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CN119948021A - A nitrogen-containing heterocyclic derivative and its composition and pharmaceutical application - Google Patents

A nitrogen-containing heterocyclic derivative and its composition and pharmaceutical application Download PDF

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Publication number
CN119948021A
CN119948021A CN202380046391.8A CN202380046391A CN119948021A CN 119948021 A CN119948021 A CN 119948021A CN 202380046391 A CN202380046391 A CN 202380046391A CN 119948021 A CN119948021 A CN 119948021A
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alkyl
group
membered
substituted
cycloalkyl
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张晨
廖雨亭
王健民
高秋
石荣华
邹思佳
陈泉龙
唐平明
余彦
李瑶
严庞科
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Tibet Haisike Pharmaceutical Co ltd
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Tibet Haisike Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体，以及在AR相关疾病如癌症中的用途。B‑L‑K(I)。A compound of general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates thereof, and use thereof in AR-related diseases such as cancer. B-L-K(I).

Description

Nitrogen-containing heterocyclic derivative, composition thereof and pharmaceutical application thereof Technical Field
The present invention relates to a compound of general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, as well as intermediates and preparation methods thereof, and uses thereof in AR related diseases such as cancer diseases.
Background
Androgen receptor (Androgen receptor, AR) is a hormone nuclear receptor, structurally divided into an N-terminal activation region (NTD), a DNA binding region (DBD) and a ligand binding region (LTD), capable of modulating gene expression that induces prostate cancer, and thus, inhibition of androgen receptor is an effective method for treating prostate cancer. Androgen receptor inhibitors such as enzalutamide, bicalutamide and the like which are currently marketed mainly exert an inhibitory effect through the action with a ligand binding domain (LTD) of an androgen receptor, but a drug resistance phenomenon caused by androgen receptor cleavage mutants (Androgen receptor SPLICE VARIANTS, AR-Vs) in which LTD fragments are deleted occurs in some patients during the course of treatment. Preclinical studies indicate that androgen receptor cleavage mutants can accelerate the progression of enzalutamide resistant prostate cancer, and how to solve the drug resistance problem becomes a concern of clinical medicine.
The small molecule degradation agent is a medicine for carrying out directional degradation on target protein by utilizing an organism ubiquitin-proteinase system (UPS). The small molecule degrading agent can target the target point which is difficult to be formed into medicine by virtue of a unique catalytic mechanism, solves the medicine resistance problem, and is a great hot spot in the medicine research and development fields of tumors, autoimmune diseases and the like at present.
PROTAC (proteolysis TARGETING CHIMERA) is a bifunctional compound capable of simultaneously combining a target protein and E3 ubiquitin ligase, and the compound can be recognized by a proteasome of a cell to cause degradation of the target protein, so that the content of the target protein in the cell can be effectively reduced. By introducing ligands capable of binding to different targeting proteins at PROTAC molecules, the PROTAC technology is enabled to be applied to the treatment of various diseases, and has received wide attention in recent years.
Molecular glue (molecular glue) is a class of small molecules that promote the contact of a target protein with the E3 ubiquitin ligase, inducing interactions between the two, and thus leading to degradation of the target protein. From a functional point of view, molecular gums promote strong interactions between the target protein and the E3 ubiquitin ligase by filling the gap between them, enhancing their binding interface (nat. Commun.,2022,13,815). Compared with the traditional small molecule inhibitor, the molecular gel has the advantages of driving the degradation of target protein in a catalytic mode and no need of having a binding pocket on the target protein, and has the potential of acting on a non-patent drug target.
Accordingly, there is a need to develop novel androgen receptor cleavage mutant (Androgen receptor SPLICE VARIANTS, AR-Vs, particularly AR-V7 mutant) inhibitors and PROTAC or other small molecule degradant drugs of E3 ubiquitin ligase for the treatment of neoplastic diseases associated with androgen receptor cleavage mutants.
Disclosure of Invention
The invention aims to provide a compound which has novel structure, good drug effect, high bioavailability, safer property and can inhibit and degrade AR or/and AR-Vs (especially AR-V7) and is used for treating diseases related to AR such as prostate cancer.
The invention provides a compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, wherein the compound is selected from compounds shown in a general formula (I),
B-L-K (I);
In certain embodiments, L is selected from a bond or-C 1-50 hydrocarbyl-, of which 1 to 20 methylene units are optionally replaced by-Ak-, -Cy-;
In certain embodiments, L is selected from a bond or-C 1-20 hydrocarbyl-, of which 1 to 20 methylene units are optionally replaced by-Ak-, -Cy-;
In certain embodiments, L is selected from a bond or-C 1-10 hydrocarbyl-, of which 1 to 10 (e.g., 1,2,3,4, 5, 6, 7, 8, 9, or 10) methylene units are optionally replaced by-Ak-, -Cy-;
In certain embodiments, each-Ak-is independently selected from Ak1, ak2, ak3, ak4, or Ak5;
In certain embodiments, each-Ak-is independently selected from -(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2- or a bond, said-CH 2 -, -ch=ch-optionally substituted with 1 to 2 substituents selected from halogen, OH, CN, NH 2、C1-6 alkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl;
In certain embodiments, each-Cy-is independently selected from Cy1, cy2, cy3, cy4, or Cy5;
In certain embodiments, each-Cy-is independently selected from a bond or an optionally substituted one of a 4-8 membered heteromonocyclic group, 4-10 membered heteromonocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, 3-7 membered monocyclic alkyl group, 4-10 membered heterocycloalkyl group, 5-12 membered spirocycloalkyl group, 5-10 membered bridged cycloalkyl group, benzoC 4-6 carbocyclyl group, benzo4-6 membered heterocyclic group, 5-10 membered heteroaryl group, or 6-10 membered aryl group, when substituted, substituted with 1 to 4R L2, said heterocyclic group, heteroaryl group, heteromonocyclic group, heterobicyclic group, or heterobridged cyclic group containing 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally substituted with 1 or 2=O;
In certain embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
In certain embodiments, L is selected from the group consisting of a bond 、-Ak1-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-;
In certain embodiments, L is selected from bond 、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Cy1-Ak1-、-Ak1-Cy2-Ak2-、-Cy1-Cy2-Cy3-、-Cy2-Cy3-、-Cy1-Ak1-Cy2-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Ak1-、-Cy1-、-Ak1-Cy2-Ak2-Ak3-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-NHCO-(CH2)s1-,s1 is selected from 0, 1, 2,3, 4, 5,6, or 7;
In certain embodiments, L is selected from the group consisting of a bond, a group shown in Table L-1, table L-2, table L-3, the left side of the group being attached to B;
In certain embodiments, L is selected from a bond or a group shown in Table L-2, the left side of which is attached to B;
In certain embodiments, L is selected from the group shown in Table L-3, the left side of which is attached to B;
In certain embodiments, L is selected from
In certain embodiments, cy1 is selected from one of the following optionally substituted with 1 to 4R L2, 4-12 membered nitrogen containing heterocyclyl, preferably 4-7 membered nitrogen containing heteromonocyclic group, 4-10 membered nitrogen containing heterobicyclic group, 5-12 membered nitrogen containing heterospirocyclic group, 7-10 membered nitrogen containing heterobridged cyclic group, said nitrogen containing heterocyclyl containing 1 to 4 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatoms are selected from S;
In certain embodiments, cy1 is selected from 4-6 membered nitrogen containing heterocycles optionally substituted with 1 to 4R L2;
In certain embodiments, L is selected from
Table L-1L groups
TABLE L-2
TABLE L-3
In certain embodiments, ak1, ak2, ak3, ak4, ak5 are each independently selected from -(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-(C≡C)q- or a bond, said-CH 2 -, -ch=ch-optionally substituted with 1 to 2 (e.g., 1 or 2) substituents selected from halogen, OH, CN, NH 2、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl;
In certain embodiments, ak1, ak2, ak3, ak4, ak5 are each independently selected from -(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-C≡C- or a bond, said-CH 2 -, -ch=ch-optionally substituted with 1 to 2 substituents selected from F, cl, br, I, OH, CN, NH 2、CF3, hydroxymethyl, methyl, ethyl, methoxy or ethoxy;
In certain embodiments, ak1, ak2, ak3, ak4, ak5 are each independently selected from -O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-SCH2-、-CH2S-、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、-C(＝O)NH- or-NHC (=o) -;
In certain embodiments, ak1, ak2, ak3, ak4 are each independently selected from -C(＝O)-、-O-、NH、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-NHCO-;
In certain embodiments, each R L is independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, each R L is independently selected from H or C 1-6 alkyl;
In certain embodiments, each R L is independently selected from H or C 1-4 alkyl;
in certain embodiments, R L are each independently selected from H, methyl, or ethyl;
In certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from one of a bond or an optionally substituted heterocyclyl, heteroaryl, heteromonocyclic, heterobicyclic, 5-12 membered heterospirocyclic, 7-10 membered heterobridged cyclic, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 membered bridged cycloalkyl, benzoC 4-6 carbocyclyl, benzo4-6 membered heterocyclyl, 5-10 membered heteroaryl, or 6-10 membered aryl, when substituted, substituted with 1 to 4R L2, the heterocyclyl, heteroaryl, heteromonocyclic, heterobicyclic, or heterobridged cyclic containing 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally substituted with 1 or 2 = O;
In certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered nitrogen containing heteromonocyclic group, a 4-10 membered nitrogen containing heteromonocyclic group, a 5-12 membered nitrogen containing heterospirocyclic group, a 7-10 membered nitrogen containing heterobridged cyclic group, a 3-7 membered monocyclic alkyl group, a 4-10 membered cycloalkyl group, a 5-12 membered spirocyclic group, a 5-10 membered bridged cycloalkyl group, a 5-10 membered heteroaryl group, or a 6-10 membered aryl group, said heteromonocyclic group, heterocyclic group, cycloalkyl group, aryl group, or heteroaryl group being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, COOH, CN, NH 2、＝O、C1-4 alkyl groups, halogen substituted C 1-4 alkyl groups, hydroxy substituted C 1-4 alkyl groups, or C 1-4 alkoxy groups, said heteromonocyclic group, heterocyclic group, or heteroaryl group containing 1 to 4 heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatoms are selected from S;
In certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azehexenyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazaheptanyl, pyridinyl, phenyl, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclopropyl, cyclopropyl-spirobutyl, cyclopropyl-spirocyclopentyl, cyclopropyl-spirocyclohexyl, cyclobutyl-spirobutyl, cyclobutyl-spiropentyl, cyclobutyl-spirocyclohexyl, cyclopentyl-spiropentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-azetidinyl, cyclopropyl-pyrrolidyl cyclopropyl-piperidinyl, cyclobutyl-azetidinyl, cyclobutyl-pyrrolidinyl, cyclobutyl-piperidinyl, cyclopentyl-azetidinyl, cyclopentyl-pyrrolidinyl, cyclopentyl-piperidinyl, cyclohexyl-azetidinyl, azetidinyl-piperidinyl pyrrolidinyl azetidinyl, piperidinyl azetidinyl, cyclobutyl spiroazetidinyl, cyclobutyl spiropyrrolidinyl, cyclobutyl spiropiperidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, a cyclohexylspiroazetidinyl group, a cyclohexylspiropyrrolidinyl group, a cyclohexylspiropiperidinyl group azetidinyl spiroazetidinyl, azetidinyl spiropyrrolidinyl azetidinyl spiropiperidinyl pyrrolidinyl spiroazetidinyl pyrrolidinyl spiropyrrolidinyl pyrrolidinyl spiro pyrrolidinyl group, When substituted, are substituted with 1 to 4R L2;
In certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from the group consisting of triazolyl optionally substituted with 1 substituent selected from F, cl, br, I, OH, NH 2、COOH、CN、＝O、C1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, or C 1-4 alkoxy;
In certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, is substituted with 1 substituent selected from F, CF 3, methyl, methoxy, =o, hydroxymethyl, COOH, CN, OH, or NH 2;
In certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: When substituted, are substituted with 1 to 4R L2;
In certain embodiments, each R L2 is independently selected from F, cl, br, I, OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -O-C 1-4 alkylene-O-C 1-4 alkyl, -O-C 1-4 alkylene-O-C 3-10 carbocyclyl, -C 1-4 alkylene-O-C 1-4 alkylene-O-C 1-4 alkyl, -C 1-4 alkylene-O-C 1-4 alkylene-O-C 3-10 carbocyclyl, -O-C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-4 to 10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4 groups selected from F, cl, br, I. OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, halogen substituted C 1-4 alkyl, Hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, each R L2 is independently selected from F, cl, br, I, OH, NH 2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -O-C 1-2 alkylene-O-C 1-2 alkyl, -O-C 1-2 alkylene-O-C 3-6 carbocyclyl, -C 1-2 alkylene-O-C 1-2 alkylene-O-C 1-2 alkyl, -C 1-2 alkylene-O-C 1-2 alkylene-O-C 3-6 carbocyclyl, -O-C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6 membered heterocyclyl, said alkyl, Alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl optionally substituted with 1 to 4C 1-4 alkyl groups selected from F, cl, br, I, OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, halogen, Hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, each R L2 is independently selected from F, cl, br, = O, COOH, CN, NHCH 3、N(CH3)2、OH、NH2, or one of optionally substituted methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclopropyl, -OCH 2CH2 -O-methyl, -OCH 2CH2 -O-cyclopropyl, -CH 2OCH2CH2 -O-methyl, -CH 2OCH2CH2 -O-cyclopropyl, when substituted, substituted with 1 to 4 substituents selected from F, CHF 2、CF3、OCHF2、OCF3, methyl, methoxy, = O, CH 2OH、COOH、CN、NHCH3、N(CH3)2、OH、NH2;
in certain embodiments, cy1, cy2, cy3 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, is substituted with 1 to 4 substituents selected from F, CF 3, OH, methyl, methoxy, =o, hydroxymethyl, COOH, CN, or NH 2;
In certain embodiments, B is selected from
In certain embodiments, B 1 is selected from C 3-20 carbocyclyl or a 4-20 membered heterocycle, optionally substituted with 1 to 4R b1, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 2 is selected from C 3-20 carbocyclyl or a 4-20 membered heterocycle, optionally substituted with 1 to 4R b2, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 3 is selected from C 3-20 carbocyclyl or a 4-20 membered heterocycle, optionally substituted with 1 to 4R b3, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, B 1 is selected from C 3-14 carbocyclyl or a 4-14 membered heterocycle, optionally substituted with 1 to 4R b1, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 2 is selected from C 3-14 carbocyclyl or a 4-14 membered heterocycle, optionally substituted with 1 to 4R b2, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 3 is selected from C 3-14 carbocyclyl or a 4-14 membered heterocycle, optionally substituted with 1 to 4R b3, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 3 is selected from a bond;
In certain embodiments, L 1 is selected from a bond or
In certain embodiments, L 2 is selected from a bond or
In certain embodiments, Y 1、Y2、Y3、Y4 is each independently selected from the group consisting of a bond, O, S, NR b5a;
In certain embodiments, each Q 1、Q2、Q3、Q4 is independently selected from
In certain embodiments, each Q 1、Q2、Q3、Q4 is independently selected from-CH 2 -;
In certain embodiments, v 1、v2、v3、v4 is each independently selected from 0, 1,2,3, or 4;
In certain embodiments, each L 1、L2 is independently selected from the group consisting of bond, -CH 2-、-OCH2-、-SCH2-、-NHCH2 -, -O-, -S-, -NH-;
In certain embodiments, B is selected from V is selected from a bond or L 1,L1、L2 is not a bond;
In certain embodiments, B is selected from
In certain embodiments, B is selected from
In certain embodiments, B is selected from
In certain embodiments, B is selected from
In certain embodiments, V is selected from the group consisting of a bond 、O、S、NRb5a、NRb5a-(Q2)v2-、-(Q2)v2-NRb5a、O-(Q2)v2-、-(Q2)v2-O、-(Q2)v2-;
In certain embodiments, V is selected from the group consisting of a bond, O, S, NR b5a、NRb5a-C1-4 alkylene, C 1-4 alkylene-NR b5a、O-C1-4 alkylene, C 1-4 alkylene-O, C 1-4 alkylene, said alkylene being optionally substituted with 1 to 4R b4 or R b5;
In certain embodiments, V is selected from the group consisting of a bond 、NH、NHC(CH3)2CH2、NHCH2C(CH3)2、CH2CH2、C(CH3)2CH2、CH2C(CH3)2、NHCH2CH2、NHCH2、OCH2、CH2NH、CH2O、NHC(CH3)2、OC(CH3)2、C(CH3)2NH、C(CH3)2O、N(CH3)CH2、N(CH3)C(CH3)2、C(CH3)2N(CH3)、CH2N(CH3)、N(CH3)、O、S;
In certain embodiments, v 2、v4 is each independently selected from 1,2,3, or 4;
In certain embodiments, Y 1、Y3 is each independently selected from the group consisting of a bond, O, S, NR b5a;
In certain embodiments, Y 2、Y4 is each independently selected from O, S, NR b5a;
In certain embodiments, Y 1、Y3 is each independently selected from the group consisting of a bond, O, S, NH;
In certain embodiments, Y 2、Y4 is each independently selected from O, S, NH;
In certain embodiments, R b5a is selected from H, C 1-4 alkyl, - (CH 2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, =o, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R b5a is selected from H, C 1-4 alkyl, - (CH 2)n-Rb22), said-CH 2 -, alkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, =o, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, or 4-8 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b5a is selected from H, methyl, ethyl, cyclopropyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、N(CH3)、CN、CF3、COOH、C1-4 alkyl, C 1-4 alkoxy;
in certain embodiments, R b5a is selected from H, CF 3、CHF2、CH2F、CH2OH、CH2CN、CH2NH2, methyl, ethyl, cyclopropyl;
In certain embodiments, B is selected from
In certain embodiments, B is selected from
In certain embodiments, B is selected from
In certain embodiments, B is selected from
In certain embodiments, b1, b2, b3 are each independently selected from 0, 1,2,3, 4;
in certain embodiments, b1, b2, b3 are each independently selected from 0, 1, 2;
In certain embodiments, B 1 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterobicyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, C 4-7 monocycloalkyl, C 6-14 and cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or 6-14 membered aryl, said B 1 being optionally substituted with 1 to 4R b2, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, B 3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterobicyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, C 4-7 monocycloalkyl, C 6-14 and cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or 6-14 membered aryl, said B 3 being optionally substituted with 1 to 4R b3, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 2 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterobicyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, C 4-7 monocycloalkyl, C 6-14 and cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or 6-14 membered aryl, said B 2 being optionally substituted with 1 to 4R b2, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, B 1 is selected from 6-7 membered heteromonocyclic group, 5-14 membered heterobicyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, C 6-8 Shan Tanhuan group, C 6-14 and cycloalkyl group, C 6-12 spirocycloalkyl group, C 5-12 bridged cycloalkyl group, benzoc 3-10 carbocyclyl group, benzo3 to 10 membered heterocyclyl group, C 12-18 tri-fused cyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group, or 6-14 membered aryl group, said B 1 being optionally substituted with 1 to 4R b2, said heteroaryl or heterocyclyl group containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, B 3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterobicyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, C 3-8 Shan Tanhuan group, C 6-14 and cycloalkyl group, C 6-12 spirocycloalkyl group, C 5-12 bridged cycloalkyl group, benzoc 3-10 carbocyclyl group, benzo3 to 10 membered heterocyclyl group, C 12-18 tri-fused cyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group, or 6-14 membered aryl group, said B 3 being optionally substituted with 1 to 4R b3, said heteroaryl or heterocyclyl group containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 2 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterobicyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, C 3-8 Shan Tanhuan group, C 6-14 and cycloalkyl group, C 6-12 spirocycloalkyl group, C 5-12 bridged cycloalkyl group, benzoc 3-10 carbocyclyl group, benzo3 to 10 membered heterocyclyl group, C 12-18 tri-fused cyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group, or 6-14 membered aryl group, said B 2 being optionally substituted with 1 to 4R b2, said heteroaryl or heterocyclyl group containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 1 is selected from one of a substituted or unsubstituted cyclohexyl, phenyl, naphthyl, thiophene, furan, pyrrole, pyrazole, imidazole, pyridine, 2-pyridone, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, 3, 4-dihydro-1H-benzopyran, 1,2,3, 4-tetrahydroquinoline, benzofuran, benzothiophene, benzopyrrole, benzoxazole, benzothiazole, benzimidazole, benzopyrazole, morpholine, cyclobutylspirocyclobutyl, cyclobutylspiroazetidine, cyclopentyl-cyclopentyl, cyclopentyl-pyrrolidinyl, carbazole, when substituted, substituted with 1 to 4R b1;
In certain embodiments, B 1 is selected from one of the following optionally substituted structures: when substituted, are substituted with 1 to 4R b1;
in certain embodiments, B 1 is selected from B 1A;
In certain embodiments, B 1 is selected from substituted or unsubstituted phenyl or pyridine, optionally substituted with 1 to 4R b1 when substituted;
In certain embodiments, B 2 is selected from one of substituted or unsubstituted phenyl, cyclohexyl, piperidine, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene, benzopyrrole, indole, benzimidazole, benzopyrazole, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3, 4-tetrahydroquinoline, 1,2,3, 4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidine, cyclopentyl, cyclopentopyrrolidinyl, When substituted, are substituted with 1 to 4R b2;
In certain embodiments, B 2 is selected from one of a substituted or unsubstituted phenyl, naphthyl, quinoline, pyrazole, pyridine, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene, benzopyrrole, indole, benzimidazole, benzopyrazole, benzothiophene, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3, 4-tetrahydroquinoline, 1,2,3, 4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidine, cyclopentyl, cyclopentyl pyrrolidinyl, when substituted, substituted with 1 to 4R b2;
in certain embodiments, B 2 is selected from one of the following optionally substituted structures: when substituted, are substituted with 1 to 4R b2;
In certain embodiments, B 2 is selected from B 2A;
In certain embodiments, B 2 is selected from pyrazoles;
In certain embodiments, B 2 is selected from Said B 2 is optionally substituted with 1 or 2R b2;
In certain embodiments, each B 1A、B2A is independently selected from one of the following optionally substituted structures: When substituted, B 1A is substituted with 1 to 4R b1, and B 2A is substituted with 1 to 4R b2;
In certain embodiments, B 3 is selected from one of a substituted or unsubstituted oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, phenyl, pyridine, naphthyl, pyrazole, pyrrole, pyrrolidinyl, piperidine, piperazine, azetidinyl, tetrahydropyranyl, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzothiazole, benzopyrazole, benzimidazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3, 4-tetrahydroquinoline, 1,2,3, 4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutyl spiroazetidinyl, cyclopentyl pyrrolidyl, cyclobutylspiropiperidinyl, When substituted, are substituted with 1 to 4R b3;
in certain embodiments, B 3 is selected from one of the following optionally substituted structures: When substituted, are substituted with 1 to 4R b3;
In certain embodiments, B 3 is linked to B 2 by a carbon-nitrogen bond;
in some embodiments of the present invention, in some embodiments, Selected from the group consisting of
In some embodiments of the present invention, in some embodiments,Selected from the group consisting of
In certain embodiments, R b1、Rb2 is each independently selected from H, F, cl, br, I, =o, = S, OH, CN, NO 2、COOH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、-C(＝O)NH2、-C(＝O)NHC1-4 alkyl, -C (=O) N (C 1-4 alkyl) 2、-C(＝O)OC1-4 alkyl, -S (=o) 2NH2、-S(＝O)2N(C1-4 alkyl) 2、-S(＝O)2NHC1-4 alkyl 、-ORb22、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-NHC(＝O)Rb22、-N(C1-4 alkyl) C (=o) R b22、-NHS(＝O)2Rb22、-N(C1-4 alkyl) S (=o) 2Rb22、-O-C3-12 carbocyclyl, -NH-C 3-12 carbocyclyl, -S-C 3-12 carbocyclyl, C 3-12 carbocyclyl, C 6-10 aryl, 5-to 12-membered heteroaryl, 4-to 12-membered heterocyclyl, and, -C 1-4 alkylene-R b22、-O-C1-4 alkylene-R b22、-C1-4 alkylene-O-C 1-4 alkylene-R b22、-C1-4 alkylene-O-C 1-4 alkylene-OR b22, said alkylene, Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, heterocyclyl, aryl or heteroaryl are optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, = O, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、CN、COOH、C1-4 alkyl, Halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -O-C 3-10 carbocyclyl, C 3-10 carbocyclyl, or a 4-to 10-membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 substituents selected from O, s, N heteroatoms;
In certain embodiments, R b1 is each independently selected from F、Cl、Br、I、＝O、＝S、OH、NH2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O- cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinyl-cyclopentyl, azetidinyl-spirocyclohexyl, Phenyl, said methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinocyclopentyl, azetidinyl spirocyclohexyl,Phenyl is optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, =o, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b1 is each independently selected from F、Cl、Br、I、＝O、＝S、OH、NH2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O- cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinyl-cyclopentyl, azetidinyl-spirocyclohexyl, Phenyl, said methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinocyclopentyl, azetidinyl spirocyclohexyl,Phenyl is optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CHF 2、CF3、NH2、N(CH3)2, methyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl;
In certain embodiments, each R b21 is independently selected from H or C 1-4 alkyl optionally substituted with 1 to 4 substituents selected from halogen, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy;
In certain embodiments, R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -NH-C 1-4 alkyl, C 3-6 cycloalkyl, said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl optionally substituted with 1 to 4 substituents selected from halogen, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy;
in certain embodiments, each R b21 is independently selected from H, methyl, ethyl, isopropyl;
in certain embodiments, R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -NH-C 1-4 alkyl, C 3-6 cycloalkyl, said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy;
In certain embodiments, each R b22 is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;
In certain embodiments, each R b22 is independently selected from H, NHCH 3、N(CH3)2, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;
in certain embodiments, R b3 is each independently selected from halogen, =o, = S, OH, CN, NO 2、COOH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio 、-(CH2)n-Rb22、-O-Rb22、-S-Rb22、-NH-Rb22、-(CH2)m1-X-(CH2)m2-Rb24、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, or heteroaryl being optionally substituted with 1 to 4 substituents selected from halogen, OH, =o, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R b3 is each independently selected from halogen, =o, = S, OH, CN, NO 2、COOH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio 、-CH2-Rb22、-CH2CH2-Rb22、-O-Rb22、-S-Rb22、-NH-Rb22、-O-CH2CH2-Rb24、-S-CH2CH2-Rb24、-NH-CH2CH2-Rb24、-O-CH2-Rb24、-S-CH2-Rb24、-NH-CH2-Rb24、-CH2-O-CH2-Rb24、-CH2-S-CH2-Rb24、-CH2-NH-CH2-Rb24、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, or heteroaryl being optionally substituted with 1 to 4 substituents selected from halogen, OH, =o, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, or 4-8 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b3 is each independently selected from F、Cl、Br、I、＝O、＝S、OH、NH2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O- cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -O-CH 2 -cyclopropyl, -O-CH 2 -cyclobutyl, -O-CH 2CH2 -methoxy, -O-CH 2CH2 -O-cyclopropyl, -O-CH 2CH2 -O-cyclobutyl, -CH 2-O-CH2CH2 -methoxy, -CH 2-O-CH2CH2 -O-cyclopropyl, -CH 2-O-CH2CH2 -O-cyclobutyl, -CH 2-O-CH2CH2 -NH-methyl, -CH 2 -methoxy, -CH 2 -ethoxy, N (CH 3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinyl cyclopentyl, azetidinyl spirocyclohexyl, Phenyl, said methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinocyclopentyl, azetidinyl spirocyclohexyl,Phenyl is optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CHF 2、CF3、NH2、N(CH3)2, methyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl;
In certain embodiments, R b2 is each independently selected from H、F、Cl、Br、I、＝O、＝S、OH、NH2、NHCH3、N(CH3)2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)(CH3)2、-S(＝O)2CH3 or an optionally substituted one of methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, morpholine, pyrrolidinocyclopentyl, azetidinyl spirocyclohexyl, cyclopropylspirobutyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentylpyridyl spirohexyl, CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH 2CH2 -O-methyl, -OCH 2CH2 -O-cyclopropyl, -CH 2OCH2CH2 -O-methyl, -CH 2OCH2CH2 -O-cyclopropyl, -CH 2OCH2CH2 -NH-methyl When substituted, is substituted with 1 to 4 substituents selected from F、Cl、Br、I、OH、CN、CHF2、CH2F、CF3、NH2、NHCH3、N(CH3)2、CH2OH、 methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyrazolyl, morpholinyl;
In certain embodiments, either R b1 and R b3、Rb2 or R b3 are directly linked to form a C 5-7 carbocyclyl, 5-to 7-membered heterocycle, optionally substituted with 1 to 4 substituents selected from halogen, OH, -NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, or C 1-4 alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
In certain embodiments, either R b1 and R b3、Rb2 or R b3 are directly linked to form a C 5-7 carbocyclyl, 5-to 7-membered heterocycle, said carbocyclyl or heterocycle optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、CH2F、CHF2、CF3, methyl, ethyl, methoxy or ethoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, any of R b1 and R b3、Rb2 and R b3 are directly linked to form a phenyl ring, pyrrolidine, piperidine, piperazine, morpholinyl, cyclohexene, cyclopentene, cyclopentane, cyclohexane, said pyrrolidine, piperidine, piperazine, morpholinyl, cyclohexene, cyclopentene, cyclopentane, cyclohexane optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、CH2F、CHF2、CF3, methyl, ethyl, methoxy, or ethoxy;
In certain embodiments, each R b4、Rb5 is independently selected from H, F, cl, br, I, OH, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl )2、CN、COOH、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6 alkyl), C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, c 6-10 aryl, 5-10 heteroaryl or 3-12 heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally being substituted with 1 to 4 groups selected from F, cl, br, I, OH, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、CN、C1-6 alkyl, Halogen substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl or a substituent of 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b4、Rb5 is each independently selected from H, F, cl, br, I, OH, NH 2、CN、NO2、COOH、NHC1-4 alkyl, N (C 1-4 alkyl) 2、C1-4 alkyl, c 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 3-8 cycloalkyl, O-C 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 3-8 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally being substituted with 1 to 4 substituents selected from F, Cl, br, I, OH, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, Cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl or a substituent of 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 substituents selected from O, s, N heteroatoms;
In certain embodiments, R b4、Rb5 is each independently selected from H, F, cl, br, I, OH, NH 2、NHCH3、N(CH3)2、CN、NO2, COOH, or one of optionally substituted methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, O-cyclopropyl, NH-cyclopropyl, morpholine, when substituted, substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl;
In certain embodiments, any R b4、Rb5 and the carbon atom to which it is attached together form a C 3-8 cycloalkyl or 3 to 8 membered heteromonocyclic ring, said cycloalkyl or heteromonocyclic ring optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, said heteromonocyclic, heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, any R b4、Rb5 and the carbon atom to which it is attached together form one of an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, when substituted, substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, or 3 to 8 heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 carbocyclyl, or 4-10 membered heterocyclyl, said carbocyclyl, alkenyl, alkynyl, heterocyclyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b23 is each independently selected from ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, said ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy;
In certain embodiments, R b24 is each independently selected from C 1-4 alkoxy, NH-C 1-4 alkyl, NH-C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-10 carbocyclyl, or 4-10 membered heterocyclyl, said alkoxy, carbocyclyl, cycloalkyl, cycloalkyloxy, heterocyclyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b24 is each independently selected from methoxy, ethoxy, propoxy, isopropoxy, -O-cyclopropyl, -O-cyclobutyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, said methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy;
In certain embodiments, each X is independently selected from NH, O, or S;
In certain embodiments, m1 are each independently selected from 0, 1,2, or 3;
in certain embodiments, m2 is each independently selected from 0, 1,2, or 3;
in certain embodiments, n is each independently selected from 0, 1,2,3, or 4;
in certain embodiments, B is selected from one of the structural fragments shown in Table B-1, table B-2, or Table B-3, the right side of which is linked to L, and B1, B2 are each independently selected from 0, 1, or 2:
Table B-1
Table B-2
Table B-3
In certain embodiments, q is each independently selected from 0, 1,2, 3,4,5, or 6;
In certain embodiments, q is each independently selected from 0, 1,2,3, or 4;
In certain embodiments, q is each independently selected from 0, 1,2, or 3;
in certain embodiments, q is each independently selected from 0, 1, or 2;
in certain embodiments, K is selected from K1, K2, K3, K4;
In certain embodiments, K1 is selected from
In certain embodiments, K1 is selected from
In certain embodiments, K2 is selected from
In certain embodiments, K2 is selected from
In certain embodiments, K3 is selected from In certain embodiments, K3 is selected from
In certain embodiments, K4 is selected from In certain embodiments, K4 is selected from
In certain embodiments, each E is independently selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-12 membered heterocyclyl, or 5-12 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 (e.g., 1,2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, E is each independently selected from C 3-10 carbocyclyl, benzenyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from O, S, N;
In certain embodiments, each E is independently selected from the group consisting of a phenyl ring, a 5-6 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 3 (e.g., 1, 2, 3) heteroatoms selected from O, S, N;
In certain embodiments, each E is independently selected from the group consisting of phenyl ring, pyridyl ring, pyridazinyl ring, pyrazinyl ring, pyrimidinyl ring, pyrrolyl ring, pyrazolyl ring, imidazolyl ring, thiazolyl ring, furanyl ring, thiophenyl ring, oxazolyl ring, indolinyl ring, isoindolinyl ring, 1,2,3, 4-tetrahydroquinolinyl, or 1,2,3, 4-tetrahydroisoquinolinyl ring;
In certain embodiments, each E is independently selected from the group consisting of a phenyl ring, a pyridyl ring, a pyridazine ring, a pyrazinyl ring, a pyrimidinyl ring, a pyrrolyl ring, a pyrazolyl ring, an imidazolyl ring, a thiazolyl ring, a furanyl ring, a thiophenyl ring, or an oxazolyl ring;
in certain embodiments, each E is independently selected from the group consisting of phenyl ring, pyridyl ring, pyridazinyl, pyrazinyl, pyrimidine ring;
In certain embodiments, each E is independently selected from a phenyl ring or a pyridine ring;
in certain embodiments, a is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;
In certain embodiments, a is selected from C 3-8 carbocyclyl, benzenyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N;
In certain embodiments, a is selected from the group consisting of a phenyl ring, a pyridyl ring, a pyridazinyl ring, a pyrazinyl ring, a pyrimidinyl ring, a pyrrolyl ring, a pyrazolyl ring, an imidazolyl ring, a thiazolyl ring, a furanyl ring, a thiophenyl ring, or an oxazolyl ring;
in certain embodiments, a is selected from a phenyl ring or a pyridine ring;
In certain embodiments, each F is independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclyl, or 5-20 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 (e.g., 1,2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, each F is independently selected from C 3-7 monocyclocyclyl, C 4-10 fused ring carbocyclyl, C 5-12 spiro carbocyclyl, C 5-10 bridged carbocyclyl, 4-7 membered heteromonocycloyl, 4-10 membered heterofused ring, 8-15 membered heterotricycloyl, 5-12 membered heterospiro, 5-10 membered heterobridged ring, C 6-14 aryl, 5-10 membered heteroaryl, said heteromonocycloyl, heterofused ring, heterospiro, heterobridged ring or heteroaryl containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each F is independently selected from the group consisting of C 3-7 monocyclocarbocyclyl, C 4-10 tetracyclocarbocyclyl, C 5-12 spirocyclic carbocyclyl, C 5-10 bridged carbocyclyl, 4-7 membered heteromonocycloyl, 4-10 membered heteroacenyl, 8-15 membered tricyclic heteroacenyl, 12-17 membered tetracycloheteroacenyl, 5-17 membered heterospirocyclic, C 6-14 aryl, 5-10 membered heteroaryl, The heteromonocyclic, heterobicyclic, heterobridged, or heteroaryl groups contain 1 to 4 heteroatoms selected from O, S or N;
In certain embodiments, each F is independently selected from the group consisting of a phenyl ring, a pyridyl ring, a pyrimidyl ring, a pyrazinyl ring, a pyridazinyl ring,
In certain embodiments, each F is independently selected from the group consisting of a phenyl ring, a pyridyl ring, a pyrimidyl ring, a pyrazinyl ring, a pyridazinyl ring,
In some embodiments of the present invention, in some embodiments, F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzopyrazinyl, benzopyrimidinyl benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, imidazopyrazinyl, imidazopyrimidinyl, imidazoyl, imidazopyrazinyl, imidazopyridinyl, and/or imidazopyridinyl pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridinyl, pyridopyridyl, pyridopyrazolyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyridines, indolopyphene, indolofuran, The left side of the connecting rod is directly connected with L;
In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH 2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq -, or a 3-12 membered heterocycle, said heterocycle optionally being substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from O, S, N;
In certain embodiments, each Q is independently selected from-O-, -S-, -CH 2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq -or a 4-7 membered heterocycle, said heterocycle optionally being substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from O, S, N;
In certain embodiments, each Q is independently selected from a bond, C (=o), qa, or Qb;
In certain embodiments, qa is selected from the group consisting of a bond, CH 2、NH、N(CH3)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH3)C(＝O)、C(＝O)N(CH3),
In certain embodiments, qb is selected from a bond, CH 2、O、S、C(＝O)、NHC(＝O)、N(CH3) C (=o);
In certain embodiments, R q is selected from H or C 1-6 alkyl;
In certain embodiments, R q is selected from H or C 1-4 alkyl;
In certain embodiments, R q is selected from H, methyl, ethyl;
In certain embodiments, each R k2 is independently selected from a bond, -C (=o) -, -S (=o) 2 -, -S (=o) -or-C (R k3)2 -;
In certain embodiments, each R k2 is independently selected from-C (=o) -, -S (=o) 2 -, or-C (R k3)2 -;
In certain embodiments, R k1 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, R k7a, said alkyl, alkoxy, cycloalkyl optionally substituted with 1 to 4 (e.g., 1, 2,3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
In certain embodiments, R k1 is selected from R k7a;
In certain embodiments, R k3 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, or a 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl, or heterocyclyl being optionally substituted with 1 to 4 (e.g., 1, 2,3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g., 1, 2,3, 4) heteroatoms selected from O, S, N;
In certain embodiments, R k1、Rk3 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CF3、CN、COOH、CONH2、C1-4 alkyl, or C 1-4 alkoxy, optionally substituted with 1 to 4 (e.g., 1,2,3, or 4) substituents selected from F, cl, br, I, OH, NH 2;
In certain embodiments, R k1、Rk3 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CF3、CN、COOH、CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, or isopropoxy, optionally substituted with 1 to 4 (e.g., 1,2,3, or 4) substituents selected from F, cl, br, I, OH, NH 2;
In certain embodiments, two R k3 and the carbon atom or ring backbone directly attached to both, two R k1 and the carbon atom or ring backbone directly attached to both together form a C 3-8 carbocyclyl or 3-8 membered heterocycle optionally substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, or C 1-4 alkoxy, the heterocyclyl containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, two R k3 and the carbon atom or ring backbone directly attached to both, two R k1 and the carbon atom or ring backbone directly attached to both together form a C 3-6 carbocyclyl or 3-7 membered heterocycle optionally substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, or C 1-4 alkoxy, the heterocyclyl containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from O, S, N;
In certain embodiments, R k4 is each independently selected from H, OH, NH 2、CN、CONH2、C1-6 alkyl, C 3-8 cycloalkyl, or a 3-8 membered heterocyclyl, optionally substituted with 1 to 4 (e.g., 1,2, 3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g., 1,2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, each R k4 is independently selected from H, OH, NH 2、CF3、CN、C1-4 alkyl;
In certain embodiments, each R k5 is independently selected from C(CH3)2、CO、CH2、CH2CH2、SO2、
In certain embodiments, each R k5 is independently selected from CO, CH 2、SO2, or
In certain embodiments, each R k6 is independently selected from CO, CH, SO, SO 2、CH2 or N;
In certain embodiments, each R k7 is independently selected from C(CH3)2、CO、CH、N、CH2、O、S、NRk7a;
In certain embodiments, each R k7 is independently selected fromC (CH 3)2、CO、CH、N、CH2、O、S、N(CH3)、N(CH2CH3), N (cyclopropyl) or NH;
In certain embodiments, each R k7 is independently selected from CO, CH, N, CH 2、O、S、N(CH3) or NH;
In certain embodiments, each R k7 is independently selected from CH 2、O、N(CH3) or NH;
In certain embodiments, R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、CF3、C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl;
In certain embodiments, R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、CF3、C1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl;
In certain embodiments, R k7a is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, heterocycloalkyl, or cycloalkyl being optionally substituted with 1 to 4 substituents selected from halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
In certain embodiments, R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CF 3、C1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 cycloalkyl;
in certain embodiments, R k7a is selected from H, CF 3, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, tetrahydropyranyl, -CH 2CF3、-CH(CH3)CF3、-CH(CH3) -cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -vinyl, -CH 2 -ethynyl, -CH 2CH2 -methoxy;
In certain embodiments, R k7a is selected from H, CF 3, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl;
In certain embodiments, R k7a is selected from H, CH 3、CH2CH3, cyclopropyl;
In certain embodiments, each R k8 is independently selected from C, N or CH;
In certain embodiments, each R k9 is independently selected from a bond, C (CH 3)2、CO、CH2、CH2CH2 or SO 2;
In certain embodiments, each R k9 is independently selected from CO, SO 2, or CH 2;
In certain embodiments, M 1 is selected from the group consisting of a bond, -CH 2 -C (=o) NH-, or-C (=o) CH 2 NH-;
In certain embodiments, M 2 is selected from-NHC (=o) -C 1-6 alkyl, -NHC (=o) -C 3-6 cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, =o, OH, NH 2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from O, S, N;
In certain embodiments, M 3 is selected from-NH-or-O-;
In certain embodiments, R k10 is selected from C 1-6 alkyl optionally substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, =o, OH, C 1-6 alkyl, or C 3-6 cycloalkyl;
In certain embodiments, G is selected from C 6-10 aryl or 5-10 membered heteroaryl, optionally substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, OH, = O, CF 3、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl, the heteroaryl containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from N, O, S;
In certain embodiments, R k11 is each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or-O-C (=o) -C 1-6 alkyl, said alkyl, alkoxy, or alkylthio being optionally substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, OH, C 1-4 alkyl or C 1-4 alkoxy;
In certain embodiments, R k12、Rk13 is each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl optionally substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, =o, OH, NH 2、C1-4 alkyl, or C 1-4 alkoxy;
In certain embodiments, R k14 is selected from a 5-6 membered heteroaryl optionally substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, OH, = O, CF 3、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl, the heteroaryl containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from N, O, S;
In certain embodiments, R k14 is selected from
In certain embodiments, K is selected from one of the structural fragments shown in Table K-1;
in certain embodiments, K is selected from one of the structural fragments shown in Table K-2;
Table K-1
Table K-2
In certain embodiments, n1, n2, n3 are each independently selected from 0, 1,2, or 3;
In certain embodiments, p1 or p2 are each independently selected from 0, 1,2, or 3;
In certain embodiments, p1 or p2 are each independently selected from 0, 1,2,3,4, or 5;
In certain embodiments, the compound of formula (I) is selected from one of the structures shown in (Ia) or (Ib);
The definition of each group is the same as the above embodiment;
in certain embodiments, the compound of formula (I) is selected from formula (Id),
R b4、Rb5 is independently selected from H, methyl, ethyl and isopropyl;
Alternatively, R b4、Rb5 taken together with the carbon atom to which it is attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 substituents selected from H, F, cl, br, I, OH, NH 2、C1-4 alkyl or C 1-4 alkoxy;
B 2 is selected from 5-6 membered heteroaryl or 6 membered aryl, preferably selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, said B 2 being optionally substituted with 1 to 3R b2, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
B 3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterobicyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, C 4-7 monocycloalkyl, C 6-14 and cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-6 membered heteroaryl or 6 membered aryl, preferably selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, said B 3 being optionally substituted by 1 to 3R b3, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R d is selected from H, F, cl, br, I, OH, COOH, CN, NH 2、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl or C 1-4 alkoxy;
the remaining groups are the same as in any of the embodiments described above.
