenophenanthrene-8-ene-5-ol 7 -yl)-2-hydroxyethane-1-sulfonamide
[0701] Example 26 was prepared by a similar synthetic route to Example 22. LCMS (ESI): [M+H]+ =672.3
[0702] Example 27: N-(4,4-difluoro-6-methyl-4-oxospiro[3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indanedionenaphthalene-1,2'-[1,3]dioxolane]-8-en-7-yl)-2-hydroxyethane-1-sulfonamide
[0703] Example 27 was prepared by a similar synthetic route according to Example 15. LCMS (ESI): [M+H] + =675.3
[0704] Example 28: N-(4,4-difluoro-6-methyl-4-oxospiro[3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indanedionenaphthalene-1,2'-[1,3]dithiolane]-8-en-7-yl)-2-hydroxyethane-1-sulfonamide
[0705] Example 28 was prepared by a similar synthetic route to Example 15. LCMS (ESI): [M+H] + =707.3
[0706] Example 29: (2-Hydroxy-N-(1 4 ,1 4 ,5 1 ,5 1 -Tetrafluoro-2 6 -methyl-3-oxo-5- 2 ,5 3 -Dihydro-5 1 H-4-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5-(4,5)-indanedionenaphthalene-8-ene-5-ol 7 -yl)ethane-1-sulfonamide
[0707] Example 29 was prepared by a similar synthetic route to Example 25. LCMS (ESI): [M+H] + =653.2
[0708] Example 30: 2-Hydroxy-N-(2,2,4',4'-tetrafluoro-6'-methyl-4'-oxospiro[cyclopropane-1,1'-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(4,5)-indenophenanthronone]-8'-en-7'-yl)ethane-1-sulfonamide
[0709] Example 30 was prepared by a similar synthetic route as Example 2. LCMS (ESI): [M+H] + =679.3
[0710] Example 31: N-(4',4'-difluoro-6'-methyl-4'-oxospiro[cyclopropane-1,1'-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5-(4,5)-indanedionaphthalene]-8'-en-7'-yl)-2-hydroxyethane-1-sulfonamide
[0711] Example 31 was prepared by a similar synthetic route to Example 2. LCMS (ESI): [M+H] + =643.3
[0712] Example 32: N-(5 6 ,8-dimethyl-2 1 ,3-diketone-2 2 ,2 3 -Dihydro-2 1 H-10-oxa-4,6-diaza-5(4,2)-pyrimidin-1(1,4)-piperidin-2(5,4)-indenocycloundecane-2 7 (2-Hydroxyethane-1-sulfonamide)
[0713] Step 1: To a solution of methyl 7-bromo-5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carboxylate (14.07 g, 49.2 mmol) and potassium carbonate (17.80 g, 129.0 mmol) in dimethyl sulfoxide (200.00 mL) was added piperidin-4-ylmethanol (5.93 g, 51.5 mmol), and the mixture was stirred at 100°C for 12 hours. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (400 mL x 2). The organic phases were combined, washed with saturated brine (250 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-16% gradient of tetrahydrofuran / petroleum ether) to give methyl 7-bromo-5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxo-2,3-dihydro-1H-indene-4-carboxylate (15.89 g, 41.70 mmol, 85% yield) as a yellow oil. LCMS (ESI): [M+H] + =382.1
[0714] Step 2: To a solution of methyl 7-bromo-5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxo-2,3-dihydro-1H-indene-4-carboxylate (8.14 g, 21.3 mmol) in dichloromethane (140.00 mL) were added triethylamine (4.32 g, 42.7 mmol), 4-dimethylaminopyridine (434 mg, 2.13 mmol) and 4-methylbenzenesulfonyl chloride (4.47 g, 23.5 mmol) at 25°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-8% gradient of tetrahydrofuran / petroleum ether) to give methyl 7-bromo-1-oxo-5-(4-(tosyloxy)methyl)piperidin-1-yl)-2,3-dihydro-1H-indene-4-carboxylate (6.63 g, 12.4 mmol, 58% yield) as a yellow oil. LCMS (ESI): [M+H] + =536.1.
[0715] Step 3: To a solution of methyl 7-bromo-1-oxo-5-(4-(tosyloxymethyl)piperidin-1-yl)-2,3-dihydro-1H-indene-4-carboxylate (1.11 g, 2.07 mmol) and tert-butyl (3-hydroxy-2-methylpropyl)carbamate (0.59 g, 3.11 mmol) in tetrahydrofuran (20.0 mL) was added sodium hydroxide (0.21 g, 3.11 mmol), and the mixture was stirred at 60 ° C for 12 hours. The reaction mixture was diluted with water (80 mL) and the pH was adjusted to 2-3 with saturated citric acid solution. The mixture was extracted with ethyl acetate solution (100 mL x 2). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-35% gradient of ethyl acetate / petroleum ether) to obtain 7-bromo-5-(4-((3-(tert-butoxycarbonyl)amino)-2-methylpropoxy)methyl)piperidin-1-yl)-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (0.46 g, 0.87 mmol, 42% yield) as a yellow oil. LCMS (ESI): [M+H] + =539.2
[0716] Step 4: 7-Bromo-5-(4-((3-(tert-Butoxycarbonyl)amino)-2-methylpropoxy)methyl)piperidin-1-yl)-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (420 mg, 0.78 mmol) was dissolved in dichloromethane (20.00 mL) and trifluoroacetic acid (5.00 mL) and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to give 5-(4-((3-amino-2-methylpropoxy)methyl)piperidin-1-yl)-7-bromo-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (500 mg, crude) as a yellow oil. LCMS (ESI): [M+H]+ = 439.1
[0717] Step 5: 5-(4-((3-amino-2-methylpropoxy)methyl)piperidin-1-yl)-7-bromo-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (0.37 g, 0.85 mmol) was dissolved in tert-butanol (7.00 mL), and N,N-diisopropylethylamine (1.10 g, 8.51 mmol) and 2-chloro-6-methylpyrimidin-4-amine (147 mg, 1.02 mmol) were added. The mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with water (20 mL) and the pH was adjusted to 2-3 with 1N hydrochloric acid. The mixture was extracted with chloroform / isopropanol (3:1, 40 mL x 3). The organic phase was dried, filtered, and concentrated. The brown oily residue was purified by flash column chromatography (silica gel, 0-10% gradient of dichloromethane / methanol) to afford 5-(4-((3-(4-amino-6-methylpyrimidin-2-yl)amino)-2-methylpropoxy)methyl)piperidin-1-yl)-7-bromo-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (470 mg, crude) as a yellow oil. LCMS (ESI): [M+H]+ = 546.3
[0718] Step 6: Dissolve N,N-diisopropylethylamine (763 mg, 5.78 mmol) and 2-chloro-1-methylpyridinium iodide (444 mg, 1.74 mmol) in tetrahydrofuran (30.00 mL). Add 5-(4-((3-(4-amino-6-methylpyrimidin-2-yl)amino)-2-methylpropoxy)methyl)piperidin-1-yl)-7-bromo-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (316 mg, 0.58 mmol) dissolved in tetrahydrofuran (120.00 ml) at 60°C and stir at 60°C for 12 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-12% gradient of tetrahydrofuran / petroleum ether) to give 2 as a colorless oil. 7 -Br-5 6 ,8-dimethyl-2 2 ,23 -Dihydro-2 1 H-10-oxa-4,6-diaza-5(4,2)-pyrimidine-1(1,4)-piperidine-a-2(5,4)-indenocycloundecane-21,3-dione (70 mg, crude product). LCMS (ESI): [M+H]+=528.2
[0719] Step 7: Put 2 7 -Br-5 6 ,8-dimethyl-2 2 ,2 3 -Dihydro-2 1 H-10-oxa-4,6-diaza-5(4,2)-pyrimidine-1(1,4)-piperidine-a-2(5,4)-indenocycloundecane-21,3-dione (53 mg, 0.1 mmol) and 2-hydroxyethane-1-sulfonamide (15 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1.00 mL). Potassium phosphate (63.6 mg, 0.3 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (14.4 mg, 0.1 mmol), and cuprous iodide (19.1 mg, 0.1 mmol) were added, and the mixture was stirred at 100°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (10.0 mL + 0.5 mL of aqueous ammonia) and extracted with ethyl acetate (20 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 6%-46% gradient of water (formic acid) / acetonitrile) to give N-(5 6 ,8-dimethyl-2 1 ,3-diketone-2 2 ,2 3 -Dihydro-2 1 H-10-oxa-4,6-diaza-5(4,2)-pyrimidin-1(1,4)-piperidin-2(5,4)-indenocycloundecane-2 7 1-Hydroxy-2-[4-(2-[4-(2-hydroxyethane-1-sulfonamide)]-2-hydroxyethane-1-sulfonamide (6 mg, 0.01 mmol, 14.7% yield). LCMS (ESI): [M+H]+=573.2.
[0720] Example 33: N-(5 6 ,8-dimethyl-2 1 ,3-diketone-1 4 -(trifluoromethyl)-2 2 ,2 3 -Dihydro-2 1 H-10-oxa-4,6-diaza-5(4,2)-pyrimidine-1(1,4)-piperidine-a-2(5,4)-indenocycloundecane-2 7 -yl)-2-hydroxyethane-1-sulfonamide
[0721] Example 33 was prepared by a similar synthetic route to Example 32. LCMS (ESI): [M+H] + =641.2
[0722] Example 34: N-((3Z,4E)-3-Ethylene-8-methyl-1,18-dioxo-12-(trifluoromethyl)-1,2,3,6,7,8,9,11,12,13,14,18,20-tetradecahydro-12,15-ethylidene[4,5-k][1]oxa[5,7,9,13]tetraazacycloheptan-17-yl)-2-hydroxyethane-1-sulfonamide
[0723] Example 34 was prepared by a similar synthetic route to Example 32. LCMS (ESI): [M+H] + =616.2
[0724] Example 35: N-((3Z,4E)-3-Ethylene-8-methyl-1,18-dioxo-1,2,3,6,8,9,11,12,13,14,18,19,20-tetradecahydro-12,15-ethylidene[4,5-k][1]oxa[5,7,9,13]tetraazacycloheptan-17-yl)-2-hydroxyethane-1-sulfonamide
[0725] Example 35 was prepared by a similar synthetic route to Example 32. LCMS (ESI): [M+H] + =548.2
[0726] Example 36: 2-Hydroxy-N-(5 6 -methyl-2 1 ,3-diketone-2 2 ,2 3 -Dihydro-2 1 H-4,6-diaza-5(4,2)-pyrimidin-1(1,4)-piperidin-2(5,4)-indenocycloundec-9-ene-2 7 -yl)ethane-1-sulfonamide
[0727] Example 36 was prepared by a similar synthetic route to Example 2. LCMS (ESI): [M+H] + =555.2
[0728] Example 37: N-(5 6 ,8-dimethyl-2 1 ,3-diketone-2 2,2 3 -Dihydro-2 1 H-4,6-diaza-5(4,2)-pyrimidin-1(1,4)-piperidin-a-2(5,4)-indenoundec-9-ene-2 7 -yl)-2-hydroxyethane-1-sulfonamide
[0729] Example 37 was prepared by a similar synthetic route to Example 2. LCMS (ESI): [M+H] + =569.2
[0730] Example 38: 2-Hydroxy-N-(8-methyl-2 1 ,3-diketone-2 2 ,2 3 -Dihydro-2 1 H-4,6-diaza-5(2,6)-pyridine-1(1,4)-piperidin-2(5,4)-indenoundec-9-ene-2 7 -yl)ethane-1-sulfonamide
[0731] Example 38 was prepared by a similar synthetic route to Example 2. LCMS (ESI): [M+H] + =554.2
[0732] Example 39: N-(5 6 ,6-dimethyl-2 1 ,3-diketone-2 2 ,2 3 -Dihydro-2 1 H-4,6-diaza-5(4,2)-pyrimidin-1(1,4)-piperidin-a-2(5,4)-indenoundec-9-ene-2 7 -yl)-2-hydroxyethane-1-sulfonamide
[0733] Example 39 was prepared by a similar synthetic route to Example 2. LCMS (ESI): [M+H] + =569.2
[0734] Example 40: 2-Hydroxy-N-(5 6 ,6,8-trimethyl-2 1 ,3-diketone-2 2 ,2 3 -Dihydro-2 1 H-4,6-diaza-5(4,2)-pyrimidine-1(1,4)-piperidin-a-2(5,4)-indenocycloundec-9-ene-2 7 -yl)ethane-1-sulfonamide
[0735] Example 40 was prepared by a similar synthetic route as Example 2. LCMS (ESI): [M+H] + =583.2
[0736] Example 41: N-(6,8-dimethyl-2 1 ,3-diketone-2 2 ,2 3 -Dihydro-2 1 H-4,6-diaza-5(2,6)-pyridine-1(1,4)-piperidin-a-2(5,4)-indenoundec-9-ene-2 7 -yl)-2-hydroxyethane-1-sulfonamide
[0737] Example 41 was prepared by a similar synthetic route to Example 2. LCMS (ESI): [M+H] + =568.3
[0738] Example 32, Example 33, Example 34, and Example 35 were separated by SFC to give Examples 32A and 32B, Examples 33A and 33B, Examples 34A and 34B, and Examples 35A and 35B, respectively.
[0739] Example 42: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3)-piperidin-5(1,2),6(1,4)-diphenylheterocyclonon-8-ene-5-yl)- 4 -yl)-2-hydroxyethane-1-sulfonamide
[0740] Step 1: A mixed solution of (4-bromophenyl)boronic acid (5.00 g, 24.90 mmol), allyl bromide (6.0 g, 49.79 mmol), potassium carbonate (10.5 g, 74.69 mmol) and palladium acetate (570 mg, 2.49 mmol) in toluene (50.00 mL) was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to give compound 1-allyl-4-bromobenzene (3.50 g, crude product) as a colorless oil. 1H NMR (400MHz, DMSO) δ7.48(dd,J=8.4,2.4Hz,2H),7.18–7.14(m,2H),6.01–5.87(m,1H),5.11–5.06(m,1H),5.06–5.03(m,1H),3.39–3.28(m,2H)ppm.
[0741] Step 2: Under nitrogen atmosphere, a mixture of 1-allyl-4-bromobenzene (3.50 g, 17.76 mmol), (5-chloro-2-(methoxycarbonyl)phenyl)boronic acid (5.70 g, 26.64 mmol), potassium carbonate (7.50 g, 53.28 mmol) and 1,1-bis(diphenylphosphino)dichloropalladium(II) (1.30 g, 1.78 mmol) in 1,4-dioxane (40.00 mL) and water (10.00 mL) was stirred at 80°C for 12 hours. The reaction mixture was poured into water (50 mL) and washed with ethyl acetate (50 mL x 10% ethanol). 3) Extraction, drying the organic phase over anhydrous sodium sulfate, filtration, concentration, and purification by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) afforded the compound 4'-allyl-5-chloro-[1,1'-biphenyl]-2-carboxylic acid methyl ester (2.60 g, crude product) as a yellow oil. LCMS (ESI): [M+H] + =287.10.
[0742] Step 3: Lithium bistrimethylsilylamide (10.50 mL, 1 M) was added to a solution containing 2-(4,4-difluoro-3-vinylpiperidinyl)-6-methylpyrimidin-4-amine (2.10 g, 8.37 mmol), methyl 4-chloro-2-(4-propan-2-phenyl)benzoate (2 g, 6.97 mmol) and THF (20 mL). The resulting mixture was stirred at 20°C for 1 hour. The reaction solution was poured into water (50 mL) and washed with ethyl acetate (50 mL x 4 ). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound 4'-allyl-5-chloro-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-[1,1'-biphenyl]-2-carboxamide (1.00 g, crude) as a yellow solid. LCMS (ESI): [M+H] + =509.20. 1H NMR(400MHz,DMSO)δppm 10.72–10.63(m,1H),7.58–7.45(m,3H),7.43–7.29(m,4H),7.23–7.17(m, 1H),6.46–6.26(m,1H),6.04–5.88(m,1H),5.85–5.68(m,1H),5.40–5.22(m ,2H),5.18–4.99(m,1H),4.46(brs,2H),3.36(d,J=6.8Hz,1H),3.13(brs, 2H),2.73–2.55(m,1H),2.24(s,3H),2.09–2.00(m,1H),1.94–1.77(m,2H).
[0743] Step 4: A solution containing 4'-allyl-5-chloro-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-[1,1'-biphenyl]-2-carboxamide (1.00 g, 1.96 mmol), Grubbs second-generation catalyst (170 mg, 0.20 mmol) and dichloromethane (200 mL) was stirred at 50°C for 2 hours. The reaction solution was concentrated and purified by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to obtain compound 5 4 -Chloro-1 4 ,1 4 -Difluoro-2 6 -methyl-3-aza-2(2,4)-pyrimidin-1(1,3)-piperidin-5(1,2),6(1,4)-diphenylheterocyclonon-8-en-4-one (460 mg, crude product) as a yellow solid. LCMS (ESI): [M+H]+=481.10.
[0744] Step 5: Under nitrogen atmosphere, containing 5 4 -Chloro-1 4 ,1 4 -Difluoro-2 6The reaction mixture of 2-methyl-3-aza-2(2,4)-pyrimidin-1(1,3)-piperidin-5(1,2),6(1,4)-diphenylheterocyclonon-8-en-4-one (460 mg, 0.96 mmol), 2-hydroxyethanesulfonamide (244 mg, 1.91 mmol), potassium phosphate (622 mg, 2.87 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (41 mg, 0.096 mmol), tris(dibenzylideneacetone)dipalladium (89 mg, 0.096 mmol) and dioxane (5 mL) was stirred at 100°C for 2 hours, poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient ethyl acetate / petroleum ether) to obtain compound N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3)-piperidin-5(1,2),6(1,4)-diphenylheterocyclonon-8-ene-5-yl)- 4 -yl)-2-hydroxyethane-1-sulfonamide (370 mg, crude) as a white solid. LCMS (ESI): [M+H]+=570.20.
[0745] The above mixture was purified by preparative HPLC (C18, 24%-64% gradient of water (hydrochloric acid) / acetonitrile) to give Example 1 as a white solid N-(1 4 ,1 4 -Difluoro-6 4 -Methoxy-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide (104 mg). LCMS (ESI): [M+H] + =570.2 1H NMR (400MHz, DMSO-d6) δppm 10.30 (s, 1H), 8.15 (br s, 1H), 7.78 (d, J = 8.4Hz, 1H), 7.50 (br d, J = 7.2Hz, 1H), 7.41-7.30 (m, 2H), 7.21 (br d,J=8.4Hz,3H),6.98(br d,J=7.2Hz,1H),6.50-6.33(m,1H),5.58(br t,J=10.0Hz,1H),4.66(br d,J=13.2Hz,1H),4.00(br dd,J=3.6,6.0Hz,1H),3.77(t,J=6.4Hz,2H),3.51-3.31(m,4H),3.04(br t,J=13.2Hz,1H),2.86-2.65(m,2H),2.30(s,3H),2.17-2.04(m,1H),1.93-1.71(m,1H)
[0746] Example 43: N-(2 4 ,2 4 -Difluoro-1 6 -methyl-7-oxo-8-aza-1(2,4)-pyrimidin-2(1,3)-piperidin-5(1,4),6(1,2)-dibenzooct-3-ene-6- 5 -yl)-2-hydroxyethane-1-sulfonamide
[0747] Example 43 was prepared by a similar synthetic route according to Example 42. LCMS (ESI): [M+H] + =556.2 1H NMR (400MHz, DMSO-d6) δppm 10.33(s,1H),7.88(d,J=8.4Hz,1H),7.81(s,1H),7.58(br d,J=8.0Hz,1H),7.47-7.36(m,2H),7.33(br d,J=8.0Hz,1H),7.26(s,1H),7.20-7.09(m,2H),6.91(br d,J=11.6Hz,1H),5.95(dd,J=8.0,11.6Hz,1H),4.97(br t,J=5.2Hz,1H),4.63(br d,J=12.0Hz,1H),4.12-3.91(m,1H),3.78(q,J=6.0Hz,2H),3.39(br t,J=6.4Hz,2H),3.30-3.15(m,1H),2.98(br t,J=12.8Hz,1H),2.68(br t,J=12.4Hz,1H),2.30(s,3H),2.16-2.01(m,1H),1.92-1.62(m,1H)
[0748] Example 44: N-((1 3 S, Z)-1 4 ,1 4 -Difluoro-2 6 -methyl-3 1 H-2(2,4)-pyrimidine-1(1,3),5(1,4)-dipiperidin-3(4,1)-triazole-4(1,2)-phenylcyclooctyl-4-nitropropane 4 -yl)-2-hydroxyethane-1-sulfonamide
[0749] N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3)-piperidin-5(1,2),6(1,4)-dibenzylcyclononane-8-ene-5 4 1-Hydroxy-2-methyl-1-thiazolinone (100 mg, 0.17 mmol) was dissolved in methanol (10.0 mL) and 10% wet palladium carbon (20.0 mg, 0.01 mmol) was added. The reaction mixture was replaced with argon three times and then replaced with hydrogen three times. The mixture was stirred at 25°C for 16 hours under a hydrogen (50 Psi) atmosphere. The reaction mixture was filtered under reduced pressure to remove palladium carbon and then concentrated under vacuum. The residue was purified by preparative HPLC (C18, 38%-78% gradient of water (formic acid) / acetonitrile) to give N-(1-hydroxy-2-methyl-1-thiazolinone) as a white solid. 4 ,1 4 -Difluoro-26 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3)-piperidin-5(1,2),6(1,4)-dibenzylcyclononane-5 4 -yl)-2-hydroxyethane-1-sulfonamide (49.8 mg, 0.08 mmol, 49.6% yield). LCMS (ESI): [M+H]+=572.2 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.88-9.44(m,1H),8.63-8.38(m,1H),7.69(d,J=8.4Hz,1H),7.48-6.82(m,7 H),5.54-4.66(m,1H),4.52-4.30(m,1H),4.02-3.83(m,1H),3.78(t,J=6.4Hz, 2H),3.41-3.34(m,2H),3.24-3.15(m,1H),3.12-2.99(m,1H),2.90-2.76(m,1 H),2.45-2.37(m,1H),2.29-2.16(m,3H),2.09-1.48(m,5H),1.30-0.99(m,2H)
[0750] Example 45: N-(2 4 ,2 4 -Difluoro-1 6 -methyl-7-oxo-8-aza-1(2,4)-pyrimidine-2(1,3)-piperidine-5(1,4),6(1,2)-dibenzylcyclosuccin-6-pyrimidine 5 -yl)-2-hydroxyethane-1-sulfonamide
[0751] N-(2 4 ,2 4 -Difluoro-1 6 -methyl-7-oxo-8-aza-1(2,4)-pyrimidine-2(1,3)-piperidin-5(1,4),6(1,2)-dibenzylcyclosuccin-3-ene-6 5 -yl)-2-hydroxyethane-1-sulfonamide (40.0 mg, 0.07 mmol) was dissolved in methanol (10.0 mL) and 10% wet palladium carbon (8.00 mg, 0.02 mmol) was added. The reaction mixture was replaced with argon protection three times and then replaced with hydrogen three times. The mixture was stirred at 25 ° C for 16 hours under a hydrogen (50 Psi) atmosphere. The reaction mixture was filtered under reduced pressure to remove palladium carbon and then concentrated under vacuum. The residue was purified by preparative HPLC (C18, 38%-78% gradient of water (formic acid) / acetonitrile) to give a white solid N-(2 4 ,2 4 -Difluoro-16 -methyl-7-oxo-8-aza-1(2,4)-pyrimidine-2(1,3)-piperidine-5(1,4),6(1,2)-dibenzylcyclosuccin-6-pyrimidine 5 -yl)-2-hydroxyethane-1-sulfonamide (8.67 mg, 0.01 mmol, 61% yield). LCMS (ESI): [M+H]+=558.2 1 H NMR (400MHz, DMSO-d6) δppm 7.84 (s, 1H), 7.79 (d, J = 8.4Hz, 1H), 7.53 (s, 2H), 7.27 (br d,J=8.4Hz,1H),7.19-7.07(m,3H),7.01(d,J=8.0Hz,1H),4.60-4.48(m,1H),3.96-3.69(m,3H),3.29-3.26(m,2H),3.05-2. 95(m,2H),2.72-2.64(m,1H),2.46-2.35(m,2H),2.31-2.15(m,4H),2.11-1.94(m,1H),1.79-1.59(m,2H),1.43-1.27(m,1H)
[0752] Example 46N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3)-piperidin-5(1,2),6(1,4)-diphenylheterocyclononane-5 4 -yl)-2-hydroxyethane-1-sulfonamide two isomers
[0753] Step 1: Change (Shun)-N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3)-piperidin-5(1,2),6(1,4)-diphenylheterocyclonon-8-ene-5 4 1-Hydroxy-2-methyl-1-thiazolinone (100 mg, 0.18 mmol) was dissolved in methanol (10.00 mL) and wet palladium carbon (20.0 mg, 0.01 mmol) was added. The reaction mixture was replaced with argon three times and then replaced with hydrogen three times. The mixture was stirred at 25°C for 16 hours under a hydrogen (50 Psi) atmosphere. The reaction mixture was filtered under reduced pressure to remove palladium carbon and then concentrated under vacuum. The residue was purified by preparative HPLC (C18, 38%-78% gradient of water (formic acid) / acetonitrile) to give N-(1-hydroxy-2-methyl-1-thiazolinone) as a white solid. 4 ,1 4-Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3)-piperidin-5(1,2),6(1,4)-diphenylheterocyclononane-5 4 -yl)-2-hydroxyethane-1-sulfonamide (10-168-H2) (49.8 mg).