As a first embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
B-L-K(I);
L is selected from a bond or a-C 1-50 hydrocarbyl-, of which 1 to 20 methylene units are optionally replaced by-Ak-, -Cy-;
each-Ak-is independently selected from -(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2- or a bond, said-CH 2 -, -ch=ch-optionally substituted with 1 to 2 substituents selected from halogen, OH, CN, NH 2、C1-6 alkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl;
q is each independently selected from 0, 1,2,3,4, 5 or 6;
R L is each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
each-Cy-is independently selected from a bond or one of optionally substituted 4-8 membered heteromonocyclic group, 4-10 membered heteromonocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, 3-7 membered monocycloalkyl group, 4-10 membered cycloalkyl group, 5-12 membered spirocyclic alkyl group, 5-10 membered bridged cycloalkyl group, benzoC 4-6 carbocyclyl group, benzo4-6 membered heterocyclyl group, 5-10 membered heteroaryl group or 6-10 membered aryl group, when substituted, substituted with 1 to 4R L2, said heterocyclyl, heteroaryl, heteromonocyclic group, heterobicyclic group, heterospirocyclic group or heterobridged cyclic group containing 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally substituted with 1 or 2 = O;
R L2 is each independently selected from F, cl, br, I, OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -O-C 1-4 alkylene-O-C 1-4 alkyl, -O-C 1-4 alkylene-O-C 3-10 carbocyclyl, -C 1-4 alkylene-O-C 1-4 alkylene-O-C 1-4 alkyl, -C 1-4 alkylene-O-C 1-4 alkylene-O-C 3-10 carbocyclyl, -O-C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-4 to 10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4 groups selected from F, cl, br, I. OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, halogen substituted C 1-4 alkyl, Hydroxy-substituted C 1-4 alkyl, a substituent of C 1-4 alkoxy, a halogen-substituted C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
B is selected from
B 1 is selected from C 3-20 carbocyclyl or a 4-20 membered heterocycle, said carbocyclyl or heterocycle optionally substituted with 1 to 4R b1, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
B 2 is selected from C 3-20 carbocyclyl or a 4-20 membered heterocycle, said carbocyclyl or heterocycle optionally substituted with 1 to 4R b2, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
b 3 is selected from C 3-20 carbocyclyl or a 4-20 membered heterocycle, said carbocyclyl or heterocycle optionally substituted with 1 to 4R b3, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
Or B 3 is selected from a bond;
l 1 is selected from a bond or
L 2 is selected from a bond or
Y 1、Y2、Y3、Y4 are each independently selected from the group consisting of a bond, O, S, NR b5a;
Q 1、Q2、Q3、Q4 are each independently selected from
V 1、v2、v3、v4 are each independently selected from 0, 1,2,3 or 4;
R b1、Rb2 are each independently selected from H, F, cl, br, I, =o, = S, OH, CN, NO 2、COOH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、-C(＝O)NH2、-C(＝O)NHC1-4 alkyl, -C (=O) N (C 1-4 alkyl) 2、-C(＝O)OC1-4 alkyl, -S (=o) 2NH2、-S(＝O)2N(C1-4 alkyl) 2、-S(＝O)2NHC1-4 alkyl 、-ORb22、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-NHC(＝O)Rb22、-N(C1-4 alkyl) C (=o) R b22、-NHS(＝O)2Rb22、-N(C1-4 alkyl) S (=o) 2Rb22、-O-C3-12 carbocyclyl, -NH-C 3-12 carbocyclyl, -S-C 3-12 carbocyclyl, C 3-12 carbocyclyl, C 6-10 aryl, 5-to 12-membered heteroaryl, 4-to 12-membered heterocyclyl, and, -C 1-4 alkylene-R b22、-O-C1-4 alkylene-R b22、-C1-4 alkylene-O-C 1-4 alkylene-R b22、-C1-4 alkylene-O-C 1-4 alkylene-OR b22, said alkylene, Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, heterocyclyl, aryl or heteroaryl are optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, = O, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、CN、COOH、C1-4 alkyl, Halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -O-C 3-10 carbocyclyl, C 3-10 carbocyclyl, or a 4-to 10-membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 substituents selected from O, s, N heteroatoms;
r b3 is each independently selected from halogen, =o, = S, OH, CN, NO 2、COOH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio 、-(CH2)n-Rb22、-O-Rb22、-S-Rb22、-NH-Rb22、-(CH2)m1-X-(CH2)m2-Rb24、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 1 to 4 substituents selected from halogen, OH, =o, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
n is each independently selected from 0,1,2, 3 or 4;
r b21 are each independently selected from H or C 1-4 alkyl optionally substituted with 1 to 4 substituents selected from halogen, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy;
R b22 is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -NH-C 1-4 alkyl, C 3-6 cycloalkyl, said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl optionally substituted with 1 to 4 substituents selected from halogen, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy;
Or R b1 and R b3、Rb2 are directly connected to R b3 to form a C 5-7 carbocyclyl, 5-to 7-membered heterocycle, said carbocyclyl or heterocycle optionally substituted with 1 to 4 substituents selected from halogen, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
R b4、Rb5 is each independently selected from H, F, cl, br, I, OH, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl )2、CN、COOH、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6 alkyl), C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, c 6-10 aryl, 5-10 heteroaryl or 3-12 heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally being substituted with 1 to 4 groups selected from F, cl, br, I, OH, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、CN、C1-6 alkyl, Halogen substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl or a substituent of 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
or any R b4、Rb5 and the carbon atom to which it is attached form C 3-8 cycloalkyl or 3 to 8 membered heteromonocyclic ring, said cycloalkyl or heteromonocyclic ring optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, said heteromonocyclic, heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b5a is selected from H, C 1-4 alkyl, - (CH 2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, =O, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
x is independently selected from NH, O or S;
m1 is independently selected from 0,1,2 or 3;
m2 is each independently selected from 0,1,2 or 3;
R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 carbocyclyl, or 4-10 membered heterocyclyl, said carbocyclyl, alkenyl, alkynyl, heterocyclyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b24 is independently selected from C 1-4 alkoxy, NH-C 1-4 alkyl, NH-C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-10 carbocyclyl, or 4-10 membered heterocyclyl, said alkoxy, carbocyclyl, cycloalkyl, cycloalkyloxy, heterocyclyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
k is selected from K1, K2, K3 and K4;
k1 is selected from
K2 is selected from
K3 is selected from
K4 is selected from
Each Q is independently selected from a bond, -O-, -S-, -CH 2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq -, or a 3-12 membered heterocyclic ring, said heterocyclic ring being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclic group containing 1 to 4 heteroatoms selected from O, S or N;
R q is selected from H or C 1-6 alkyl;
A is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S or N;
F is each independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S or N;
r k2 are each independently selected from the group consisting of bond, -C (=O) -, -S (=O) 2 -, -S (=O) -or-C (R k3)2 -;
R k1 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, R k7a, said alkyl, alkoxy or cycloalkyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、CF3、C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl;
Each R k3 is independently selected from H, F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;
Or two R k3 and the carbon atom or ring backbone directly attached to both, two R k1 and the carbon atom or ring backbone directly attached to both together form a C 3-8 carbocyclyl or 3-8 membered heterocycle optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, the heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;
Each R k4 is independently selected from H, OH, NH 2、CN、CONH2、C1-6 alkyl, C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;
M 1 is selected from the group consisting of bond, -CH 2 -C (=O) NH-, or-C (=O) CH 2 NH-;
M 2 is selected from-NHC (=o) -C 1-6 alkyl, -NHC (=o) -C 3-6 cycloalkyl or a 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, =o, OH, NH 2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;
M 3 is selected from-NH-or-O-;
R k10 is selected from C 1-6 alkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, =o, OH, C 1-6 alkyl or C 3-6 cycloalkyl;
R k11 is each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or-O-C (=o) -C 1-6 alkyl, said alkyl, alkoxy or alkylthio being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, C 1-4 alkyl or C 1-4 alkoxy;
R k12、Rk13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, =o, OH, NH 2、C1-4 alkyl or C 1-4 alkoxy;
R k14 is selected from a 5-6 membered heteroaryl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, CF 3、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said heteroaryl containing 1 to 4 heteroatoms selected from N, O or S;
G is selected from C 6-10 aryl or 5-10 membered heteroaryl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, CF 3、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said heteroaryl containing 1 to 4 heteroatoms selected from N, O or S;
n1, n2, n3 are each independently selected from 0, 1,2 or 3;
p1 or p2 are each independently selected from 0, 1,2,3,4 or 5.
As a second embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
B is selected from
Or B is selected fromV is selected from a bond or L 1;
L 1、L2 is not a bond;
b 1 is selected from 6-7 membered heteromonocyclic group, 5-14 membered heterobicyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, C 6-8 Shan Tanhuan group, C 6-14 and cycloalkyl group, C 6-12 spirocycloalkyl group, C 5-12 bridged cycloalkyl group, benzoC 3-10 carbocyclyl group, benzo3-10 membered heterocyclyl group, C 12-18 tri-merging-ring group, 12-18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, said B 1 is optionally substituted with 1 to 4R b2, said heteroaryl or heterocyclyl group containing 1 to 4 heteroatoms selected from O, S, N;
b 3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterobicyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, C 3-8 Shan Tanhuan group, C 6-14 and cycloalkyl group, C 6-12 spirocycloalkyl group, C 5-12 bridged cycloalkyl group, benzoC 3-10 carbocyclyl group, benzo3-10 membered heterocyclyl group, C 12-18 tri-merging-ring group, 12-18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, said B 3 is optionally substituted with 1 to 4R b3, said heteroaryl or heterocyclyl group containing 1 to 4 heteroatoms selected from O, S, N;
B 2 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterobicyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, C 3-8 Shan Tanhuan group, C 6-14 and cycloalkyl group, C 6-12 spirocycloalkyl group, C 5-12 membered bridged cycloalkyl group, benzoC 3-10 carbocyclyl group, benzo 3 to 10 membered heterocyclyl group, C 12-18 tri-fused cyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, said B 2 is optionally substituted with 1 to 4R b2, said heteroaryl or heterocyclyl group containing 1 to 4 heteroatoms selected from O, S, N;
R b4、Rb5 is each independently selected from H, F, cl, br, I, OH, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、CN、COOH、NO2、C1-4 alkyl, c 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 3-8 cycloalkyl, C 6-10 aryl, O-C 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, 5-6 membered heteroaryl or 3-8 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, Cl, br, I, OH, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, Cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl or a substituent of 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 substituents selected from O, s, N heteroatoms;
R b5a is selected from H, C 1-4 alkyl, - (CH 2)n-Rb22), said-CH 2 -, alkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, =O, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
The remaining groups are as defined in the first embodiment of the invention.
As a third embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
Ak1, ak2, ak3, ak4, ak5 are each independently selected from -(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-(C≡C)q- or a bond, said-CH 2 -, -CH=CH-optionally substituted with 1 to 2 substituents selected from F, cl, br, I, OH, CN, NH 2、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl;
Cy1, cy2, cy3, cy4 or Cy5 are each independently selected from one of a bond or an optionally substituted 4-7 membered heteromonocyclic group, 4-10 membered heteromonocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, 3-7 membered monocycloalkyl group, 4-10 membered fused cycloalkyl group, 5-12 membered spirocycloalkyl group, 5-10 membered bridged cycloalkyl group, benzoC 4-6 carbocyclyl group, benzo4-6 membered heterocyclic group, 5-10 membered heteroaryl group or 6-10 membered aryl group, which when substituted is substituted with 1 to 4R L2, said heterocyclic group, heteroaryl group, heteromonocyclic group, heterospirocyclic group or heterobridged cyclic group containing 1 to 4 heteroatoms selected from O, S, N, which when heteroatom is selected from S is optionally substituted with 1 or 2=O;
q is each independently selected from 0,1,2, 3 or 4;
R L is independently selected from H or C 1-6 alkyl;
the remaining groups are as defined in the first or second embodiments of the invention.
As a fourth embodiment of the present invention, a compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof;
k2 is selected from
K3 is selected from
A is selected from C 3-8 carbocyclyl, benzenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S or N;
F is each independently selected from the group consisting of C 3-7 monocyclocarbocyclyl, C 4-10 fused ring carbocyclyl, C 5-12 spiro carbocyclyl, C 5-10 bridged carbocyclyl, 4-7 membered heteromonocycloyl, 4-10 membered heterofused ring, 8-15 membered tricyclic heterofused ring, 12-17 membered tetracyclic heterofused ring, 5-17 membered heterospiro, C 6-14 aryl, 5-10 membered heteroaryl, The heteromonocyclic, heterobicyclic, heterobridged, or heteroaryl groups contain 1 to 4 heteroatoms selected from O, S or N;
Represents a ring selected from aromatic or non-aromatic ring groups;
E is each independently selected from C 3-10 carbocyclyl, benzenyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S or N;
Each Q is independently selected from a bond, -O-, -S-, -CH 2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq -, or a 4-7 membered heterocyclic ring, said heterocyclic ring being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclic group containing 1 to 4 heteroatoms selected from O, S or N;
r q is selected from H or C 1-4 alkyl;
R k1、Rk3 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CF3、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH or NH 2;
or two R k3 and the carbon atom or ring backbone directly attached to both, two R k1 and the carbon atom or ring backbone directly attached to both together form a C 3-6 carbocyclyl or 3-7 membered heterocycle optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, the heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;
R k4 is independently selected from H, OH, NH 2、CF3, CN or C 1-4 alkyl;
R k5 are each independently selected from C(CH3)2、C(＝O)、CH2、CH2CH2、S(＝O)2、
R k6 are each independently selected from C (=o), CH, S (=o) 2、CH2, or N;
R k7 are each independently selected from C(CH3)2、C(＝O)、CH、N、CH2、O、S、NRk7a;
Each R k8 is independently selected from C, N or CH;
R k9 are each independently selected from the group consisting of a bond, C (CH 3)2、C(＝O)、CH2、CH2CH2 or S (=o) 2;
R ka is selected from O, S or NH;
R k7a is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、CF3、C1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl;
R k14 is selected from
The remaining groups are as defined in the first, second, or third embodiments of the invention.
As a fifth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
B is selected from
V is selected from bonds 、O、S、NRb5a、NRb5a-(Q2)v2-、-(Q2)v2-NRb5a、O-(Q2)v2-、-(Q2)v2-O、-(Q2)v2-;
V 2、v4 are each independently selected from 1,2,3 or 4;
Y 1、Y3 are each independently selected from the group consisting of a bond, O, S, NR b5a;
y 2、Y4 are each independently selected from O, S, NR b5a;
Ak1, ak2, ak3, ak4, ak5 are each independently selected from -(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-C≡C- or a bond, said-CH 2 -, -CH=CH-optionally substituted with 1 to 2 substituents selected from F, cl, br, I, OH, CN, NH 2、CF3, hydroxymethyl, methyl, ethyl, methoxy or ethoxy;
q is each independently selected from 0,1,2 or 3;
R L is independently selected from H or C 1-4 alkyl;
k1 is selected from
K4 is selected from
Q is selected from a bond, C (=o);
qa is selected from bond, CH 2、NH、N(CH3)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH3)C(＝O)、C(＝O)N(CH3),
Qb is selected from a bond, CH 2、O、S、C(＝O)、NHC(＝O)、N(CH3) C (=o);
E. Each a is independently selected from the group consisting of a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrazine ring group, a pyrimidine ring group, a pyrrole ring group, a pyrazole ring group, an imidazole ring group, a thiazole ring group, a furan ring group, a thiophene ring group, or an oxazole ring;
F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzopyrazinyl, benzopyrimidinyl benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, imidazopyrimidinyl imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, The left side of the connecting rod is directly connected with L;
R ka is selected from O, S or NH;
R k7 are each independently selected from C (CH 3)2、CH2、O、N(CH3)、N(CH2CH3), N (cyclopropyl) or NH;
R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CF 3、C1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 cycloalkyl;
p1 or p2 are each independently selected from 0,1,2 or 3;
The remaining groups are as defined in any of the second, third or fourth embodiments of the invention.
As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
R L is selected from H, methyl or ethyl;
q is each independently selected from 0,1 or 2;
Cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azehexenyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazaheptanyl, pyridinyl, phenyl, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclopropyl, cyclopropyl-spirobutyl, cyclopropyl-spirocyclopentyl, cyclopropyl-spirocyclohexyl, cyclobutyl-spirobutyl, cyclobutyl-spiropentyl, cyclobutyl-spirocyclohexyl, cyclopentyl-spiropentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-azetidinyl, cyclopropyl-pyrrolidyl cyclopropyl-piperidinyl, cyclobutyl-azetidinyl, cyclobutyl-pyrrolidinyl, cyclobutyl-piperidinyl, cyclopentyl-azetidinyl, cyclopentyl-pyrrolidinyl, cyclopentyl-piperidinyl, cyclohexyl-azetidinyl, azetidinyl-piperidinyl pyrrolidinyl azetidinyl, piperidinyl azetidinyl, cyclobutyl spiroazetidinyl, cyclobutyl spiropyrrolidinyl, cyclobutyl spiropiperidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiroazetidinyl, cyclobutyl spiropyrrolidinyl, cyclobutyl spiropiperidinyl, cyclopentyl-containing-, cyclohexyl spiropyrrolidinyl, cyclohexyl spiropiperidinyl, and azetidinyl spiroazetidinyl azetidinyl spiro azetidinyl radical pyrrolidinyl spiroazetidinyl pyrrolidinyl spiropyrrolidinyl pyrrolidinyl spiro pyrrolidinyl group, When substituted, are substituted with 1 to 4R L2;
R L2 is each independently selected from F, cl, br, I, OH, NH 2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -O-C 1-2 alkylene-O-C 1-2 alkyl, -O-C 1-2 alkylene-O-C 3-6 carbocyclyl, -C 1-2 alkylene-O-C 1-2 alkylene-O-C 1-2 alkyl, -C 1-2 alkylene-O-C 1-2 alkylene-O-C 3-6 carbocyclyl, -O-C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6 membered heterocyclyl, said alkyl, Alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl optionally substituted with 1 to 4C 1-4 alkyl groups selected from F, cl, br, I, OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, halogen, Hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
B 1 is selected from one of substituted or unsubstituted phenyl, naphthyl, thiophene, furan, pyrrole, pyrazole, imidazole, pyridine, 2-pyridone, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, 3, 4-dihydro-1H-benzopyran, 1,2,3, 4-tetrahydroquinoline, benzofuran, benzothiophene, benzopyrrole, benzoxazole, benzothiazole, benzimidazole, benzopyrazole, morpholine, cyclobutylspirocyclobutyl, cyclobutylspiroazetidine, cyclopentyl-pyrrolidyl, carbazole, when substituted, substituted with 1 to 4R b1;
Or B 1 is selected from one of the following optionally substituted structures: when substituted, are substituted with 1 to 4R b1;
Or B 1 is selected from B 1A;
B 2 is selected from one of substituted or unsubstituted phenyl, naphthyl, quinoline, pyrazole, pyridine, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene, benzopyrrole, indole, benzimidazole, benzopyrazole, benzothiophene, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3, 4-tetrahydroquinoline, 1,2,3, 4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidine, cyclopentyl pyrrolidinyl, when substituted, substituted with 1 to 4R b2;
or B 2 is selected from one of the following optionally substituted structures: when substituted, are substituted with 1 to 4R b2;
Or B 2 is selected from B 2A;
Each B 1A、B2A is independently selected from one of the following optionally substituted structures: When substituted, B 1A is substituted with 1 to 4R b1, and B 2A is substituted with 1 to 4R b2;
B 3 is selected from one of substituted or unsubstituted oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, tetrahydrofuranyl, phenyl, pyridine, naphthyl, pyrazole, pyrrole, pyrrolidinyl, piperidine, piperazine, azetidinyl, tetrahydropyranyl, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzothiazole, benzopyrazole, benzimidazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3, 4-tetrahydroquinoline, 1,2,3, 4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidine, cyclopentyl-pyrrolidinyl, cyclobutylspiropiperidinyl, when substituted, is substituted with 1 to 4R b3;
Or B 3 is selected from one of the following optionally substituted structures: When substituted, are substituted with 1 to 4R b3;
V is selected from the group consisting of a bond, O, S, NR b5a、NRb5a-C1-4 alkylene, C 1-4 alkylene-NR b5a、O-C1-4 alkylene, C 1-4 alkylene-O, C 1-4 alkylene, said alkylene being optionally substituted with 1 to 4R b4 or R b5;
R b1 is each independently selected from F、Cl、Br、I、＝O、＝S、OH、NH2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O- cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinyl-cyclopentyl, azetidinyl-spirocyclohexyl, Phenyl, said methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinocyclopentyl, azetidinyl spirocyclohexyl,Phenyl is optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CHF 2、CF3、NH2、N(CH3)2, methyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl;
r b3 is each independently selected from F、Cl、Br、I、＝O、＝S、OH、NH2、N(CH3)2、NHCH3、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O- cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -O-CH 2 -cyclopropyl, -O-CH 2 -cyclobutyl, -O-CH 2CH2 -methoxy, -O-CH 2CH2 -O-cyclopropyl, -O-CH 2CH2 -O-cyclobutyl, -CH 2-O-CH2CH2 -methoxy, -CH 2-O-CH2CH2 -O-cyclopropyl, -CH 2-O-CH2CH2 -O-cyclobutyl, -CH 2-O-CH2CH2 -NH-methyl, -CH 2 -methoxy, -CH 2 -ethoxy, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinyl cyclopentyl, azetidinyl spirocyclohexyl, azacyclocyclohexyl, Phenyl, said methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinocyclopentyl, azetidinyl spirocyclohexyl,Phenyl is optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CHF 2、CF3、NH2、N(CH3)2, methyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl;
R b2 is each independently selected from H、F、Cl、Br、I、＝O、＝S、OH、NH2、NHCH3、N(CH3)2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)(CH3)2、-S(＝O)2CH3 or an optionally substituted one of methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxacyclopentyl, oxetanyl, morpholine, pyrrolidinyl cyclopentyl, azetidinyl spirohexyl, cyclopropyl spirobutyl, cyclobutylspirobutyl spirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentylpyridyl spirohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH 2CH2 -O-methyl, -OCH 2CH2 -O-cyclopropyl, -CH 2OCH2CH2 -O-methyl, -CH 2OCH2CH2 -O-cyclopropyl, -CH 2OCH2CH2 -NH-methyl When substituted, is substituted with 1 to 4 substituents selected from F、Cl、Br、I、OH、CN、CHF2、CH2F、CF3、NH2、NHCH3、N(CH3)2、CH2OH、 methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyrazolyl, morpholinyl;
Alternatively, any of R b1 and R b3、Rb2 and R b3 are directly linked to form a C 5-7 carbocyclyl, 5-to 7-membered heterocycle, said carbocyclyl or heterocycle optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, -NH 2、CN、CH2F、CHF2、CF3, methyl, ethyl, methoxy or ethoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
K is selected from one of the structural fragments shown in the table K-1;
The remaining groups are as defined in any of the second, third, fourth or fifth embodiments of the invention.
As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
Cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: When substituted, are substituted with 1 to 4R L2;
Each R L2 is independently selected from F, cl, br, = O, COOH, CN, NHCH 3、N(CH3)2、OH、NH2, or one of optionally substituted methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclopropyl, -OCH 2CH2 -O-methyl, -OCH 2CH2 -O-cyclopropyl, -CH 2OCH2CH2 -O-methyl, -CH 2OCH2CH2 -O-cyclopropyl, when substituted, substituted with 1 to 4 substituents selected from F, CHF 2、CF3、OCHF2、OCF3, methyl, methoxy, = O, CH 2OH、COOH、CN、NHCH3、N(CH3)2、OH、NH2;
B is selected from one of the structural fragments shown in the table B-1, the table B-2 or the table B-3, the right side of the structural fragment is connected with L, and B1 and B2 are respectively and independently selected from 0,1 or 2;
K is selected from one of the structural fragments shown in the table K-2;
The remaining groups are as defined in any of the second, third, fourth, fifth or sixth embodiments of the invention.
As an eighth embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
L is selected from bond 、-Ak1-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-;
Ak1, ak2, ak3, ak4, ak5 are each independently selected from -O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、-C(＝O)NH- or-NHC (=O) -;
V is selected from bonds 、NH、NHC(CH3)2CH2、NHCH2C(CH3)2、CH2CH2、C(CH3)2CH2、CH2C(CH3)2、NHCH2CH2、NHCH2、OCH2、CH2NH、CH2O、NHC(CH3)2、OC(CH3)2、C(CH3)2NH、C(CH3)2O、N(CH3)CH2、N(CH3)C(CH3)2、C(CH3)2N(CH3)、CH2N(CH3)、N(CH3)、O、S;
The remaining groups are as defined in any of the second, third, fourth, fifth or sixth embodiments of the invention.
As a ninth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
L is selected from a bond or one of the structural fragments shown in Table L-1 or Table L-2 or Table L-3, wherein the left side of the group is as defined for the remainder of the group attached to B as in any of the second, third, fourth, fifth or sixth embodiments of the invention.
The present invention relates to a compound selected from one of the structures of table E-1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.
Table E-1
The present invention relates to a pharmaceutical composition comprising a compound of the invention described above or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention described above or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
In some embodiments, the pharmaceutical compositions of the present invention may be in unit dosage form (the amount of the primary drug in a unit dosage form is also referred to as "formulation specification").
By "effective amount" or "therapeutically effective amount" in the present application is meant that a sufficient amount of a compound of the present disclosure is administered that will alleviate to some extent one or more symptoms of the disease or disorder being treated (e.g., inhibiting or degrading AR or an AR shear mutant-related disease such as prostate cancer). In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is that amount comprising a compound of the present disclosure that is required to provide clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to 1-1500mg、1-1200mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、80-1000mg、80-800mg.
In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000mg、20-800mg、40-800mg、40-400mg、25-200mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、300mg、320mg、400mg、480mg、500mg、600mg、640mg、840mg a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof.
A method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound of the invention, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, preferably 1-1500mg, said disease preferably inhibiting or degrading AR or an AR-shear mutant related disease (e.g., prostate cancer).
A method for treating a disease in a mammal comprising administering a pharmaceutical compound of the invention or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof to a subject at a daily dose of 1-1000 mg/day, which may be a single dose or divided doses, and in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg/day, 320 mg/day, 400 mg/day, 600 mg/day, 1000 mg/day.
The present invention relates to a kit comprising a single or multiple dose form of a composition comprising a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in an amount equivalent to the amount of the compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.
The invention relates to application of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic or the pharmaceutical composition in preparing medicaments for treating diseases related to activity or expression quantity of AR or AR shear mutant.
The invention relates to application of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal of the compound or the stereoisomer, the solvate, the metabolite, the pharmaceutically acceptable salt or eutectic crystal of the compound or the prodrug in preparation of medicines for treating and inhibiting or degrading diseases related to AR or AR shear mutants.
The invention relates to the application of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal or the pharmaceutical composition of the invention, wherein the disease is selected from prostate cancer.
The amount of a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof is in each case converted in the form of the free base.
Unless otherwise stated, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the present invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the present invention are optionally replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12C、13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), the isotopes of oxygen include 16O、17 O and 18 O, the isotopes of sulfur include 32S、33S、34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
"Halogen" means F, cl, br or I.
"Halo substituted" means F, cl, br or I substituted, including but not limited to 1 to 10 substituents selected from F, cl, br or I, 1 to 6 substituents selected from F, cl, br or I, 1 to 4 substituents selected from F, cl, br or I. "halo substituted" is simply referred to as "halo".
"Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group including, but not limited to, alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the various branched isomers thereof, and alkyl groups appearing herein are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent, or tetravalent.
"Hydrocarbyl" refers to a substituted or unsubstituted, straight or branched, saturated or unsaturated group consisting of carbon and hydrogen atoms. The hydrocarbyl group may be monovalent, divalent, trivalent, or tetravalent.
"Alkylene" refers to substituted or unsubstituted straight and branched chain divalent saturated hydrocarbon radicals including- (CH 2)v - (v being an integer from 1 to 10), with alkylene embodiments including but not limited to methylene, ethylene, propylene, butylene, and the like.
"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyl groups as herein presented are defined as described above. Cycloalkyl groups may be monovalent, divalent, trivalent, or tetravalent.
"Heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group including, but not limited to, 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted N, S in the ring of the heterocycloalkyl group being oxidizable to various oxidation states. Heterocycloalkyl groups can be attached to heteroatoms or carbon atoms, heterocycloalkyl groups can be attached to aromatic or non-aromatic rings, and heterocycloalkyl groups can be attached to bridged or spiro rings, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl group may be monovalent, divalent, trivalent, or tetravalent.
"Alkenyl" refers to substituted or unsubstituted straight and branched chain unsaturated hydrocarbon groups having at least 1, typically 1,2 or 3 carbon-carbon double bonds, with backbones including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms, alkenyl examples including but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-pentadienyl and the like, as defined herein. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.
"Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbyl groups having at least 1, typically 1,2 or 3 carbon-carbon triple bonds, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone, alkynyl embodiments including but not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, trivalent decynyl, divalent or the like.
"Alkoxy" refers to a substituted or unsubstituted-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy.
"Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic group, a4 to 12 membered bicyclic group, or a 10 to 15 membered tricyclic ring system, and which may be attached to an aromatic or non-aromatic ring, which is optionally monocyclic, bridged, or spiro. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, phencycliyl, naphtyl,"Carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent, or tetravalent.
"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring that may be a 3 to 8 membered monocyclic group, a 4 to 12 membered bicyclic group, or a 10 to 15 membered tricyclic ring system, and that contains 1 or more (including but not limited to 2,3,4, or 5) heteroatoms selected from N, O or S, and that the optionally substituted C, N, S in the ring of the heterocyclyl may be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or a carbon atom, the heterocyclic group may be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxacyclyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithianyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [ 2.3.5 ] dioxanyl, 2.1.5 [ 2.5 ] dioxanyl, 2.5.5 ] oxazinyl, 573.5.5 [ 2.5 ] oxazinyl, and adamantyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent, or tetravalent.
"Spiro" or "spirocyclic group" refers to a polycyclic group having one atom (referred to as a spiro atom) shared between substituted or unsubstituted monocyclic rings, the number of ring atoms in the spiro system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more of the rings may contain 0 or more (including, but not limited to, 1,2, 3, or 4) double bonds, and optionally may contain 0 to 5 heteroatoms selected from N, O or S (=o) n.
"Spiro" or "spirocyclic group" may be monovalent, divalent, trivalent, or tetravalent.
"Fused ring" or "fused ring group" refers to a polycyclic group wherein each ring in the system shares an adjacent pair of atoms with the other rings in the system, wherein one or more of the rings may contain 0 or more (including but not limited to 1,2,3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (=o) n or O, n being 0, 1, or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: "fused" or "fused-ring" groups may be monovalent, divalent, trivalent, or tetravalent.
"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly attached, which may contain 0 or more double bonds, and any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S (=o) n or O, where n is 0,1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include
Cubane and adamantane. "bridged ring" or "bridged ring radical" can be monovalent, divalent, trivalent, or tetravalent.
"Carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spiro" ring system consisting of only carbon atoms.
"Carbon-fused", "fused carbocyclyl" or "carbon-fused cyclic" refers to a "fused ring" in which the ring system has only carbon atoms.
"Carbon bridged ring", "bridged carbocyclyl" or "carbon bridged cyclyl" refers to a "bridged ring" in which the ring system has only carbon atoms.
"Heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic group" refers to a "heterocyclyl" or "heterocycle" of a monocyclic system.
"Heterobicyclic", "fused-ring heterocyclyl" or "heterobicyclic" refers to a "fused ring" containing a heteroatom.
"Heterospiro", "spiroheterocyclyl" or "heterospirocyclyl" refers to a "spiro" containing heteroatoms.
"Heterobridged ring", "bridged heterocyclic group" or "heterobridged heterocyclic group" refers to a "bridged ring" that contains a heteroatom.
"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclyl or heterocycle wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include a phenyl ring, a naphthyl ring,The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the aryl ring.
"Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains 1 to 5 selected heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (=o) n, n being 0, 1, 2), the number of ring atoms in the heteroaryl ring including but not limited to 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, pyridone, pyrazinone, and,Etc. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclyl or heterocycle wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which includeHeteroaryl groups as herein appear, the definition of which is consistent with the definition. Heteroaryl groups may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment sites are located on the heteroaryl ring.
"5 Membered ring and 5 membered heteroaryl" refers to a fused heteroaryl group of 5 and 5 membered, wherein at least 1 of the 2 rings contains more than 1 heteroatom (including but not limited to O, S or N) and the entire group is aromatic, non-limiting examples include pyrrolopyrrole, pyrazolopyrrole, pyrazolopyrazole, pyrrolofuran, pyrazolofuran, pyrrolothiene, pyrazolothiophene.
"5-And 6-membered heteroaryl" refers to a 5-and 6-membered fused heteroaryl, wherein at least 1 of the 2 fused rings contains 1 or more heteroatoms (including but not limited to O, S or N), and the entire group is aromatic, non-limiting examples of which include benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl.
"Substituted" or "substituted" means substituted with 1 or more (including but not limited to 2,3, 4, or 5) substituents including but not limited to H, F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, hydroxyalkyl, =o, carbonyl, aldehyde, carboxylic acid, formate 、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m- alkenyl-R a、ORd, or- (CH 2)m -alkynyl-R a (where m, n is 0,1, or 2), arylthio, thiocarbonyl, silane, or-NR bRc, and the like, wherein R b and R c are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively R b and R c may form a five-or six-membered cycloalkyl or heterocyclyl, each of R a and R d is independently selected from the group consisting of aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, bridged ring, or spirocyclic, and the like.
"Containing 1 to 5 heteroatoms selected from O, S, N" means containing 1,2,3,4, or 5 heteroatoms selected from O, S, N.
"1 To X are selected from the group consisting of substituted" means substituted with 1,2,3, X are selected from the group consisting of substituted, X is selected from any integer between 1 and 10. For example, "1 to 4R k substitutions" means substitution with 1,2,3, or 4R k. As "1 to 5 selected..substituents" means substituted with 1,2,3,4, or 5 selected..substituents. By "the hetero-bridge ring is optionally substituted with 1 to 4 substituents selected from H or F" is meant that the hetero-bridge ring is optionally substituted with 1,2,3 or 4 substituents selected from H or F.
The X-Y membered ring (X, Y is an integer and 3.ltoreq.x < Y, X < y.ltoreq.20 is selected from any integer between 4 and 20) includes X, X +1, x+2, x+3, x+4. The ring includes heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" means 4-, 5-, 6-or 7-membered heteromonocyclic ring, and "5-10 membered heteromonocyclic ring" means 5-, 6-, 7-, 8-, 9-or 10-membered heteromonocyclic ring.
C x-y carbocycle (including aryl, cycloalkyl, monocyclic carbocyclyl, spirocyclic carbocyclyl, and cyclic carbocyclyl, or bridged carbocycle) includes a C x、Cx+1、Cx+2、Cx+3、Cx+4….Cy membered ring (x is an integer and 3.ltoreq.x < y, y is selected from any integer between 4 and 20), for example C 3-6 cycloalkyl "refers to C 3、C4、C5 or C 6 cycloalkyl.
When a group has one or more bondable sites, any one or more of the sites of the group may be bonded to other groups by chemical bonds. When the chemical bond is not positioned and a hydrogen atom exists in the connectable site, the number of H atoms in the site is correspondingly reduced along with the number of the connected chemical bonds to become a group with a corresponding valence when the chemical bond is connected. For exampleIt means that any of the ligatable sites on the piperidinyl group may be attached to other groups by 1 chemical bond, including at leastThese 4 connection schemes, even though H atoms are drawn on-N-,Also includeFor exampleThe R group on the piperidinyl group may be on C, may be on N, and includes at least
When the exemplified linking group does not indicate its linking direction, the linking direction includes the direction of the reading order from left to right and from right to left, for example, A-L-B, and when L is selected from the group consisting of-M-W-, A-M-W-B and A-W-M-B are included.
"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. "optionally F-substituted alkyl" means that the alkyl group may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl group is substituted with F and cases where the alkyl group is not substituted with F.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"Pharmaceutical composition" refers to one or more compounds of the present invention, or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and mixtures of other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
"Formulation specification" refers to the weight of the principal drug contained in each individual, tablet or other unit of formulation.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"Animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
"Stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers, diastereomers and conformational isomers.
"Tautomer" refers to a functional group isomer produced by rapid movement of an atom in a molecule at two positions, such as keto-enol isomers and amide-imine alcohol isomers.
"IC 50" is the concentration of drug or inhibitor required to inhibit a given biological process (or a component of the process such as an enzyme, receptor, cell, etc.) in half.
Detailed Description
The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.
The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art starting from commercially available chemicals and/or compounds described in the chemical literature. "commercially available chemicals" are obtained from regular commercial sources and suppliers include Taitan technology, an Naiji chemistry, shanghai de mer, chengdu Kelong chemical, shaoguan chemical technology, nanjing medical stone, yamamokan and Bailingwei technology, among others.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 -6 (ppm). NMR was performed using a (Bruker AVANCE III and Bruker Avance 300) magnetonuclear instrument with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) and an internal standard of Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X14.6mm, 3.5. Mu.M);
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm;
Column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
SEM:THP:Boc: t-Butoxycarbonyl; ms:TBS:Bn: DIPEA, N-diisopropylethylamine, DMF, N-dimethylformamide, DMAc, N-dimethylacetamide, DMSO, dimethyl sulfoxide, DCM, dichloromethane, cbz: NMP, N-methylpyrrolidone, TEA, triethylamine and MsCl, methanesulfonyl chloride.
Synthesis of intermediate 1:
first step 1B preparation of hydrochloride
1A (90 g,0.50 mol) was dissolved in 500mL of 2mol/L ethyl acetate hydrochloride solution and reacted at room temperature for 5 hours. The reaction system was concentrated under reduced pressure to give crude hydrochloride salt of 1B (59 g).
LCMS m/z=82.3[M+1]+
Second step, preparation of intermediate 1
The crude 1B hydrochloride (59 g) was dissolved in 500mL DMSO, sodium bicarbonate (42 g,0.50 mol) was added, and after stirring at room temperature for 10min, 100mL DIPEA and 1C (165.6 g,0.60 mol) were added and reacted at 85℃for 5h. The reaction solution was cooled to room temperature, 5L of water was added, and the solid was collected by filtration, washed with 500mL of water and dried by air blast to give crude intermediate 1 (40 g).
EXAMPLE 1 preparation of Compound 1
First step 1b preparation
1A (1.0 g,3.4 mmol) (see WO 2012123745), 1A (0.92 g,5.1 mmol), TEA (2.06 g,20.4 mmol), cuprous iodide (130 mg,0.68 mmol) and (PPh 3)2PdCl2 (240 mg,0.34 mmol) were added to a reaction flask, 5mL DMF was added under nitrogen protection, the reaction mixture was cooled to room temperature, added to 50mL ethyl acetate, the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 1b (1.0 g, yield: 85%).
Second step 1c preparation
1B (1.0 g,2.88 mmol) and sodium carbonate (0.61 g,5.76 mmol) were added to 10mL DMF and allowed to react at 85℃for 1.5h. The reaction solution was cooled to room temperature, added to 100mL of ethyl acetate, washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 1c (0.6 g, yield: 84%).
LCMS m/z=248.2[M+1]+
Third step, preparation of 1e
1C (0.58 g,2.33 mmol), 1d (0.95 g,2.33 mmol) (see Journal of Organic Chemistry,2003,68,8075-8079 for synthesis), cuprous iodide (89 mg,0.47 mmol) and (1S, 2S) - (+) -N, N' -dimethyl-1, 2-cyclohexanediamine (CAS: 87583-89-9) (0.71 g,4.99 mmol) were added to the reaction flask, and 10mL of DMF was added under nitrogen, and the mixture was allowed to react at 100℃for 2 hours. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 1e (0.6 g, yield: 49%).
LCMS m/z=526.1[M+1]+
Fourth step, preparation of Compound 1
1E (0.2 g,0.38 mmol) and p-toluene sulfonic acid (0.19 g,1.10 mmol) were dissolved in 5mL acetonitrile and reacted at room temperature for 12h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product, 1f (0.1 g,0.36 mmol) and DIPEA (0.29 g,2.24 mmol) were dissolved in 5mL DMF and warmed to 80℃for reaction for 5h. The reaction solution was cooled to room temperature, 100mL of ethyl acetate was added, the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give compound 1 (0.1 g, yield: 39%).
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.98(s,1H),7.90(s,1H),7.86(s,1H),7.80–7.64(m,4H),6.86–6.78(m,1H),6.57(dd,1H),5.01–4.89(m,1H),4.45–4.30(m,2H),4.17–4.03(m,2H),3.94–3.76(m,1H),2.98–2.63(m,3H),2.23–2.06(m,1H).
LCMS m/z=682.1[M+1]+
EXAMPLE 2 preparation of the trifluoroacetate salt of Compound 2
First step, preparation of 2b
2A (5.0 g,25.57 mmol) was added to 50mL of water, 15mL of concentrated sulfuric acid was slowly added and reacted at 60℃for 1h. The reaction solution was cooled to 0℃and 5mL of an aqueous solution of sodium nitrite (1.76 g,25.51 mmol) was added dropwise, and the mixture was stirred at 0-5℃for 30min. The reaction mixture was warmed to 40℃and 10mL of an aqueous solution of potassium iodide (8.49 g,51.14 mmol) was added dropwise thereto, followed by reaction at 50℃for 1 hour. The reaction solution was cooled to room temperature, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with 1mol/L aqueous hydrochloric acid (50 mL), then with 50mL of saturated aqueous sodium thiosulfate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-100:1) to give 2b (5.0 g, yield: 64%).
Second step 2d preparation
2C (5.0 g,49.93 mmol) was dissolved in 50mL of acetic acid, iodine (12.67 g,49.92 mmol) was added at room temperature and reacted at room temperature for 12h. The reaction solution was added to 200mL of water, the pH was adjusted to 8 with solid potassium carbonate, extracted with ethyl acetate (100 ml×3), the organic phases were combined, washed with 50mL of saturated aqueous sodium thiosulfate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-5:1) to give 2d (2.0 g, yield: 18%).
Third step, preparation of 2e
2D (2.0 g,8.85 mmol) and 1-chloro-2-isocyanatoethane (0.95 g,9.0 mmol) were added to 20mL acetonitrile and heated to 90℃under reflux for 2h. The reaction solution was cooled to room temperature, 5mL of methanol was added, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-2:1) to give 2e (2.0 g, yield: 73%).
Fourth step, preparation of 2f
2E (2.0 g,6.03 mmol) and potassium carbonate (1.25 g,9.04 mmol) were added to 20mL acetonitrile and heated to 80℃under reflux for 12h. The reaction solution was cooled to room temperature, 5mL of methanol was added, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 2f (1.5 g, yield: 84%).
LCMS m/z=296.2[M+1]+
Fifth step, 2g of preparation
2F (1.0 g,3.39 mmol), 1A (0.92 g,5.08 mmol), TEA (2.06 g,20.36 mmol), cuprous iodide (130 mg,0.68 mmol) and (PPh 3)2PdCl2 (240 mg,0.34 mmol) were added to a reaction flask, 5mL DMF was added under nitrogen, the reaction was warmed to 50℃for 0.5h, the reaction solution was cooled to room temperature, 50mL ethyl acetate was added, the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 2g (0.8 g, yield: 68%).
LCMS m/z=349.3[M+1]+
Sixth step, 2h preparation
2G (0.6 g,1.72 mmol), 2b (0.6 g,1.96 mmol), cuprous iodide (59 mg,0.31 mmol) and (1S, 2S) - (+) -N, N' -dimethyl-1, 2-cyclohexanediamine (0.6 g,4.22 mmol) were added to the reaction flask, and 6mL of DMF was added under nitrogen protection and the mixture was allowed to react at 100℃for 2 hours. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 2h (0.6 g, yield: 66%).
LCMS m/z=527.1[M+1]+
Seventh step, preparation of compound 2 trifluoroacetate salt
2H (0.2 g,0.38 mmol) and p-toluene sulfonic acid (0.26 g,1.51 mmol) were dissolved in 10mL acetonitrile and reacted at room temperature for 12h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product, 1f (0.1 g,0.36 mmol) and DIPEA (0.3 g,2.32 mmol) were dissolved in 5mL DMF and warmed to 80℃for reaction for 5h. The reaction solution was cooled to room temperature, 100mL of ethyl acetate was added, the organic phase was washed with a saturated aqueous sodium chloride solution (50 mL. Times.3), dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was subjected to Pre-HPLC (instrument and preparative column: preparation of liquid phase using Glison GX-281, preparative column model is Sunfire C18,5 μm, inner diameter. Times. Length=30 mm. Times.150 mm). The preparation method comprises dissolving the crude product with methanol and dimethyl sulfoxide, and filtering with 0.45 μm filter membrane to obtain sample solution. Mobile phase system acetonitrile/water (0.1% tfa). Gradient elution method acetonitrile was eluted 60% by 5% gradient (elution time 15 min), and lyophilized to give the trifluoroacetate salt of Compound 2 (0.05 g).
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.05(s,1H),7.90–7.79(m,2H),7.74–7.62(m,2H),6.90–6.82(m,1H),6.71(dd,1H),5.13–5.01(m,1H),4.45–4.32(m,2H),4.32–4.15(m,2H),4.15–3.90(m,5H),2.98–2.80(m,1H),2.69–2.50(m,2H),2.09–1.96(m,1H).
LCMS m/z=683.0[M+1]+
EXAMPLE 3 preparation of Compound 3
First step preparation of 3b
3A (4.1 g,19.80 mmol) and 4-iodo-1H-pyrazole (4.22 g,21.75 mmol) were dissolved in 40mL acetonitrile, solid cesium carbonate (9.68 g,29.70 mmol) was added and reacted at 80℃for 3H. The reaction solution was cooled to room temperature, 30mL of water and 100mL of ethyl acetate were added, the solution was separated, the organic phase was washed with 30mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:9) to give 3b (2.40 g, yield: 38%).
Second step, preparation of 3c
3B (2.30 g,7.18 mmol) was dissolved in 20mL tetrahydrofuran, 4mL water was added, and lithium hydroxide monohydrate (0.6 g,14.3 mmol) was added and reacted at room temperature for 30min. To the reaction solution was added dropwise 1mol/L diluted hydrochloric acid to adjust pH to 6, 50mL of ethyl acetate was added, the solution was separated, the organic phase was washed with 20mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 1 (2.0 g). 4- (trifluoromethyl) benzene-1, 2-diamine (1.0 g,5.7 mmol) was dissolved in 10mL pyridine, and crude 1 (1.6 g) and triphenyl phosphite (5.3 g,17.1 mmol) were added and heated to 200℃for 20min of microwave reaction. The reaction solution was cooled to room temperature, 80mL of ethyl acetate was added, the organic phase was washed with water (100 mL. Times.3), then 50mL of saturated aqueous sodium chloride solution was used, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =68:32) to give 3c (0.3 g, yield: 12%).
LCMS m/z=433.2[M+1]+
Third step, preparation of Compound 3
3C (100 mg,0.23 mmol) was added to a 50mL single port flask, 8mL dry DMF was added, crude intermediate 1 (116 mg), triethylamine (70 mg,0.69 mmol) was added, nitrogen was replaced three times, PPh 3)2PdCl2 (16 mg,0.023 mmol) and cuprous iodide (8 mg,0.042 mmol) were added, nitrogen was replaced three times, and 50℃was reacted for 2h.
1H NMR(400MHz,CDCl3)δ8.31(s,1H),8.20–7.30(m,6H),6.84–6.72(m,1H),6.54(dd,1H),5.00–4.88(m,1H),4.40–4.28(m,2H),4.10–3.97(m,2H),3.88–3.72(m,1H),3.34–3.07(m,2H),3.05–2.62(m,5H),2.43–2.06(m,3H).
LCMS m/z=642.4[M+1]+
EXAMPLE 5 preparation of Compound 5
First step, preparation of 5b 5a (4.1 g,19.80 mmol) and 4-iodo-1H-pyrazole (4.22 g,21.75 mmol) were dissolved in 40mL acetonitrile, cesium carbonate (9.68 g,29.70 mmol) was added and reacted at 80℃for 3H. The reaction solution was cooled to room temperature, 30mL of water and 100mL of ethyl acetate were added, the solution was separated, the organic phase was washed with 30mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:9) to give 5b (2.40 g, yield: 38%).
Second step, preparation of 5c
5B (2.30 g,7.18 mmol) was dissolved in 20mL tetrahydrofuran, 4mL water was added, lithium hydroxide monohydrate (0.6 g,14.3 mmol) was added and reacted at room temperature for 30min. To the reaction solution was added dropwise 1mol/L diluted hydrochloric acid to adjust pH to 6, 50mL of ethyl acetate was added, the solution was separated, the organic phase was washed with 20mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (2.0 g). The crude product (2.0 g) was cooled to 0℃and 40mL of borane tetrahydrofuran solution (1.0 mol/L) was slowly added and reacted at room temperature for 16h. The reaction solution was cooled to 0 ℃, methanol was slowly added dropwise until no bubbles were generated, the system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =3:1) to give 5C (1.1 g, yield: 55%).
LCMS m/z=279.1[M+1]+
Third step, preparation of 5d
5C (0.4 g,1.44 mmol) was dissolved in 15mL of dichloromethane, triethylamine (0.44 g,4.35 mmol) was added, cooled to 0℃and MsCl (0.2 g,1.75 mmol) was slowly added dropwise and reacted at room temperature for 16h. To the reaction system was added 50mL of water, extracted with 100mL of ethyl acetate, the organic phase was washed with 50mL of saturated aqueous sodium bicarbonate solution, further washed with 50mL of 0.5mol/L hydrochloric acid, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =3:1) to give 5d (0.5 g, yield: 98%).
LCMS m/z=357.0[M+1]+
Fourth step, preparation of 5e
5- (Trifluoromethyl) -1H-indazole (0.2 g,1.07 mmol) was dissolved in 5mL DMF, cesium carbonate (0.70 g,2.15 mmol) was added, warmed to 90℃and slowly added in portions for 5d (0.46 g,1.29 mmol), reacted at 90℃for 16H. The reaction system was cooled to room temperature, 50mL of water was added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1), to give 5e (0.25 g, yield: 52%).
Fifth step, preparation of Compound 5
5E (0.15 g,0.34 mmol), crude intermediate 1 (0.14 g), TEA (0.10 g,0.99 mmol), cuI (7 mg,0.037 mmol) and PdCl 2(PPh3)2 (24 mg,0.034 mmol) were added to the reaction flask and reacted for 1h under nitrogen with 5mL of DMF at 50 ℃. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1:1), to give compound 5 (0.12 g, yield: 54%).
1H NMR(400MHz,CDCl3)δ8.13–8.04(m,2H),7.96(s,1H),7.69–7.62(m,1H),7.59–7.53(m,1H),7.40–7.33(m,1H),6.80–6.74(m,1H),6.72–6.62(m,2H),6.51(dd,1H),4.99–4.87(m,1H),4.83(s,2H),4.34–4.20(m,2H),4.00–3.87(m,2H),3.75–3.60(m,1H),2.95–2.65(m,5H),2.65–2.46(m,2H),2.26–2.00(m,3H).
LCMS m/z=656.6[M+1]+
EXAMPLE 6 preparation of Compound 6
First step, preparation of 6b
Compound 6A (1.00 g,4.12 mmol) and 6A (1.01 g,4.5 mmol) were dissolved in tetrahydrofuran (50 mL), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (CAS: 161265-03-8) (0.24 g, 0.015 mmol), potassium phosphate (2.62 g,12.34 mmol) and palladium acetate (0.05 g,0.22 mmol) were added, nitrogen was replaced three times, and the reaction was 80℃for 16h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =4:1) to give 6b (1.00 g, yield: 71%).
Second step, preparation of 6c
In a 250mL reaction flask, 6b (1.00 g,2.92 mmol), 1C (0.72 g,2.91 mmol), cuI (0.11 g,0.58 mmol), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (CAS: 67579-81-1) (0.17 g,1.2 mmol), potassium phosphate (1.86 g,8.76 mmol) and DMF (30 mL) were added sequentially and reacted at 100℃for 16h. The reaction solution was cooled to room temperature, 100mL of ethyl acetate was added, the organic phase was washed with water (100 ml×3) and 30mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =3:1) to give 6c (0.72 g, yield 49%).
Third step, 6d preparation
In a 50mL reaction flask, 6C (0.50 g,0.98 mmol) was dissolved in 20mL acetonitrile and p-toluenesulfonic acid monohydrate (0.51 g,2.68 mmol) was added and reacted at 25℃for 16h. The reaction solution was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate solution, extracted with 30mL of methylene chloride, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 6d (0.38 g).
LCMS m/z=409.4[M+1]+
Fourth step, preparation of Compound 6
In a 50mL reaction flask, the crude product 6d (0.15 g), 1f (0.12 g,0.43 mmol), DIPEA (0.10 g,0.77 mmol) and DMSO (10 mL) were added in this order and reacted at 90℃for 3h. The reaction solution was cooled to room temperature, 10mL of water was added, a yellow solid was precipitated, and the resulting mixture was suction-filtered, and the cake was washed with water (5 ml×3), then dissolved in a mixed solvent of dichloromethane/methanol (v/v) =10:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by separation with a silica gel column (dichloromethane/methanol (v/v) =15:1) to give compound 6 (0.13 g, yield: 25%).
1H NMR(400MHz,CDCl3)δ8.56–8.46(m,2H),7.92(s,1H),7.85–7.61(m,5H),6.86–6.79(m,1H),6.58(dd,1H),5.00–4.89(m,1H),4.42–4.31(m,2H),4.18–4.05(m,2H),3.94–3.79(m,1H),3.04–2.60(m,3H),2.22–2.08(m,1H).
EXAMPLE 7 preparation of Compound 7
First step preparation of 7b
In a 1L reaction flask, crude intermediate 1 (10.00 g), 7a (8.72 g,29.65 mmol) was dissolved in DMF (200 mL), pdCl 2(PPh3)2 (2.08 g,2.96 mmol), cuI (1.13 g,5.93 mmol) and TEA (18.00 g,177.88 mmol) were added, nitrogen was displaced three times, and the reaction was carried out at 55℃for 1h. The reaction solution was cooled to room temperature, 500mL of ethyl acetate was added, 100mL of water was added, flocculent solid was precipitated, suction filtration was performed, the filtrate was allowed to stand for delamination, the organic phase was washed with water (50 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by beating with 50mL of a mixed solvent of dichloromethane/methyl tert-butyl ether (v/v) =1:5, and filtration was performed to give crude product 7b (7.00 g).
LCMS m/z=504.7[M+1]+
Second step, preparation of 7c
The crude 7b (2.00 g) was dissolved in methylene chloride (30 mL), trifluoroacetic acid (30 mL) was added at room temperature, and the reaction was carried out at 25℃for 2h. The reaction system was concentrated under reduced pressure, 200mL of methylene chloride was added, the pH was adjusted to 9 with saturated aqueous sodium hydrogencarbonate, the solution was separated, the aqueous phase was extracted with methylene chloride (50 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by separation with a silica gel column (methylene chloride/methanol (v/v) =12:1) to give 7c (1.54 g, two-step yield: 45% from compound 7 a).
LCMS m/z=404.1[M+1]+
Third step, preparation of 7f
To the glass tube was added 7d (2.00 g,8.23 mmol) and 7e (15 mL), and the reaction was sealed at 50℃for 16h. The reaction system was cooled to room temperature, 100mL of ethyl acetate was added, washed with water (50 mL. Times.3) and 50mL of a saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 7f (1.95 g).
LCMS m/z=249.1[M+1]+
Fourth step, preparation of Compound 7
In a 50mL reaction flask, the above crude 7f (0.025 g), 7C (0.04 g,0.099 mmol), cuI (0.04 g,0.021 mmol), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (CAS: 67579-81-1) (0.006g, 0.042 mmol), potassium phosphate (0.063 g, 0.297mmol) and DMF (10 mL) were added sequentially and reacted at 100℃for 16h. The reaction solution was cooled to room temperature, ethyl acetate (50 mL), washing with water (50 mL. Times.3) and 50mL of saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 7 (0.015 g, yield: 27%).
1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.93(s,1H),7.72–7.63(m,2H),6.85–6.78(m,1H),6.72–6.52(m,2H),4.98–4.89(m,1H),4.36(t,2H),4.09(t,2H),3.88–3.77(m,5H),3.54–3.45(m,4H),2.95–2.64(m,3H),2.19–2.08(m,1H).
EXAMPLE 8 preparation of Compound 8
First step, preparation of 8c
8A (0.20 g,0.65 mmol) and 8b (0.13 g,0.65 mmol) were added to a glass vial, toluene (3 mL) and methanol (3 mL) were added, tetrakis (triphenylphosphine) palladium (0.015 g,0.013 mmol) and sodium carbonate (0.14 g,1.32 mmol) were added, nitrogen was displaced three times, and the reaction was performed at 110℃for 2h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether) to give 8c (0.115 g, yield: 53%).
Second step preparation of Compound 8
In a 50mL reaction flask, 8C (0.11 g,0.33 mmol), 7C (0.133 g,0.33 mmol), cuI (0.013 g,0.068 mmol), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (CAS: 67579-81-1) (0.019 g,0.13 mmol), potassium phosphate (0.21 g,0.99 mmol) and DMF (15 mL) were added in this order and reacted at 100℃for 16h. The reaction solution was cooled to room temperature, ethyl acetate (100 mL) was then added, the mixture was washed with water (100 mL. Times.3) and 50mL of a saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 8 (0.025 g, yield: 12%).
1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.92(s,1H),7.82–7.73(m,4H),7.68(d,1H),7.63–7.45(m,4H),6.85–6.81(m,1H),6.58(dd,1H),5.00–4.89(m,1H),4.45–4.33(m,2H),4.17–4.05(m,2H),3.92–3.80(m,1H),2.98–2.65(m,3H),2.20–2.09(m,1H).
EXAMPLE 9 preparation of Compound 9
Compound 9 was obtained by the synthesis method of example 8, starting from compounds 9a and 9 b.
'1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.93(s,1H),7.82–7.47(m,8H),7.42–7.36(m,1H),6.84–6.80(m,1H),6.57(dd,1H),4.98–4.89(m,1H),4.45–4.30(m,2H),4.17–4.05(m,2H),3.93–3.76(m,1H),2.96–2.69(m,3H),2.18–2.08(m,1H).
LCMS m/z=658.0[M+1]+
EXAMPLE 10 preparation of Compound 10
First step, preparation of 10b
In a 250mL reaction flask, 10a (5.00 g,25.77 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), cooled to 0℃and 60% sodium hydride (1.55 g) was added in portions, and after continuing the reaction at 0℃for 1h, 2- (trimethylsilyl) ethoxymethyl chloride (5.17 g,31.00 mmol) was added dropwise and the reaction was continued at 25℃for 2h. To the reaction solution were added 30mL of water and 200mL of ethyl acetate, the organic phase was washed with water (30 mL. Times.3) and 30mL of saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1) to give 10b (6.97 g, yield: 83%).
LCMS m/z=325.0[M+1]+
Second step, preparation of 10c
In a 100mL reaction flask, compound 10b (0.51 g,1.57 mmol), 7C (0.58 g,1.44 mmol), cuI (0.14 g, 0.385 mmol), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (CAS: 67579-81-1) (0.20 g,1.41 mmol), potassium phosphate (0.92 g,4.33 mmol) and DMF (20 mL) were sequentially added, nitrogen was replaced three times, and the reaction was performed at 120℃for 8 hours. The reaction solution was cooled to room temperature, ethyl acetate (300 mL) was then added, the mixture was washed with water (100 mL. Times.3) and 50mL of a saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (petroleum ether/ethyl acetate (v/v) =1:1) to give 10c (0.43 g, yield: 50%).
Third step, preparation of 10d
To a 100mL reaction flask was added 10C (0.43 g,0.72 mmol) and dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added dropwise and reacted at 25℃for 1h. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 9 with aqueous sodium hydrogencarbonate, a yellow solid was precipitated, and the mixture was suction-filtered, and the cake was washed 3 times with 10mL of water, then dissolved in a mixed solvent of methylene chloride/methanol (v/v) =10:1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by separation with a silica gel column (methylene chloride/methanol (v/v) =10:1), to give 10d (0.25 g, yield: 74%).