[0754] The mixture (49.8 mg) was separated by SFC (chromatographic column: ChiralPak IH, 250*30 mm, 10 μm, mobile phase: CO2-MeOH (0.1% NH3H2O), gradient: isocratic 35%, flow rate: 80 mL / min, column temperature: 40°C) to give Example 46A (16 mg) and Example 46B (18 mg).
[0755] Example 46A: White solid (16 mg). SFC analysis (Chiralpak IH-3 column, 50 x 4.6 mm ID, 3 μm; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / methanol; gradient: from 5% to 40% of B in 1.5 min, hold 40% for 1 min, then 5% of B for 0.5 min; flow rate: 4 mL / min). Chiral column peak elution at 1.475 min; LCMS (ESI): [M+H]+ = 572.2. 1 H NMR (400MHz, DMSO-d6) δppm10.62-9.62(m,1H),8.59-8.37(m,1H),7.68(d,J=8.4Hz,1H),7.42-7.32(m,2H),7.30-7.17(m,3H),7.07(br s,2H),5.37-4.72(m,1H),4.49-4.35(m,1H),4.00-3.87(m,1H),3.77(t,J=6.4Hz,2H),3.29-3.16(m,2H), 3.13-3.05(m,1H),2.86-2.78(m,1H),2.45-2.38(m,1H),2.26(s,3H),2.07-1.51(m,6H),1.21-1.03(m,2H)
[0756] Example 46B: White solid (18 mg). SFC analysis (Chiralpak IH-3 column, 50 x 4.6 mm ID, 3 μm; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / methanol; gradient: from 5% to 40% of B in 1.5 min, hold 40% for 1 min, then 5% of B for 0.5 min; flow rate: 4 mL / min). Chiral column peak elution position at 1.561 min; LCMS (ESI): [M+H]+ = 572.2. 1 H NMR (400MHz, DMSO-d6) δppm10.62-9.62(m,1H),8.59-8.37(m,1H),7.68(d,J=8.4Hz,1H),7.42-7.32(m,2H),7.30-7.17(m,3H),7.07(br s,2H),5.37-4.72(m,1H),4.49-4.35(m,1H),4.00-3.87(m,1H),3.77(t,J=6.4Hz,2H),3.29-3.16(m,2H), 3.13-3.05(m,1H),2.86-2.78(m,1H),2.45-2.38(m,1H),2.26(s,3H),2.07-1.51(m,6H),1.21-1.03(m,2H)
[0757] Example 47: N-(6 4 ,6 4 -Difluoro-5- 6 -methyl-3-oxo-4-aza-5(4,2)-pyrimidine-6(1,3)-piperidine-1(1,3)-azetidine-2(1,2)-benzene-10(1,3)-cyclobutane-7-en-2 5 -yl)-2-hydroxyethane-1-sulfonamide
[0758] Step 1: Add triethyl phosphoacetate (5.47 g, 26.03 mmol) and sodium hydroxide (5.68 g, 142 mmol) to tetrahydrofuran (500 mL) and stir at 0°C for 1 hour. Then, add a solution of tert-butyl 6-oxyylidene-2-azaspiro[3.3]heptane-2-carboxylate (25.0 g, 118 mmol) in tetrahydrofuran (20.0 mL) dropwise to the reaction mixture and stir at 25°C under nitrogen for 1 hour. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of tetrahydrofuran / petroleum ether) to give tert-butyl 6-(2-ethoxy-2-oxyideneethylidene)-2-azaspiro[3.3]heptane-2-carboxylate (31.0 g, 110 mmol, 93.0% yield) as a colorless oil. 1 H NMR(400MHz,CHLOROFORM-d)δppm4.25-4.01(m,3H),3.99-3.90(m,2H),3.85-3.75(m,1H),3.33-3.19(m ,1H),3.09-2.97(m,1H),2.53-2.41(m,1H),2.38-2.27(m,1H),1.45(d,J=2.4Hz,9H),1.36-1.21(m,3H)
[0759] Step 2: Dissolve tert-butyl 6-(2-ethoxy-2-oxyylideneethyl)-2-azaspiro[3.3]heptane-2-carboxylate in ethanol (300 mL) and add wet palladium on carbon (3.10 g). Stir under a hydrogen atmosphere at 25°C and 25 psi for 12 hours. The reaction mixture was filtered and the filtrate was collected. The filtrate was spin-dried to give tert-butyl 6-(2-ethoxy-2-oxyylideneethyl)-2-azaspiro[3.3]heptane-2-carboxylate as a colorless oil (23.0 g, 85.8 mmol, 74% yield). 1 H NMR(400MHz,CHLOROFORM-d)δppm 4.04(q,J=7.0Hz,2H),3.93-3.80(m,2H),3.78-3.69(m,2H),2.57-2.37(m,1H) ,2.34-2.23(m,4H),1.86-1.73(m,2H),1.43-1.26(m,9H),1.17(t,J=7.0Hz,3H)
[0760] Step 3: Dissolve tert-butyl 6-(2-ethoxy-2-oxyylideneethyl)-2-azaspiro[3.3]heptane-2-carboxylate (23.0 g, 85.8 mmol) in tetrahydrofuran (230 mL) and add dropwise 2.5 M lithium aluminum hydride tetrahydrofuran solution (24.0 mL, 60.13 mmol). Stir at 0°C under nitrogen for 1 hour. The reaction mixture is quenched with water (24 mL), 15% aqueous sodium hydroxide solution (24 mL), and water (48 mL). The filtrate is dried, filtered, and dried to obtain tert-butyl 6-(2-hydroxyethyl)-2-azaspiro[3.3]heptane-2-carboxylate (20.0 g, crude) as a colorless oil. 1 H NMR(400MHz,CHLOROFORM-d)δppm 3.85(s,2H),3.73(s,2H),3.51(t,J=6.4Hz,2H),2.31-2.09(m,3H),1.83-1.68(m,2H),1.56(q,J=6.8Hz,2H),1.36(s,9H)
[0761] Step 4: Dissolve tert-butyl 6-(2-hydroxyethyl)-2-azaspiro[3.3]heptane-2-carboxylate (25.0 g, 104 mmol) in dichloromethane (500 mL). Add Dess-Martin periodinane (24.50 g, 57.1 mmol) at 0°C and stir at 25°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (500 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of tetrahydrofuran / petroleum ether) to afford tert-butyl 6-(2-oxyylideneethyl)-2-azaspiro[3.3]heptane-2-carboxylate (27.0 g, 102 mmol, 98.0% yield) as a colorless oil. 1 H NMR(400MHz,CHLOROFORM-d)δppm 9.72(t,J=1.6Hz,1H),3.97(s,2H),3.83(s,2H),2.74-2.50(m,3H),2.48-2.34(m,2H),1.95-1.83(m,2H),1.45(s,9H)
[0762] Step 5: Dissolve methyltriphenylphosphonium bromide (9.80 g, 40.9 mmol) and 1 M potassium tert-butoxide solution (81.90 mL, 81.9 mmol) in tetrahydrofuran (500 mL). Stir at 80°C for 1 hour, then cool to room temperature and add tert-butyl 6-(2-oxyylideneethyl)-2-azaspiro[3.3]heptane-2-carboxylate (13.0 g, 54.3 mmol). Stir at 25°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (500 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / petroleum ether) to give tert-butyl 6-(prop-2-en-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (9.7 g, 40.0 mmol, 74.0% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δppm 5.72-5.55(m,1H),5.01-4.81(m,2H),3.80-3.60(m,4H),2.25-1.92(m,5H),1.75-1.64(m,2H),1.29(s,8H)
[0763] Step 6: Add 6-(prop-2-en-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (4.00 g, 16.8 mmol) to a mixture of trifluoroformic acid (8.00 mL) and dichloromethane (32.0 mL) and stir at 25°C for 1 hour. The reaction mixture was evaporated to dryness to afford 6-(prop-2-en-1-yl)-2-azaspiro[3.3]heptane trifluoroacetate (4.0 g, 94% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δppm 8.65(br d,J=1.2Hz,2H),5.16-4.84(m,2H),4.13-3.77(m,4H),2.42-2.24(m,2H),2.22-2.01(m,3H),1.94-1.74(m,2H)
[0764] Step 7: Dissolve 4-bromo-N-[2-(3-vinyl-4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2-fluorobenzamide (1.00 g, 2.20 mmol) in anhydrous toluene (20.0 mL), add potassium carbonate (0.93 g, 6.59 mmol) and 6-(prop-2-en-1-yl)-2-azaspiro[3.3]heptane trifluoroacetate (0.83 g, 3.29 mmol), and stir at 105°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-11% gradient of tetrahydrofuran / petroleum ether) to afford 2-(6-allyl-2-azaspiro[3.3]heptane-2-yl)-4-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)benzamide (600.00 mg, 1.05 mmol, 48.0% yield) as a yellow oil. LCMS (ESI): [M+H]+ = 574.1
[0765] Step 8: 2-(6-allyl-2-azaspiro[3.3]heptane-2-yl)-4-bromo-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)benzamide (600.00 mg, 1.05 mmol) was dissolved in dichloromethane (240 mL), Grubbs second-generation catalyst (89.0 mg, 0.10 mmol) was added, and stirred at 50 ° C for 4 hours under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of tetrahydrofuran / petroleum ether) to obtain a yellow solid 2 5 Bromine-6 4 ,6 4 -Difluoro-5- 6 -methyl-4-aza-5(4,2)-pyrimidine-6(1,3)-piperidine-1(1,3)-azetidine-2(1,2)-benzene-10(1,3)-cyclobutanamide-7-en-3-one (200 mg, 0.38 mmol, 35.0% yield). LCMS (ESI): [M+H]+=546.1
[0766] Step 9: Put 2 5 Bromine-6 4 ,6 4 -Difluoro-5- 64-Methyl-4-aza-5(4,2)-pyrimidine-6(1,3)-piperidine-1(1,3)-azetidine-2(1,2)-benzene-10(1,3)-cyclobutanamide-7-en-3-one (62.1 mg, 0.50 mmol) was dissolved in N,N-dimethylformamide (6.00 mL), potassium phosphate (211 mg, 0.99 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (47.5 mg, 0.33 mmol), and cuprous iodide (63.0 mg, 0.33 mmol) were added, and the mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (50.0 + 0.5 mL of aqueous ammonia) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 34%-74% gradient of water (ammonia) / acetonitrile) to give (E)-N-(6 4 ,6 4 -Difluoro-5- 6 -methyl-3-oxo-4-aza-5(4,2)-pyrimidine-6(1,3)-piperidine-1(1,3)-azetidine-2(1,2)-benzene-10(1,3)-cyclobutane-7-en-2 5 -yl)-2-hydroxyethane-1-sulfonamide (29.0 mg, 0.05 mmol, 15.0% yield). LCMS (ESI): [M+H]+=589.3. 1 H NMR (400MHz, DMSO-d6) δppm10.13(s,1H),10.04-9.66(m,1H),7.32(d,J=8.4Hz,1H),6.92(s,1H),6.60(br d,J=8.8Hz,1H),6.31(s,1H),5.69-5.56(m,1H),5.34(br dd,J=9.0,14.4Hz,1H),5.13-4.70(m,1H),4.24-3.84(m,4H),3.82-3.69(m,5H),3.64(br d,J=7.6Hz,1H),3.26(brt,J=6.8Hz,2H),2.76-2.58(m,1H),2.39(br d,J=9.0Hz,2H),2.31(s,3H),2.26-2.17(m,1H),2.13-1.63(m,6H)
[0767] Example 48: N-(1 4 ,1 4 -Difluoro-2 6-methyl-4-oxo-3-aza-2(2,4)-pyrimidin-6(2,5)-pyridin-1(1,3)-piperidin-5(1,2)-benzeneheterocyclonon-7-ene-5-yl- 4 -yl)-2-hydroxyethane-1-sulfonamide
[0768] Example 49: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-6(2,5)-pyridin-1(1,3)-piperidin-5(1,2)-benzeneheterocyclononane-5-(2,5)-pyridin-1(1,3)-piperidin-5- ... 4 -yl)-2-hydroxyethane-1-sulfonamide
[0769] Step 1: Under nitrogen, 5-vinyl-2-chloropyridine (800 mg, 5.60 mmol), (5-chloro-2-(methoxycarbonyl)phenyl)boronic acid (1.00 g, 4.66 mmol), tetrakis(triphenylphosphine)palladium (275 mg, 0.23 mmol), and potassium carbonate (1.32 g, 9.33 mmol) were dissolved in 1,4-dioxane (20.00 mL). The reaction mixture was stirred at 80°C for 3 hours, then cooled to room temperature and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-10% dichloromethane / methanol) to give 2-(5-vinylpyridin-2-yl)-4-chlorobenzoic acid (500 mg, 1.93 mmol, 41.4% yield) as a yellow solid. LCMS (ESI): [M+H] + =260.00.