LCMS m/z=470.2[M+1]+
Fourth step, preparation of 10f
In a 100mL reaction flask, 10e (2.00 g,8.20 mmol), cyclopropylboronic acid (1.06 g,12.34 mmol), potassium phosphate (9.04 g,42.59 mmol), tricyclohexylphosphine (0.46 g,1.64 mmol), palladium acetate (0.31 g,1.38 mmol), toluene (20 mL) and water (1 mL) were added in this order, nitrogen was replaced three times, and the reaction was performed at 100℃under nitrogen protection for 16h. The reaction solution was cooled to room temperature, a solid was precipitated, 200mL of water was added, extraction was performed with 300mL of ethyl acetate, the organic phase was washed with 50mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =4:1) to give 10f (1.15 g, yield: 89%).
LCMS m/z=159.2[M+1]+
Fifth step, preparation of 10g
In a 100mL reaction flask, 10f (0.50 g,3.16 mmol) and acetonitrile (15 mL) were added, cooled to 0℃and isoamyl nitrite (0.52 g,4.44 mmol) was added, after continuing the reaction at 0℃for 10min, copper bromide (0.90 g,4.03 mmol) was added and the reaction at 25℃for 16min. To the reaction solution was added 50mL of water, 200mL of ethyl acetate was added, washed with water (50 mL. Times.3) and 30mL of saturated aqueous sodium chloride, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1) to give 10g (0.70 g, yield: 99%).
Sixth step preparation of Compound 10
In a 100mL reaction flask, 10g (0.044 g,0.20 mmol), 10d (0.096 g,0.20 mmol), cuI (0.008 g,0.042 mmol), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (CAS: 67579-81-1) (0.0117 g,0.077 mmol), potassium phosphate (0.13 g,0.61 mmol) and DMF (10 mL) were sequentially added, nitrogen was replaced three times, and the reaction was performed at 110℃for 16h. The reaction solution was cooled to room temperature, ethyl acetate (100 mL) was then added, the mixture was washed with water (50 mL. Times.3) and 30mL of a saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 10 (0.025 g, yield: 20%).
1H NMR(400MHz,CDCl3)δ8.20–8.15(m,1H),8.02–7.95(m,2H),7.84(s,1H),7.73(s,1H),7.68(d,1H),7.62–7.54(m,2H),7.41–7.36(m,1H),6.85–6.78(m,1H),6.57(dd,1H),5.00–4.89(m,1H),4.45–4.30(m,2H),4.15–4.03(m,2H),3.92–3.77(m,1H),2.99–2.65(m,3H),2.18–2.08(m,1H),2.06–1.94(m,1H),1.10–1.00(m,2H),0.80–0.72(m,2H).
EXAMPLE 11 preparation of Compound 11
First step, preparation of 11b
11A (2.00 g,8.33 mmol) was dissolved in hydrochloric acid (15 mL), cooled to 0℃and sodium nitrite (0.63 g,9.13 mmol) was added, and after 0℃reaction for 1.5h, 10mL of an aqueous solution of potassium iodide (4.15 g,25.00 mmol) was added and 25℃reaction was carried out for 16h. The reaction solution was poured into 20mL of 6mol/L aqueous sodium hydroxide solution, extracted with 30mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (pure petroleum ether) to give 11b (2.31 g, yield: 79%).
Second step 11c preparation
To the glass tube was added 11b(2.30g,6.55mmol)、PdCl2(PPh3)2(0.46g,0.66mmol)、CuI(0.25g,1.31mmol)、TEA(3.98g,39.33mmol) and 1mol/L of a solution of propyne in tetrahydrofuran (7.21 mL,7.21 mmol), DMF (10 mL) was added, nitrogen was replaced three times, and the reaction was sealed at 25℃under nitrogen for 2 hours. Ethyl acetate (100 mL) was added to the reaction mixture, which was washed with water (100 mL. Times.3) and 50mL of a saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether) to give 11c (0.88 g, yield: 51%).
Third step, preparation of Compound 11
In a 100mL reaction flask, 11C (0.053 g,0.20 mmol), 10d (0.096 g,0.20 mmol), cuI (0.008 g,0.042 mmol), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (CAS: 67579-81-1) (0.0117 g,0.077 mmol), potassium phosphate (0.13 g,0.61 mmol) and DMF (10 mL) were sequentially added, nitrogen was replaced three times, and the reaction was performed at 110℃for 16h. The reaction solution was cooled to room temperature, ethyl acetate (100 mL) was then added, the mixture was washed with water (50 mL. Times.3) and 50mL of a saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 11 (0.011 g, yield: 8%).
1H NMR(400MHz,CDCl3)δ8.65(s,1H),7.92–7.87(m,2H),7.82(d,1H),7.77–7.72(m,2H),7.67(s,1H),7.64–7.53(m,2H),6.78–6.73(m,1H),6.50(dd,1H),4.93–4.83(m,1H),4.38–4.26(m,2H),4.10–3.96(m,2H),3.86–3.70(m,1H),2.90–2.57(m,3H),2.15–1.98(m,4H).
EXAMPLE 12 preparation of Compound 12
First step, preparation of 12b
In a 50mL reaction flask, 12a (2.00 g,8.91 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), cooled to 0℃and borane tetrahydrofuran complex (1.15 g,13.38 mmol) was added dropwise and reacted for 16h at 25 ℃. To the reaction solution was added 20mL of a saturated aqueous ammonium chloride solution, 300mL of ethyl acetate was added, and the mixture was washed with water (20 mL. Times.3) and 30mL of a saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 12b (1.87 g).
Second step 12c preparation
In a 50mL reaction flask, the crude product 12b (0.50 g) and methylene chloride (15 mL) were added, DMF (0.017 g) and SOCl 2 (0.56 g) were added and reacted at 25℃for 2h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1) to give 12c (376 mg, two-step yield from compound 12 a: 69%).
Third step, preparation of Compound 12
In a 50mL reaction flask, 10d (0.096 g,0.20 mmol), cesium carbonate (0.11 g,0.34 mmol) and DMF (10 mL) were added sequentially, cooled to 0℃and 12C (0.04 g,0.17 mmol) was added and reacted at 25℃for 3h. To the reaction solution was added 20mL of water, 100mL of ethyl acetate was added, washed with water (30 mL. Times.3) and 30mL of saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by prep-TLC (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 12 (34 mg, yield: 26%).
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.76–7.66(m,3H),7.65–7.56(m,3H),7.47–7.40(m,1H),7.18–7.11(m,1H),6.76–6.72(m,1H),6.49(dd,1H),5.41(s,2H),4.91–4.81(m,1H),4.35–4.24(m,2H),4.07–3.96(m,2H),3.83–3.69(m,1H),2.90–2.55(m,3H),2.14–2.00(m,1H).
LCMS m/z=662.8[M+1]+
EXAMPLE 13 preparation of Compound 13
First step, preparation of 13c
DMF (3 mL) was added to 13a (0.30 g,2.04 mmol), 13b (0.58 g,2.49 mmol) and potassium carbonate (0.86 g,6.22 mmol) were added with stirring at room temperature, nitrogen was replaced three times, and the reaction was continued for 2h at 80 ℃. The reaction solution was cooled to room temperature, 20mL of ethyl acetate and 20mL of water were added, and the organic phase was separated, washed with saturated aqueous sodium chloride (20 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:20-1:10) to give 13c (0.65 g, yield: 89%).
Second step, preparation of 13e
13C (0.70 g,1.94 mmol), 1C (0.57 g,2.30 mmol), cuI (0.074 g,0.39 mmol), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (CAS: 67579-81-1) (0.11 g,0.77 mmol), potassium phosphate (1.23 g,5.79 mmol) and DMF (10 mL) were added sequentially, nitrogen was replaced three times, and the reaction was performed by microwaves at 130℃for 5h. The reaction solution was cooled to room temperature, 50mL of ethyl acetate and 50mL of water were added, and the organic phase was separated, washed with saturated aqueous sodium chloride (30 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:20-1:3) to give 13e (0.05 g, yield: 5%).
Third step, preparation of p-toluenesulfonate salt of 13f
Acetonitrile (3 mL) was added to 13e (0.05 g,0.095 mmol), and p-toluenesulfonic acid (0.05 g,0.29 mmol) was added with stirring at room temperature and reacted at 25℃for 15h. The reaction solution was concentrated under reduced pressure to give p-toluenesulfonate (0.04 g) of crude 13 f.
Fourth step preparation of Compound 13
DMF (5 mL) was added to the crude 13f p-toluenesulfonate (0.035 g) above, 1f (0.023 g,0.083 mmol) and DIPEA (0.074 g,0.57 mmol) were added with stirring at room temperature, nitrogen was replaced three times, 80℃for 3h at room temperature. The reaction solution was cooled to room temperature, 20mL of ethyl acetate and 20mL of water were added, the organic phase was separated, the organic phase was washed with saturated brine (20 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:10-1:1) to give compound 13 (0.006 g, yield: 11%).
1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.97(s,1H),7.84–7.63(m,4H),7.47–7.41(m,1H),7.28–7.23(m,1H),6.86–6.80(m,1H),6.57(dd,1H),5.00–4.88(m,1H),4.45–4.32(m,2H),4.18–4.06(m,2H),3.92–3.79(m,1H),2.98–2.64(m,3H),2.20–2.08(m,1H).
EXAMPLE 14 preparation of Compound 14
First step 14b preparation
1, 4-Dioxahexacyclic ring (15 mL) was added to a solution of cyclopent-2-en-1-one (0.50 g,6.09 mmol), 14a (2.05 g,9.14 mmol) and (1, 5-cyclooctadiene) chlororhodium (I) dimer (CAS: 12092-47-6) (0.09 g,0.18 mmol), and a solution of sodium carbonate (1.03 g,9.72 mmol) in water (5 mL) was added with stirring at room temperature, nitrogen was replaced three times, and the reaction was continued at 90℃for 4h. The reaction solution was cooled to room temperature, 30mL of ethyl acetate and 30mL of water were added, and the organic phase was separated, washed with saturated aqueous sodium chloride (20 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:20-1:10) to give 14b (0.80 g, yield: 50%).
Second step 14c preparation
Methanol (15 mL) was added to 14b (0.80 g,3.05 mmol), cooled to 0℃and sodium borohydride (0.23 g,6.08 mmol) was added and reacted at 25℃for 2h. The reaction solution was cooled to 0 ℃,10 mL of saturated aqueous ammonium chloride solution was added, 30mL of ethyl acetate and 20mL of water were added, the organic phase was separated, the organic phase was washed with 20mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20-1:3), to give crude product 1 (0.40 g). Dichloromethane (10 mL) was added to crude 1 (0.25 g), cooled to 0 ℃, and methylsulfonyl chloride (0.22 g,1.92 mmol) and triethylamine (0.29 g,2.87 mmol) were added and reacted for 2h at 25 ℃. The reaction solution was cooled to 0 ℃, saturated 10mL of saturated aqueous sodium bicarbonate solution was added, 30mL of dichloromethane and 20mL of water were added, the organic phase was separated, the organic phase was washed with 20mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20-1:4) to give crude product 2 (0.40 g). In a 50mL reaction flask, crude 2 (0.27 g), 1C (0.23 g,0.93 mmol), cesium carbonate (0.77 g,2.36 mmol) and DMF (10 mL) were added in this order and reacted at 80℃for 5h. The reaction solution was cooled to room temperature, 30mL of ethyl acetate and 30mL of water were added, and the organic phase was separated, washed with saturated aqueous sodium chloride (30 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:20-1:4) to give 14c (0.27 g, yield: 59%).
Third step, preparation of p-toluenesulfonate salt of 14d
Acetonitrile (10 mL) was added to 14C (0.25 g,0.51 mmol) and p-toluene sulfonic acid (0.26 g,1.51 mmol) was added with stirring at room temperature and reacted at 25 ℃ for 15h. The reaction solution was concentrated under reduced pressure to give p-toluenesulfonate (0.18 g) as crude 14 d.
Fourth step preparation of Compound 14
DMF (10 mL) was added to the crude 14d p-toluenesulfonate (0.18 g) above, 1f (0.13 g,0.47 mmol) and DIPEA (0.42 g,3.25 mmol) were added with stirring at room temperature, nitrogen was replaced three times, and the reaction was 80℃for 5h. The reaction solution was cooled to room temperature, 20mL of ethyl acetate and 20mL of water were added, the organic phase was separated, washed with saturated aqueous sodium chloride (20 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:10-1:1), and the obtained crude product was purified by prep-TLC (DCM: meOH (v/v) =35:1) to give compound 14 (0.02 g, yield: 7%).
1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.72–7.56(m,4H),7.56–7.36(m,2H),6.84–6.78(m,1H),6.55(dd,1H),4.99–4.81(m,2H),4.43–4.30(m,2H),4.14–4.02(m,2H),3.98–3.75(m,2H),2.96–2.65(m,3H),2.62–2.07(m,6H),1.89–1.74(m,1H).
EXAMPLE 15 preparation of Compound 15
First step, preparation of 15c
In a 50mL reaction flask, 15a (1.00 g,5.04 mmol), 15b (0.48 g,5.51 mmol), cesium carbonate (3.28 g,10.07 mmol) and DMF (20 mL) were added sequentially and reacted at 80℃for 3h. The reaction solution was cooled to room temperature, 50mL of ethyl acetate and 50mL of water were added, the organic phase was separated, washed with saturated brine (30 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:20-1:4) to give 15c (0.55 g, yield: 41%).
Second step, 15d preparation
Dichloromethane (15 mL) was added to 15C (0.55 g,2.07 mmol), cooled to 0 ℃, and methylsulfonyl chloride (0.47 g,4.10 mmol) and triethylamine (0.63 g,6.22 mmol) were added and reacted for 2h at 25 ℃. The reaction solution was cooled to 0 ℃,10 mL of saturated aqueous sodium bicarbonate solution was added, 40mL of dichloromethane and 20mL of water were added, the organic phase was separated, the organic phase was washed with 20mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20-1:4) to give 15d (0.61 g, yield: 86%).
Third step, 15e preparation
In a 50mL reaction flask, 15d (0.20 g,0.58 mmol), 1C (0.17 g,0.69 mmol), cesium carbonate (0.57 g,1.75 mmol) and DMF (10 mL) were added sequentially and reacted at 80℃for 5h. The reaction solution was cooled to room temperature, 30mL of ethyl acetate and 30mL of water were added, the organic phase was separated, washed with saturated brine (30 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:20-1:4) to give 15e (0.27 g, yield: 94%).
Fourth step, preparation of p-toluenesulfonate salt of 15f
Acetonitrile (10 mL) was added to 15e (0.27 g,0.55 mmol), p-toluenesulfonic acid (0.28 g,1.63 mmol) was added with stirring at room temperature and reacted at 25℃for 15h. The reaction solution was concentrated under reduced pressure to give p-toluenesulfonate (0.22 g) as crude product 15 f.
Fifth step, preparation of Compound 15
DMF (10 mL) was added to the crude 15f p-toluenesulfonate (0.15 g) above, 1f (0.11 g,0.399 mmol) and DIPEA (0.49 g,3.79 mmol) were added with stirring at room temperature, nitrogen was replaced three times, and the reaction was 80℃for 5h. The reaction solution was cooled to room temperature, 20mL of ethyl acetate and 20mL of water were added, the organic phase was separated, washed with saturated aqueous sodium chloride (20 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:10-1:1), and the obtained crude product was purified by prep-TLC (DCM: meOH (v/v) =35:1) to give compound 15 (0.05 g, yield: 19%).
1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.74–7.50(m,4H),7.44–7.33(m,1H),6.93–6.84(m,1H),6.84–6.75(m,1H),6.54(dd,1H),5.07–4.88(m,2H),4.44–4.27(m,2H),4.15–3.70(m,6H),3.64–3.47(m,1H),3.00–2.64(m,3H),2.60–2.35(m,2H),2.20–2.05(m,1H).
LCMS m/z=651.2[M+1]+
EXAMPLE 16 preparation of Compound 16
First step, 16c preparation
16A (1.00 g,3.26 mmol), 16b (0.28 g,3.29 mmol), cuI (0.13 g,0.68 mmol), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (CAS: 67579-81-1) (0.19 g,1.34 mmol), potassium phosphate (2.10 g,9.90 mmol) and DMF (20 mL) were added sequentially, nitrogen was replaced three times, and the reaction was performed at 140℃for 5 hours. The reaction solution was cooled to room temperature, 50mL of ethyl acetate and 50mL of water were added, and the organic phase was separated, washed with saturated aqueous sodium chloride (30 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:20-1:3) to give 16c (0.35 g, yield: 41%).
Second step, 16d preparation
Anhydrous tetrahydrofuran (15 mL) was added to 16C (0.30 g,1.14 mmol), nitrogen was replaced three times, lithium bis trimethylsilylamide (0.38 g,2.27 mmol) was added at-78 ℃, after continuing the reaction at-78 ℃ for 1h, N-bromosuccinimide (0.24 g,1.35 mmol) was added, and after completion of the addition, stirring was carried out at-78 ℃ for 3h. To the reaction solution was added 20mL of saturated aqueous ammonium chloride solution, 30mL of ethyl acetate and 20mL of water, the organic phase was separated, washed with 20mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20-1:4) to give 16d (0.11 g, yield: 28%).
Third step preparation of Compound 16
In a 25mL reaction flask, 16d (0.10 g,0.29 mmol), 7C (0.12 g,0.30 mmol), cesium carbonate (0.28 g,0.86 mmol) and DMF (5 mL) were added sequentially and reacted at 60℃for 3h. The reaction solution was cooled to room temperature, 30mL of ethyl acetate and 30mL of water were added, the organic phase was separated, washed with saturated aqueous sodium chloride (20 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:10-1:1), and the obtained crude product was purified by prep-TLC (DCM: meOH (v/v) =20:1) to give compound 16 (0.05 g, yield: 26%).
1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.80–7.72(m,2H),7.70–7.56(m,3H),7.54–7.44(m,1H),6.84–6.77(m,1H),6.55(dd,1H),5.13–5.02(m,1H),5.01–4.86(m,1H),4.42–4.30(m,2H),4.12–4.03(m,2H),4.03–3.90(m,2H),3.88–3.75(m,1H),2.98–2.65(m,5H),2.18–2.08(m,1H).
LCMS m/z=665.1[M+1]+
EXAMPLE 17 preparation of Compound 17
Compound 17 was obtained by the synthesis method of example 10 starting from compounds 17a and 10 d.
'1H NMR(400MHz,CDCl3)δ8.42–8.34(m,1H),8.19(s,1H),8.14(d,1H),8.10(s,1H),8.02(d,1H),7.95(s,1H),7.89(s,1H),7.85–7.61(m,5H),6.86–6.80(m,1H),6.57(dd,1H),4.99–4.88(m,1H),4.45–4.32(m,2H),4.17–4.05(m,2H),3.93–3.77(m,1H),2.97–2.65(m,3H),2.19–2.07(m,1H).
LCMS m/z=621.2[M+1]+
EXAMPLE 18 preparation of Compound 18
Compound 18 was obtained by the synthesis method of example 10, starting with compound 18 a.
'1H NMR(400MHz,CDCl3)δ8.22(s,1H),7.92(s,1H),7.86(s,1H),7.78(s,1H),7.69–7.58(m,3H),7.55–7.51(m,1H),7.24–7.19(m,1H),6.75(d,1H),6.50(dd,1H),4.92–4.82(m,1H),4.35–4.27(m,2H),4.07–3.97(m,2H),3.83–3.69(m,1H),2.89–2.58(m,3H),2.12–2.02(m,1H),2.02–1.91(m,1H),1.08–1.00(m,2H),0.85–0.70(m,2H).
EXAMPLE 19 preparation of Compound 19
First step, preparation of 19b
In a 50mL reaction flask, 19A (0.50 g,2.52 mmol), 19A (0.25 g,2.47 mmol), cesium carbonate (1.64 g,5.03 mmol) and DMF (10 mL) were added sequentially and reacted at 80℃for 3h. The reaction solution was cooled to room temperature, 50mL of ethyl acetate and 50mL of water were added, and the organic phase was washed with saturated brine (30 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20-1:4) to give 19b (0.06 g, yield: 9%).
Second step 19c preparation
Dichloromethane (5 mL) was added to 19b (0.06 g,0.21 mmol), cooled to 0 ℃, methylsulfonyl chloride (0.048 g,0.42 mmol) and triethylamine (0.064 g,0.63 mmol) were added and reacted for 2h at 25 ℃. The reaction system was cooled to room temperature, 10mL of saturated aqueous sodium hydrogencarbonate solution was then added, 10mL of methylene chloride and 10mL of water were added, the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:20-1:4) to give 19c (0.058 g, yield: 77%).
Third step, preparation of Compound 19
In a 25mL reaction flask, 19C (0.061 g,0.17 mmol), 7C (0.07 g,0.17 mmol), cesium carbonate (0.17 g,0.52 mmol) and DMF (4 mL) were added sequentially and reacted at 80℃for 5h. The reaction solution was cooled to room temperature, 20mL of ethyl acetate and 10mL of water were added, and the organic phase was washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:10-1:1) to give compound 19 (0.02 g, yield: 18%).
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.74–7.57(m,4H),7.52–7.42(m,1H),7.15–7.07(m,1H),6.86–6.77(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.43–4.20(m,3H),4.15–4.00(m,2H),3.90–3.75(m,1H),3.66–3.50(m,2H),3.04–2.60(m,5H),2.35–2.06(m,5H).
LCMS m/z=665.2[M+1]+
EXAMPLE 20 preparation of Compound 20
First step, preparation of 20b
In a 25mL reaction flask, 20A (0.10 g,0.48 mmol), 20A (41.82 mg,0.48 mmol) and 1, 2-dichloroethane (5 mL) were sequentially added, and after stirring at room temperature for 5min, sodium triacetoxyborohydride (152.60 mg,0.72 mmol) was added and reacted at room temperature for 3h. 20mL of ethyl acetate and 10mL of saturated aqueous sodium bicarbonate were added, the organic phase was washed with 10mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (ethyl acetate/petroleum ether (v/v) =1:20-1:1) to give 20b (83 mg, yield: 62%).
Second step, preparation of 20c
Dichloromethane (5 mL) was added to 20b (0.08 g,0.29 mmol), cooled to 0 ℃, and methylsulfonyl chloride (0.066 g,0.58 mmol) and triethylamine (0.088 g,0.87 mmol) were added and reacted for 2h at 25 ℃. The reaction solution was cooled to 0 ℃,10 mL of saturated aqueous sodium bicarbonate solution was added, 10mL of dichloromethane and 10mL of water were added, the organic phase was separated, the organic phase was washed with 20mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20-1:3) to give 20C (0.09 g, yield: 87%).
Third step preparation of Compound 20
In a 25mL reaction flask, 20C (0.061 g,0.17 mmol), 7C (0.07 g,0.17 mmol), cesium carbonate (0.17 g,0.52 mmol) and DMF (4 mL) were added sequentially and reacted at 80℃for 5h. The reaction solution was cooled to room temperature, 20mL of ethyl acetate and 10mL of water were added, the organic phase was washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:10-1:1), and the obtained crude product was purified by prep-HPLC (dichloromethane: methanol (v/v) =30:1) to give compound 20 (0.02 g, yield: 18%).
1H NMR(400MHz,CDCl3)δ9.07(s,1H),7.78–7.42(m,6H),6.84–6.76(m,1H),6.55(dd,1H),5.00–4.84(m,2H),4.45–4.30(m,2H),4.13–4.02(m,2H),3.95–3.75(m,3H),3.15–2.40(m,8H),2.23–2.07(m,2H).
LCMS m/z=665.8[M+1]+
EXAMPLE 21 preparation of Compound 21
Compound 21 was obtained by the synthesis method of example 20, starting from compounds 21A and 21A.
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.77–7.41(m,6H),6.84–6.76(m,1H),6.59–6.50(m,1H),4.99–4.87(m,1H),4.44–4.27(m,2H),4.25–4.00(m,3H),3.88–3.64(m,3H),3.15–2.65(m,4H),2.49–1.93(m,8H).
LCMS m/z=679.3[M+1]+
EXAMPLE 22 preparation of Compound 22
In a 25mL reaction flask, 22a (10.25 mg,0.052 mmol), 10d (20 mg,0.043 mmol), cesium carbonate (28.02 mg,0.086 mmol) and DMF (3 mL) were added sequentially and reacted at 80℃for 3h. The reaction was cooled to room temperature, 20mL of ethyl acetate and 10mL of water were added, the solution was separated, the organic phase was washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by prep-TLC (DCM: meOH (v/v) =30:1) to give compound 22 (0.01 g, yield: 36%).
1H NMR(400MHz,CDCl3)δ8.32(s,1H),8.10–7.95(m,2H),7.90–7.60(m,6H),6.86–6.78(m,1H),6.62–6.52(m,1H),4.99–4.89(m,1H),4.45–4.30(m,2H),4.18–4.02(m,2H),3.94–3.76(m,1H),3.04–2.61(m,3H),2.22–2.06(m,1H).
EXAMPLE 23 preparation of Compound 23
First step, preparation of 23b
In a 50mL reaction flask, 23A (0.5 g,2.52 mmol), 23A (0.61 g,2.54 mmol) and potassium carbonate (0.7 g,5.07 mmol) were added, and 10mL DMSO was added and reacted at 100℃for 4h. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, washed with saturated aqueous sodium chloride (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 23b (0.5 g, yield: 48%).
LCMS m/z=418.5[M+1]+
Second step, preparation of 23c
23B (0.5 g,1.20 mmol), 1C (0.29 g,1.17 mmol), cuI (45 mg,0.24 mmol) and (1S, 2S) - (+) -N, N '' dimethyl-1, 2-cyclohexanediamine (CAS: 87583-89-9) (0.36 g,2.53 mmol) were added to the flask and reacted for 2h under nitrogen with 10mL DMF at 100 ℃. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 23c (0.4 g, yield: 59%).
LCMS m/z=585.2[M+1]+
Third step, preparation of p-toluenesulfonate salt of 23d
23C (0.2 g,0.34 mmol) and p-toluene sulfonic acid (0.19 g,1.10 mmol) were dissolved in 5mL acetonitrile and reacted at room temperature for 12h. The reaction system was concentrated under reduced pressure to give crude 23d of p-toluenesulfonate (0.2 g).
LCMS m/z=485.2[M+1]+
Fourth step preparation of Compound 23
The crude 23d p-toluenesulfonate (0.2 g), 1f (0.094 g,0.34 mmol) and DIPEA (0.26 g,2.01 mmol) were dissolved in 5mL DMF and reacted at 90℃for 2h. The reaction system was cooled to room temperature, added to 100mL of ethyl acetate, washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give compound 23 (0.05 g, yield: 20%).
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.98(s,1H),7.91–7.86(m,1H),7.77(s,1H),7.72(dd,1H),7.70–7.65(m,2H),7.60–7.53(m,1H),7.41(dd,1H),6.84–6.80(m,1H),6.60–6.53(m,2H),4.98–4.88(m,1H),4.43–4.32(m,2H),4.15–4.04(m,2H),3.90–3.76(m,1H),2.96–2.64(m,3H),2.20–2.06(m,1H),1.62–1.52(m,6H).
LCMS m/z=741.2[M+1]+
EXAMPLE 24 preparation of Compound 24
First step 24b preparation
In a 100mL reaction flask, 24a (3.00 g,23.79 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to 0℃and 60% sodium hydride (1.14 g) was added, followed by stirring at 0℃for 1h, and then 2- (trimethylsilyl) ethoxymethyl chloride (4.36 g,26.15 mmol) was added dropwise and reacted at room temperature for 3h. To the reaction system was added 50mL of water, 500mL of ethyl acetate was added, washed with water (50 mL. Times.3) and 50mL of saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1) to give 24b (3.87 g, yield: 64%).
LCMS m/z=257.1[M+1]+
Second step 24c preparation
In a 100mL reaction flask, 24b (2.00 g,7.81 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), lithium aluminum hydride (0.44 g,11.59 mmol) was added at 0deg.C, and the reaction was carried out at 0deg.C for 3h. To the reaction system was added 20mL of water, 200mL of ethyl acetate, washing with water (50 mL. Times.3) and 50mL of saturated aqueous sodium chloride, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1) to give 24c (1.75 g, yield: 98%).
LCMS m/z=229.1[M+1]+
Third step, 24d preparation
In a 50mL reaction flask, 24C (0.5 g,2.19 mmol), triethylamine (0.45 g,4.45 mmol) and methanesulfonyl chloride (0.37 g,3.23 mmol) were added sequentially at 0℃and reacted for 16h at 0 ℃. The reaction solution was quenched with 20mL of saturated aqueous ammonium chloride, extracted with 100mL of ethyl acetate, the organic phase was washed with 20mL of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel column (petroleum ether/ethyl acetate (v/v) =10:1) to give 24d (0.28 g, yield: 52%).
Fourth step 24e preparation
In a 50mL reaction flask, 7C (0.28 g,0.69 mmol), cesium carbonate (0.37 g,1.14 mmol) and DMF (15 mL) were added sequentially, 24d (0.14 g,0.57 mmol) was added dropwise and reacted at 25℃for 2h. To the reaction system was added 25mL of water, 100mL of ethyl acetate was added, washed with water (25 mL. Times.3) and 25mL of saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give 24e (0.10 g, yield: 29%).
LCMS m/z=614.8[M+1]+
Fifth step, 24f preparation
In a 50mL reaction flask, 24e (0.15 g,0.24 mmol) and methylene chloride (10 mL) were added sequentially, trifluoroacetic acid (10 mL) was added dropwise, and the reaction was carried out at 25℃for 1h. The reaction solution was concentrated under reduced pressure, 100mL of methylene chloride was added, the pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution, the mixture was extracted with 100mL of methylene chloride, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by separation with a silica gel column (methylene chloride/methanol (v/v) =12:1) to give 24f (0.10 g, yield: 86%).
LCMS m/z=484.7[M+1]+
Sixth step preparation of Compound 24
In a 50mL reaction flask, 24f (0.046 g,0.095 mmol), cesium carbonate (0.057 g,0.17 mmol) and DMF (5 mL) were added sequentially, 24A (0.02 g,0.087 mmol) was added dropwise (see WO2007018314 for synthesis) and reacted at 25℃for 2h. To the reaction system was added 10mL of water, 100mL of ethyl acetate was added, washed with water (10 mL. Times.3) and 10mL of saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 24 (0.036 g, yield: 61%).
1H NMR(400MHz,CDCl3)δ7.74–7.54(m,6H),7.52–7.43(m,1H),7.28–7.24(m,1H),7.09(d,1H),6.77(s,1H),6.55(dd,1H),5.44(s,2H),5.00–4.82(m,3H),4.42–4.30(m,2H),4.14–4.01(m,2H),3.89–3.72(m,1H),3.04–2.85(m,1H),2.85–2.64(m,2H),2.14–2.00(m,1H).
LCMS m/z=676.2[M+1]+
EXAMPLE 25 preparation of Compound 25
First step 25b preparation
DMF (5 mL) was added to 25a (0.20 g,0.85 mmol), NBS (0.15 g,0.84 mmol) was slowly added with stirring at room temperature and reacted for 1h at room temperature. To the reaction solution were added 20mL of ethyl acetate and 20mL of water, the solution was separated, the organic phase was washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20-1:10) to give 25b (0.20 g, yield: 76%).
Second step 25c preparation
In a microwave tube, 25b (0.20 g,0.64 mmol), 1C (0.16 g,0.64 mmol), cuI (0.024 g,0.13 mmol), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexane diamine (0.036 g,0.25 mmol), potassium phosphate (0.41 g,1.93 mmol) and DMF (4 mL) were added in this order, and after the addition, the reaction was carried out at 140℃for 5 hours by microwave. The reaction solution was cooled to room temperature, 30mL of ethyl acetate and 30mL of water were added, the solution was separated, the organic phase was washed with saturated aqueous sodium chloride (20 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:20-1:3) to give 25c (0.03 g, yield: 10%).
Third step, preparation of p-toluenesulfonate salt of 25d
Acetonitrile (3 mL) was added to 25C (0.04 g,0.083 mmol), p-toluenesulfonic acid (0.043 g,0.25 mmol) was added with stirring at room temperature and reacted for 15h at 25 ℃. The reaction solution was concentrated under reduced pressure to give p-toluenesulfonate (0.02 g) as a crude product of 25 d.
Fourth step preparation of Compound 25
DMF (3 mL) was added to the crude 25d p-toluenesulfonate (0.03 g) above, 1f (0.022 g,0.08 mmol) and DIPEA (0.10 g,0.77 mmol) were added with stirring at room temperature, nitrogen was replaced three times, and the reaction was carried out at 80℃for 3h. The reaction solution was cooled to room temperature, 20mL of ethyl acetate and 20mL of water were added, the solution was separated, the organic phase was washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:10-1:1) to give compound 25 (0.006 g, yield: 12%).
1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.39–8.32(m,2H),8.10(s,1H),8.01(s,1H),7.82(s,1H),7.77(dd,1H),7.73–7.62(m,2H),7.58–7.48(m,2H),6.82–6.74(m,1H),6.55(dd,1H),4.99–4.90(m,1H),4.45–4.32(m,2H),4.17–4.05(m,2H),3.94–3.80(m,1H),2.97–2.65(m,3H),2.21–2.06(m,1H).
EXAMPLE 26 preparation of Compound 26
Compound 26 was obtained by the synthesis method of example 19, starting from compounds 26A and 26A.
1H NMR(400MHz,CDCl3)δ8.20–7.28(m,6H),6.86–6.76(m,1H),6.63–6.40(m,2H),5.01–4.89(m,1H),4.45–4.30(m,3H),4.30–4.02(m,5H),4.01–3.73(m,3H),3.28–2.60(m,4H),2.18–2.06(m,1H).
EXAMPLE 27 preparation of Compound 27
First step, preparation of 27b
In a 25mL reaction flask, 27A (0.20 g,1.01 mmol), 27A hydrochloride (0.14 g), cesium carbonate (0.99 g,3.04 mmol) and DMF (5 mL) were added in order and reacted at 80℃for 15h. The reaction solution was cooled to room temperature, 30mL of ethyl acetate and 20mL of water were added, the solution was separated, the organic phase was washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:20-1:4) to give 27b (0.06 g, yield: 24%).
Second step, preparation of 27c
Dichloromethane (5 mL) was added to 27b (0.06 g,0.24 mmol), cooled to 0 ℃, methanesulfonyl chloride (0.055 g,0.48 mmol) and triethylamine (0.073 g,0.72 mmol) were added and reacted for 2h at 25 ℃. The reaction solution was cooled to 0 ℃,20 mL of saturated aqueous sodium bicarbonate solution was added, 20mL of dichloromethane and 10mL of water were added, the solution was separated, the organic phase was washed with 20mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20-1:4) to give 27C (0.065 g, yield: 82%).