[0770] Step 2: 2-(4,4-difluoro-3-allylpiperidin-1-yl)-6-methylpyrimidin-4-amine (516 mg, 1.93 mmol), 2-(5-vinylpyridin-2-yl)-4-chlorobenzoic acid (500 mg, 1.93 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.24 g, 5.78 mmol) and 4-dimethylaminopyridine (960 mg, 7.70 mmol) were dissolved in dichloroethane (20.00 mL) at 20 ° C, heated to 80 ° C and stirred for 24 hours. After the reaction was complete, sodium bicarbonate solution (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-20% ethyl acetate / petroleum ether) to give 2-(5-vinylpyridin-2-yl)-4-chloro-N-(2-(4,4-difluoro-3-allylpiperidin-1-yl)-6-methylpyrimidin-4-yl)benzamide (140 mg, 0.27 mmol, 14.2% yield) as a colorless oil. LCMS (ESI): [M+H] + =510.20.
[0771] Step 3: Under nitrogen atmosphere at 20°C, 2-(5-vinylpyridin-2-yl)-4-chloro-N-(2-(4,4-difluoro-3-allylpiperidin-1-yl)-6-methylpyrimidin-4-yl)benzamide (140 mg, 0.27 mmol) was dissolved in dry dichloroethane (120.00 mL), Grubbs second-generation catalyst (25 mg, 0.03 mmol) was added, and the reaction was heated under reflux for 16 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 0-20% ethyl acetate / petroleum ether) to obtain 5 4 -Chloro-1 4 ,1 4 -Difluoro-2 6 -methyl-3-aza-2(2,4)-pyrimidin-6(2,5)-pyridin-1(1,3)-piperidin-5(1,2)-benzheterocyclonon-7-en-4-one (50 mg, 0.10 mmol, yield 38.4%), as a white solid. LCMS (ESI): [M+H] + =482.10.
[0772] Step 4: Under nitrogen atmosphere at 20℃, 4 -Chloro-1 4 ,1 4 -Difluoro-2 6-Methyl-3-aza-2(2,4)-pyrimidin-6(2,5)-pyridin-1(1,3)-piperidin-5(1,2)-benzeneheterocyclonon-7-en-4-one (50 mg, 0.10 mmol), 2-hydroxyethylsulfonamide (39 mg, 0.31 mmol), potassium phosphate (87 mg, 0.41 mmol), cuprous iodide (29 mg, 0.15 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (44 mg, 0.31 mmol) were dissolved in N,N-dimethylformamide (5.00 mL), and the resulting reaction mixture was stirred at 100 ° C for 16 hours. After the reaction was complete, cold water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated to obtain the crude product, which was purified by flash column chromatography (silica, 50-70% ethyl acetate / petroleum ether) to obtain N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-6(2,5)-pyridin-1(1,3)-piperidin-5(1,2)-benzeneheterocyclonon-7-ene-5-yl- 4 -yl)-2-hydroxyethane-1-sulfonamide (25 mg, 0.044 mmol, yield 42.2%), as a white solid. LCMS (ESI): [M+H] + =571.20, 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.24(s,1H),9.90(s,1H),8.53(s,1H),7.75(d,J=8.6Hz,2H),7.55(d,J= 7.7Hz,1H),7.43–7.35(m,2H),7.35–7.08(m,1H),6.52(d,J=11.3Hz,1H),6 .09–5.92(m,1H),4.96(t,J=5.6Hz,1H),3.94–3.43(m,6H),3.38–3.36(m, 2H),2.35–2.21(m,1H),2.27(s,3H),2.17–1.89(m,2H),1.86–1.66(m,2H).
[0773] Step 5: At 20℃, N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-6(2,5)-pyridin-1(1,3)-piperidin-5(1,2)-benzeneheterocyclonon-7-ene-5-yl- 4-yl)-2-hydroxyethane-1-sulfonamide (20 mg, 0.035 mmol) and 10% wet palladium / carbon (20 mg) were dissolved in methanol (5.00 mL), and formic acid (0.16 g, 3.52 mmol) was added to replace the hydrogen atmosphere. The mixture was stirred at 20°C for 24 hours until the reaction was complete. After concentration under reduced pressure, the product N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-6(2,5)-pyridin-1(1,3)-piperidin-5(1,2)-benzeneheterocyclononane-5-(1,2)- 4 -yl)-2-hydroxyethane-1-sulfonamide (10 mg, 0.017 mmol, yield 49.9%), as a white solid. LCMS (ESI): [M+H] + =573.20, 1 H NMR(400MHz,DMSO-d6)δppm 10.17(s,1H),9.14(s,1H),8.23(s,1H),7.76–7.69(m,1H),7.63(d,J=8.4Hz,1H),7.55–7. 45(m,2H),7.35(dd,J=8.4,2.2Hz,1H),7.31–7.16(m,1H),4.97(s,1H),4.52–4.29(m,1H),4 .07–3.89(m,1H),3.86–3.70(m,2H),3.38–3.32(m,2H),3.31–3.04(m,2H),2.85–2.74(m,1 H),2.48–2.37(m,1H),2.26(s,3H),2.07–1.70(m,4H),1.67–1.49(m,1H),1.18–0.97(m,2H)
[0774] Example 50: N-(1 4 ,1 4 -Difluoro-2 6 -Methoxy-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3)-piperidin-5(1,2),6(1,4)-diphenylheterocyclonon-8-ene-5-yl)- 4 -yl)-2-hydroxyethane-1-sulfonamide
[0775] Step 1: Under nitrogen atmosphere, a mixed solution of (4-bromophenyl)boronic acid (5.00 g, 24.90 mmol), allyl bromide (6.00 g, 49.79 mmol), potassium carbonate (10.50 g, 74.69 mmol), and palladium acetate (570 mg, 2.49 mmol) in toluene (50.00 mL) was stirred at 80°C for 12 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain compound 1-allyl-4-bromobenzene (2.60 g, 13.19 mmol, yield 53.0%) as a colorless oil.
[0776] Step 2: Under nitrogen atmosphere, a mixed solution of 1-allyl-4-bromobenzene (2.60 g, 13.19 mmol), (5-chloro-2-(methoxycarbonyl)phenyl)phenyl)boric acid (4.20 g, 19.79 mmol), potassium carbonate (5.60 g, 39.58 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (999 mg, 1.32 mmol), 1,4-dioxane (40.00 mL) and water (10.00 mL) was stirred at 80°C for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain methyl 4'-allyl-5-chloro-[1,1'-biphenyl]-2-carboxylate (1.80 g, 6.28 mmol, 47.6% yield) as a yellow oil. LCMS (ESI): [M+H] + =287.00.
[0777] Step 3: Under nitrogen atmosphere at 0°C, lithium bis(trimethylsilyl)amide (10 mL, 1.0 M) was added dropwise to a solution containing 2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methoxypyrimidin-4-amine (1.90 g, 6.91 mmol) and tetrahydrofuran (20.00 mL). After stirring for 30 minutes, 4'-allyl-5-chloro-[1,1'-biphenyl]-2-carboxylic acid methyl ester (1.80 g, 6.28 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at 20°C for 1 hour, and a saturated ammonium chloride solution (50 mL) was added dropwise to quench the reaction. The reaction was then quenched with ethyl acetate (30 mL x 4% acetic acid). 3) Extraction, drying the organic phase over anhydrous sodium sulfate, filtration, concentration, and purification by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) afforded the compound 4'-allyl-5-chloro-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methoxypyrimidin-4-yl)-[1,1'-biphenyl]-2-carboxamide (1.30 g, 2.48 mmol, 39.4% yield) as a white solid. LCMS (ESI): [M+H] + =525.20.
[0778] Step 4: A solution of 4'-allyl-5-chloro-N-(2-(4,4-difluoro-3-vinylpiperidin-1-yl)-6-methoxypyrimidin-4-yl)-[1,1'-biphenyl]-2-carboxamide (1.30 g, 2.48 mmol) and Grubbs second-generation catalyst (214 mg, 0.25 mmol) in dichloromethane (300.00 mL) was stirred at 50°C for 2 hours. The reaction solution was concentrated and purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain product 5. 4 -Chloro-1 4 ,1 4 -Difluoro-2 6 -Methoxy-3-aza-2(2,4)-pyrimidin-1(1,3)-piperidin-5(1,2),6(1,4)-diphenylheterocyclonon-8-en-4-one (1.10 g, 2.21 mmol, yield 89.4%), as a gray solid. LCMS (ESI): [M+H] + =497.20.
[0779] Step 5: Under nitrogen atmosphere, 4 -Chloro-1 4 ,1 4 -Difluoro-2 6A solution of 2-methoxy-3-aza-2(2,4)-pyrimidin-1(1,3)-piperidin-5(1,2),6(1,4)-diphenylheterocyclonon-8-en-4-one (1.00 g, 2.01 mmol), 2-hydroxyethanesulfonamide (509 mg, 4.02 mmol), potassium phosphate (1.30 g, 6.04 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (85 mg, 0.207 mmol), tris(dibenzylideneacetone)dipalladium (188 mg, 0.20 mmol) in dioxane (10.00 mL) was stirred at 100° C. for 2 hours. The reaction mixture was poured into water (30 mL) and washed with ethyl acetate (30 mL x 40 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient ethyl acetate / petroleum ether) to obtain compound N-(1 4 ,1 4 -Difluoro-2 6 -Methoxy-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3)-piperidin-5(1,2),6(1,4)-diphenylheterocyclonon-8-ene-5-yl)- 4 -yl)-2-hydroxyethane-1-sulfonamide (800 mg, 1.37 mmol, yield 67.9%), as a gray solid. LCMS (ESI): [M+H] + =586.20.
[0780] Example 51A to Example 51B: N-(1 4 ,1 4 -Difluoro-2 6 -methoxy-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3)-piperidin-5(1,2),6(1,4)-dibenzylcyclononane-5 4 -yl)-2-hydroxyethane-1-sulfonamide two isomers
[0781] Step 1: N-(1 4 ,1 4 -Difluoro-2 6 -Methoxy-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3)-piperidin-5(1,2),6(1,4)-dibenzylcyclononane-8-ene-5 4-yl)-2-hydroxyethane-1-sulfonamide (530 mg, 0.91 mmol) was dissolved in methanol (30.0 mL) and wet palladium carbon (300 mg, 0.01 mmol) was added. The reaction mixture was replaced with argon protection three times and then replaced with hydrogen three times. The mixture was stirred at 25 ° C for 16 hours under a hydrogen (50 Psi) atmosphere. The reaction mixture was filtered under reduced pressure to remove palladium carbon and then concentrated under vacuum. The residue was purified by preparative HPLC (C18, 36%-76% gradient of water (ammonia + ammonium bicarbonate) / acetonitrile) to give a white solid N-(1 4 ,1 4 -Difluoro-2 6 -methoxy-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3)-piperidin-5(1,2),6(1,4)-dibenzylcyclononane-5 4 -yl)-2-hydroxyethane-1-sulfonamide (76.86 mg, 0.13 mmol, 14.0% yield). LCMS (ESI): [M+H]+=588.3. 1 H NMR (400MHz, DMSO-d6) δppm 10.19 (br s, 1H), 8.53 (br s, 1H), 7.69 (d, J = 8.4Hz, 1H), 7.36 (br s,2H),7.31(dd,J=2.0,8.4Hz,1H),7.26(d,J=2.0Hz,1H),7.07(br s,2H),6.76(br s,1H),5.27-4.70(m,1H),4.38(br d,J=13.2Hz,1H),3.94(br d,J=12.8Hz,1H),3.82(s,3H),3.78(t,J=6.8Hz,2H),3.35(t,J=6.4Hz,2H),3.21(br t,J=10.4Hz,1H),3.08(br d,J=12.0Hz,1H),2.89-2.78(m,1H),2.47-2.38(m,1H),2.06-1.85(m,3H),1.82-1.56(m,2H),1.23-1.02(m,2H)
[0782] The above product was separated by SFC (chromatographic column type: DAICEL CHIRALPAK AD (250mm*30mm, 10um), mobile phase type: CO2-EtOH (0.1% NH3H2O), gradient: isocratic 40%, flow rate: 80mL / min, column temperature: 40°C) to obtain two stereoisomers.
[0783] Example 51A: White solid (25.62 mg). SFC analysis (column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm; mobile phase: phase A: carbon dioxide, phase B: ethanol (0.05% ethylene glycol); gradient: phase B maintained at 40%; flow rate: 4 mL / min). LCMS (ESI): [M+H] + = 588.3. 1 H NMR (400MHz, DMSO-d6) δppm 10.19 (s, 1H), 8.54 (br s, 1H), 7.69 (d, J = 8.4Hz, 1H), 7.37 (br d,J=2.0Hz,2H),7.31(dd,J=2.0,8.4Hz,1H),7.26(d,J=2.0Hz,1H),7.07(br s,2H),6.77(br s,1H),5.22-4.73(m,1H),4.38(br d,J=13.2Hz,1H),3.94(br d,J=12.4Hz,1H),3.82(s,3H),3.78(t,J=6.8Hz,2H),3.38-3.34(m,2H),3.21(br t,J=10.4Hz,1H),3.08(br d,J=12.0Hz,1H),2.91-2.78(m,1H),2.48-2.38(m,1H),2.07-1.75(m,4H),1.64(br d,J=2.8Hz,1H),1.22-1.01(m,2H)
[0784] Example 51B: White solid (23.86 mg). SFC analysis (column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm; mobile phase: phase A: carbon dioxide, phase B: ethanol (0.05% ethylene glycol); gradient: phase B maintained at 40%; flow rate: 4 mL / min). LCMS (ESI): [M+H] + = 588.3. 1H NMR (400MHz, DMSO-d6) δppm 8.49(br s,1H),7.68(d,J=8.0Hz,1H),7.37(br s,2H),7.28(dd,J=2.0,8.4Hz,1H),7.23(d,J=1.6Hz,1H),7.07(br s,2H),6.76(br s,1H),4.38(br d,J=13.6Hz,1H),3.94(br d,J=12.8Hz,1H),3.82(s,3H),3.77(t,J=6.8Hz,2H),3.35(br s,2H),3.21(br t,J=10.4Hz,1H),3.08(br d,J=12.0Hz,1H),2.89-2.79(m,1H),2.46-2.40(m,1H),2.03-1.76(m,4H),1.64(br d,J=3.2Hz,1H),1.20-1.04(m,2H)
[0785] Example 52: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-6 2 ,4-dioxo-6 1 ,6 2 -Dihydro-3-aza-2(2,4)-pyrimidin-6(1,4)-pyridin-1(1,3)-piperidin-5(1,2)-benzeneheterocyclononane-5 4 -yl)-2-hydroxyethane-1-sulfonamide
[0786] Step 1: Under nitrogen atmosphere, a mixed solution of 4-bromopyridin-2(1H)-one (5.00 g, 28.74 mmol), methyl 4-chloro-2-iodobenzoate (12.80 g, 43.10 mmol), potassium carbonate (12.20 g, 86.21 mmol), and cuprous iodide (8.40 g, 43.10 mol) in N,N-dimethylformamide (50.00 mL) was stirred at 100 ° C for 12 hours. The reaction solution was poured into water (100 mL) and washed with ethyl acetate (50 mL x 10% acetic acid). 3) Extraction, drying the organic phase over anhydrous sodium sulfate, filtration, and concentration followed by purification by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) afforded methyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-4-chlorobenzoate (900 mg, 2.63 mmol, 9.1% yield) as a colorless oil. LCMS (ESI): [M+H] + =341.90.
[0787] Step 2: Under nitrogen atmosphere, a mixed solution of dioxane (15.00 mL) and water (3.00 mL) containing methyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-4-chlorobenzoate (900 mg, 2.63 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (607 mg, 3.94 mmol), potassium carbonate (1.10 g, 7.88 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (199 mg, 0.26 mmol) was stirred at 80°C for 12 hours. The reaction mixture was poured into water (50 mL) and washed with ethyl acetate (50 mL x 10% acetic acid). 3) Extraction, drying the organic layer over anhydrous sodium sulfate, filtration, and concentration followed by purification by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) afforded methyl 4-chloro-2-(2-oxo-4-vinylpyridin-1(2H)-yl)benzoate (700 mg, 2.42 mmol, 92.0% yield) as a white solid. LCMS (ESI): [M+H] + =290.00.
[0788] Step 3: Under nitrogen atmosphere at 0°C, lithium bis(trimethylsilyl)amide (3.60 mL, 1.0 M) was added dropwise to a tetrahydrofuran (10 mL) solution containing 2-(4,4-difluoro-3-allylpiperidin-1-yl)-6-methylpyrimidin-4-amine (778 mg, 2.90 mmol). After stirring for 30 minutes, methyl 4-chloro-2-(2-oxo-4-vinylpyridin-1(2H)-yl)benzoate (700 mg, 2.42 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at 20°C for 12 hours, poured into water (50 mL), and then washed with ethyl acetate (50 mL x 10 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound N-(2-(3-allyl-4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-chloro-2-(2-oxo-4-vinylpyridin-1(2H)-yl)benzamide (300 mg, 0.57 mmol, yield 23.6%) as a yellow oil. LCMS (ESI): [M+H] + =526.20.
[0789] Step 4: A solution of N-(2-(3-allyl-4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-chloro-2-(2-oxo-4-vinylpyridin-1(2H)-yl)benzamide (300 mg, 0.57 mmol) and Grubbs second-generation catalyst (49 mg, 0.21 mmol) in dichloromethane (60.00 mL) was stirred at 50° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain compound 5. 4 -Chloro-1 4 ,1 4 -Difluoro-2 6 -methyl-6 1 ,6 2 -Dihydro-3-aza-2(2,4)-pyrimidin-6(1,4)-pyridin-1(1,3)-piperidin-5(1,2)-benzeneheterocyclonon-7-ene-6- 2 ,4-dione (200 mg, 0.40 mmol, yield 70.4%), as a yellow oil. LCMS (ESI): [M+H] + =498.20.
[0790] Step 5: Under nitrogen atmosphere, 4 -Chloro-1 4 ,1 4 -Difluoro-2 6 -methyl-6 1 ,6 2 -Dihydro-3-aza-2(2,4)-pyrimidin-6(1,4)-pyridin-1(1,3)-piperidin-5(1,2)-benzeneheterocyclonon-7-ene-6- 2 ,4-dione (200 mg, 0.40 mmol), 2-hydroxyethanesulfonamide (102 mg, 0.80 mmol), potassium phosphate (261 mg, 1.21 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (17 mg, 0.040 mmol), tris(dibenzylideneacetone)dipalladium (38 mg, 0.040 mmol) in dioxane (5.00 mL) was stirred at 100 ° C for 12 hours, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient ethyl acetate / petroleum ether) to give compound N-(1 4 ,1 4 -Difluoro-2 6 -methyl-6 2 ,4-dioxo-6 1 ,6 2-Dihydro-3-aza-2(2,4)-pyrimidin-6(1,4)-pyridin-1(1,3)-piperidin-5(1,2)-benzeneheterocyclonon-7-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide (100 mg, 0.17 mmol, yield 42.7%), as a yellow solid. LCMS (ESI): [M+H] + =587.20.
[0791] Step 6: At 25°C, 4 ,1 4 -Difluoro-2 6 -methyl-6 2 ,4-dioxo-6 1 ,6 2 -Dihydro-3-aza-2(2,4)-pyrimidin-6(1,4)-pyridin-1(1,3)-piperidin-5(1,2)-benzeneheterocyclonon-7-ene-5-ol 4 A mixed solution of 2-hydroxy-1-hydroxyethane-1-sulfonamide (100 mg, 0.17 mmol) and wet palladium carbon (363 mg, 0.34 mmol) in tetrahydrofuran (10 mL) was stirred under a hydrogen atmosphere (15 psi) for 12 hours. The reaction solution was filtered, concentrated, and purified by column chromatography (C18, 0-100% gradient of acetonitrile / water) to give compound N-(1 4 ,1 4 -Difluoro-2 6 -methyl-6 2 ,4-dioxo-6 1 ,6 2 -Dihydro-3-aza-2(2,4)-pyrimidin-6(1,4)-pyridin-1(1,3)-piperidin-5(1,2)-benzeneheterocyclononane-5 4 -yl)-2-hydroxyethane-1-sulfonamide (9.0 mg, 0.015 mmol, yield 9.0%), as a white solid. 1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.73(s,1H),8.02–7.85(m,2H),7.39–7.16 (m,4H),7.03–6.90(m,1H),4.98(s,1H),4.47–4.12(m,2H),3.83–3.71(m...
Claims
1. A compound having the following structure, and a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof: in, Cy2 represents or or or Among them, * indicates the site connected to Y, and the wavy line indicates the site connected to L1; in, Indicates a single bond or a double bond; Among them, X1 represents CR W1 or N; Among them, X2 represents CR W2 or N; Among them, X3 represents CR W3 or N; Among them, X4 represents CR W4 or N; Among them, X5 represents CR W5 or N; Among them, X6 represents CR W6 or N; Among them, X7 represents CR W7 or N; Among them, R W1 , R W2 , R W3 , R W4 , R W5 , R W6 , R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Alternatively, the chemical bond between X2 and X3 can also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, 2, or 3 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Or the chemical bond between X5, X6 or X6, X7 can be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, 2, or 3 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring; Wherein, Y represents absence, -CH2-, -O-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups: or Cy3; Wherein, * indicates the site connected to ring A; the wavy line indicates the site connected to Y2; Wherein, Cy1 and Cy3 each independently represent a substituted or unsubstituted 3-10-membered saturated or unsaturated cycloalkyl, 6-10-membered saturated or unsaturated spirocycloalkyl, 6-10-membered saturated or unsaturated bridged cycloalkyl, 6-10-membered saturated or unsaturated condensed cycloalkyl, 3-10-membered saturated or unsaturated heterocycloalkyl, 6-10-membered saturated or unsaturated spiroheterocycloalkyl, 6-10-membered saturated or unsaturated bridged heterocycloalkyl, 6-10-membered condensed heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, wherein each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; Wherein, Y1 represents -(CR a R b ) m -; Y2 means -(CR a R b ) n -; Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、PO(R a R b ),-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、-C≡C-、 5-6 Genso Hoji, replaced by; Among them, R L Indicates L2-R M ; Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2.-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-; Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted with C1-C6 alkyl or C3-C6 cycloalkyl; Or, L2-R M express Wherein, m and n each independently represent an integer from 0 to 10; Among them, R a , R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a , R b Together with the atoms to which they are connected, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S, N and Se.