Third step preparation of Compound 27
In a 25mL reaction flask, 27C (0.066 g,0.20 mmol), 7C (0.80 g,0.20 mmol), cesium carbonate (0.20 g,0.61 mmol) and DMF (4 mL) were added sequentially and reacted at 80℃for 15h. The reaction solution was cooled to room temperature, 20mL of ethyl acetate and 10mL of water were added, the solution was separated, the organic phase was washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (v/v) =1:10-1:1) to give compound 27 (0.025 g, yield: 20%).
1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.76–7.60(m,3H),7.52–7.45(m,1H),7.42–7.34(m,1H),6.84–6.77(m,1H),6.62–6.51(m,2H),5.23–5.10(m,1H),5.00–4.88(m,1H),4.70–4.58(m,2H),4.52–4.41(m,2H),4.40–4.28(m,2H),4.12–4.01(m,2H),3.88–3.74(m,1H),3.00–2.64(m,3H),2.20–2.05(m,1H).
EXAMPLE 29 preparation of Compound 29
First step 29b preparation
29A (4.1 g,19.80 mmol) and 4-iodo-1H-pyrazole (4.22 g,21.75 mmol) were dissolved in 40mL acetonitrile, cesium carbonate (9.68 g,29.70 mmol) was added and reacted at 80℃for 3H. The reaction solution was cooled to room temperature, 30mL of water and 100mL of ethyl acetate were added, the solution was separated, the organic phase was washed with 30mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by chromatography on silica gel (ethyl acetate/petroleum ether (v/v) =1:9) to give 29b (2.40 g, yield: 38%).
1H NMR(400MHz,CDCl3)δ7.55(s,2H),4.19(q,2H),2.95–2.70(m,4H),2.26–1.96(m,2H),1.23(t,3H).
LCMS m/z=321.1[M+1]+。
Second step 29c preparation
29B (2.30 g,7.18 mmol) was dissolved in THF (20 mL), 4mL of water and lithium hydroxide monohydrate (0.6 g,14.3 mmol) were added and reacted at room temperature for 30min. To the reaction solution was added dropwise 1mol/L hydrochloric acid to adjust pH to 6, 50mL of ethyl acetate was added, the solution was separated, the organic phase was washed with 20mL of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 1 (2.0 g). The crude 1 (0.51 g) was dissolved in DCM (10 mL) and 1-chloro-N, N, 2-trimethylpropenamine (0.35 g,2.62 mmol) was slowly added dropwise and reacted at room temperature for 2h. TEA (0.53 g,5.24 mmol) and 2-chloro-4- (trifluoromethyl) aniline (0.34 g,1.74 mmol) were added to the reaction solution and reacted at room temperature for 3 hours. To the reaction solution was added 20mL of saturated aqueous sodium hydrogencarbonate solution, extracted with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel column (ethyl acetate/petroleum ether (v/v) =1:3) to give 29c (0.45 g, yield: 52%).
Third step 29d preparation
29C (2.0 g,4.26 mmol) was dissolved in10 mL THF, cooled to 0deg.C, and 1mol/L borane in tetrahydrofuran (8.5 mL,8.5 mmol) was added and reacted at room temperature for 18h. The reaction solution was cooled to 0 ℃, 5mL of methanol was added, 40mL of ethyl acetate and 30mL of water were added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by separation with a silica gel column (petroleum ether/ethyl acetate (v/v) =10:1-3:1) to give 29d (1.5 g, yield: 77%).
LCMS m/z=456.4[M+1]+
Fourth step preparation of Compound 29
29D (0.32 g,0.70 mmol), crude intermediate 1 (0.35 g), TEA (0.21 g,2.08 mmol), cuI (27 mg,0.14 mmol) and PdCl 2(PPh3)2 (98 mg,0.14 mmol) were added to the reaction flask and reacted for 3h under nitrogen with 8mL DMF at 55 ℃. The reaction solution was cooled to room temperature, 40mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 100mL of a mixed solvent of DCM/MeOH (v/v) =5:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:1.5) to give compound 29 (88 mg, yield: 19%).
1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.70–7.60(m,2H),7.53(s,1H),7.48–7.42(m,1H),7.29(dd,1H),6.82–6.77(m,1H),6.54(dd,1H),6.45(d,1H),5.12–4.88(m,2H),4.39–4.27(m,2H),4.10–3.98(m,2H),3.85–3.72(m,1H),3.65(d,2H),2.95–2.55(m,5H),2.53–2.37(m,2H),2.23–1.97(m,3H).
LCMS m/z=665.2[M+1]+
EXAMPLE 30 preparation of Compound 30
Compound 30 was obtained by the synthesis method of example 23, starting from compounds 30A and 30A.
1H NMR(400MHz,CDCl3)δ8.04–7.95(m,2H),7.92(d,1H),7.79–7.72(m,2H),7.71–7.65(m,2H),7.60–7.54(m,1H),7.41(dd,1H),6.82(d,1H),6.61–6.53(m,2H),4.99–4.90(m,1H),4.44–4.32(m,2H),4.16–4.05(m,2H),3.92–3.77(m,1H),2.98–2.65(m,3H),2.20–2.07(m,1H),1.58–1.53(m,6H).
EXAMPLE 31 preparation of Compound 31
First step preparation of 31b
In a 50mL reaction flask, sodium nitrite (0.18 g,2.61 mmol) was added, concentrated sulfuric acid (1.17 g) was slowly added dropwise at 0℃and after stirring for 10min, glacial acetic acid (0.59 g,9.83 mmol) was added, after 25℃for 1h, a solution of 31a (0.50 g,2.17 mmol) in glacial acetic acid (0.57 mL) was added dropwise and after 25℃for 1h, a solution of potassium iodide (3.65 g,22.00 mmol) in water (5 mL) was added and then reacted for 3h at 25 ℃. The reaction system was adjusted to pH 10 with 1mol/L aqueous sodium hydroxide solution, extracted with 50mL of ethyl acetate, the organic phase was washed with 30mL of saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (pure petroleum ether) to give 31b (0.28 g, yield: 38%).
Second step, preparation of 31c
In a 50mL reaction flask, 31b (0.50 g,1.47 mmol), 31A (0.19 g,1.51 mmol), potassium carbonate (0.61 g,4.41 mmol) and DMF (15 mL) were added sequentially and reacted at 90℃for 4h. The reaction system was cooled to room temperature, 10mL of water and 200mL of ethyl acetate were added, the organic phase was washed three times with 50mL of water and 30mL of saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10:1) to give 31c (0.09 g, yield: 18%).
Third step, preparation of 31d
In a 50mL reaction flask, 31C (0.12 g,0.35 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), lithium aluminum hydride (0.02 g,0.53 mmol) was added at 0deg.C, and the reaction was continued at 0deg.C for 3h. To the reaction system were added 10mL of water and 100mL of ethyl acetate, the organic phase was washed three times with 50mL of water and 30mL of saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1) to give 31d (0.08 g, yield: 74%).
LCMS m/z=311.0[M+1]+
Fourth step, preparation of 31e
In a 50mL reaction flask, 31d (0.08 g,0.26 mmol) was dissolved in dichloromethane (5 mL), thionyl chloride (0.093 g,0.78 mmol) was added at 0deg.C and reacted for 1h at 0deg.C. The reaction solution was concentrated under reduced pressure to give crude product 31e (0.085 g).
Fifth step, preparation of Compound 31
In a 50mL reaction flask, 7C (0.10 g,0.248 mmol), cesium carbonate (0.17 g,0.52 mmol) and DMF (5 mL) were added in this order, and the crude product 31e (0.085 g) was added dropwise and reacted at 25℃for 2h. 10mL of water and 100mL of ethyl acetate were added to the reaction system, the organic phase was washed three times with 50mL of water and 30mL of a saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 31 (0.03 g, yield: 17%).
1H NMR(400MHz,CDCl3)δ8.10–7.47(m,7H),6.84–6.78(m,1H),6.61–6.52(m,1H),5.35–4.85(m,3H),4.44–4.30(m,2H),4.14–4.02(m,2H),3.90–3.75(m,1H),3.10–2.66(m,3H),2.20–2.04(m,1H).
LCMS m/z=696.1[M+1]+
EXAMPLE 32 preparation of the trifluoroacetate salt of Compound 32
The trifluoroacetate salt of compound 32 was obtained by freeze-drying the compound 32A and 32A as starting materials by acidic preparation (acetonitrile/water (0.1% tfa)) according to the synthetic method of example 23.
'1H NMR(400MHz,CDCl3)δ7.99(s,2H),7.84(d,1H),7.79(s,1H),7.75–7.64(m,3H),7.55(dd,1H),7.47(dd,1H),7.04(d,1H),6.87–6.79(m,1H),6.57(dd,1H),5.00–4.89(m,1H),4.45–4.32(m,2H),4.17–4.05(m,2H),3.93–3.77(m,1H),3.00–2.64(m,3H),2.20–2.06(m,1H),1.53(s,6H).
EXAMPLE 33 preparation of Compound 33
First step 33a preparation
33A (4.0 g,20.15 mmol), 33B (3.91 g,20.16 mmol) and potassium carbonate (2.78 g,20.12 mmol) were added to 20mL DMSO and reacted at 100℃for 16h. The reaction was cooled to room temperature, added to 100mL of ethyl acetate, the organic phase was washed with 50mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-10:1) to give 33a (7.51 g, yield: > 99%).
Second step 33b preparation
33A (1.0 g,2.68 mmol) and N-Boc-4-aminophenylboronic acid pinacol ester (CAS: 330793-01-6) (0.86 g,2.69 mmol) were added to the reaction flask, 10mL DME and 3mL water were added under nitrogen protection, pd (PPh 3)4 (62 mg,0.054 mmol) and Cs 2CO3 (2.18 g,6.69 mmol) were added, nitrogen was replaced three times, and the reaction was microwaved at 90℃for 4h. The reaction solution was cooled to room temperature, added to 50mL ethyl acetate, washed with 50mL saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 33b (0.8 g, yield: 68%).
LCMS m/z=438.2[M+1]+
Third step 33c preparation
33B (0.8 g,1.83 mmol) was dissolved in10 mL dichloromethane and 5mL trifluoroacetic acid and reacted at room temperature for 6h. The reaction system was concentrated under reduced pressure, 50mL of ethyl acetate was added, the mixture was washed with 50mL of saturated aqueous sodium hydrogencarbonate, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 33c (0.4 g, yield: 65%).
Fourth step, 33d preparation
33C (0.4 g,1.18 mmol) was added to 5mL of water, concentrated sulfuric acid (0.8 mL) was slowly added and reacted at 60℃for 1h. The reaction system was cooled to 0℃and 5mL of an aqueous solution of sodium nitrite (0.081 g,1.17 mmol) was added dropwise, after 30min of reaction at 5℃2mL of an aqueous solution of KI (0.39 g,2.35 mmol) was added dropwise at 40℃and the reaction was carried out for 1h at 50 ℃. The reaction system was cooled to room temperature, extracted with ethyl acetate (50 ml×3), the organic phase was washed with 50mL of 1mol/L aqueous hydrochloric acid and 50mL of saturated aqueous sodium thiosulfate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-2:1) to give 33d (0.2 g, yield: 38%).
LCMS m/z=449.3[M+1]+
Fifth step, preparation of Compound 33
33D (0.05 g,0.11 mmol), crude intermediate 1 above (0.056 g), TEA (0.067 g,0.66 mmol), cuI (4.2 mg,0.022 mmol) and PdCl 2(PPh3)2 (7.7 mg,0.01 mmol) were added to the reaction flask and 2mL of DMF was added under nitrogen protection at 55℃for 2h. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 20mL of DCM, dried over anhydrous sodium sulfate, and the crude product was purified by chromatography on silica gel column (petroleum ether/dichloromethane/ethyl acetate (v/v) =1:1:2) to give compound 33 (0.03 g, yield: 42%).
1H NMR(400MHz,CDCl3)δ8.25(s,1H),8.05(s,1H),7.94(s,1H),7.88–7.79(m,2H),7.73–7.63(m,2H),7.55–7.42(m,4H),6.83(d,1H),6.58(dd,1H),4.98–4.89(m,1H),4.45–4.35(m,2H),4.17–4.07(m,2H),3.94–3.82(m,1H),2.97–2.65(m,3H),2.20–2.06(m,1H).
LCMS m/z=658.1[M+1]+
EXAMPLE 34 preparation of Compound 34
First step, preparation of 34b
34A (0.2 g, 0.284 mmol) (see WO 2018066545) was dissolved in 2mL DMF and 60% sodium hydride (5.3 mg) was added at room temperature and after 15min at room temperature 4-iodobenzyl bromide (0.32 g,1.08 mmol) was added and reacted at room temperature for 2h. The reaction system was added to 50mL of ethyl acetate, washed with 50mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 34b (0.2 g, yield: 51%).
Second step preparation of Compound 34
34B (0.2 g,0.46 mmol), crude intermediate 1 above (0.23 g), TEA (0.28 g,2.77 mmol), cuI (18 mg,0.095 mmol) and PdCl 2(PPh3)2 (32 mg,0.046 mmol) were added to the reaction flask and reacted for 2h under nitrogen with 2mL of DMF at 55 ℃. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the filter cake was washed with 10mL of water, the filter cake was dissolved with 20mL of DCM, dried over anhydrous sodium sulfate, and the crude product was purified by chromatography on silica gel column (petroleum ether/dichloromethane/ethyl acetate (v/v) =1:1:2, to give compound 34 (0.05 g, yield: 17%).
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.76–7.62(m,3H),7.56–7.48(m,2H),7.46–7.36(m,2H),6.88(d,2H),6.82(d,1H),6.56(dd,1H),5.10(s,2H),4.99–4.87(m,1H),4.43–4.33(m,2H),4.16–4.05(m,2H),3.92–3.77(m,1H),2.97–2.65(m,3H),2.36(s,3H),2.24–2.06(m,4H).
EXAMPLE 35 preparation of Compound 35
First step, preparation of 35b
In a 25mL reaction flask, 35A (0.18 g,0.86 mmol), 35A (0.21 g,0.84 mmol) and 1, 2-dichloroethane (6 mL) were sequentially added (see WO2020211822 for synthesis), and after stirring at room temperature for 5min, sodium triacetoxyborohydride (0.27 g,1.27 mmol) was added and reacted at room temperature for 16h. To the reaction solution were added 30mL of ethyl acetate and 10mL of saturated aqueous sodium hydrogencarbonate, and the organic phase was washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20-1:4) to give 35b (0.16 g, yield: 43%).
Second step preparation of Compound 35
In a 25mL reaction flask, 35b (66.24 mg,0.15 mmol), the crude intermediate 1(50mg)、PdCl2(PPh3)2(10.53mg,0.015mmol)、CuI(5.71mg,0.030mmol)、TEA(91.07mg,0.90mmol) above, and DMF (5 mL) were added sequentially and reacted at 55℃for 1h under nitrogen. The reaction solution was cooled to room temperature, 20mL of ethyl acetate and 10mL of water were added, the organic phase was washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (ethyl acetate/petroleum ether (v/v) =1:10-1:1), and the obtained crude product was further purified by prep-TLC (ethyl acetate/petroleum ether (v/v) =2:1) to give compound 35 (0.015 g, yield: 15%).
1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.74–7.48(m,6H),6.85–6.77(m,1H),6.56(dd,1H),5.04–4.88(m,2H),4.44–4.27(m,2H),4.14–4.02(m,2H),3.99–3.75(m,5H),3.73–3.57(m,2H),2.97–2.63(m,3H),2.20–2.06(m,1H).
EXAMPLE 36 preparation of Compound 36
First step, preparation of 36B
36A (2.0 g,15.4 mmol) was added to a 100mL three-necked flask under nitrogen, dried dichloromethane (40 mL) was added, triethylamine (3.1 g,30.64 mmol) was added, cooled to 0℃and methanesulfonyl chloride (2.1 g,18.33 mmol) was slowly added and reacted at room temperature for 16h. Dichloromethane (30 mL) was added to the reaction system, a saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and an organic phase was separated, washed with saturated aqueous sodium hydrogencarbonate (100 ml×2), water (800 ml×2) and saturated aqueous sodium chloride solution (80 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 36B (2.7 g).
LCMS m/z=209.1[M+1]+
Second step, preparation of 36b and 36b
The crude 36B (1.0 g) above and potassium carbonate (1.24 g,8.97 mmol) were added to a 100mL single-necked flask, dried DMF (15 mL) was added, and 36a (0.87 g,4.48 mmol) was added and reacted at 85℃for 16h. The reaction was cooled to room temperature, slowly poured into water (200 mL), extracted with ethyl acetate (50 ml×3), the organic phase was washed with saturated aqueous sodium chloride (50 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel column (petroleum ether: ethyl acetate (v/v) =89:11) to give 36b (0.46 g, yield: 33%) and 36b' (0.33 g, yield: 24%) respectively.
36B and 36B' are each one of the isomers of structure 36B-a or 36B-B.
Third step, 36c preparation
36B (0.46 g,1.5 mmol) was dissolved in a mixed solvent of tetrahydrofuran (12 mL) and water (3 mL), and lithium hydroxide monohydrate (315 mg,7.51 mmol) was added and reacted at room temperature for 16h. The reaction system was adjusted to pH 5 with 0.5mol/L hydrochloric acid solution, extracted with ethyl acetate (40 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =42:58) to give a crude product (0.31 g). The crude product (310 mg) was put into a 50mL single-necked flask, dried methylene chloride (20 mL) was added, 1-chloro-N, N, 2-trimethylpropenamine (213 mg,1.59 mmol) was added, and after reacting at room temperature for 1 hour, triethylamine (321 mg,3.17 mmol) and 2-chloro-4- (trifluoromethyl) aniline (206 mg,1.05 mmol) were sequentially added and reacted at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =87:13) to give 36c (200 mg, yield: 41%).
LCMS m/z=470.1[M+1]+
36C is one of the isomers of structure 36c-A or 36 c-B.
Fourth step, 36d preparation
36C (200 mg,0.43 mmol) was added to a 50mL single-necked flask, dried tetrahydrofuran (4 mL) was added, nitrogen was replaced three times, and a 1mol/L borane solution in tetrahydrofuran (0.86 mL) was added and reacted at room temperature for 16h. 10mL of methanol was added to the reaction system, the pH was adjusted to 5 by adding 0.5mol/L hydrochloric acid solution, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride (20 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =42:58) to give 36d (0.1 g, yield: 51%).
LCMS m/z=456.1[M+1]+
36D is one of the isomers of structure 36d-A or 36 d-B.
Fifth step, preparation of Compound 36
36D (100 mg,0.22 mmol) was added to a 50mL single port flask, dry DMF (10 mL) was added, crude intermediate 1 (110 mg) above, triethylamine (66 mg,0.65 mmol) was added, nitrogen was replaced three times, pdCl 2(PPh3)2 (16 mg,0.023 mmol) and CuI (7 mg,0.037 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 60℃for 3h. The reaction system was cooled to room temperature, a saturated aqueous ammonium chloride solution (80 mL) was slowly added, extraction was performed with ethyl acetate (60 ml×3), the organic phase was washed with a saturated aqueous sodium chloride solution (50 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =22:78) to give compound 36 (70 mg, yield: 48%).
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.75–7.63(m,1H),7.60(s,1H),7.53–7.47(m,2H),7.42–7.33(m,1H),6.80(d,1H),6.66(d,1H),6.55(dd,1H),4.99–4.88(m,1H),4.75–4.57(m,2H),4.41–4.30(m,2H),4.12–4.01(m,2H),3.88–3.75(m,1H),3.37(t,2H),2.99–2.63(m,5H),2.58–2.28(m,3H),2.20–2.07(m,1H).
LCMS m/z=665.1[M+1]+
Compound 36 is one of the isomers of structure 36-a or 36-B.
EXAMPLE 37 preparation of Compound 37
First step, preparation of 37c
36B' (0.33 g,1.08 mmol) was dissolved in a mixed solvent of tetrahydrofuran (12 mL) and water (3 mL), and lithium hydroxide monohydrate (226.8 mg,5.41 mmol) was added and reacted at room temperature for 16h. The reaction system was adjusted to pH 5 with 0.5mol/L hydrochloric acid solution, extracted with ethyl acetate (40 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =42:58) to give a crude product (0.22 g). The crude product (220 mg) was put into a 50mL single-necked flask, dried methylene chloride (20 mL) was added, 1-chloro-N, N, 2-trimethylpropenamine (151 mg,1.13 mmol) was added, and after reacting at room temperature for 1 hour, triethylamine (228 mg,2.25 mmol) and 2-chloro-4- (trifluoromethyl) aniline (147 mg,0.75 mmol) were sequentially added and reacted at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =87:13) to give 37a (110 mg, yield: 31%).
LCMS m/z=470.1[M+1]+
37A is one of the isomers of structure 36c-a or 36 c-B.
Second step, preparation of 37b
37A (110 mg,0.23 mmol) was added to a 50mL single-necked flask, dried tetrahydrofuran (4 mL) was added, nitrogen was replaced three times, and a 1mol/L borane tetrahydrofuran solution (0.47 mL) was added and reacted at room temperature for 16h. To the reaction system was added 8mL of methanol, 0.5mol/L hydrochloric acid solution was added to adjust pH to 5, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride (20 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =42:58) to give 37b (0.017 g, yield: 16%).
LCMS m/z=456.1[M+1]+
37B is one of the isomers of structure 36d-A or 36 d-B.
Third step, preparation of Compound 37
37B (17 mg,0.037 mmol) was added to a 50mL single port flask, dry DMF (5 mL) was added, crude intermediate 1 (19 mg) above, triethylamine (11 mg,0.11 mmol) was added, nitrogen was replaced three times, pdCl 2(PPh3)2 (3 mg,0.0043 mmol) and CuI (2 mg,0.0105 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 60℃for 3h. The reaction system was cooled to room temperature, a saturated aqueous ammonium chloride solution (50 mL) was slowly added, extraction was performed with ethyl acetate (30 ml×3), the organic phase was washed with a saturated aqueous sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =22:78) to give compound 37 (5 mg, yield: 20%).
1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.67(d,1H),7.61(s,1H),7.56–7.48(m,2H),7.39(dd,1H),6.80(d,1H),6.69(d,1H),6.55(dd,1H),4.98–4.80(m,2H),4.61(br.s,1H),4.40–4.30(m,2H),4.12–4.02(m,2H),3.86–3.74(m,1H),3.38(d,2H),2.98–2.62(m,6H),2.50–2.31(m,2H),2.20–2.07(m,1H).
LCMS m/z=665.1[M+1]+
Compound 37 is one of the isomers of structure 36-a or 36-B.
EXAMPLE 38 preparation of Compound 38
First step 38b preparation
38A (2.0 g,9.66 mmol) and potassium carbonate (4 g,28.94 mmol) were added to a 100mL single-necked flask, dried DMF (30 mL) was added, and 38A (1.89 g,9.74 mmol) was added and reacted at 85℃for 16h. The reaction was cooled to room temperature, slowly poured into water (300 mL), extracted with ethyl acetate (80 ml×3), the organic phase was washed with saturated aqueous sodium chloride (80 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =92:8), 38b (0.7 g, yield: 23%),
LCMS m/z=321.1[M+1]+
Second step 38c preparation
38B (0.7 g,2.19 mmol) was dissolved in a mixed solvent of tetrahydrofuran (16 mL) and water (4 mL), and lithium hydroxide monohydrate (460 mg,10.96 mmol) was added and reacted at room temperature for 16h. The reaction system was adjusted to pH 5 with 0.5mol/L hydrochloric acid solution, extracted with ethyl acetate (60 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride solution (50 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =47:53) to give a crude product (0.51 g). The crude product (300 mg) was added to a 50mL single-necked flask, dried methylene chloride (10 mL) was added, and N, N, N '' -tetramethyl chloroformyl amidine hexafluorophosphate (428 mg,1.53 mmol) and 2-chloro-4- (trifluoromethyl) aniline (199mg, 1.02 mmol) were sequentially added, and N-methylimidazole (418 mg,5.09 mmol) was added to react at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =89:11) to give 38c (200 mg, yield: 42%).
LCMS m/z=470.1[M+1]+
Third step, 38d preparation
38C (200 mg,0.43 mmol) was added to a 50mL single-necked flask, dried tetrahydrofuran (4 mL) was added, nitrogen was replaced three times, and a 1mol/L borane tetrahydrofuran solution (0.86 mL) was added and reacted at room temperature for 16h. To the reaction system was added 5mL of methanol, 0.5mol/L hydrochloric acid solution was added to adjust the pH to 5, extraction was performed with ethyl acetate (20 ml×3), the organic phase was washed with saturated aqueous sodium chloride (20 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =42:58) to give 38d (80 mg, yield: 41%).
LCMS m/z=456.1[M+1]+
Fourth step preparation of Compound 38
38D (80 mg,0.176 mmol) was added to a 50mL single port flask, dry DMF (10 mL) was added, crude intermediate 1 (91 mg) above and triethylamine (55 mg,0.54 mmol) were added, nitrogen was replaced three times, pdCl 2(PPh3)2 (13 mg,0.0185 mmol) and CuI (6 mg,0.0315 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 60℃for 2h. The reaction system was cooled to room temperature, a saturated aqueous ammonium chloride solution (80 mL) was slowly added, extraction was performed with ethyl acetate (60 ml×3), the organic phase was washed with a saturated aqueous sodium chloride solution (50 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =31:69) to give compound 38 (50 mg, yield: 43%).
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.70–7.64(m,1H),7.61(s,1H),7.53–7.45(m,2H),7.38–7.31(m,1H),6.81(d,1H),6.63–6.52(m,2H),4.98–4.89(m,1H),4.52–4.30(m,3H),4.12–4.00(m,2H),3.88–3.75(m,1H),3.44–3.32(m,1H),3.32–3.20(m,1H),3.16–3.01(m,1H),2.96–2.65(m,3H),2.57–2.30(m,2H),2.23–2.07(m,2H),1.80–1.62(m,1H).
LCMS m/z=665.1[M+1]+
EXAMPLE 39 preparation of Compound 39
Compound 39 was obtained by the method of example 33 using, as a starting material, compound 33a and 3- (Boc-amino) phenylboronic acid pinacol ester.
1H NMR(400MHz,CDCl3)δ8.25(s,1H),8.04(s,1H),7.94(s,1H),7.87–7.79(m,2H),7.74–7.59(m,3H),7.55–7.47(m,1H),7.41–7.32(m,2H),6.83(d,1H),6.58(dd,1H),4.99–4.88(m,1H),4.46–4.32(m,2H),4.20–4.08(m,2H),3.94–3.80(m,1H),2.96–2.65(m,3H),2.19–2.07(m,1H).
LCMS m/z=658.2[M+1]+
EXAMPLE 40 preparation of Compound 40
First step 40b preparation
40A (1 g,8.61 mmol) was dissolved in dimethyl sulfoxide (20 mL), cooled to 0deg.C, and 60% sodium hydride (62 mg) was added and reacted at room temperature for 1h. The reaction system was cooled to 0℃and 2-chloro-1-fluoro-4- (trifluoromethyl) benzene (1.7 g,8.56 mmol) was added and reacted at room temperature for 2h. Water (200 mL) was added, extracted with ethyl acetate (50 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride (40 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =74:26) to give 40b (360 mg, yield: 14%).
LCMS m/z=295.1[M+1]+
Second step 40c preparation
40B (360 mg,1.22 mmol) was added to a 100mL single-port flask, dried dichloromethane (20 mL) was added, triethylamine (360 mg,3.56 mmol) was added, cooled to 0 ℃, methanesulfonyl chloride (205 mg,1.79 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 2h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =90:10) to give 40c (0.31 g, yield: 68%).
LCMS m/z=373.1[M+1]+
Third step, 40d preparation
40C (310 mg,0.83 mmol) was added to a 100mL single-necked flask, dried DMF (10 mL) was added, potassium carbonate (345 mg,2.5 mmol) was added, 4-iodo-1H-pyrazole (161 mg,0.83 mmol) was added, and reacted at 85℃for 16H. The reaction system was cooled to room temperature, added to water (120 mL), extracted with ethyl acetate (30 ml×3), the organic phase was washed with saturated aqueous sodium chloride (30 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =87:13) to give 40d (0.31 g, yield: 79%).
LCMS m/z=471.1[M+1]+
40D is one of the isomers of structure 40d-A or 40 d-B.
Fourth step preparation of Compound 40
40D (130 mg,0.277 mmol) was added to a 50mL single port flask, dry DMF (10 mL) was added, crude intermediate 1 (136 mg) above, triethylamine (52 mg,0.51 mmol) was added, nitrogen was replaced three times, pdCl 2(PPh3)2 (19 mg,0.027 mmol) and CuI (8 mg,0.042 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 60℃for 3h. The reaction system was cooled to room temperature, saturated aqueous ammonium chloride solution (50 mL) was slowly added, extraction was performed with ethyl acetate (40 ml×3), the organic phase was washed with saturated aqueous sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was purified by separation with a silica gel column (petroleum ether: ethyl acetate (v/v) =28:72), the crude product was prepared by Prep-HPLC (apparatus: waters 2767 preparation liquid phase; column: sunfire@prepc18 (19×250 nm), mobile phase a: acetonitrile; mobile phase B: water (containing 5mmol/L ammonia water), gradient elution: mobile phase a content from 40-90%, flow rate: 12mL/min; column temperature: room temperature; detection wavelength: 210nm; sample was dissolved with DMF, filtered with 0.45um filter head, sample liquid prepared; elution time: 15 min), and freeze-dried to give compound 40 (30 mg, yield: 16%).
1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.72–7.53(m,4H),7.48(dd,1H),7.01(d,1H),6.81(d,1H),6.55(dd,1H),4.99–4.88(m,1H),4.80–4.70(m,1H),4.42–4.18(m,3H),4.14–4.01(m,2H),3.90–3.73(m,1H),2.95–2.64(m,3H),2.32–1.98(m,7H),1.85–1.69(m,2H).
EXAMPLE 41 preparation of Compound 41
First step, preparation of 41b
41A (1.17 g,3.4 mmol) (see WO 2016058544), 1A (0.92 g,5.08 mmol), TEA (2.06 g,20.4 mmol), cuI (130 mg,0.68 mmol) and PdCl 2(PPh3)2 (240 mg,0.34 mmol) were reacted for 0.5h under nitrogen with 5mL of DMF at 50 ℃. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 41b (1.0 g, yield: 74%).
Second step, preparation of 41c
41B (1.0 g,2.52 mmol) and sodium carbonate (0.53 g,5.0 mmol) were added to 10mL DMF and 2mL water was added and reacted at 85℃for 1.5h. The reaction solution was cooled to room temperature, added to 100mL of ethyl acetate, washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 41c (0.6 g, yield: 80%).
Third step, preparation of 41d
41C (0.4 g,1.35 mmol), 33a (0.5 g,1.34 mmol), cuI (13 mg,0.068 mmol), (1S, 2S) - (+) -N, N' -dimethyl-1, 2-cyclohexanediamine (0.095 g,0.67 mmol) and potassium carbonate (0.28 g,2.03 mmol) were reacted for 2h under nitrogen with 10mL DMF at 100 ℃. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 41d (0.4 g, yield: 55%).
Fourth step, preparation of p-toluenesulfonate salt of 41e
41D (0.2 g,0.37 mmol) and p-toluenesulfonic acid monohydrate (0.21 g,1.10 mmol) were dissolved in 5mL acetonitrile and reacted at room temperature for 3h. The reaction system was concentrated under reduced pressure to give p-toluenesulfonate (0.16 g) as crude 41 e.
Fifth step preparation of Compound 41
The crude product 41e, p-toluenesulfonate (0.16 g), 1f (0.12 g,0.43 mmol) and DIPEA (0.29 g,2.24 mmol) were dissolved in 5mL DMF and reacted at 80℃for 5h. The reaction system was cooled to room temperature, added to 100mL of ethyl acetate, washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give compound 41 (0.05 g, yield: 17%).
1H NMR(400MHz,CDCl3)δ8.46(s,1H),8.22(s,1H),8.00(s,1H),7.93–7.82(m,3H),7.75–7.62(m,3H),7.58–7.47(m,1H),7.37–7.29(m,1H),6.85(d,1H),6.59(dd,1H),4.99–4.90(m,1H),4.53–4.40(m,2H),4.30–4.17(m,2H),4.07–3.94(m,1H),2.97–2.64(m,3H),2.20–2.07(m,1H).
EXAMPLE 42 preparation of Compound 42
First step preparation of 42b
42A (1.15 g,4.96 mmol) was dissolved in10 mL 1, 4-dioxane, 42A (1.25 g,5.94 mmol) was added, 1mL methanesulfonic acid was added, and the reaction was continued for 16h at 100 ℃. The reaction system was cooled to room temperature, saturated aqueous sodium hydrogencarbonate solution was added dropwise to adjust the pH to 9, extraction was performed with 50mL of ethyl acetate, the organic phase was washed with 30mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1:0-9:1) to give 42b (1.0 g, yield: 48%).
LCMS m/z=423.2[M+1]+
Second step preparation of Compound 42
42B (0.5 g,1.18 mmol), crude intermediate 1 above (0.52 g) was dissolved in 10mL DMF, TEA (0.36 g,3.56 mmol) was added, and CuI (0.034 g,0.18 mmol), pdCl 2(PPh3)2 (0.12 g,0.17 mmol) was added under nitrogen and reacted at 50℃for 2h. The reaction system was cooled to room temperature, 10mL of water was added, after stirring at room temperature for 5min, suction filtration was performed, the cake was washed with 5mL of water, the cake was collected, dissolved with 50mL of methylene chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4:1-1:4) to give compound 42 (0.2 g, yield: 27%).
1H NMR(400MHz,DMSO-d6)δ13.90–13.50(m,1H),11.06(s,1H),8.55–8.15(m,2H),8.14–7.55(m,5H),6.91(d,1H),6.75(dd,1H),5.13–5.03(m,1H),4.52–4.38(m,2H),4.19–3.92(m,3H),2.97–2.80(m,1H),2.67–2.50(m,2H),2.10–1.97(m,1H).
LCMS m/z=632.6[M+1]+
EXAMPLE 43 preparation of Compound 43
First step, preparation of 43b
43A (1.0 g,4.79 mmol) was dissolved in10 mL 1, 4-dioxane, 43A (1.35 g,5.77 mmol) was added, 1mL methanesulfonic acid was added, and the reaction was continued at 100℃for 16h. The reaction system was cooled to room temperature, saturated aqueous sodium hydrogencarbonate solution was then added dropwise to adjust the pH to 9, extraction was performed with 50mL of ethyl acetate, the organic phase was washed with 30mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1:0-9:1) to give 43b (0.86 g, yield: 43%).