2. A compound having the following formula (I-1), and its pharmaceutically acceptable salts, stereoisomers, isotopic isomers, and tautomers: in, Indicates a single bond or a double bond; Among them, X1 represents CR W1 or N; Among them, X2 represents CR W2 or N; Among them, X3 represents CR W3 or N; Among them, X4 represents CR W4 or N; Among them, X5 represents CR W5 or N; Among them, X6 represents CR W6 or N; Among them, X7 represents CR W7 or N; Among them, R W1 , R W2 , R W3 , R W4 , R W5 , R W6 , R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Alternatively, the chemical bond between X2 and X3 can also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, 2, or 3 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Or the chemical bond between X5, X6 or X6, X7 can be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, 2, or 3 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring; Wherein, Y represents absence, -CH2-, -O-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups: or Cy3; Wherein, * indicates the site connected to ring A; the wavy line indicates the site connected to Y2; Wherein, Cy1 and Cy3 each independently represent a substituted or unsubstituted 3-10-membered saturated or unsaturated cycloalkyl, 6-10-membered saturated or unsaturated spirocycloalkyl, 6-10-membered saturated or unsaturated bridged cycloalkyl, 6-10-membered saturated or unsaturated condensed cycloalkyl, 3-10-membered saturated or unsaturated heterocycloalkyl, 6-10-membered saturated or unsaturated spiroheterocycloalkyl, 6-10-membered saturated or unsaturated bridged heterocycloalkyl, 6-10-membered condensed heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, wherein each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; Where Y1 represents -(CR a R b ) m -; Y2 means -(CR a R b ) n -; Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、-C≡C-、 5-6 Genso Hoji, replaced by; Among them, R L Indicates L2-R M ; Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2.-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-; Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted with C1-C6 alkyl or C3-C6 cycloalkyl; Or, L2-R M express Wherein, m and n each independently represent an integer from 0 to 10; Among them, R a , R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a , R b Together with the atoms to which they are connected, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S, N and Se.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X1 represents CH or N, preferably CH.
4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X2 represents CH or N, preferably CH.
5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X3 represents CH or N, preferably CH.
6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X2 and X3 is fused with ring B to form a group with the following structure:
7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X4 represents CH or N, preferably N.
8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X5 means CR W5 or N, where R W5 It represents hydrogen, halogen, CH3O, CF3, CHF2, CH2F, NH2, -N(CH3)2, CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X6 means CR W6 or N, where R W6 It represents hydrogen, halogen, -CH3O, -CF3, -CHF2, -CH2F, -NH2, -N(CH3)2, -CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X7 represents CH or N, preferably N.
11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X5 and X6 is fused with ring A to form a group with the following structure:
12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X6 and X7 is fused with ring A to form a group with the following structure:
13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: Cy1 represents the following groups: Among them, when When it represents a double bond, R means it does not exist; When it represents a single bond, R represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3; Wherein, R1, R1', R2, R2', R3, R3', R4, R4' each independently represents hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl; Or R1, R1' pair, R2, R2' pair, R3, R3' pair, R4, R4' pair together with the carbon atom connected thereto form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, 2 heteroatoms selected from O, S, N, Se; and further, the ring may also be selected from 0, 1, 2 or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -OR a or substituted with an oxo substituent; Where W1 represents -(CR s R t ) o -; Among them, R s , R t Each independently represents hydrogen or C1-C6 alkyl; Among them, o represents 1 or 2; Among them, X8 represents CR W8 or N; Among them, X9 represents CR W9 or N; Among them, X 10 Represents CR W10 or N; Among them, X 11 Represents CR W11 or N; Among them, R W8 , R W9 , R W10 , R W11 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a , -C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b .
14. The compound according to claim 13, or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer, wherein: X8 represents CH or N.
15. The compound according to claim 13, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X9 represents CH or N.
16. The compound according to claim 13, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 10 Indicates CH or N.
17. The compound according to claim 13, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 11 Indicates CH or N.
18. The compound according to claim 13, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: R1, R1', R2, R2', R3, R3', R4 and R4' each independently represent hydrogen.
19. The compound according to claim 13, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: W1 represents -CH2 or -CH2CH2.
20. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: Y represents the following groups: absent, -CH2-, -O-, -Se-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups:
21. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, stereoisomer, isotope isomer, or tautomer, wherein: Y represents -O- or -NH-.
22. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y stands for 23. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, stereoisomer, isotope isomer, or tautomer, wherein: Y stands for 24. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: Y represents Cy3, wherein Cy3 represents the following group: Among them, when When it represents a double bond, G means it does not exist; When it represents a single bond, G represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3; wherein G1, G1', G2, G2', G3, G3', G4, G4' each independently represents hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl; Or G1, G1' pair, G2, G2' pair, G3, G3' pair, G4, G4' pair together with the carbon atom connected thereto form a 3-6 membered (hetero) ring, wherein the ring may contain 0, 1, 2 heteroatoms selected from O, S, N, Se; and further, the ring may also be selected from 0, 1, 2 or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, OR a or substituted with an oxo substituent; Where W2 represents -(CR i R j ) p -; Among them, R i , R j Each independently represents hydrogen or C1-C6 alkyl; Where p represents 1 or 2; Among them, X 12 Represents CR W12 or N; Among them, X 13 Represents CR W13 or N; Among them, X 14 Represents CR W14 or N; Among them, X 15 Represents CR W15 or N; Among them, R W12 , R W13 , R W14 , R W15 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b .
25. The compound according to claim 24, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 12 Indicates CH or N.
26. The compound according to claim 24, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 13 Indicates CH or N.
27. The compound according to claim 24, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 14 Indicates CH or N.
28. The compound according to claim 24, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 15 Indicates CH or N.
29. The compound according to claim 24, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: G1, G1', G2, G2', G3, G3', G4 and G4' each independently represent hydrogen.
30. The compound according to claim 24, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: W2 represents -CH2 or -CH2CH2.
31. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: L1 represents -C(O)NR a -、-NR a C(O)-, 32. The compound according to claim 31, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer or tautomer thereof, wherein L1 represents -C(O)NH-.
33. The compound according to claim 31, or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer, wherein L1 represents 34. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, stereoisomer, isotope isomer, or tautomer, wherein: Y1 means -(CR a R b ) m -.
35. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y1 represents -NR-C(=O)-, -OC(=O)-, or -C(=O)O-.
36. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y1 represents -O(CR a R b ) m -or-(CR a R b ) m O-.
37. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y1 means -CR a =CR a -or-CR a R b -CR a =CR b -.
38. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y2 means -(CR a R b ) n -.
39. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, stereoisomer, isotope isomer, or tautomer, wherein: Y2 stands for -NR a -C(=O)-.
40. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, stereoisomer, isotope isomer, or tautomer, wherein: Y2 represents -O(CR a R b ) n -or-(CR a R b ) n O-.
41. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y2 represents -CR a =CR a -, -CR a =CR b -CR a R b - or -CR a R b -CR a =CR b -.
42. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y 2 It represents pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or triazolyl.
43. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: -Y1-Y2- represents -CR a =CR a -, -CR a R b CR a =CR b -.
44. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: -Y1-Y2- means -CR a R b -NR a C(O)-.
45. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: -Y1-Y2- means 46. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: R L Display-NHS(O)2CH2CH2OH, -NHS(O)2CH2CH3, -NHS(O)2CH3.
47. A compound having a structure of formula (II) or formula (III), a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, in, Cy2 represents or or or Among them, * indicates the site connected to Y, and the wavy line indicates the site connected to L1; in, Indicates a single bond or a double bond; Among them, X 1 Represents CR W1 or N; Among them, X 2 Represents CR W2 or N; Among them, X 3 Represents CR W3 or N; Among them, X 4 Represents CR W4 or N; Among them, X 5 Represents CR W5 or N; Among them, X 6 Represents CR W6 or N; Among them, X 7 Represents CR W7 or N; Among them, R W1 , R W2 , R W3 , R W4 , R W5 , R W6 , R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Alternatively, the chemical bond between X2 and X3 can also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Or the chemical bond between X5, X6 or X6, X7 can be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0-3 of the following substituents: deuterium, halogen, cyano, nitro, oxo, hydroxy C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C3-C6 cycloalkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b , -SF5 or -NR a R b substituted by a substituent; Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring; Wherein, Y represents absence, -CH2-, -O-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups: or Cy3; Wherein, * indicates the site connected to ring A; the wavy line indicates the site connected to Y2; Among them, when When it represents a double bond, R means it does not exist; When it represents a single bond, R represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3; Wherein, R1, R1', R2, R2', R3, R3', R4, R4' each independently represents hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl; Or R1, R1' pair, R2, R2' pair, R3, R3' pair, R4, R4' pair together with the carbon atom connected thereto form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, 2 heteroatoms selected from O, S, N, Se; and further, the ring may also be selected from 0, 1, 2 or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -OR a or substituted with an oxo substituent; wherein Cy3 each independently represents a substituted or unsubstituted 3-10-membered saturated or unsaturated cycloalkyl, a 6-10-membered saturated or unsaturated spirocycloalkyl, a 6-10-membered saturated or unsaturated bridged cycloalkyl, a 6-10-membered saturated or unsaturated condensed cycloalkyl, a 3-10-membered saturated or unsaturated heterocycloalkyl, a 6-10-membered saturated or unsaturated spiro heterocycloalkyl, 6-10 membered saturated or unsaturated bridged heterocycloalkyl, 6-10 membered fused heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein the substituents are selected from the group independently representing hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Among them, Y 1 Indicates -(CR a R b ) m -;Y 2 Indicates -(CR a R b ) n -; Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、PO(R a R b ),-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、-C≡C-、 5-6 Genso Hoji, replaced by; Among them, R L Indicates L2-R M ; Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2.-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-; Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted with C1-C6 alkyl or C3-C6 cycloalkyl; Or, L2-R M express Wherein, m and n each independently represent an integer from 0 to 10; Among them, R a , R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a , R b Together with the atoms to which they are connected, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S, Se and N.
48. A compound having the structure of formula (II-1) or formula (III-1), or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof: in, Indicates a single bond or a double bond; Among them, X 1 Represents CR W1 or N; Among them, X 2 Represents CR W2 or N; Among them, X 3 Represents CR W3 or N; Among them, X 4 Represents CR W4 or N; Among them, X 5 Represents CR W5 or N; Among them, X 6 Represents CR W6 or N; Among them, X 7 Represents CR W7 or N; Among them, R W1 , R W2 , R W3 , R W4 , R W5 , R W6 , R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Alternatively, the chemical bond between X2 and X3 can also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, oxo, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Or the chemical bond between X5, X6 or X6, X7 can be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0-3 of the following substituents: deuterium, halogen, cyano, nitro, oxo, hydroxy C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C3-C6 cycloalkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)R a , -C(=O)NR a R b , -SF5 or -NR a R b substituted by a substituent; Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring; Wherein, Y represents absence, -CH2-, -O-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups: or Cy3; Wherein, * indicates the site connected to ring A; the wavy line indicates the site connected to Y2; Among them, when When it represents a double bond, R means it does not exist; When it represents a single bond, R represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3; Wherein, R1, R1', R2, R2', R3, R3', R4, R4' each independently represents hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl; Or R1, R1' pair, R2, R2' pair, R3, R3' pair, R4, R4' pair together with the carbon atom connected thereto form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, 2 heteroatoms selected from O, S, N, Se; and further, the ring may also be selected from 0, 1, 2 or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -OR a or substituted with an oxo substituent; Wherein, Cy3 each independently represents a substituted or unsubstituted 3-10-membered saturated or unsaturated cycloalkyl, 6-10-membered saturated or unsaturated spirocycloalkyl, 6-10-membered saturated or unsaturated bridged cycloalkyl, 6-10-membered saturated or unsaturated condensed cycloalkyl, 3-10-membered saturated or unsaturated heterocycloalkyl, 6-10-membered saturated or unsaturated spiroheterocycloalkyl, 6-10-membered saturated or unsaturated bridged heterocycloalkyl, 6-10-membered condensed heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, wherein the substituents are selected from each independently representing hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Among them, Y 1 Indicates -(CR a R b ) m -;Y 2 Indicates -(CR a R b ) n -; Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、PO(R a R b ),-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、-C≡C-、 5-6 Genso Hoji, replaced by; Among them, R L Indicates L2-R M ; Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2.-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-; Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted with C1-C6 alkyl or C3-C6 cycloalkyl; Or, L2-R M express Wherein, m and n each independently represent an integer from 0 to 10; Among them, R a , R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a , R b Together with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S and N.
49. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X1 represents CH or N, preferably CH.
50. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X2 represents CH or N, preferably CH.
51. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X3 represents CH or N, preferably CH.
52. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X2 and X3 is fused with ring B to form a group with the following structure:
53. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X4 represents CH or N, preferably N.
54. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X5 means CR W5 or N, where R W5 It represents hydrogen, halogen, CH3O, CF3, CHF2, CH2F, NH2, -N(CH3)2, CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
55. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X6 means CR W6 or N, where R W6 It represents hydrogen, halogen, -CH3O, -CF3, -CHF2, -CH2F, -NH2, -N(CH3)2, -CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
56. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X7 represents CH or N, preferably N.
57. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X5 and X6 is fused with ring A to form a group with the following structure:
58. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X6 and X7 is fused with ring A to form a group with the following structure:
59. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: Y represents the following groups: absent, -CH2-, -O-, -Se-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups:
60. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y represents -O-, -Se- or -NH-.
61. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: Y stands for 62. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y stands for 63. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: Y represents Cy3, wherein Cy3 represents the following group: Among them, when When it represents a double bond, G means it does not exist; When it represents a single bond, G represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3; wherein G1, G1', G2, G2', G3, G3', G4, G4' each independently represents hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl; Or G1, G1' pair, G2, G2' pair, G3, G3' pair, G4, G4' pair together with the carbon atom connected thereto form a 3-6 membered (hetero) ring, wherein the ring may contain 0, 1, 2 heteroatoms selected from O, S, N, Se; and further, the ring may also be selected from 0, 1, 2 or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, OR a or substituted with an oxo substituent; Where W2 represents -(CR i R j ) p -; Among them, R i , R j Each independently represents hydrogen or C1-C6 alkyl; Where p represents 1 or 2; Among them, X 12 Represents CR W12 or N; Among them, X 13 Represents CR W13 or N; Among them, X 14 Represents CR W14 or N; Among them, X 15 Represents CR W15 or N; Among them, R W12 , R W13 , R W14 , R W15 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b .
64. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 12 Indicates CH or N.
65. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 13 Indicates CH or N.
66. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 14 Indicates CH or N.
67. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 15 Indicates CH or N.
68. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: G1, G1', G2, G2', G3, G3', G4 and G4' each independently represent hydrogen.
69. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: W2 represents -CH2 or -CH2CH2.
70. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: L1 represents -C(O)NR a -、-NR a C(O)-, 71. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer or tautomer thereof, wherein L1 represents -C(O)NH-.
72. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein L1 represents 73. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y1 means -(CR a R b ) m -.
74. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y1 represents -NR-C(=O)-, -OC(=O)-, or -C(=O)O-.
75. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y1 represents -O(CR a R b ) m -or-(CR a R b ) m O-.
76. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y1 means -CR a =CR a -or-CR a R b -CR a =CR b -.
77. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y2 means -(CR a R b ) n -.
78. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y2 stands for -NR a -C(=O)-.
79. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y2 represents -O(CR a R b ) n -or-(CR a R b ) n O-.
80. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y2 represents -CR a =CR a -, -CR a =CR b -CR a R b - or -CR a R b -CR a =CR b -.
81. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: Y 2 It represents pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or triazolyl.
82. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: -Y1-Y2- represents -CR a =CR a -, -CR a R b CR a =CR b -.
83. The compound according to claim 46, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: -Y1-Y2- means -CR a R b -NR a C(O)-.
84. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: -Y1-Y2- means- 85. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, wherein: R L Display-NHS(O)2CH2CH2OH, -NHS(O)2CH2CH3, -NHS(O)2CH3.
86. A compound having the following formula (I-3), a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, in, X 1 Represents CR W1 or N; Among them, X 2 Represents CR W2 or N; Among them, X 3 Represents CR W3 or N; Among them, X 4 Represents CR W4 or N; Among them, X 5 Represents CR W5 or N; Among them, X 6 Represents CR W6 or N; Among them, X 7 Represents CR W7 or N; Among them, R W1 , R W2 , R W3 , R W4 , R W5 , R W6 , R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Alternatively, the chemical bond between X2 and X3 can also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; Or the chemical bond between X5, X6 or X6, X7 can be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring; Wherein, R represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3; Wherein, X represents CR9R9', O, NR a ; Wherein, R1, R1', R2, R2', R3, R3', R4, R4', R5, R5', R6, R6', R7, R7', R9, R9' each independently represents hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl; Or R1, R1' pair, R2, R2' pair, R3, R3' pair, R4, R4' pair, R5, R5' pair, R6, R6' pair, R7, R7' pair, R9, R9' pair together with the carbon atom connected thereto form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, 2 heteroatoms selected from O, S, N, Se; and further, the ring may also be selected from 0, 1, 2 or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -OR a or substituted with an oxo substituent; Among them, Y 1 Indicates -(CR a R b ) m -;Y 2 Indicates -(CR a R b ) n -; Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、PO(R a R b ),-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -, —C≡C—, 5-6 Genso Hoji, replaced by; Among them, R L Indicates L2-R M ; Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2.-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-; Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted with C1-C6 alkyl or C3-C6 cycloalkyl; Or, L2-R M express Wherein, m and n each independently represent an integer from 0 to 10; Among them, R a , R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a , R b Together with the atoms to which they are connected, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S, Se and N.
87. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X1 represents CH or N, preferably CH.
88. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X2 represents CH or N, preferably CH.
89. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X3 represents CH or N, preferably CH.
90. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X2 and X3 is fused with ring B to form a group with the following structure:
91. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X4 represents CH or N, preferably N.
92. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X5 means CR W5 or N, where R W5 It represents hydrogen, halogen, -CH3O, -CF3, -CHF2, CH2F, NH2, -N(CH3)2, -CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
93. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X6 means CR W6 or N, where R W6 It represents hydrogen, halogen, -CH3O, -CF3, -CHF2, -CH2F, -NH2, -N(CH3)2, -CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
94. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X7 represents CH or N, preferably N.
95. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X5 and X6 is fused with ring A to form a group with the following structure:
96. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X6 and X7 is fused with ring A to form a group with the following structure:
97. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: L1 represents -C(O)NR a -、-NR a C(O)-, 98. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer or tautomer thereof, wherein L1 represents -C(O)NH-.
99. The compound according to claim 86, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein L1 represents 100. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y1 means -(CR a R b ) m -.
101. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y1 represents -NR-C(=O)-, -OC(=O)-, or -C(=O)O-.
102. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y1 represents -O(CR a R b ) m -or-(CR a R b ) m O-.
103. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y1 means -CR a =CR a -or-CR a R b -CR a =CR b -.
104. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y2 means -(CR a R b ) n -.
105. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y2 stands for -NR a -C(=O)-.
106. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y2 represents -O(CR a R b ) n -or-(CR a R b ) n O-.
107. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y2 represents -CR a =CR a -, -CR a =CR b -CR a R b - or -CR a R b -CR a =CR b -.
108. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y 2 It represents pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or triazolyl.
109. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: -Y1-Y2- represents -CR a =CR a -,-CR a R b CR a =CR b -.
110. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: -Y1-Y2- means -CR a R b -NR a C(O)-.
111. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: -Y1-Y2- indicates 112. The compound according to claim 86, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: R L Display-NHS(O)2CH2CH2OH, -NHS(O)2CH2CH3, -NHS(O)2CH3.
113. A compound having the structure of formula I-1-1 or formula I-1-2, or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, in, X 1 Represents CR W1 or N; Among them, X 2 Represents CR W2 or N; Among them, X 3 Represents CR W3 or N; Among them, X 4 Represents CR W4 or N; Among them, X 5 Represents CR W5 or N; Among them, X 6 Represents CR W6 or N; Among them, X 7 Represents CR W7 or N; Among them, R W1 , R W2 , R W3 , R W4 , R W5 , R W6 , R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Alternatively, the chemical bond between X2 and X3 can also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; Or the chemical bond between X5, X6 or X6, X7 can be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; Wherein, R represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3; Wherein, X represents CR9R9', O, NR a ; wherein R1, R1', R2, R2', R3, R3', R4, R4', R5, R5', R6, R6', R7, R7', R9, R9' each independently represents hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl; Or R1, R1' pair, R2, R2' pair, R3, R3' pair, R4, R4' pair, R5, R5' pair, R6, R6' pair, R7, R7' pair, R9, R9' pair together with the carbon atom connected thereto form a 3-6 membered (hetero) ring, wherein the ring may arbitrarily contain 0, 1, 2 heteroatoms selected from O, S, N, Se; and further, the ring may also be selected from 0, 1, 2 or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, OR a or substituted with an oxo substituent; Among them, R L Indicates L2-R M ; Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2.-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-; Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted with C1-C6 alkyl or C3-C6 (hetero)cycloalkyl; Or, L2-R M express Wherein, m and n each independently represent an integer from 0 to 10; Among them, R a , R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a , R b Together with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated (hetero) ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S, Se and N.
114. The compound according to claim 113, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X1 represents CH or N, preferably CH.
115. The compound according to claim 113, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X2 represents CH or N, preferably CH.
116. The compound according to claim 113, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X3 represents CH or N, preferably CH.
117. The compound according to claim 113, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X2 and X3 is fused with ring B to form a group with the following structure:
118. The compound according to claim 113, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X4 represents CH or N, preferably N.
119. The compound according to claim 113, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X5 means CR W5 or N, where R W5 It represents hydrogen, halogen, -CH3O, -CF3, -CHF2, -CH2F, -NH2, -N(CH3)2, -CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
120. The compound according to claim 113, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X6 means CR W6 or N, where R W6 It represents hydrogen, halogen, -CH3O, -CF3, -CHF2, -CH2F, -NH2, -N(CH3)2, -CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
121. The compound according to claim 113, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X7 represents CH or N, preferably N.
122. The compound according to claim 113, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X5 and X6 is fused with ring A to form a group with the following structure:
123. The compound according to claim 113, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X6 and X7 is fused with ring A to form a group with the following structure:
124. The compound according to claim 113, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: L1 represents -C(O)NR a -、-NR a C(O)-, 125. The compound according to claim 113, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: R L Display-NHS(O)2CH2CH2OH, -NHS(O)2CH2CH3, -NHS(O)2CH3.