LCMS m/z=423.0[M+1]+
Second step preparation of Compound 43
43B (0.45 g,1.07 mmol) and the crude intermediate 1 (0.46 g) were dissolved in 10mL of DMF, TEA (0.32 g,3.16 mmol) was added, cuI (0.03 g,0.16 mmol) and PdCl 2(PPh3)2 (0.11 g,0.16 mmol) were added under nitrogen and reacted at 50℃for 2h. The reaction system was cooled to room temperature, 10mL of water was added, after stirring at room temperature for 5min, suction filtration was performed, the cake was washed with 5mL of water, the cake was collected, the cake was dissolved with 50mL of methylene chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =4:1-1:4) to give compound 43 (0.18 g, yield: 27%).
1H NMR(400MHz,DMSO-d6)δ13.13–12.98(m,1H),11.06(s,1H),8.20–8.13(m,1H),8.12–8.07(m,1H),7.96–7.55(m,4H),7.36(dd,1H),6.89(d,1H),6.74(dd,1H),5.13–5.02(m,1H),4.50–4.37(m,2H),4.17–4.05(m,2H),4.03–3.90(m,1H),2.97–2.81(m,1H),2.66–2.50(m,2H),2.08–1.96(m,1H).
LCMS m/z=632.1[M+1]+
EXAMPLE 44 preparation of Compound 44
First step 44b preparation
44A (1.0 g,4.1 mmol), di-tert-butyl dicarbonate (1.79 g,8.20 mmol), TEA (0.82 g,8.10 mmol), DMAP (0.1 g,0.82 mmol) were dissolved in 20mL of dichloromethane and reacted at room temperature for 12h. The reaction system was added to 50mL of dichloromethane, the organic phase was washed with 50mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-9:1) to give crude product 1 (1.2 g). The crude 1 (1.17 g), tert-butyl 3-ethynylazatidine-1-carboxylate (0.92 g,5.08 mmol), TEA (2.06 g,20.36 mmol), cuI (130 mg,0.68 mmol) and PdCl 2(PPh3)2 (240 mg,0.34 mmol) were added to the reaction flask and reacted for 0.5h under nitrogen with 5mL of DMF at 50 ℃. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (50 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give crude product 2 (1.1 g). The crude product 2 (1.0 g) and sodium carbonate (0.53 g,5.0 mmol) were added to 10mL DMF and 2mL of water were added and reacted at 85℃for 12h. The reaction solution was cooled to room temperature, added to 100mL of ethyl acetate, washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 44b (0.6 g, yield: 56%).
Second step 44c preparation
44B (0.4 g,1.35 mmol), 33a (0.5 g,1.34 mmol), cuI (13 mg,0.068 mmol), (1S, 2S) - (+) -N, N' -dimethyl-1, 2-cyclohexanediamine (0.095 g,0.67 mmol) and potassium carbonate (0.28 g,2.03 mmol) were added to the reaction flask and reacted for 2h under nitrogen protection with 10mL DMF at 100 ℃. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 44c (0.4 g, yield: 55%).
Third step 44d preparation of p-toluenesulfonic acid
44C (0.2 g,0.37 mmol) and p-toluenesulfonic acid monohydrate (0.21 g,1.10 mmol) were dissolved in 5mL acetonitrile and reacted at room temperature for 3h. The reaction system was concentrated under reduced pressure to give p-toluenesulfonate salt (0.173 g) of crude 44 d.
LCMS m/z=442.4[M+1]+
Fourth step preparation of Compound 44
The crude 44d p-toluenesulfonate (0.173 g), 1f (0.12 g,0.43 mmol) and DIPEA (0.29 g,2.24 mmol) were dissolved in 5mL DMF and reacted at 80℃for 5h. The reaction system was cooled to room temperature, added to 100mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give compound 44 (0.06 g, yield: 20%).
1H NMR(400MHz,CDCl3)δ8.43(s,1H),8.27(s,1H),8.19(s,1H),7.96(s,1H),7.92–7.83(m,2H),7.74–7.66(m,2H),7.64–7.57(m,1H),7.48–7.39(m,1H),7.38–7.31(m,1H),6.89–6.84(m,1H),6.61(dd,1H),4.99–4.89(m,1H),4.53–4.40(m,2H),4.27–4.16(m,2H),4.05–3.93(m,1H),2.98–2.65(m,3H),2.19–2.08(m,1H).
EXAMPLE 45 preparation of Compound 45
First step 45b preparation
In a 50mL reaction flask, 45a (1.0 g,6.43 mmol), 3-dimethyl-5-nitroindolin-2-one (1.32 g,6.40 mmol) and potassium carbonate (1.77 g,12.81 mmol) were added, 10mL DMSO was added and reacted at 100℃for 4h. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 45b (1.5 g, yield: 69%).
Second step 45c preparation
45B (1.0 g,2.93 mmol) was dissolved in 20mL of ethanol and 10mL of saturated aqueous ammonium chloride, and iron powder (1.64 g,29.29 mmol) was added and reacted at room temperature for 6h. The reaction system was concentrated under reduced pressure, 50mL of ethyl acetate and 50mL of water were added, the filtrate was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 45c (0.7 g).
LCMS m/z=312.1[M+1]+
Third step, 45d preparation
The crude 45C (0.37 g) was added to 5mL of water, and 0.8mL of concentrated sulfuric acid was slowly added and reacted at 60℃for 1h. The reaction system was cooled to 0℃and 5mL of an aqueous solution of sodium nitrite (0.081 g,1.17 mmol) was added dropwise, after 30min reaction at 5℃and 2mL of an aqueous solution of KI (0.39 g,2.35 mmol) at 40℃were added dropwise, and the reaction was carried out for 1h at 50 ℃. The reaction system was cooled to room temperature, extracted with ethyl acetate (50 mL. Times.3), the organic phase was washed with 1mol/L aqueous hydrochloric acid (50 mL) and saturated aqueous sodium thiosulfate (50 mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-2:1) to give 45d (0.2 g, two-step yield from compound 45 b: 31%).
LCMS m/z=423.4[M+1]+
Fourth step preparation of Compound 45
45D (0.046 g,0.11 mmol), crude intermediate 1 above (0.056 g), TEA (0.067 g,0.66 mmol), cuI (4.2 mg,0.022 mmol) and PdCl 2(PPh3)2 (7.7 mg,0.01 mmol) were added to the reaction flask and 2mL of DMF was added under nitrogen protection at 55℃for 2h. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 20mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/dichloromethane/ethyl acetate (v/v) =1:1:2) to give compound 45 (0.02 g, yield: 29%).
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.87–7.77(m,1H),7.73–7.65(m,2H),7.52(dd,1H),7.39–7.30(m,2H),6.95–6.88(m,1H),6.85–6.81(m,1H),6.58(dd,1H),4.99–4.90(m,1H),4.44–4.35(m,2H),4.18–4.07(m,2H),3.93–3.80(m,1H),2.96–2.66(m,3H),2.20–2.09(m,1H),1.48(s,6H).
EXAMPLE 46 preparation of Compound 46
First step, preparation of 46b
To the reaction flask were added 46a (1.0 g,3.27 mmol) (see WO 2022003557), 4-iodopyrazole (0.61 g,3.14 mmol) and potassium carbonate (0.87 g,6.30 mmol) dissolved in 10mL DMF and reacted at 80℃for 4h. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 46b (0.4 g, yield: 32%).
Second step preparation of trifluoroacetate salt of 46c
46B (0.4 g,0.99 mmol) was dissolved in 5mL dichloromethane and 5mL trifluoroacetic acid and reacted at room temperature for 2h. The reaction system was concentrated under reduced pressure to give crude trifluoroacetate salt of 46c (0.23 g).
Third step, preparation of 46d
The crude 46C trifluoroacetate salt (0.23 g), 3-chloro-4-fluorobenzotrifluoride (0.2 g,1.0 mmol) and potassium carbonate (0.55 g,3.98 mmol) were dissolved in 5mL DMF and reacted at 80℃for 4h. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 46d (0.04 g, yield: 8%).
LCMS m/z=482.1[M+1]+
Fourth step preparation of Compound 46
46D (0.04 g,0.083 mmol), crude intermediate 1 above (0.042 g), TEA (0.05 g,0.49 mmol), cuI (3.2 mg,0.017 mmol) and PdCl 2(PPh3)2 (5.8 mg,0.0083 mmol) were added to the reaction flask and reacted for 2h at 55℃under nitrogen. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 20mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel column (petroleum ether/dichloromethane/ethyl acetate (v/v) =1:1:2) to give compound 46 (0.02 g, yield: 35%).
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.71–7.63(m,1H),7.62–7.51(m,3H),7.47–7.40(m,1H),7.04(d,1H),6.84–6.76(m,1H),6.55(dd,1H),5.02–4.88(m,2H),4.43–4.26(m,2H),4.13–4.00(m,2H),3.88–3.75(m,1H),3.48–3.38(m,2H),3.25–3.10(m,2H),3.07–2.95(m,2H),2.95–2.65(m,3H),2.50–2.35(m,2H),2.23–2.06(m,3H).
LCMS m/z=691.3[M+1]+
EXAMPLE 47 preparation of Compound 47
First step, 47B preparation
47A (1.0 g,4.81 mmol), di-tert-butyl dicarbonate (1.16 g,5.32 mmol) and TEA (0.73 g,7.21 mmol) were dissolved in 50mL tetrahydrofuran and reacted at room temperature for 12h. The reaction system was added to 100mL of water, extracted with ethyl acetate (50 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-9:1) to give 47B (1.3 g, yield: 88%).
Second step, 47C preparation
47B (1.05 g,3.4 mmol), 1A (0.92 g,5.08 mmol), TEA (2.06 g,20.36 mmol), cuI (130 mg,0.68 mmol) and PdCl 2(PPh3)2 (240 mg,0.34 mmol) were added to the reaction flask and reacted for 0.5h under nitrogen with 10mL DMF at 50 ℃. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 47C (1.05 g, yield: 85%).
Third step, preparation of 47a
47C (0.91 g,2.52 mmol) and sodium carbonate (0.53 g,5.0 mmol) were added to 10mL DMF and 2mL water was added and reacted at 85℃for 12h. The reaction solution was cooled to room temperature, added to 100mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 47a (0.5 g, yield: 76%).
LCMS m/z=262.2[M+1]+
Fourth step, 47b preparation
47A (0.35 g,1.34 mmol), 1- (2, 6-dichloro-4- (trifluoromethyl) phenyl) -4-iodo-1H-pyrazole (0.55 g,1.35 mmol) (see J.Org. Chem.,2003,68,8075-8079), cuI (13 mg,0.068 mmol), (1S, 2S) - (+) -N, N' -dimethyl-1, 2-cyclohexanediamine (0.095 g,0.67 mmol) and potassium carbonate (0.28 g,2.03 mmol) were added to the reaction flask and reacted at 100℃for 2H under nitrogen protection with 10mL DMF. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give 47b (0.5 g, yield: 69%).
LCMS m/z=540.1[M+1]+
Fifth step, preparation of p-toluenesulfonate salt of 47c
47B (0.2 g,0.37 mmol) and p-toluenesulfonic acid monohydrate (0.21 g,1.10 mmol) were dissolved in 5mL acetonitrile and reacted at room temperature for 3h. The reaction system was concentrated under reduced pressure to give p-toluenesulfonate salt (0.16 g) of crude 47 c.
LCMS m/z=440.0[M+1]+
Sixth step preparation of Compound 47
The crude product 47C, p-toluenesulfonate (0.16 g), 1f (0.12 g,0.43 mmol) and DIPEA (0.29 g,2.24 mmol) were dissolved in 5mL DMF and reacted at 80℃for 5h. The reaction system was cooled to room temperature, 100mL of ethyl acetate was added, the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give compound 47 (0.05 g, yield: 17%).
1H NMR(400MHz,CDCl3)δ8.01(s,2H),7.87(s,1H),7.80–7.64(m,4H),6.86–6.80(m,1H),6.62–6.53(m,1H),4.99–4.89(m,1H),4.45–4.32(m,2H),4.15–4.03(m,2H),3.95–3.80(m,1H),2.98–2.65(m,3H),2.37(s,3H),2.19–2.07(m,1H).
LCMS m/z=696.0[M+1]+
EXAMPLE 48 preparation of Compound 48 trifluoroacetate salt
First step 48b preparation
48A (0.68 g,3 mmol) was added to 20mL of DMF, 60% sodium hydride (0.096 g) was added at 0deg.C, and after 1h reaction at room temperature, 3-chloro-4-fluorobenzotrifluoride (0.6 g,3.02 mmol) was added and reacted for 16h at 25deg.C. 100mL of ethyl acetate was added to the reaction system, the organic phase was washed with 200mL of purified water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give 48b (1.1 g, yield: 90%).
Second step 48c preparation
48B (1.1 g,2.7 mmol) was added to 20mL of dichloromethane, 5mL of trifluoroacetic acid was added and reacted at 25℃for 2h. The reaction solution was concentrated under reduced pressure, 100mL of methylene chloride was added, and the organic phase was washed with 50mL of a saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 48c (0.8 g, yield: 97%).
Third step, 48d preparation
48C (0.8 g,2.62 mmol) was added to 40mL of dichloroethane, 4-iodobenzaldehyde (0.63 g,2.72 mmol) was added and after reaction at room temperature for 2h, sodium triacetoxyborohydride (0.84 g,3.96 mmol) was added and reacted at 25℃for 15h. 50mL of methylene chloride was added to the reaction system, and the organic phase was washed with 50mL of saturated aqueous sodium hydrogencarbonate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =1:1) to give 48d (1.0 g, yield: 73%).
LCMS m/z=522.0[M+1]+
Fourth step, preparation of compound 48 trifluoroacetate salt
48D (0.26 g,0.5 mmol) was dissolved in 8mL DMF and the crude intermediate 1 (0.34 g), TEA (0.5 g,4.94 mmol), cuI (0.019 g,0.1 mmol) and PdCl 2(PPh3)2 (0.07 g,0.1 mmol) were added sequentially, nitrogen was replaced three times, and reacted at 60℃for 1h. The reaction solution was cooled to room temperature, 40mL of water was added, filtration was performed, the cake was washed with 20mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:3), and the crude product was subjected to Pre-HPLC (apparatus and preparative column: preparation of liquid phase using Glison GX-281, preparative column model number was Sunfire C18,5 μm, inner diameter×length=30 mm×150 mm). The preparation method comprises dissolving the crude product with methanol and dimethyl sulfoxide, and filtering with 0.45 μm filter membrane to obtain sample solution. Mobile phase system acetonitrile/water (0.1% tfa). Gradient elution method acetonitrile was eluted 60% by 5% gradient (elution time 15 min), and lyophilized to give the trifluoroacetate salt of compound 48 (90 mg).
1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.77(d,1H),7.73–6.93(m,7H),6.83–6.76(m,1H),6.59(dd,1H),4.98–4.89(m,1H),4.73–3.77(m,10H),2.95–2.65(m,3H),2.60–1.85(m,9H).
LCMS m/z=731.2[M+1]+
EXAMPLE 49 preparation of Compound 49
First step, preparation of 49b-1 and 49b-2
49A (0.8 g,5.47 mmol) was dissolved in 40mL DMF and cesium carbonate (3.54 g,10.86 mmol) was added and 49A (1.50 g,5.97 mmol) was added in four portions at 90℃for a reaction time of 6h at 90 ℃. The reaction system was cooled to room temperature, 100mL of water was added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =3:1) to give 49b-1 (0.6 g, yield: 36%) and 49b-2 (0.2 g, yield: 12%) respectively.
Second step, 49d preparation
49C (2.96 g,10.0 mmol) and cyclopropylboronic acid (5.16 g,60.07 mmol) were dissolved in 70mL 1, 4-dioxane and 15mL water, potassium phosphate (12.76 g,60.11 mmol) was added, and bis-tricyclohexylphosphine palladium dichloride (2.22 g,3.01 mmol) was added under nitrogen atmosphere and reacted at 100℃for 16h. The reaction system was cooled to room temperature, 80mL of water was added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =5:1), to give 49d (2.1 g, yield: 96%).
LCMS m/z=219.2[M+1]+
Third step, 49e preparation
49D (0.5 g,2.29 mmol) was dissolved in10 mL of methanol, 0.2g of 10% Pd/C was added and the mixture was allowed to react at room temperature under a hydrogen balloon atmosphere for 4 hours. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to give crude 49e (0.4 g).
Fourth step, 49f preparation
The crude product 49e (0.12 g) and 49b-1 (0.10 g,0.33 mmol) were dissolved in 8mL of ethanol and 8mL of toluene and reacted under nitrogen atmosphere at 100℃for 16h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =2:1) to give 49f (0.11 g, yield: 71%).
LCMS m/z=470.3[M+1]+
Fifth step, preparation of 49g of p-toluenesulfonate
49F (0.1 g,0.21 mmol) was dissolved in10 mL acetonitrile, and p-toluenesulfonic acid monohydrate (0.24 g,1.26 mmol) was added and reacted at 35℃for 4h. The reaction system was cooled to room temperature and concentrated under reduced pressure to give 49g of crude p-toluenesulfonate (0.33 g).
LCMS m/z=370.3[M+1]+
Sixth step preparation of Compound 49
The crude 49g of p-toluenesulfonate (0.33 g) was dissolved in 5mL of DMSO, DIPEA (0.21 g,1.62 mmol) and 1f (83 mg,0.30 mmol) were added and reacted at 80℃for 3h. The reaction was cooled to room temperature, 35mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (dichloromethane/methanol (v/v) =15:1) to give compound 49 (40 mg, yield: 21%).
1H NMR(400MHz,DMSO-d6)δ12.9–12.4(m,1H),11.07(s,1H),8.74–8.20(m,3H),7.94–7.84(m,1H),7.72(d,1H),7.15–6.90(m,2H),6.87–6.77(m,1H),6.51–6.42(m,1H),6.08–5.92(m,1H),5.15–5.02(m,1H),4.75–4.60(m,2H),4.57–4.42(m,2H),3.00–2.80(m,1H),2.70–2.45(m,3H),2.14–1.90(m,2H),1.12–0.75(m,6H),0.73–0.60(m,2H).
LCMS m/z=626.4[M+1]+
EXAMPLE 50 preparation of Compound 50
Compound 50 was obtained by the synthesis method of example 49, starting from compounds 49e and 49 b-2.
1H NMR(400MHz,DMSO-d6)δ12.66–12.40(m,1H),11.07(s,1H),8.78(s,1H),8.72–8.44(m,1H),8.24–8.04(m,1H),7.78(d,1H),7.73(d,1H),7.15–6.93(m,2H),6.83(dd,1H),6.50–6.43(m,1H),5.88–5.76(m,1H),5.14–5.03(m,1H),4.75–4.62(m,2H),4.60–4.50(m,2H),2.99–2.80(m,1H),2.67–2.50(m,3H),2.14–1.86(m,2H),1.14–0.75(m,6H),0.71–0.60(m,2H).
EXAMPLE 51 preparation of Compound 51
First step, preparation of 51b
51A (2.2 g,9.88 mmol) was dissolved in 20mL of methanol and sodium borohydride (0.37 g,9.78 mmol) was added at 0deg.C and reacted for 0.5h at room temperature. To the reaction solution were added 50mL of ethyl acetate and 50mL of water, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 51b (2.05 g, yield: 92%).
Second step, preparation of 51c
51B (0.15 g,0.67 mmol) was dissolved in 5mL of THF solvent, triphenylphosphine (0.26 g,0.99 mmol) and 3-fluoro-5-iodophenol (0.16 g,0.67 mmol) were added, DEAD (0.21 g,1.21 mmol) was added at 0deg.C, and the reaction was carried out at room temperature for 19h. To the reaction solution were added 50mL of ethyl acetate and 50mL of water, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 51c (0.13 g, yield: 44%).
Third step preparation of Compound 51
Compound 51 was obtained by the synthesis method of example 48, starting from compound 51 c.
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.71–7.62(m,2H),7.61–7.54(m,1H),7.53–7.46(m,1H),6.84–6.78(m,1H),6.74–6.63(m,2H),6.56(dd,1H),6.51–6.43(m,1H),5.66(q,1H),4.98–4.89(m,1H),4.42–4.32(m,2H),4.13–4.02(m,2H),3.88–3.76(m,1H),2.95–2.66(m,3H),2.18–2.07(m,1H),1.62(d,3H).
EXAMPLE 52 preparation of Compound 52
First step, preparation of 52b
52A (0.5 g,2.54 mmol), 52A (1.01 g,3.81 mmol) and triphenylphosphine (1.33 g,5.07 mmol) were added to 10mL tetrahydrofuran under nitrogen, DIAD (1.54 g,7.62 mmol) was added dropwise at 0deg.C, and the reaction was carried out at room temperature for 3h. The reaction system was added to 50mL of water, extracted with ethyl acetate (50 mL. Times.3), the organic phase was washed with 50mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =1:0-1:1) to give 52b (0.5 g, yield: 44%).
Second step preparation of Compound 52
Compound 52 was obtained by the synthesis method of example 51, starting with compound 52 b.
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.74–7.66(m,1H),7.66–7.58(m,1H),7.48–7.39(m,1H),7.34–7.27(m,1H),7.15(dd,1H),6.99–6.90(m,1H),6.88–6.80(m,1H),6.71(d,1H),6.59(dd,1H),5.75(q,1H),4.98–4.90(m,1H),4.47–4.37(m,2H),4.17–4.05(m,2H),3.98–3.85(m,1H),2.96–2.65(m,3H),2.18–2.08(m,1H),1.71(d,3H).
EXAMPLE 53 preparation of Compound 53
First step 53b preparation
53A (0.24 g,1.01 mmol) was dissolved in10 mL DMF and potassium carbonate (0.28 g,2.03 mmol) and 53A (0.24 g,1.21 mmol) were added and reacted at 90℃for 12h. The reaction system was cooled to room temperature, 30mL of ethyl acetate and 50mL of purified water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =4:1) to give 53b (0.4 g, yield: 95%).
Third step, preparation of Compound 53
Compound 53 was obtained by the synthesis method of example 52, starting with compound 53 b.
1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.73–7.65(m,1H),7.65–7.55(m,1H),7.49–7.40(m,1H),7.07–6.97(m,1H),6.92–6.81(m,1H),6.78–6.68(m,2H),6.68–6.58(m,1H),6.48(dd,1H),4.92–4.82(m,1H),4.35–4.23(m,2H),4.07–3.95(m,2H),3.82–3.67(m,1H),2.90–2.55(m,3H),2.14–1.97(m,1H).
EXAMPLE 54 preparation of Compound 54
First step, preparation of 54b
54A (3 g,13.48 mmol) was dissolved in 45mL chloroform and bromine (2.1 g,13.14 mmol) was added at 0℃and reacted at room temperature for 16h. To the reaction system was added 60mL of methylene chloride, and the organic phase was washed with 100mL of saturated aqueous sodium bicarbonate and 50mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =87:13) to give 54b (1.5 g, yield: 37%).
LCMS m/z=301.1[M+1]+
Second step, preparation of 54c
29B (2.30 g,7.18 mmol) was dissolved in THF (20 mL), 4mL of water and lithium hydroxide monohydrate (0.6 g,14.3 mmol) were added and reacted at room temperature for 30min. To the reaction solution was added dropwise 1mol/L hydrochloric acid to adjust pH to 6, 50mL of ethyl acetate was added, the solution was separated, the organic phase was washed with 20mL of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 1 (2.0 g). Crude 1 (1.74 g) was added to a 100mL single-necked flask, dried dichloromethane (20 mL) was added, DIPEA (1.54 g,11.91 mmol) was added, and 54b (1.2 g,4.0 mmol) was slowly added dropwise at 0deg.C and reacted for 16h at room temperature. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =73:27) to give a crude product (1.0 g). The crude product (1 g) was dissolved in 30mL of toluene, and ammonium acetate (1.5 g,19.46 mmol) was added and reacted at 90℃for 16h. The reaction was cooled to room temperature, concentrated under reduced pressure, dichloromethane (100 mL) and 100mL of purified water were added, the organic phase was washed with 50mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was purified by separation with a silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =7:3), the crude product was prepared by Prep-HPLC (apparatus: waters 2767 preparation liquid phase; column: sunfire@prepc18 (19×250 nm), mobile phase a: acetonitrile, mobile phase B: water (containing 5mmol/L of ammonium acetate), gradient elution: mobile phase a content from 60 to 90%, flow rate: 12mL/min, column temperature: room temperature, detection wavelength: 210nm, sample was dissolved with DMF, filtered with a 0.45um filter head, prepared into sample liquid, elution time: 18 min), 54c (45 mg, yield: 2%).
LCMS m/z=493.2[M+1]+
Third step, preparation of Compound 54
54C (45 mg,0.091 mmol) was added to a 50mL single port flask, dry DMF (8 mL) was added, crude intermediate 1 (47 mg) above, TEA (28 mg,0.277 mmol) was added, pdCl 2(PPh3)2 (12 mg,0.017 mmol) and CuI (7 mg,0.037 mmol) were added under nitrogen atmosphere and reacted at 50℃for 2h. The reaction system was cooled to room temperature, a saturated aqueous ammonium chloride solution (80 mL) was slowly added, extraction was performed with ethyl acetate (50 ml×3), the organic phase was washed with a saturated aqueous sodium chloride solution (60 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =27:73) to give compound 54 (20 mg, yield: 31%).
1H NMR(400MHz,CDCl3)δ9.62(s,1H),8.48–8.30(m,1H),8.17–8.02(m,1H),7.85–7.40(m,6H),6.84–6.75(m,1H),6.54(dd,1H),4.99–4.88(m,1H),4.40–4.29(m,2H),4.11–4.00(m,2H),3.88–3.72(m,1H),3.24–3.08(m,2H),2.98–2.65(m,5H),2.35–2.00(m,3H).
LCMS m/z=702.2[M+1]+
EXAMPLE 55 preparation of Compound 55
First step, preparation of 55b
To the reaction flask were added 55A (0.5 g,2.11 mmol) (see WO 2021262596), 55A (0.97 g,3.17 mmol), tetrakis (triphenylphosphine) palladium (0.24 g,0.21 mmol) and potassium carbonate (0.58 g,4.2 mmol) dissolved in 20mL of 1, 4-dioxane and 4mL of water and reacted at 100℃for 12h. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =1:0-1:2) to give 55b (0.5 g, yield: 82%).
LCMS m/z=290.1[M+1]+
Second step, preparation of 55c
55B (0.5 g,1.73 mmol), cuI (0.49 g,2.57 mmol) and KI (0.43 g,2.59 mmol) and isoamyl nitrite (0.36 g,3.07 mmol) were dissolved in 70mL acetonitrile and reacted at 70℃for 2h. The reaction system was concentrated under reduced pressure, added to 50mL of ethyl acetate and 50mL of water, filtered, the aqueous phase was extracted with 50mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (petroleum ether: ethyl acetate (v/v) =1:0-1:2), to give 55c (0.2 g, yield: 29%).
Third step, preparation of Compound 55
55C (0.044 g,0.11 mmol), crude intermediate 1 above (0.056 g), TEA (0.067 g,0.66 mmol), cuI (4.2 mg,0.022 mmol) and PdCl 2(PPh3)2 (7.7 mg,0.01 mmol) were added to the reaction flask and 2mL of DMF was added under nitrogen atmosphere and reacted at 55℃for 2h. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 20mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: dichloromethane: ethyl acetate (v/v) =1:1:2) to give compound 55 (0.025 g, yield: 37%).
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.75(s,1H)7.68(d,1H),7.63–7.55(m,1H),7.48–7.40(m,1H),7.32–7.24(m,1H),7.23–7.08(m,2H),6.86–6.79(m,1H),6.57(dd,1H),4.99–4.89(m,1H),4.45–4.32(m,2H),4.18–4.05(m,2H),3.94–3.80(m,1H),2.97–2.62(m,3H),2.22–2.07(m,1H).
LCMS m/z=610.0[M+1]+
EXAMPLE 56 preparation of Compound 56
Compound 56 was obtained by the synthesis method of example 34, starting from compounds 34a and 56 a.
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.75–7.65(m,3H),7.57–7.49(m,2H),7.23–7.11(m,2H),6.82(d,1H),6.57(dd,1H),6.45(t,1H),5.13(s,2H),4.98–4.89(m,1H),4.43–4.32(m,2H),4.15–4.05(m,2H),3.92–3.76(m,1H),2.95–2.65(m,3H),2.37(s,3H),2.19(s,3H),2.17–2.08(m,1H).
EXAMPLE 57 preparation of Compound 57
Compound 57 was obtained by the synthesis method of example 34, starting from compounds 34a and 57 a.
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.76–7.64(m,3H),7.56–7.49(m,2H),7.41(t,1H),6.82(d,1H),6.73–6.61(m,2H),6.57(dd,1H),5.09(s,2H),4.98–4.89(m,1H),4.44–4.35(m,2H),4.17–4.06(m,2H),3.95–3.82(m,1H),2.95–2.65(m,3H),2.36(s,3H),2.19(s,3H),2.17–2.08(m,1H).
EXAMPLE 58 preparation of Compound 58
First step, preparation of 58b
58A (2.40 g,7.83 mmol) was dissolved in a mixed solvent of 20mL 1, 4-dioxane and 2mL water, 58A (2.05 g,7.82 mmol), pd (dppf) Cl 2. DCM (0.64 g,0.79 mmol) and potassium phosphate (3.32 g,15.64 mmol) were added, nitrogen was replaced three times, and the reaction was performed at 80℃for 19h. The reaction system was cooled to room temperature, 100mL of ethyl acetate and 100mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 58b (2.1 g, yield: 85%).
LCMS m/z=315.2[M+1]+
Second step, preparation of 58c
15ML of methylmagnesium bromide (3 mol/L tetrahydrofuran solution) was added to 5mL of ultra-dry tetrahydrofuran, cooled to 0℃and 58b (1.18 g,3.76 mmol) of ultra-dry tetrahydrofuran (10 mL) was added dropwise and reacted at 0℃for 3h. 50mL of saturated aqueous ammonium chloride solution was added dropwise to the reaction solution at 0℃and extracted with 150mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1-5:1) to give crude product 58C (1.21 g).
Third step, 58d preparation
4-Iodopyrazole (0.55 g,2.84 mmol) was dissolved in 5mL of THF solvent, triphenylphosphine (1.13 g,4.31 mmol) and crude 58C (0.91 g) were added, DEAD (0.87 g,5.0 mmol) was added at 0deg.C, and reacted for 19h at 60deg.C. The reaction solution was cooled to room temperature, 50mL of ethyl acetate and 50mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 58d (0.11 g, yield: 8%).
Fourth step preparation of Compound 58
58D (135 mg,0.275 mmol), the crude intermediate 1 (0.094 g), TEA (85 mg,0.84 mmol), cuI (11 mg,0.0578 mmol) and PdCl 2(PPh3)2 (39 mg,0.056 mmol) were added to the reaction flask and reacted for 3h under nitrogen with 8mL of DMF at 55 ℃. The reaction solution was cooled to room temperature, 20mL of water was added, suction filtration was performed, the cake was washed with 5mL of water, the cake was dissolved with 40mL of a mixed solvent of DCM/MeOH (v/v) =5:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane/methanol (v/v) =10:1-5:1) to give compound 58 (36 mg, yield: 19%).
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.75–7.71(m,1H),7.69–7.64(m,3H),7.60–7.52(m,1H),7.45–7.34(m,3H),7.16–7.09(m,2H),6.80(d,1H),6.55(dd,1H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.99–2.64(m,3H),2.18–2.08(m,1H),2.00(s,6H).
EXAMPLE 59 preparation of Compound 59
First step 59b preparation
59A (0.6 g,1.96 mmol) was dissolved in 10mL of 1, 4-dioxane and 1mL of water, and 59A (2.05 g,7.76 mmol), pd (dppf) Cl 2. DCM (0.64 g,0.79 mmol) and potassium phosphate (3.32 g,15.64 mmol) were added and reacted under nitrogen at 80℃for 19h. The reaction solution was cooled to room temperature, 100mL of ethyl acetate and 100mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 59b (0.58 g, yield: 93%).
Second step 59c preparation
59B (0.37 g,1.17 mmol) was dissolved in 5mL of methanol and sodium borohydride (0.045 g,1.19 mmol) was added at 0deg.C and reacted for 0.5h at room temperature. 25mL of ethyl acetate and 35mL of water were added, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 59c (0.17 g, yield: 46%).
Third step 59d preparation
4-Iodopyrazole (0.10 g,0.52 mmol) was dissolved in10 mL THF, triphenylphosphine (0.21 g,0.8 mmol) and 59C (0.17 g,0.53 mmol) were added, DEAD (0.16 g,0.92 mmol) was added at 0deg.C, and the reaction was continued for 19h at 40deg.C. The reaction solution was cooled to room temperature, 50mL of ethyl acetate and 50mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1), to give 59d (0.19 g, yield: 74%).
Fourth step preparation of Compound 59
59D (190 mg,0.38 mmol), crude intermediate 1 above (0.13 g), TEA (120 mg,1.19 mmol), cuI (14 mg,0.074 mmol) and PdCl 2(PPh3)2 (53 mg,0.076 mmol) were added to the reaction flask and 15mL DMF was added under nitrogen at 55℃for 3h. The reaction solution was cooled to room temperature, 20mL of water was added, suction filtration was performed, the cake was washed with 5mL of water, the cake was dissolved with 40mL of a mixed solvent of DCM/MeOH (v/v) =5:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane/methanol (v/v) =10:1-5:1) to give compound 59 (66 mg, yield: 25%).
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.79–7.72(m,1H),7.70–7.54(m,4H),7.45–7.38(m,1H),7.31–7.23(m,1H),7.05(dd,1H),6.98(dd,1H),6.80(d,1H),6.55(dd,1H),5.54(q,1H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.18–2.08(m,1H),1.93(d,3H).
EXAMPLE 60 preparation of Compound 60
First step, preparation of 60b
60A (1.01 g,3.3 mmol) was dissolved in 10mL of 1, 4-dioxane and 1mL of water, and 60A (0.97 g,3.3 mmol), pd (dppf) Cl2.DCM (0.27 g,0.33 mmol) and potassium phosphate (2.10 g,9.89 mmol) were added and reacted at 80℃under nitrogen for 19h. The reaction system was cooled to room temperature, 100mL of ethyl acetate and 100mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 60b (0.95 g, yield: 83%).
Second step, preparation of 60c
60B (0.5 g,1.44 mmol) was dissolved in 5mL tetrahydrofuran/methanol (v/v) =10:1 mixed solvent, sodium borohydride (0.13 g,3.44 mmol) was added at 0℃and reacted for 1.5h at 60 ℃. The reaction solution was cooled to room temperature, 40mL of ethyl acetate and 35mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 60c (0.412 g, yield: 94%).
Third step, 60d preparation
4-Iodopyrazole (0.25 g,1.29 mmol) was dissolved in10 mL THF, triphenylphosphine (0.51 g,1.94 mmol) and 60C (0.412 g,1.35 mmol) were added, DEAD (CAS: 1972-28-7) (0.39 g,2.24 mmol) was added at 0℃and reacted at room temperature for 19h. To the reaction solution were added 50mL of ethyl acetate and 50mL of water, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 60d (0.21 g, yield: 34%).