126. A compound having the structure of formula I-1-3, a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, or a tautomer, in, X 1 Represents CR W1 or N; Among them, X 2 Represents CR W2 or N; Among them, X 3 Represents CR W3 or N; Among them, X 4 Represents CR W4 or N; Among them, X 5 Represents CR W5 or N; Among them, X 6 Represents CR W6 or N; Among them, X 7 Represents CR W7 or N; Among them, X8 represents CR W8 or N; Among them, X9 represents CR W9 or N; Among them, X 10 Represents CR W10 or N; Among them, X 11 Represents CR W11 or N; Among them, R W1 , R W2 , R W3 , R W4 , R W5 , R W6 , R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Among them, R W8 , R W9 , R W10 , R W11 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Alternatively, the chemical bond between X2 and X3 can also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; Or the chemical bond between X5, X6 or X6, X7 can be fused with ring A to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring; Wherein, Y represents absence, -CH2-, -O-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups: or Cy3; Wherein, * indicates the site connected to ring A; the wavy line indicates the site connected to Y2; Wherein, Cy3 each independently represents a substituted or unsubstituted 3-10-membered saturated or unsaturated cycloalkyl, 6-10-membered saturated or unsaturated spirocycloalkyl, 6-10-membered saturated or unsaturated bridged cycloalkyl, 6-10-membered saturated or unsaturated condensed cycloalkyl, 3-10-membered saturated or unsaturated heterocycloalkyl, 6-10-membered saturated or unsaturated spiroheterocycloalkyl, 6-10-membered saturated or unsaturated bridged heterocycloalkyl, 6-10-membered condensed heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, wherein the substituents are selected from each independently representing hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Among them, Y 1 Indicates -(CR a R b ) m -;Y 2 Indicates -(CR a R b ) n -; Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、PO(R a R b ),-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -, —C≡C-, 5-6 Genso Hoji, replaced by; Among them, R L Indicates L2-R M ; Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2.-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-; Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted with C1-C6 alkyl or C3-C6 cycloalkyl; Or, L2-R M express Wherein, m and n each independently represent an integer from 0 to 10; Among them, R a , R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a , R b Together with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S and N.
127. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X1 represents CH or N, preferably CH.
128. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X2 represents CH or N, preferably CH.
129. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X3 represents CH or N, preferably CH.
130. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X2 and X3 is fused with ring B to form a group with the following structure:
131. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X4 represents CH or N, preferably N.
132. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X5 means CR W5 or N, where R W5 It represents hydrogen, halogen, CH3O, CF3, CHF2, CH2F, NH2, -N(CH3)2, CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
133. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X6 means CR W6 or N, where R W6 It represents hydrogen, halogen, CH3O, CF3, CHF2, CH2F, NH2, -N(CH3)2, CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
134. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X7 represents CH or N, preferably N.
135. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X5 and X6 is fused with ring A to form a group with the following structure:
136. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X6 and X7 is fused with ring A to form a group with the following structure:
137. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: Y represents the following groups: absent, -CH2-, -O-, -Se-, -NR a -、-C(O)NR a 、-NR a C(O)- or the following groups:
138. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y represents -O- or -NH-.
139. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y stands for 140. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y stands for 141. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: Y represents Cy3, wherein Cy3 represents the following group: Among them, when When it represents a double bond, G means it does not exist; When it represents a single bond, G represents hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, -C(O)CH3; wherein G1, G1', G2, G2', G3, G3', G4, G4' each independently represents hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl; Or G1, G1' pair, G2, G2' pair, G3, G3' pair, G4, G4' pair together with the carbon atom connected thereto form a 3-6 membered (hetero) ring, wherein the ring may contain 0, 1, 2 heteroatoms selected from O, S, N, Se; and further, the ring may also be selected from 0, 1, 2 or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, OR a or substituted with an oxo substituent; Where W2 represents -(CR i R j ) p -; Among them, R i , R j Each independently represents hydrogen or C1-C6 alkyl; Where p represents 1 or 2; Among them, X 12 Represents CR W12 or N; Among them, X 13 Represents CR W13 or N; Among them, X 14 Represents CR W14 or N; Among them, X 15 Represents CR W15 or N; Among them, R W12 , R W13 , R W14 , R W15 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b .
142. The compound according to claim 141, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 12 Indicates CH or N.
143. The compound according to claim 141, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 13 Indicates CH or N.
144. The compound according to claim 141, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 14 Indicates CH or N.
145. The compound according to claim 141, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X 15 Indicates CH or N.
146. The compound according to claim 141, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: G1, G1', G2, G2', G3, G3', G4 and G4' each independently represent hydrogen.
147. The compound according to claim 141, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: W2 represents CH2 or CH2CH2.
148. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: L1 represents -C(O)NR a -、-NR a C(O)-, 149. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer or tautomer thereof, wherein L1 represents -C(O)NH-.
150. The compound according to claim 126, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein L1 represents 151. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y1 means -(CR a R b ) m -.
152. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y1 represents -NR-C(=O)-, -OC(=O)-, or -C(=O)O-.
153. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y1 represents -O(CR a R b ) m -or-(CR a R b ) m O-.
154. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y1 means -CR a =CR a -or-CR a R b -CR a =CR b -.
155. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y2 means -(CR a R b ) n -.
156. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y2 stands for -NR a -C(=O)-.
157. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y2 represents -O(CR a R b ) n -or-(CR a R b ) n O-.
158. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y2 represents -CR a =CR a -, -CR a =CR b -CR a R b - or -CR a R b -CR a =CR b -.
159. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y 2 It represents pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or triazolyl.
160. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: -Y1-Y2- represents -CR a =CR a -,-CR a R b CR a =CR b -.
161. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: -Y1-Y2- means -CR a R b -NR a C(O)-.
162. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: -Y1-Y2- means 163. The compound according to claim 126, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: R L Display-NHS(O)2CH2CH2OH, -NHS(O)2CH2CH3, -NHS(O)2CH3.
164. A compound having the structure of formula I-1-4, a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope isomer, a tautomer, in, X 1 Represents CR W1 or N; Among them, X 2 Represents CR W2 or N; Among them, X 3 Represents CR W3 or N; Among them, R W1 , R W2 , R W3 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Alternatively, the chemical bond between X2 and X3 can also be fused with ring B to form a 4-8 membered saturated or unsaturated (hetero) ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, N, and Se; and the ring can also be selected from 0 to 3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, oxo, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;- C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; Wherein, Cy1 represents a substituted or unsubstituted 3-10-membered saturated or unsaturated cycloalkyl, a 6-10-membered saturated or unsaturated spirocycloalkyl, a 6-10-membered saturated or unsaturated bridged cycloalkyl, a 6-10-membered saturated or unsaturated condensed cycloalkyl, a 3-10-membered saturated or unsaturated heterocycloalkyl, a 6-10-membered saturated or unsaturated spiroheterocycloalkyl, a 6-10-membered saturated or unsaturated bridged heterocycloalkyl, a 6-10-membered condensed heterocycloalkyl, a 6-10-membered aryl, or a 5-10-membered heteroaryl, wherein each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; Wherein, L1 represents -C(O)NR a -、-NR a C(O)- or 5-6 membered heteroaromatic ring; Among them, Y 1 Indicates -(CR a R b ) m -;Y 2 Indicates -(CR a R b ) n -; Among them, arbitrarily-CR a R b - can be -O-, -S-, -Se-, -NR a -、-NR a SO2-、-NR a C(=O)-, -C(=O)NR a -, -OC(=O)-, -C(=O)O-, -SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、PO(R a R b ),-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、-C≡C-、 5-6 Genso Hoji, replaced by; Among them, R L Indicates L2-R M ; Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2.-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-; Among them, Cy2 represents or Among them, * indicates the site connected to Y2, and the wavy line indicates the site connected to L1; Among them, X 5 Represents CR W5 or N; Among them, X 6 Represents CR W6 or N; Among them, X 7 Represents CR W7 or N; Among them, R W5 , R W6 , R W7 Each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b ; Or the chemical bond between X5, X6 or X6, X7 can be fused with ring A to form a 4-8 membered saturated or unsaturated ring, a 4-8 membered saturated or unsaturated heterocyclic ring, the ring can arbitrarily contain 0, 1, 2 heteroatoms selected from O, S, N, Se; and the ring can also be selected from 0-3 of the following substituents: each independently represents hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl C1-C 10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, deuterated C1-C 10 Alkyl, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkyl, halogenated C2-C 10 Alkenyl, halogenated C2-C 10 Alkynyl, halo C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a 、-SO3R a 、-SO2R a 、-S(O)R a 、-O-halogenated C1-C 10 Alkyl, -SR a 、-C(O)OR a 、-C(O)R a 、-OC(O)R a 、-NR a C(O)R b 、-C(O)NR a R b 、-NR a C(O)OR b 、-OC(O)NR a R b 、-OC(O)OR a 、-SF5、-PO(R a R b )、-P(R a R b ) or -NR a R b ;-C0-C 10 Alkyl OR a 、-C0-C 10 Alkyl SO3R a 、-C0-C 10 Alkyl SO2R a 、-C0-C 10 AlkylS(O)R a 、-C0-C 10 Alkyl O-halogenated C1-C 10 Alkyl, -C0-C 10 Alkyl SR a 、-C0-C 10 Alkyl C(O)OR a 、-C0-C 10 Alkyl C(O)R a 、-C0-C 10 AlkylOC(O)R a 、C0-C 10 Alkyl-NR a C(O)R b 、-C0-C 10 Alkyl C(O)NR a R b 、-C0-C 10 Alkyl NR a C(O)OR b 、-C0-C 10 Alkyl OC(O)NR a R b 、-C0-C 10 Alkyl OC(O)OR a 、-C0-C 10 Alkyl SF5, -C0-C 10 Alkyl PO(R a R b ),-C0-C 10 Alkyl P(R a R b ) or -C0-C 10 Alkyl NR a R b substituted by a substituent; wherein G1, G1', G2, G2', G3, G3' each independently represents hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl; Or G1, G1' pair, G2, G2' pair, G3, G3' pair together with the carbon atom connected thereto form a 3-6 membered ring, or a 3-6 membered heterocyclic ring, wherein the ring may arbitrarily contain 0, 1, 2 heteroatoms selected from O, S, N, Se; and further, the ring may also be selected from 0, 1, 2 or 3 halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, OR a or substituted with an oxo substituent; Among them, R M represents 0-3 selected from halogen, C1-C6 alkyl, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted with C1-C6 alkyl or C3-C6 (hetero)cycloalkyl; Or, L2-R M express Wherein, m and n each independently represent an integer from 0 to 10; Among them, R a , R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a , R b Together with the atoms to which they are connected, they form a 3-6 membered saturated or unsaturated ring, or a 3-6 membered saturated or unsaturated heterocyclic ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S, Se and N.
165. The compound according to claim 164, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X1 represents CH or N, preferably CH.
166. The compound according to claim 164, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X2 represents CH or N, preferably CH.
167. The compound according to claim 164, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X3 represents CH or N, preferably CH.
168. The compound according to claim 164, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X2 and X3 is fused with ring B to form a group with the following structure:
169. The compound according to claim 164, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X5 means CR W5 or N, where R W5 It represents hydrogen, halogen, CH3O, CF3, CHF2, CH2F, NH2, -N(CH3)2, CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
170. The compound according to claim 164, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: X6 means CR W6 or N, where R W6 It represents hydrogen, halogen, CH3O, CF3, CHF2, CH2F, NH2, -N(CH3)2, CN, -OH, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -C(O)NH2.
171. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: X7 represents CH or N, preferably N.
172. The compound according to claim 164, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof, wherein: The chemical bond between X5 and X6 is fused with ring A to form a group with the following structure:
173. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: The chemical bond between X6 and X7 is fused with ring A to form a group with the following structure:
174. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: L1 represents -C(O)NR a -、-NR a C(O)-, 175. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, L1 represents -C(O)NH-.
176. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, L1 represents 177. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y1 means -(CR a R b ) m -.
178. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y1 represents -NR-C(=O)-, -OC(=O)-, or -C(=O)O-.
179. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y1 represents -O(CR a R b ) m -or-(CR a R b ) m O-.
180. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y1 means -CR a =CR a -or-CR a R b -CR a =CR b -.
181. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y2 means -(CR a R b ) n -.
182. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y2 stands for -NR a -C(=O)-.
183. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y2 represents -O(CR a R b ) n -or-(CR a R b ) n O-.
184. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y2 represents -CR a =CR a -, -CR a =CR b -CR a R b - or -CR a R b -CR a =CR b -.
185. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: Y 2 It represents pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or triazolyl.
186. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: -Y1-Y2- represents -CR a =CR a -, -CR a R b CR a =CR b -.
187. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: -Y1-Y2- means -CR a R b -NR a C(O)-.
188. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: -Y1-Y2- indicates 189. The compound according to claim 164, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, tautomer, wherein: R L Display-NHS(O)2CH2CH2OH, -NHS(O)2CH2CH3, -NHS(O)2CH3.
190. A compound having the following structure:
191. A pharmaceutical composition comprising the compound described in any one of claims 1-162, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, or tautomer thereof.
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