Fourth step preparation of Compound 60
60D (210 mg,0.44 mmol), the crude intermediate 1 (0.15 g), TEA (130 mg,1.28 mmol), cuI (17 mg,0.089 mmol) and PdCl 2(PPh3)2 (62 mg,0.088 mmol) were added to the reaction flask and reacted under nitrogen with 10mL DMF at 55℃for 3.5h. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 5mL of water, the cake was dissolved with 40mL of DCM/MeOH (v/v) =5:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane/methanol (v/v) =10:1-5:1) to give compound 60 (54 mg, yield: 18%).
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.79–7.73(m,1H),7.70–7.62(m,2H),7.61–7.55(m,2H),7.45–7.39(m,1H),7.32–7.26(m,1H),7.07(dd,1H),6.99(dd,1H),6.80(d,1H),6.55(dd,1H),5.34(s,2H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.12–4.03(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.20–2.08(m,1H).
EXAMPLE 61 preparation of Compound 61
First step 61b preparation
18ML of methylmagnesium bromide (3 mol/L tetrahydrofuran solution) was added to 5mL of ultra-dry tetrahydrofuran, a solution of 61a (3.01 g,11.49 mmol) in ultra-dry tetrahydrofuran (30 mL) was added dropwise at 0℃and reacted for 3h. 100mL of saturated aqueous ammonium chloride solution was added dropwise to the reaction solution at 0℃and extracted with 250mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1-5:1) to give 61b (1.65 g, yield: 55%).
Second step 61c preparation
61B (0.3 g,1.14 mmol) and phenol (0.13 g,1.38 mmol) were dissolved in 5mL of carbon tetrachloride, boron trifluoride etherate (0.32 g,2.25 mmol) was added at 0deg.C and reacted at room temperature for 2h. To the reaction solution was added 50mL of water, extracted with 40mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 61c (0.32 g, yield: 83%).
Third step 61d preparation
61C (320 mg,0.95 mmol), 1A (170 mg,0.94 mmol), TEA (29 mg,2.88 mmol), cuI (36 mg,0.19 mmol) and PdCl 2(PPh3)2 (135 mg,0.19 mmol) were added to the reaction flask and reacted under nitrogen with 5mL of DMF at 55℃for 3.5h. The reaction solution was cooled to room temperature, 50mL of water was then added, extraction was performed with 100mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (dichloromethane/methanol (v/v) =10:1-5:1) to give 61d (172 mg, yield: 47%).
Fourth step 61e preparation
61D (0.3 g,0.77 mmol) was dissolved in10 mL of dichloromethane, and 2- [ N, N-bis (trifluoromethanesulfonyl) amino ] pyridine (0.33 g,0.92 mmol), DMAP (9 mg,0.074 mmol) and TEA (0.12 g,1.19 mmol) were added and reacted at room temperature for 1h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 61e (0.15 g, yield: 37%).
Fifth step, 61f preparation
61E (0.15 g, 0.284 mmol) was dissolved in a mixed solvent of 10mL 1, 4-dioxane and 1mL water, and 2-chloro-4- (trifluoromethyl) phenylboronic acid pinacol ester (0.08 g,0.26 mmol), potassium phosphate (0.17 g,0.8 mmol) and Pd (dppf) Cl2.DCM (0.021 g,0.026 mmol) were added and reacted at 80℃under nitrogen for 19h. The reaction solution was cooled to room temperature, 100mL of ethyl acetate and 100mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 61f (0.14 g, yield: 97%).
Compound 61 was obtained by the synthesis method of example 41, starting from compound 61 f.
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.75–7.70(m,1H),7.67(d,1H),7.59–7.51(m,1H),7.49–7.40(m,1H),7.39–7.31(m,4H),7.30–7.25(m,2H),7.25–7.20(m,2H),6.81(d,1H),6.56(dd,1H),4.98–4.89(m,1H),4.43–4.32(m,2H),4.14–4.04(m,2H),3.90–3.77(m,1H),2.96–2.64(m,3H),2.20–2.07(m,1H),1.71(s,6H).
EXAMPLE 62 preparation of Compound 62
First step, preparation of 62B
62A (10.00 g,34.96 mmol) (see WO 2022032026) and tert-butyl 3-iodoazetidine-1-carboxylate (11.88 g,41.96 mmol) were dissolved in100 mL DMA, zinc powder (13.72 g,211.08 mmol) was added, and 2-amidinopyridine hydrochloride (CAS: 51285-26-8) (1.10 g,6.98 mmol) was added to react with nickel chloride ethylene glycol dimethyl ether complex (CAS: 29046-78-4) (1.54 g,7.01 mmol) under nitrogen at 100℃for 16h. The reaction system was cooled to room temperature, 300mL of water and 200mL of ethyl acetate were added, the filtrate was separated by filtration, the aqueous phase was extracted with 200mL of ethyl acetate, the organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =4:1) to give 62B (2.9 g, yield: 23%).
Second step, preparation of 62C
62B (2.9 g,8.0 mmol) was dissolved in 40mL of methanol, potassium carbonate (6.63 g,48 mmol) was added and reacted with cesium carbonate (5.21 g,15.99 mmol) at 60℃for 16h. The reaction was cooled to room temperature, 100mL of DCM was added, filtration was performed, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2:1) to give 62C (1.8 g, yield: 84%).
Third step, preparation of 62a-1
62C (1.8 g,6.76 mmol) was dissolved in 30mL acetonitrile, KI (1.68 g,10.12 mmol) and CuI (1.93 g,10.13 mmol) were added and isoamyl nitrite (1.43 g,12.21 mmol) was slowly added dropwise and reacted at 50℃for 16h. The reaction system was cooled to room temperature, 100mL of saturated aqueous sodium thiosulfate solution was added, filtration was carried out, the filtrate was extracted with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =3:1) to give 62a-1 (1.4 g, yield: 55%).
Fourth step, preparation of 62b
62A-1 (0.58 g,1.54 mmol) was dissolved in 15mL of 1, 4-dioxane and 1mL of water, 62a (0.45 g,1.61 mmol), pd (dppf) Cl2.DCM (0.13 g,0.16 mmol) and potassium phosphate (0.98 g,4.62 mmol) were added, nitrogen was replaced three times, and the reaction was performed at 80℃for 19h. The reaction system was cooled to room temperature, 80mL of ethyl acetate and 100mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 62b (0.46 g, yield: 74%).
Fifth step, 62c preparation
62B (0.46 g,1.14 mmol) was dissolved in10 mL tetrahydrofuran/methanol (v/v) =10:1, lithium borohydride (0.097 g,4.45 mmol) was added at 0℃and reacted for 2h at 60 ℃. The reaction solution was cooled to room temperature, 50mL of ethyl acetate and 50mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 62c (0.41 g, yield: 96%).
Sixth step, 62d preparation
62C (0.200 g,0.53 mmol) was dissolved in 5mL of dichloromethane and pyridine (0.13 g,1.64 mmol) and MsCl (0.073 g,0.64 mmol) were added at 0deg.C and reacted for 2h at room temperature. 20mL of methylene chloride and 20mL of water were added, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 1. The crude product 1 was dissolved in 5mL of acetonitrile, cesium carbonate (0.52 g,1.60 mmol) and 34a (0.18 g,0.81 mmol) were added and reacted at 60℃for 19h. The reaction system was cooled to room temperature, 50mL of ethyl acetate and 50mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 62d (0.13 g, yield: 42%).
Seventh step preparation of Compound 62
62D (0.13 g,0.22 mmol) and p-toluene sulfonic acid (0.15 g,0.87 mmol) were dissolved in 5mL acetonitrile and reacted at room temperature for 12h. The reaction solution was concentrated under reduced pressure to obtain crude product 2. The crude 2, sodium bicarbonate (0.074 g,0.88 mmol), 1f (0.073 g,0.26 mmol) and DIPEA (0.11 g,0.85 mmol) were dissolved in 5mL DMSO and reacted at 80℃for 3h. The reaction solution was cooled to room temperature, 100mL of ethyl acetate was then added, the organic phase was washed with a saturated aqueous sodium chloride solution (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-1:2) to give compound 62 (0.05 g, yield: 31%).
1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.76–7.66(m,3H),7.58–7.51(m,2H),7.51–7.42(m,1H),7.40–7.22(m,4H),6.87(d,1H),6.65–6.55(m,2H),5.18(s,2H),4.99–4.89(m,1H),4.58–4.46(m,2H),4.39–4.26(m,1H),4.20–4.10(m,2H),2.98–2.65(m,3H),2.41(s,3H),2.24(s,3H),2.19–2.09(m,1H).
LCMS m/z=733.4[M-1]-
Biological test case
1. Inhibition of 22RV1 cell proliferation assay
Prostate cancer cells 22RV1 were purchased from ATCC with RPMI1640+10% fbs as cell culture medium and cultured in 37 ℃ 5% co 2 incubator. Cells in exponential growth phase were collected on the first day, cell suspensions were adjusted to the corresponding concentrations with 1% css-FBS phenol red free medium, plated, cells were 2000 cells/well, and incubated overnight. The next day, different concentrations of the compound were added and placed in incubator for further incubation for 7 days. After the incubation, 50. Mu.L of CellTiter-Glo reagent, which had been melted and equilibrated to room temperature in advance, was added to each well according to the protocol of CellTiter-Glo kit (Promega, G7573), and the mixture was homogenized for 2 minutes with a microplate shaker, and after 10 minutes of standing at room temperature, the fluorescence signal value was measured with an enzyme-labeled instrument (PHERASTAR FSX). As a result, the inhibition ratios of the respective concentrations of the compounds were calculated by the process of the formula (1), and IC 50 values having 50% inhibition ratios of the compounds were calculated using DoseResp functions using origin9.2 software. Where RLU compound is a readout of the drug-treated group and RLU control is an average of the DMSO solvent control group. Inhibit% = [1-RLU compound/RLUcontrol ] ×100% formula (1)
The results of IC 50 values inhibiting 22RV1 cell proliferation are shown in Table 1.
TABLE 1 IC 50 values of the compounds of the invention for inhibition of 22RV1 cells
Conclusion the compounds of the present invention, e.g., the compounds of the examples, have inhibitory effect on prostate cell 22RV 1.
Degradation experiments of AR cleavage mutant 7 (AR-V7) in 2.22RV1 cells
Prostate cancer cells 22RV1 were purchased from ATCC with 1640+10% fbs as cell culture medium and cultured in 37 ℃ 5% co 2 incubator. Cells in exponential growth phase were collected on the first day, cell suspensions were plated at corresponding concentrations with 1% css-FBS phenol red free medium, 1mL per well in 6-well plates, and the number of cells was 300000 cells/well. The following day 1% css-FBS phenol red free medium containing the test compound was added, one well was added with 0.2% DMSO 1% css-FBS phenol red free medium as DMSO vehicle control, and 6 well plates were incubated in 37℃in 5% CO 2 incubator. after 24 or 48 hours, the cells were trypsinized, collected in 1.5mL centrifuge tubes, 15 μl of RIPA lysate (containing 1X protease inhibitor cocktail (Protease Inhibitor cocktail)) was added to each well, and after 15 minutes of lysis on ice, 12000g,4 ℃ and centrifugation for 10 minutes. The supernatant protein samples were collected and protein quantification was performed by BCA method. AR-V7 was detected using full-automatic protein expression quantitative analysis, the experimental procedure was as follows, with the protein concentration to be measured diluted to 2mg/mL. mu.L of the diluted protein sample was taken and added to 1. Mu.L of 5 XMaster Mix (kit supply), and the prepared sample was denatured at 95℃for 5 minutes and placed on ice for use. The primary antibodies were diluted with Antibody Diluent II (kit provided) in the ratio of 1:10 and 1:500 for AR V7 (CST, 19672S) and beta-actin (CST, 3700), respectively. The secondary antibody is a 1:1 mixed goat anti-mouse and goat anti-rabbit secondary antibody, and the color developing solution is Lumino-S and Peroxide mixed in a 1:1. And sequentially adding the prepared reagents into a detection plate according to the instruction of the kit, and detecting on the machine. Western banding processing the Western bands were automatically simulated according to signal values using the full automatic protein expression quantitative analysis software "Compass for SW". The degradation rate of AR-V7 (2) relative to vehicle control at different drug concentrations was calculated according to formula (2). Wherein AR-V7 compound is the relative peak area of AR-V7 in the administration group, and AR-V7 solvent is the relative peak area of AR-V7 in the vehicle control group. AR-V7% = (1-AR-V7 compound/AR-V7solvent). Times.100% formula (2)
DC 50 calculation the compound concentration DC 50 values at 50% AR-V7 degradation were calculated using Graphpad software and analyzed using log (inhibitor) vs. response-Variable slope (four parameters) function, following the procedure of formula (2).
The results of the DC 50 values of the degraded AR-V7 protein are shown in Table 2.
TABLE 2 DC 50 values of the compounds of the invention for 48 hours degradation of 22RV1 cell AR-V7 protein
Conclusion the compounds of the invention, e.g. the compounds of the examples, have a good degradation of AR-V7 in prostate cell 22RV 1.
3. Rat pharmacokinetic testing
Experimental purposes the subject is administered to SD rats by intravenous and intragastric administration at a single dose, the concentration of the subject in the rat plasma is determined, and the pharmacokinetic profile of the subject in the rat is assessed.
Test animals, male SD rats, 200-250 g, 6-8 weeks old, 6/compound. Purchased from Chengdu laboratory animals Inc.
Test method 6 SD rats were randomly grouped by body weight on the day of the test. The water is not forbidden for 12-14 h after 1 day of administration, and the feed is fed for 4h after administration.
TABLE 3 Table 3
* The dosages are calculated as the free base.
Sampling, namely, taking 0.1mL of blood through the orbit after and before administration and after isoflurane anesthesia, and placing the blood into a EDTAK centrifuge tube. Plasma was collected by centrifugation at 5000rpm at 4℃for 10 min.
Plasma time points for IV & PO group collection: 0,5min,15min,30min,1,2,4,6,8,24h.
All samples were stored at-60 ℃ prior to analytical detection. The samples were quantitatively analyzed by LC-MS/MS.
TABLE 4 pharmacokinetic parameters of the compounds of the invention in rat plasma
* Injection i.g. (intragastric) administration of compound-indicating no test:
conclusion the compounds of the invention, e.g. the examples, have better oral absorption in rats.
4. Mouse pharmacokinetic test
4.1 Test animals, male ICR mice, 25-30 g, 6/compound. Purchased from Chengdu laboratory animals Inc.
4.2 Design of the trial 6 ICR mice were randomized by body weight on the day of the trial. The water is not forbidden for 12-14 h after 1 day of administration, and the feed is fed for 4h after administration.
TABLE 5 dosing information
Note that intravenous vehicle 5% dma+5% solutol+90% saline;
Oral (gavage) vehicle 5% dmso+5% solutol+30% peg400+60% (20% sbe-CD);
* The dosages are calculated as the free base.
Isoflurane was anesthetized before and after dosing by orbital blood extraction of 0.1mL, placed in EDTAK centrifuge tubes, centrifuged at 5000rpm,4 ℃ for 10min, and plasma was collected. Blood sampling time points of the venous group and the gastric lavage group are: 0,5,15,30min,1,2,4,7,24h. All samples were stored at-60℃prior to analytical detection and the samples were quantitatively analyzed by LC-MS/MS.
TABLE 6 pharmacokinetic parameters of the inventive compounds in mouse plasma
* I.g. (lavage) administration of the compound;
Conclusion the compounds of the invention, e.g. the examples, have better oral absorption in mice.
5. Beagle pharmacokinetic testing
The test animals, namely male beagle dogs, about 8-10 kg, and 6 compounds, are purchased from Beijing Mas Biotechnology Co.
Test method 6 beagle dogs were randomly grouped by body weight on the day of the test. The water is not forbidden for 14-18 h after 1 day of feeding, and the feed is fed for 4h after the feeding.
TABLE 7 dosing information
Note that intravenous vehicle 5% dma+5% solutol+90% saline;
Oral (gavage) vehicle 5% dmso+5% solutol+30% peg400+60% (20% sbe-CD);
* The dosages are calculated as the free base.
Blood 1mL was taken through the jugular vein or the limb vein before and after administration and placed in EDTAK centrifuge tubes. Plasma was collected by centrifugation at 5000rpm at 4℃for 10 min. Blood sampling time points of the venous group and the gastric lavage group are: 0,5,15,30min,1,2,4,6,8,10,12,24,48h. All samples were stored at-80℃and were quantitatively analyzed by LC-MS/MS.
Conclusion the compounds of the present invention, such as the examples, have better oral absorption in dogs.
6. Monkey pharmacokinetic testing
The test animals are male cynomolgus monkeys, 3-5 kg, 3-6 ages, 4 animals/compound. Purchased from western mountain biotechnology limited, su.
Test method 4 monkeys were randomly grouped by body weight on the day of the test. The water is not forbidden for 14-18 h after 1 day of feeding, and the feed is fed for 4h after the feeding.
TABLE 8 dosing information
Note that intravenous vehicle 5% dma+5% solutol+90% saline;
Oral (gavage) vehicle 5% dmso+5% solutol+30% peg400+60% (20% sbe-CD);
* The dosages are calculated as the free base.
1.0ML of blood was taken through the vein of the extremities before and after administration and placed in a EDTAK centrifuge tube. Plasma was collected by centrifugation at 5000rpm at 4℃for 10 min. Blood sampling time points of the venous group and the gastric lavage group are: 0,5,15,30min,1,2,4,6,8,10,12,24h. All samples were stored at-80℃and were quantitatively analyzed by LC-MS/MS.
Conclusion the compounds of the invention, e.g. the examples, have better oral absorption in monkeys.
HERG Potassium ion channel action test
Experiment platform electrophysiological manual patch clamp system
Cell line Chinese Hamster Ovary (CHO) cell line stably expressing hERG potassium ion channel
Experimental methods CHO (CHINESE HAMSTER Ovary) cells stably expressing the hERG potassium channel, hERG potassium channel currents were recorded using whole cell patch clamp technique at room temperature. The glass microelectrode is formed by drawing a glass electrode blank (BF 150-86-10, sutter) through a drawing instrument, the tip resistance after the electrode inner liquid is poured is about 2-5MΩ, and the glass microelectrode can be connected to a patch clamp amplifier after being inserted into an amplifier probe. The clamp voltage and data recording are controlled and recorded by pClamp 10 software through a computer, the sampling frequency is 10kHz, and the filtering frequency is 2kHz. After whole cell recordings were obtained, the cells were clamped at-80 mV and the step voltage inducing hERG potassium current (I hERG) was applied from-80 mV to a depolarization voltage of 2s to +20mV, repolarized to-50 mV for 1s and back to-80 mV. This voltage stimulus was administered every 10s, and the administration was started after the hERG potassium current had stabilized (at least 1 minute). Each test concentration of the compound was administered for at least 1 minute, and at least 2 cells were tested per concentration (n.gtoreq.2).
Data processing the data analysis and processing adopts pClamp 10,GraphPad Prism 5 and Excel software. The extent of Inhibition of hERG potassium current (-peak of induced hERG tail current at 50 mV) by different compound concentrations was calculated using the following formula%inhibition = [1- (I/Io) ]. Times.100%
Wherein Inhibition% represents the percent Inhibition of the compound on hERG potassium current, and I and Io represent the magnitude of hERG potassium current after and before dosing, respectively.
Compound IC 50 was calculated by fitting the following equation using GRAPHPAD PRISM 5 software, y=bottom+ (Top-Bottom)/(1+10 ((LogIC 50 -X) × HillSlope))
Wherein X is the Log value of the detection concentration of the sample, Y is the inhibition percentage under the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages respectively.
Conclusion the compounds of the invention, e.g., the example compounds, do not have a significant inhibitory effect on hERG potassium channel current.
8. Liver microsome stability test
The experiment adopts five hepatic microsomes of human, canine, rat and mouse as in vitro models to evaluate the metabolic stability of the test subjects.
Under the condition of 37 ℃,1 mu M of the test substance is incubated with microsomal protein and coenzyme NADPH together, the reaction is stopped after a certain time (5, 10,20,30,60 min), ice-cold acetonitrile containing an internal standard is added, the concentration of the test substance in a sample is detected by adopting an LC-MS/MS method, T 1/2 is obtained according to the ln value of the drug residual rate in an incubation system and the incubation time, and the intrinsic clearance CL int(mic) of the liver microsomes and the intrinsic clearance CL int(Liver) of the liver are further calculated.
Conclusion the compounds of the present invention, e.g. the examples, have good liver microsomal stability.
CYP450 enzyme inhibition test
The objective of this study was to evaluate the effect of the test substances on the activity of 5 isoenzymes (CYP 1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A 4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system. The specific probe substrate of CYP450 isozymes is respectively incubated with human liver microsomes and test substances with different concentrations, reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH) is added to start the reaction, after the reaction is finished, the metabolic products generated by the specific substrates are quantitatively detected by processing the samples and adopting liquid chromatography-tandem mass spectrometry (LC-MS/MS), the change of the CYP enzyme activity is measured, the IC 50 value is calculated, and the inhibition potential of the test substances on each CYP enzyme subtype is evaluated.
Conclusion the compounds of the invention, e.g. the compounds of the examples, do not have a significant inhibitory effect on the 5 isozymes of human liver microsomal cytochrome P450.
Caco2 permeability test
The assay uses a monolayer of Caco-2 cells incubated in triplicate in a 96-well Transwell plate. A transport buffer solution (HBSS, 10mM HEPES,pH 7.4.+ -. 0.05) containing the compound of the invention (2. Mu.M) or the control compound digoxin (10. Mu.M), nadolol (2. Mu.M) and metoprolol (2. Mu.M) was added to the apical or basal side dosing wells. Transport buffer containing DMSO was added to the corresponding receiving wells. After incubation for 2 hours at 37±1 ℃, the cell plates were removed and appropriate amounts of samples were taken from each of the top and bottom ends into a new 96-well plate. The protein was then precipitated by adding acetonitrile containing an internal standard. Samples were analyzed using LC MS/MS and the concentrations of the compounds of the invention and control compounds were determined. The concentration data were used to calculate apparent permeability coefficients from the apical to basal side of the monolayer cells, and basal to apical transport, and thus the efflux rate. The integrity of the monolayer after incubation for 2 hours was assessed by leakage of fluorescein.
Conclusion the compounds of the present invention, e.g. the examples, have a certain Caco2 permeability.
11. Experiment of inhibiting growth of mouse 22RV1 subcutaneous transplantation tumor model by the compound
Cell culture 22RV1 cells (from ATCC) were cultured in vitro by adding 10% foetal calf serum and 10. Mu.g/mL of recombinant insulin medium, 37℃and 5% CO 2. Passaging is routinely performed 2 times a week. Cells were harvested, counted and inoculated while the cells remained in the exponentially growing phase.
Animals, BALB/c nude mice, males, 4-6 weeks old, weighing 14-20 g. Is provided by Beijing Vitolihua laboratory animal technology Co.
Tumor inoculation, in which experimental mice were subcutaneously inoculated with 5X 10 6 RV1 cells on the right back, the cells were resuspended in PBS and matrigel (1:1), tumor growth was observed periodically, castration was performed when tumors grew to an average volume of 80mm 3 by anesthetizing the mice with isoflurane, surgical castration was performed through a scrotal midline incision, bilateral access was allowed, after exposure of each testis, the spermatic cord was ligated with 5-0vicryl sutures, and then the testes were excised, and then scrotum and skin were sutured with 5-0Vicyryl, respectively, after which the animals were observed continuously until complete recovery. After castration, the tumor may shrink (tumor regression), beginning the grouping and treatment when the average tumor volume regrows to around 100mm 3, day 0.
Administration of the compounds of the invention, in accordance with a given dose, orally (PO), once daily (QD), 10 mice per group, all groups being administered for 28 days.
Experimental observations and end-of-week 3 mice weights were measured and tumor measurements were made. The experiment was ended 28 days after dosing, and all mice were euthanized. Tumor volume calculation formula tumor volume (mm 3)＝1/2×(a×b2) (where a represents the long diameter and b represents the short diameter), raw data were measured by balance and vernier caliper.
Conclusion the compounds of the present invention, e.g., the example compounds, have some inhibitory effect on the growth of the murine 22RV1 subcutaneous engraftment tumor model.
HEK293 cell proliferation assay
Human embryonic kidney 293 cells HEK293 were purchased from ATCC, complete medium emem+10% fbs, cultured in 37 ℃ 5% co 2 incubator. Cells in exponential growth phase were collected, cell suspensions were adjusted to the corresponding concentrations with complete medium and plated to give 1000 cells/well and a volume of 180 μl per well. The next day 20. Mu.L of the compound was added and the incubation in incubator continued for 7 days. After the completion of the incubation, 50. Mu.L of CTG solution previously melted and equilibrated to room temperature was added to each well according to the protocol of CellTiter-Glo kit (Promega, G7573), and the mixture was homogenized for 2 minutes with a microplate shaker, and after 10 minutes at room temperature, the fluorescence signal value was measured with an enzyme-labeled instrument (PHERASTAR FSX). Chemiluminescence readings were plotted using GRAPHPAD PRIM 8.0.0 software using a four parameter nonlinear regression model to plot S-type concentration curves and calculate IC 50 values. As a result, the proliferation rate Growth of each concentration of the compound was calculated by the treatment of the formula (3), and the concentration IC 50 value of the compound at a proliferation rate of 50% was calculated by using GRAPHPAD PRIM 8.0.0 software. Where RLU compound is a readout of the drug-treated group and RLU control is an average of the solvent control group. Growth% = RLU compound/RLUcontrol ×100% formula (3)
Conclusion the compounds of the invention, e.g. the example compounds, have a weak inhibitory effect on HEK293 in human embryonic kidney 293 cells.

Claims (15)

一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，化合物选自通式(I)所示的化合物， B-L-K (I)；A compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compound represented by general formula (I), B-L-K (I); L选自键或-C1-50烃基-，所述烃基中有1至20个亚甲基单元任选被-Ak-、-Cy-替换；L is selected from a bond or -C 1-50 hydrocarbon group-, wherein 1 to 20 methylene units in the hydrocarbon group are optionally replaced by -Ak-, -Cy-; 每个-Ak-各自独立地选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自卤素、OH、CN、NH2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基的取代基所取代；Each -Ak- is independently selected from -( CH2 ) q- , -( CH2 ) q -O-, -O-( CH2 ) q- , -( CH2 ) q -S-, -S-( CH2 )q-, -( CH2 ) q -NR L- , -NR L- ( CH2 ) q- , -( CH2 ) q - NR L C(＝O)-, -NR L ( CH2 ) qC (＝O)-, -( CH2 ) q -C(＝O)NR L -, -C(＝O)-, -C(＝O)-( CH2 ) q -NR L -, -(C≡C) q- , -CH＝CH-, -Si( RL ) 2- , -Si(OH)( RL )-, -Si(OH) 2- , -P(＝O)(OR L )-, -P(＝O)( RL )-, -S-, -S(＝O)-, -S(＝O) 2- or a bond, wherein the -CH2-, -CH＝CH- are optionally substituted by 1 to 2 substituents selected from halogen, OH, CN, NH2 , C1-6 alkyl, C1-6 alkoxy, halogen-substituted C1-6 alkyl, hydroxy-substituted C1-6 alkyl, cyano-substituted C1-6 alkyl; q各自独立的选自0、1、2、3、4、5或6；q is each independently selected from 0, 1, 2, 3, 4, 5 or 6; RL各自独立的选自H、C1-6烷基、3-7元杂环基、3-7元环烷基、苯基或5-6元杂芳基，所述的杂环基或杂芳基含有1至4个选自O、S、N的杂原子；R and L are each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S and N; 每个-Cy-各自独立地选自键或者或者任选取代的如下基团之一：4-8元杂单环基、4-10元杂并环基、5-12元杂螺环基、7-10元杂桥环基、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂芳基、杂单环基、杂并环基、杂螺环基或杂桥环基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；each -Cy- is independently selected from a bond or one of the following groups which are optionally substituted: a 4-8 membered heteromonocyclic group, a 4-10 membered heterocycloalkyl group, a 5-12 membered heterospirocyclic group, a 7-10 membered heterobridged cyclic group, a 3-7 membered monocycloalkyl group, a 4-10 membered cycloalkyl group, a 5-12 membered spirocyclic group, a 5-10 membered bridged cycloalkyl group, a benzoC4-6 carbocyclic group, a benzo4 to 6 membered heterocyclic group, a 5-10 membered heteroaryl group or a 6-10 membered aryl group, when substituted, substituted by 1 to 4 R L2 , wherein the heterocyclic group, heteroaryl group, heteromonocyclic group, heterocycloalkyl group, heterospirocyclic group or heterobridged cyclic group contains 1 to 4 heteroatoms selected from O, S and N, and when the heteroatom is selected from S, is optionally substituted by 1 or 2 =O; RL2各自独立地选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-4亚烷基-O-C1-4烷基、-O-C1-4亚烷基-O-C3-10碳环基、-C1-4亚烷基-O-C1-4亚烷基-O-C1-4烷基、-C1-4亚烷基-O-C1-4亚烷基-O-C3-10碳环基、-O-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-4至10元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R L2 are each independently selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , ＝O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-4 alkylene-OC 1-4 alkyl, -OC 1-4 alkylene-OC 3-10 carbocyclyl, -C 1-4 alkylene-OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-OC 1-4 alkylene-OC 3-10 carbocyclyl, -OC 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-C 3-10 carbocyclyl, 0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , ＝O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N; B选自 B is selected from B1选自C3-20碳环基或4-20元杂环，所述碳环基或杂环任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子； B1 is selected from C 3-20 carbocyclic group or 4-20 membered heterocyclic ring, wherein the carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b1 , and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; B2选自C3-20碳环基或4-20元杂环，所述碳环基或杂环任选被1至4个Rb2所取代，所述的杂环基含有1至4个选自O、S、N的杂原子； B2 is selected from C3-20 carbocyclic group or 4-20 membered heterocyclic ring, wherein the carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 Rb2 , and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; B3选自C3-20碳环基或4-20元杂环，所述碳环基或杂环任选被1至4个Rb3所取代，所述的杂环基含有1至4个选自O、S、N的杂原子； B3 is selected from C3-20 carbocyclic group or 4-20 membered heterocyclic ring, wherein the carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 Rb3 , and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; 或者B3选自键； or B 3 is selected from a bond; L1选自键或 L 1 is selected from a bond or L2选自键或 L2 is selected from a bond or Y1、Y2、Y3、Y4各自独立地选自键、O、S、NRb5a；Y 1 , Y 2 , Y 3 , and Y 4 are each independently selected from a bond, O, S, or NR b5a ; Q1、Q2、Q3、Q4各自独立地选自 Q 1 , Q 2 , Q 3 and Q 4 are each independently selected from v1、v2、v3、v4各自独立地选自0、1、2、3或4；v 1 , v 2 , v 3 , v 4 are each independently selected from 0, 1, 2, 3 or 4; Rb1、Rb2各自独立的选自H、F、Cl、Br、I、＝O、＝S、OH、CN、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、NH2、NHC1-4烷基、N(C1-4烷基)2、-C(＝O)NH2、-C(＝O)NHC1-4烷基、-C(＝O)N(C1-4烷基)2、-C(＝O)OC1-4烷基、-S(＝O)2NH2、-S(＝O)2N(C1-4烷基)2、-S(＝O)2NHC1-4烷基、-ORb22、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-NHC(＝O)Rb22、-N(C1-4烷基)C(＝O)Rb22、-NHS(＝O)2Rb22、-N(C1-4烷基)S(＝O)2Rb22、-O-C3-12碳环基、-NH-C3-12碳环基、-S-C3-12碳环基、C3-12碳环基、C6-10芳基、5至12元杂芳基、4至12元杂环基、-C1-4亚烷基-Rb22、-O-C1-4亚烷基-Rb22、-C1-4亚烷基-O-C1-4亚烷基-Rb22、-C1-4亚烷基-O-C1-4亚烷基-ORb22，所述的亚烷基、烷基、烯基、炔基、烷氧基、烷硫基、碳环基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、-O-C3-10碳环基、C3-10碳环基或4至10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b1 and R b2 are each independently selected from H, F, Cl, Br, I, ＝O, ＝S, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -C(＝O)NH 2 , -C(＝O)NHC 1-4 alkyl, -C(＝O)N(C 1-4 alkyl) 2 , -C(＝O)OC 1-4 alkyl, -S(＝O) 2 NH 2 , -S(＝O) 2 N(C 1-4 alkyl) 2 , -S(＝O) 2 NHC 1-4 alkyl, -OR b22 , -C(＝O)R b22 , -S(＝O) 2 R b22 -P(＝O)(R b22 ) 2 , -NHC(＝O)R b22 , -N(C 1-4 alkyl)C(＝O)R b22 , -NHS(＝O) 2 R b22 , -N(C 1-4 alkyl)S(＝O) 2 R b22 , -OC 3-12 carbocyclyl, -NH-C 3-12 carbocyclyl, -SC 3-12 carbocyclyl, C 3-12 carbocyclyl , C 6-10 aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -C 1-4 alkylene-R b22 , -OC 1-4 alkylene-R b22 , -C 1-4 alkylene-OC 1-4 alkylene-R b22 , -C 1-4 alkylene-OC 1-4 alkylene-OR b22 , the alkylene, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, NH2 , NHC1-4alkyl , N( C1-4alkyl ) 2 , CN, COOH, C1-4alkyl , halogen-substituted C1-4alkyl , cyano-substituted C1-4alkyl , hydroxy-substituted C1-4alkyl , C1-4alkoxy , C2-4alkenyl , C2-4alkynyl, -OC3-10carbocyclyl, C3-10carbocyclyl or 4 to 10 membered heterocyclyl, and the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S and N; Rb3各自独立的选自卤素、＝O、＝S、OH、CN、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-(CH2)n-Rb22、-O-Rb22、-S-Rb22、-NH-Rb22、-(CH2)m1-X-(CH2)m2-Rb24、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自卤素、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、C2-4炔基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b3 is each independently selected from halogen, ＝O, ＝S, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, -(CH 2 ) n -R b22 , -OR b22 , -SR b22 , -NH-R b22 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , -N(R b21 ) 2 , -C(＝O)N(R b21 ) 2 , -C(＝O)OR b21 , -C(＝O)R b22 , -S(＝O) 2 R b22 , -P(＝O)(R b22 ) 2 , -S(＝O) 2 N(R b21 ) 2 , -NR b21 C(＝O)R b22 , -NR b21 S(＝O) 2 R b22 , C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents selected from halogen, OH, ＝O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 1-4 alkyl substituted with halogen, C 1-4 alkyl substituted with cyano, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S and N; n各自独立的选自0、1、2、3或4；n is each independently selected from 0, 1, 2, 3 or 4; Rb21各自独立的选自H或C1-4烷基，所述的烷基任选被1至4个选自卤素、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C1-4烷氧基的取代基所取代；R b21 is independently selected from H or C 1-4 alkyl, wherein the alkyl is optionally substituted with 1 to 4 substituents selected from halogen, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy; Rb22各自独立的选自H、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-NH-C1-4烷基、C3-6环烷基，所述的烷基、烷氧基、环烷基、烯基、炔基任选被1至4个选自卤素、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C1-4烷氧基的取代基所取代；R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -NH-C 1-4 alkyl, C 3-6 cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl are optionally substituted with 1 to 4 substituents selected from halogen, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy; 或Rb1与Rb3、Rb2与Rb3任其一直接连接形成C5-7碳环基、5至7元杂环基，所述的碳环基或者杂环基任选被1至4个选自卤素、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子；or R b1 and R b3 , R b2 and R b3 are directly connected to form a C 5-7 carbocyclic group or a 5- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from halogen, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl or C 1-4 alkoxy, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S and N; Rb4、Rb5各自独立的选自H、F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、 COOH、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C3-12环烷基、C6-10芳基、5-10元杂芳基或3-12元杂环基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、C1-6烷基、卤素取代的C1-6烷基、氰基取代的C1-6烷基、C1-6烷氧基、C2-6炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 2 , CN, C1-6 alkyl, halogen-substituted C1-6 alkyl, cyano-substituted C1-6 alkyl, C1-6 alkoxy, C2-6 alkynyl, C3-8 cycloalkyl or 3 to 8 heterocyclic substituents, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N; 或任意Rb4、Rb5和与其相连接的碳原子共同形成C3-8环烷基或3至8元杂单环基，所述的环烷基或杂单环基任选被1至4个选自F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂单环基、杂芳基或杂环基含有1至4个选自O、S、N的杂原子；or any of R b4 , R b5 and the carbon atom to which they are attached together form a C 3-8 cycloalkyl or a 3- to 8-membered heteromonocyclic group, wherein the cycloalkyl or heteromonocyclic group is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6-membered heteroaryl or 3-8 heterocyclic group, wherein the heteromonocyclic group, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N; Rb5a选自H、C1-4烷基、-(CH2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b5a is selected from H, C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(═O)N(R b21 ) 2 , -C(═O)R b22 , C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the -CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, ═O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N; X各自独立的选自NH、O或S；X is each independently selected from NH, O or S; m1各自独立的选自0、1、2或3；m1 is independently selected from 0, 1, 2 or 3; m2各自独立的选自0、1、2或3；m2 are each independently selected from 0, 1, 2 or 3; Rb23各自独立的选自C2-4烯基、C2-4炔基、C3-10碳环基或4-10元杂环基，所述的碳环基、烯基、炔基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, wherein the carbocyclyl, alkenyl, alkynyl or heterocyclyl is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S and N; Rb24各自独立的选自C1-4烷氧基、NH-C1-4烷基、NH-C3-6环烷基、C3-6环烷基氧基、C3-10碳环基或4-10元杂环基，所述的烷氧基、碳环基、环烷基、环烷基氧基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b24 is each independently selected from C 1-4 alkoxy, NH-C 1-4 alkyl, NH-C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, wherein the alkoxy, carbocyclyl, cycloalkyl, cycloalkyloxy, heterocyclyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N; K选自K1、K2、K3、K4；K is selected from K1, K2, K3, K4; K1选自 K1 is selected from K2选自 K2 is selected from K3选自 K3 is selected from K4选自 K4 is selected from Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq-或3-12元杂环基，所述的杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；Q is each independently selected from a bond, -O-, -S-, -CH2-, -NRq- , -C (=O)-, -NRqC (=O)-, -C(=O) NRq- or a 3-12 membered heterocyclyl, said heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, NH2 , CN, COOH, CONH2 , C1-4 alkyl or C1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N; Rq选自H或C1-6烷基； Rq is selected from H or C1-6 alkyl; A选自C3-10碳环基、C6-10芳基、3-10元杂环基或5-10元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子；A is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N; F各自独立地选自C3-20碳环基、C6-20芳基、3-20元杂环基或5-20元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子；F is each independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N; Rk2各自独立地选自键、-C(＝O)-、-S(＝O)2-、-S(＝O)-或-C(Rk3)2-；R k2 are each independently selected from a bond, -C(=O)-, -S(=O) 2 -, -S(=O)- or -C(R k3 ) 2 -; Rk1各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-6环烷基、Rk7a，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；R k1 is each independently selected from H, F, Cl, Br, I, OH, ＝O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, R k7a , wherein the alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, ＝O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl; Rk7a选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基的取代基所取代；R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl; Rk3各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-8环烷基或3-8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, wherein the heterocyclyl contains 1 to 4 heteroatoms selected from O, S or N; 或者两个Rk3和与二者直接相连的碳原子或环骨架、两个Rk1和与二者直接相连的碳原子或 环骨架共同形成C3-8碳环基或3-8元杂环基，所述碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；or two R k3 and the carbon atom or ring skeleton directly connected to them, two R k1 and the carbon atom or ring skeleton directly connected to them together form a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; Rk4各自独立地选自H、OH、NH2、CN、CONH2、C1-6烷基、C3-8环烷基或3-8元杂环基，所述的烷基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；R k4 are each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, ＝O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, wherein the heterocyclyl contains 1 to 4 heteroatoms selected from O, S or N; M1选自键、-CH2-C(＝O)NH-或-C(＝O)CH2NH-； M1 is selected from a bond, -CH2 - C(=O)NH- or -C(=O) CH2NH- ; M2选自-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6环烷基或4-10元杂环基，所述的烷基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子； M2 is selected from -NHC(=O) -C1-6 alkyl, -NHC(=O) -C3-6 cycloalkyl or 4-10 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, =O, OH, NH2 , C1-4 alkyl or C1-4 alkoxy, wherein the heterocyclyl contains 1 to 4 heteroatoms selected from O, S or N; M3选自-NH-或-O-； M3 is selected from -NH- or -O-; Rk10选自C1-6烷基，所述的烷基任选被1至4个选自F、Cl、Br、I、＝O、OH、C1-6烷基或C3-6环烷基的取代基所取代；R k10 is selected from C 1-6 alkyl, wherein the alkyl is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, =O, OH, C 1-6 alkyl or C 3-6 cycloalkyl; Rk11各自独立的选自H、F、Cl、Br、I、＝O、OH、SH、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-O-C(＝O)-C1-6烷基，所述的烷基、烷氧基或烷硫基任选被1至4个选自F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代；R k11 is each independently selected from H, F, Cl, Br, I, ＝O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -OC(＝O)-C 1-6 alkyl, wherein the alkyl, alkoxy or alkylthio is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, C 1-4 alkyl or C 1-4 alkoxy; Rk12、Rk13各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, ＝O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy; Rk14选自5-6元杂芳基，所述的杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个选自N、O或S的杂原子；R k14 is selected from 5-6 membered heteroaryl, said heteroaryl is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said heteroaryl contains 1 to 4 heteroatoms selected from N, O or S; G选自C6-10芳基或5-10元杂芳基，所述的芳基或者杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个选自N、O或S的杂原子；G is selected from C 6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, and the heteroaryl contains 1 to 4 heteroatoms selected from N, O or S; n1、n2、n3各自独立的选自0、1、2或3；n1, n2, n3 are each independently selected from 0, 1, 2 or 3; p1或p2各自独立的选自0、1、2、3、4或5。p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B选自 B is selected from 或者B选自V选自键或L1；Or B is selected from V is selected from a bond or L 1 ; L1、L2不为键；L 1 and L 2 are not bonds; B1选自6-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C6-8单碳环基、C6-14并环烷基、C6-12螺环烷基、C5-12桥环烷基、苯并C3-10碳环基、苯并3至10元杂环基、C12-18三并环基、12至18元杂三环基、5-10元杂芳基或6-14元芳基，所述B1任选被1至4个 Rb2取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子； B1 is selected from a 6-7 membered heteromonocyclic group, a 5-14 membered heterocycloalkyl group, a 5-12 membered heterospirocyclic group, a 7-10 membered heterobridged cyclic group, a C6-8 monocarbocyclic group, a C6-14 cycloalkyl group, a C6-12 spirocycloalkyl group, a C5-12 bridged cycloalkyl group, a benzoC3-10 carbocyclic group, a benzo3 to 10 membered heterocyclic group, a C12-18 tricycloalkyl group, a 12 to 18 membered heterotricyclic group, a 5-10 membered heteroaryl group or a 6-14 membered aryl group, wherein B1 is optionally substituted by 1 to 4 Rb2 , wherein the heteroaryl group or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N; B3选自4-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C3-8单碳环基、C6-14并环烷基、C6-12元螺环烷基、C5-12元桥环烷基、苯并C3-10碳环基、苯并3至10元杂环基、C12-18三并环基、12至18元杂三环基、5-10元杂芳基或6-14元芳基，所述B3任选被1至4个Rb3取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子； B3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocycloalkyl group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, C3-8 monocarbocyclic group, C6-14 cycloalkyl group, C6-12 membered spirocycloalkyl group, C5-12 membered bridged cycloalkyl group, benzo C3-10 carbocyclic group, benzo 3 to 10 membered heterocyclic group, C12-18 tricycloalkyl group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, said B3 is optionally substituted by 1 to 4 Rb3 , and said heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N; B2选自4-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C3-8单碳环基、C6-14并环烷基、C6-12元螺环烷基、C5-12元桥环烷基、苯并C3-10碳环基、苯并3至10元杂环基、C12-18三并环基、12至18元杂三环基、5-10元杂芳基或6-14元芳基，所述B2任选被1至4个Rb2取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子； B2 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocycloalkyl group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, C3-8 monocarbocyclic group, C6-14 cycloalkyl group, C6-12 membered spirocycloalkyl group, C5-12 membered bridged cycloalkyl group, benzo C3-10 carbocyclic group, benzo 3 to 10 membered heterocyclic group, C12-18 tricycloalkyl group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, said B2 is optionally substituted by 1 to 4 Rb2 , and said heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N; Rb4、Rb5各自独立的选自H、F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、COOH、NO2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、C3-8环烷基、C6-10芳基、O-C3-8环烷基、NH-C3-8环烷基、5-6元杂芳基或3-8元杂环基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 3-8 cycloalkyl, C 6-10 aryl, OC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, 5-6 membered heteroaryl or 3-8 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 4 groups selected from F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, halogen or The alkyl group is substituted with a C 1-4 alkyl, a C 1-4 alkyl substituted with a cyano group, a C 1-4 alkoxy group, a C 2-4 alkynyl group, a C 3-6 cycloalkyl group or a 3 to 8 heterocyclic group, wherein the heteroaryl group or the heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N; Rb5a选自H、C1-4烷基、-(CH2)n-Rb22，所述的-CH2-、烷基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-6元杂芳基或4-8元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子。R b5a is selected from H, C 1-4 alkyl, -(CH 2 ) n -R b22 , wherein the -CH 2 - and alkyl are optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N. 根据权利要求2所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 2 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L选自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、 -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-；L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2- Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-C y2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1 -Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy 4-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3 -Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3- Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak 1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2 -Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, - Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4 -Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-C y2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy 3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3- Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-C y1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2 -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1 -Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy 2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-; Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-(C≡C)q-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自F、Cl、Br、I、OH、CN、NH2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基的取代基所取代；Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -( CH2 ) q- , -( CH2 ) q -O-, -O-( CH2 ) q- , -( CH2 ) q -S-, -S-( CH2 ) q- , -( CH2 ) q -NR L -, -NR L -(CH2) q- , -( CH2 )q-NR L C(＝ O )-, -( CH2 ) q -C(＝O)NR L -, -C(＝O)-, -C(＝O)-( CH2 ) q -NR L -, -CH＝CH-, -(C≡C) q- or a bond, wherein -CH2- and -CH＝CH- are optionally substituted by 1 to 2 members selected from F, Cl, Br, I, OH, CN, NH2 , C1-4 alkyl, C substituted by a C 1-4 alkoxy group, a halogen-substituted C 1-4 alkyl group, a hydroxy-substituted C 1-4 alkyl group, or a cyano-substituted C 1-4 alkyl group; Cy1、Cy2、Cy3、Cy4或Cy5各自独立地选自键或任选取代的如下基团之一：4-7元杂单环基、4-10元杂并环基、5-12元杂螺环基、7-10元杂桥环基、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂芳基、杂单环基、杂并环基、杂螺环基或杂桥环基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups which are optionally substituted: a 4-7 membered heteromonocyclic group, a 4-10 membered heterocycloalkyl group, a 5-12 membered heterospirocyclic group, a 7-10 membered heterobridged cyclic group, a 3-7 membered monocycloalkyl group, a 4-10 membered cycloalkyl group, a 5-12 membered spirocyclic group, a 5-10 membered bridged cycloalkyl group, a benzoC4-6 carbocyclic group, a benzo4 to 6 membered heterocyclic group, a 5-10 membered heteroaryl group or a 6-10 membered aryl group, when substituted, substituted by 1 to 4 R L2 , wherein the heterocyclic group, heteroaryl group, heteromonocyclic group, heterocycloalkyl group, heterospirocyclic group or heterobridged cyclic group contains 1 to 4 heteroatoms selected from O, S and N, and when the heteroatom is selected from S, is optionally substituted by 1 or 2 =O; q各自独立的选自0、1、2、3或4；q is each independently selected from 0, 1, 2, 3 or 4; RL各自独立的选自H或C1-6烷基。 RL are each independently selected from H or C1-6 alkyl. 根据权利要求3所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 3 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: K2选自 K2 is selected from K3选自 K3 is selected from A选自C3-8碳环基、苯基、4-7元杂环基，或5-6元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子； A is selected from C 3-8 carbocyclyl, phenyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N; F各自独立地选自C3-7单环碳环基、C4-10并环碳环基、C5-12螺环碳环基、C5-10桥环碳环基、4-7元杂单环基、4-10元杂并环基、8-15元三环杂并环基、12-17元四环杂并环基、5-17元杂螺环基、C6-14芳基、5-10元杂芳基、所述杂单环基、杂并环基、杂螺环基、杂桥环基或杂芳基含有1至4个选自O、S或N的杂原子；F is independently selected from C 3-7 monocyclic carbocyclyl, C 4-10 cyclocarbocyclyl, C 5-12 spirocyclic carbocyclyl, C 5-10 bridged carbocyclyl, 4-7 membered heteromonocyclic, 4-10 membered heterocyclocyclyl, 8-15 membered tricyclic heterocyclocyclyl, 12-17 membered tetracyclic heterocyclocyclyl, 5-17 membered heterospirocyclic, C 6-14 aryl, 5-10 membered heteroaryl, The heteromonocyclic group, heterocyclic group, heterospirocyclic group, heterobridged ring group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N; 表示环选自芳香环或非芳香环； indicates that the ring is selected from an aromatic ring or a non-aromatic ring; E各自独立地选自C3-10碳环基、苯基、4-12元杂环基、5-12元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子；E is each independently selected from C 3-10 carbocyclyl, phenyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N; Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq-或4-7元杂环基，所述的杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；Q is each independently selected from a bond, -O-, -S-, -CH2-, -NRq- , -C (=O)-, -NRqC (=O)-, -C(=O) NRq- or a 4-7 membered heterocyclic group, said heterocyclic group being optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, NH2 , CN, COOH, CONH2 , C1-4 alkyl or C1-4 alkoxy, said heterocyclic group containing 1 to 4 heteroatoms selected from O, S or N; Rq选自H或C1-4烷基； Rq is selected from H or C1-4 alkyl; Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基，所述烷基或烷氧基任选被1至4个选自F、Cl、Br、I、OH或NH2的取代基所取代；R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH or NH 2 ; 或者两个Rk3和与二者直接相连的碳原子或环骨架、两个Rk1和与二者直接相连的碳原子或环骨架共同形成C3-6碳环基或3-7元杂环基，所述碳环基或杂环基，任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；or two R k3 and the carbon atom or ring skeleton directly connected to the two, two R k1 and the carbon atom or ring skeleton directly connected to the two together form a C 3-6 carbocyclic group or a 3-7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; Rk4各自独立的选自H、OH、NH2、CF3、CN或C1-4烷基；R k4 are each independently selected from H, OH, NH 2 , CF 3 , CN or C 1-4 alkyl; Rk5各自独立地选自C(CH3)2、C(＝O)、CH2、CH2CH2、S(＝O)2、 R k5 are each independently selected from C(CH 3 ) 2 , C(=O), CH 2 , CH 2 CH 2 , S(=O) 2 , Rk6各自独立地选自C(＝O)、CH、S(＝O)、S(＝O)2、CH2或N；R k6 are each independently selected from C(═O), CH, S(═O), S(═O) 2 , CH 2 or N; Rk7各自独立地选自C(CH3)2、C(＝O)、CH、N、CH2、O、S、NRk7a；R k7 are each independently selected from C(CH 3 ) 2 , C(=O), CH, N, CH 2 , O, S, NR k7a ; Rk8各自独立地选自C、N或CH；R k8 are each independently selected from C, N or CH; Rk9各自独立地选自键、C(CH3)2、C(＝O)、CH2、CH2CH2或S(＝O)2；R k9 are each independently selected from a bond, C(CH 3 ) 2 , C(=O), CH 2 , CH 2 CH 2 or S(=O) 2 ; Rka选自O、S或NH； Rka is selected from O, S or NH; Rk7a选自H、C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基的取代基所取代；R k7a is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl; Rk14选自 R k14 is selected from 根据权利要求4所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 4 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B选自 B is selected from V选自键、O、S、NRb5a、NRb5a-(Q2)v2-、-(Q2)v2-NRb5a、-O-(Q2)v2-、-(Q2)v2-O-、-(Q2)v2-；V is selected from bonds, O, S, NR b5a , NR b5a -(Q 2 ) v2 -, -(Q 2 ) v2 -NR b5a , -O-(Q 2 ) v2 -, -(Q 2 ) v2 -O-, -(Q 2 ) v2 -; v2、v4各自独立地选自1、2、3或4；v 2 and v 4 are each independently selected from 1, 2, 3 or 4; Y1、Y3各自独立地选自键、O、S、NRb5a；Y 1 and Y 3 are each independently selected from a bond, O, S, or NR b5a ; Y2、Y4各自独立地选自O、S、NRb5a；Y 2 and Y 4 are each independently selected from O, S, and NR b5a ; Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-C≡C-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自F、Cl、Br、I、OH、CN、NH2、CF3、羟甲基、甲基、乙基、甲氧基或乙氧基的取代基所取代；Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -( CH2 ) q- , -( CH2 ) q -O-, -O-( CH2 ) q- , -( CH2 ) q -S-, -S-( CH2 ) q- , -( CH2 ) q -NR L -, -NR L -( CH2 ) q- , -( CH2 ) q -NR L C(=O)-, -( CH2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-( CH2 ) q -NR L -, -CH=CH-, -C≡C-, or a bond, wherein -CH2- , -CH=CH- are optionally substituted by 1 to 2 residues selected from F, Cl, Br, I, OH, CN , NH2, CF3 , hydroxymethyl, methyl, ethyl, methoxy or ethoxy substituents; q各自独立的选自0、1、2或3；q is each independently selected from 0, 1, 2 or 3; RL各自独立的选自H或C1-4烷基；R L are each independently selected from H or C 1-4 alkyl; K1选自 K1 is selected from K4选自 K4 is selected from Q选自键、C(＝O)；Q is selected from a bond, C(═O); Qa选自键、CH2、NH、N(CH3)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH3)C(＝O)、C(＝O)N(CH3)、 Qa is selected from a bond, CH 2 , NH, N(CH 3 ), O, S, C(═O), NHC(═O), C(═O)NH, N(CH 3 )C(═O), C(═O)N(CH 3 ), Qb选自键、CH2、O、S、C(＝O)、NHC(＝O)、N(CH3)C(＝O)；Qb is selected from a bond, CH2 , O, S, C(=O), NHC(=O), N( CH3 )C(=O); E、A各自独立地选自苯环基、吡啶环基、哒嗪环基、吡嗪环基、嘧啶环基、吡咯环基、吡唑环基、咪唑环基、噻唑环基、呋喃环基、噻吩环基或噁唑环基；E and A are each independently selected from a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrazine ring group, a pyrimidine ring group, a pyrrole ring group, a pyrazole ring group, an imidazole ring group, a thiazole ring group, a furan ring group, a thiophene ring group or an oxazole ring group; F各自独立地选自环丁基、环戊基、环己基、双环[1.1.1]戊烷基、6,7-二氢-5H-环戊[c]吡啶基、2,3-二氢-1H-茚基、苯基、萘基、蒽基、菲基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、2-吡啶酮、苯并噁唑基、吡啶并咪唑基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并吡啶基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基、苯并三嗪基、吡咯并吡咯基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并哒嗪基、吡咯并吡嗪基、咪唑并嘧啶基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并哒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吡唑并哒嗪基、吡唑并吡嗪基、嘧啶并吡啶基、嘧啶并吡嗪基、嘧啶并哒嗪基、嘧啶并嘧啶基、吡啶并吡啶基、吡啶并吡唑、吡啶并吡嗪基、吡啶并哒嗪基、哒嗪并哒嗪基、哒嗪并吡嗪基、吡嗪并吡嗪基、吲哚并吡啶基、吲哚并噻吩基、吲哚并呋喃基、 其左侧与L直接连接； F is independently selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzo pyrimidinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyridinyl, pyridopyridinyl, pyridopyrazol, pyridopyrazinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyridinyl, indolothienyl, indolofuranyl, Its left side is directly connected to L; Rka选自O、S或NH； Rka is selected from O, S or NH; Rk7各自独立地选自C(CH3)2、CH2、O、N(CH3)、N(CH2CH3)、N(环丙基)或NH；R k7 are each independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N(cyclopropyl) or NH; Rk7a选自H、甲基、乙基、丙基、异丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基，所述甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基任选被1至4个选自F、Cl、Br、I、OH、CN、CF3、C1-4烷基、C1-4烷氧基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、C3-6环烷基的取代基所取代；R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 cycloalkyl; p1或p2各自独立的选自0、1、2或3。p1 and p2 are each independently selected from 0, 1, 2 or 3. 根据权利要求5所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 5 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: RL选自H、甲基或乙基； RL is selected from H, methyl or ethyl; q各自独立的选自0、1或2；q is each independently selected from 0, 1 or 2; Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、吡啶基、苯基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个RL2取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups which are substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azacyclohexenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, pyridyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclo Butylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, Cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinazetidinyl, azetidinpyrrolidinyl, azetidinpiperidinyl, pyrrolidinazetidinyl, pyrrolidinpyrrolidinyl, pyrrolidinpiperidinyl, piperidinylazetidinyl, piperidinylpyrrolidinyl, piperidinylpiperidinyl, cyclobutylspiroazacyclotidinyl heterocyclobutyl, cyclobutyl spiropyrrolidinyl, cyclobutyl spiropiperidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiropyrrolidinyl, cyclohexyl spiropiperidinyl, azetidinyl spiroazetidinyl, azetidinyl spiropyrrolidinyl, azetidinyl spiropiperidinyl, pyrrolidinyl spiroazetidinyl, pyrrolidinyl spiropyrrolidinyl, pyrrolidinyl spiropiperidinyl, piperidinyl spiroazetidinyl, piperidinyl spiropiperidinyl, When substituted, it is replaced by 1 to 4 R L2 ; RL2各自独立地选自F、Cl、Br、I、OH、NH2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-2亚烷基-O-C1-2烷基、-O-C1-2亚烷基-O-C3-6碳环基、-C1-2亚烷基-O-C1-2亚烷基-O-C1-2烷基、-C1-2亚烷基-O-C1-2亚烷基-O-C3-6碳环基、-O-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至6元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R L2 are each independently selected from F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CN, ═O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, —OC 1-2 alkylene-OC 1-2 alkyl, —OC 1-2 alkylene-OC 3-6 carbocyclyl, —C 1-2 alkylene-OC 1-2 alkylene-OC 1-2 alkyl, —C 1-2 alkylene-OC 1-2 alkylene-OC 3-6 carbocyclyl, —OC 0-2 alkylene-C 3-6 carbocyclyl, —C 0-2 alkylene-C 3-6 carbocyclyl, 0-2 -alkylene-4 to 6-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, COOH, CN, NH2 , NHC1-4alkyl , N( C1-4alkyl ) 2 , =O, C1-4alkyl , halogen-substituted C1-4alkyl , hydroxy-substituted C1-4alkyl , C1-4alkoxy , halogen-substituted C1-4alkoxy , and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; B1选自取代或未取代的如下基团之一：苯基、萘基、噻吩、呋喃、吡咯、吡唑、咪唑、吡啶、2-吡啶酮、嘧啶、吡嗪、哒嗪、喹啉、异喹啉、喹唑啉、3,4-二氢-1H-苯并吡喃、1,2,3,4-四氢喹啉、苯并呋喃、苯并噻吩、苯并吡咯、苯并噁唑、苯并噻唑、苯并咪唑、苯并吡唑、吗啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基、咔唑，当被取代时，被1至4个Rb1取代；B 1 is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, thiophene, furan, pyrrole, pyrazole, imidazole, pyridine, 2-pyridone, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, 3,4-dihydro-1H-benzopyran, 1,2,3,4-tetrahydroquinoline, benzofuran, benzothiophene, benzopyrrole, benzoxazole, benzothiazole, benzimidazole, benzopyrazole, morpholine, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, carbazole, and when substituted, is substituted by 1 to 4 R b1 ; 或者B1选自任选取代的如下结构之一： 当被取代时，被1至4个Rb1取代；Or B 1 is selected from one of the following optionally substituted structures: When substituted, it is substituted with 1 to 4 R b1 ; 或者B1选自B1A；or B1 is selected from B1A ; B2选自取代或未取代的如下基团之一：苯环基、萘基、喹啉、吡唑、吡啶、咪唑、三氮唑、噻唑、噁唑、异噁唑、噻吩、苯并吡咯、吲哚、苯并咪唑、苯并吡唑、苯并噻吩、苯并噻唑、吡唑并四氢吡咯、3-哒嗪酮、2-吡啶酮、1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基，当被取代时，被1至4个Rb2取代； B2 is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, quinoline, pyrazole, pyridine, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene, benzopyrrole, indole, benzimidazole, benzopyrazole, benzothiophene, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, when substituted, substituted by 1 to 4 Rb2 ; 或者B2选自任选取代的如下结构之一： 当被取代时，被1至4个Rb2取代；Or B2 is selected from one of the following structures which are optionally substituted: When substituted, it is substituted with 1 to 4 R b2 ; 或者B2选自B2A；or B 2 is selected from B 2A ; B1A、B2A各自独立地选自任选取代的如下结构之一： 当被取代时，B1A被1至4个Rb1取代，B2A被1至4个Rb2取代；B 1A and B 2A are each independently selected from one of the following optionally substituted structures: When substituted, B 1A is substituted with 1 to 4 R b1 and B 2A is substituted with 1 to 4 R b2 ; B3选自取代或未取代的如下基团之一：氧杂环丁基、环丁基、环戊基、环己基、氮杂环丁基、四氢呋喃基、苯基、吡啶、萘基、吡唑、吡咯、吡咯烷基、哌啶、哌嗪、氮杂环己烯基、四氢吡喃基、咪唑、噻吩、噻唑、噁唑、异噁唑、三氮唑、2-吡啶酮、苯并吡咯、苯并吡咯烷、苯并噻吩、苯并噻唑、苯并吡唑、苯并咪唑、吡唑并四氢吡咯、3-哒嗪酮、1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基、环丁基螺哌啶基，当被取代时，被1至4个Rb3取代； B3 is selected from one of the following groups, substituted or unsubstituted: oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, phenyl, pyridine, naphthyl, pyrazole, pyrrole, pyrrolidinyl, piperidine, piperazine, azacyclohexenyl, tetrahydropyranyl, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzothiazole, benzopyrazole, benzimidazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, cyclobutylspiropiperidinyl, when substituted, substituted by 1 to 4 Rb3 ; 或者B3选自任选取代的如下结构之一： 当被取代时，被1至4个Rb3取代； Or B3 is selected from one of the following optionally substituted structures: When substituted, it is substituted with 1 to 4 R b3 ; V选自键、O、S、NRb5a、NRb5a-C1-4亚烷基、C1-4亚烷基-NRb5a、O-C1-4亚烷基、C1-4亚烷基-O、C1-4亚烷基，所述的亚烷基任选被1至4个Rb4或Rb5所取代；V is selected from a bond, O, S, NR b5a , NR b5a -C 1-4 alkylene, C 1-4 alkylene-NR b5a , OC 1-4 alkylene, C 1-4 alkylene-O, C 1-4 alkylene, wherein the alkylene is optionally substituted with 1 to 4 R b4 or R b5 ; Rb1各自独立的选自F、Cl、Br、I、＝O、＝S、OH、NH2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O-环丙基、-O-环丁基、-S-环丙基、-S-环丁基、-CH2-环丙基、-CH2-环丁基、-NH-环丙基、-NH-环丁基、甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基，所述的甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基任选被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、N(CH3)2、甲基、甲氧基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基的取代基所取代；R b1 is each independently selected from F, Cl, Br, I, =O, =S, OH, NH 2 , CN, NO 2 , -C(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O) 2 (CH 3 ) 2 , -S(=O) 2 CH 3 , -O-cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , N(CH 3 ) 2 , methyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl; Rb3各自独立的选自F、Cl、Br、I、＝O、＝S、OH、NH2、N(CH3)2、NHCH3、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O-环丙基、-O-环丁基、-NH-环丙基、-NH-环丁基、-S-环丙基、-S-环丁基、-CH2-环丙基、-CH2-环丁基、-O-CH2-环丙基、-O-CH2-环丁基、-O-CH2CH2-甲氧基、-O-CH2CH2-O-环丙基、-O-CH2CH2-O-环丁基、-CH2-O-CH2CH2-甲氧基、-CH2-O-CH2CH2-O-环丙基、-CH2-O-CH2CH2-O-环丁基、-CH2-O-CH2CH2-NH-甲基、-CH2-甲氧基、-CH2-乙氧基、甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基，所述的甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基任选被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、N(CH3)2、甲基、甲氧基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基的取代基所取代；R b3 is each independently selected from F, Cl, Br, I, =O, =S, OH, NH 2 , N(CH 3 ) 2 , NHCH 3 , CN, NO 2 , -C(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O) 2 (CH 3 ) 2 , -S(=O) 2 CH 3 , -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -S-cyclopropyl, -S -cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -O-CH 2 -cyclopropyl, -O-CH 2 -cyclobutyl, -O-CH 2 CH 2 -methoxy, -O-CH 2 CH 2 -O-cyclopropyl, -O-CH 2 CH 2 -O-cyclobutyl, -CH 2 -O-CH 2 CH 2 -methoxy, -CH 2 -O-CH 2 CH 2 -O-cyclopropyl, -CH 2 -O-CH 2 CH 2 -O-cyclobutyl, -CH 2 -O -CH 2 CH 2 -NH-methyl, -CH 2 -methoxy, -CH 2 -O -CH 2 CH 2 -O-cyclopropyl, -CH 2 -O-CH 2 CH 2 -O-cyclobutyl, -CH 2 -O-CH 2 CH 2 -NH-methyl, -CH 2 -methoxy, -CH 2 -ethoxy, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl and spirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , N(CH 3 ) 2 , methyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl; Rb2各自独立的选自H、F、Cl、Br、I、＝O、＝S、OH、NH2、NHCH3、N(CH3)2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)(CH3)2、-S(＝O)2CH3或者任选取代的如下基团之一：甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、环丙基螺环丁基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基、-CH2-环丙基、-CH2-环丁基、-CH2-吗啉、-CH2-吡唑、-OCH2-环丙基、-O-环丙基、-O-环丁基、-NH-环丙基、-NH-环丁基、-OCH2CH2-O-甲基、-OCH2CH2-O-环丙基、-CH2OCH2CH2-O-甲基、-CH2OCH2CH2-O-环丙基、-CH2OCH2CH2-NH-甲基、当被取代时，被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CH2F、CF3、NH2、NHCH3、N(CH3)2、 CH2OH、甲基、乙基、异丙基、甲氧基、乙氧基、乙烯基、乙炔基、丙炔基、环丙基、环丁基、吡咯烷基、哌啶基、吡唑基、吗啉基的取代基所取代；R b2 is each independently selected from H, F, Cl, Br, I, ═O, ═S, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , CN, NO 2 , -C(═O)CH 3 , -C(═O)NH 2 , -C(═O)NH-CH 3 , -C(═O)N(CH 3 ) 2 , -S(═O) 2 NH 2 , -P(═O)(CH 3 ) 2 , -S(═O) 2 CH 3 or one of the following groups which are optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, cyclopropyl spirocyclobutyl, cyclobutyl spirocyclobutyl, cyclobutyl spirocyclopentyl, cyclobutyl spirocyclohexyl, cyclopentyl spirocyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -O-methyl, -CH 2 OCH 2 CH 2 -O -cyclopropyl, -CH 2 OCH 2 CH 2 -NH-methyl, when substituted, by 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CHF 2 , CH 2 F, CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CH 2 OH, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyrazolyl, morpholinyl; 作为选择，Rb1与Rb3、Rb2与Rb3任其一直接连接形成C5-7碳环基、5至7元杂环基，所述的碳环基或者杂环基任选被1至4个选自F、Cl、Br、I、OH、-NH2、CN、CH2F、CHF2、CF3、甲基、乙基、甲氧基或乙氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子；Alternatively, any one of R b1 and R b3 , R b2 and R b3 is directly linked to form a C 5-7 carbocyclic group or a 5- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, -NH 2 , CN, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, methoxy or ethoxy, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S and N; K选自表K-1所示的结构片段之一。K is selected from one of the structural fragments shown in Table K-1. 根据权利要求6所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 6 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一： 当被取代时，被1至4个RL2取代； Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or a substituted or unsubstituted one of the following groups: When substituted, it is replaced by 1 to 4 R L2 ; RL2各自独立地选自F、Cl、Br、＝O、COOH、CN、NHCH3、N(CH3)2、OH、NH2或任选取代的如下基团之一：甲基、乙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基、吗啉、-CH2-环丙基、-CH2-吗啉、-CH2-吡唑、-OCH2-环丙基、-O-环丙基、-OCH2CH2-O-甲基、-OCH2CH2-O-环丙基、-CH2OCH2CH2-O-甲基、-CH2OCH2CH2-O-环丙基，当被取代时，被1至4个选自F、CHF2、CF3、OCHF2、OCF3、甲基、甲氧基、＝O、CH2OH、COOH、CN、NHCH3、N(CH3)2、OH、NH2的取代基所取代；R L2 is each independently selected from F, Cl, Br, =O, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 or one of the following optionally substituted groups: methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclopropyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -O -methyl, -CH 2 OCH 2 CH 2 -O-cyclopropyl, when substituted, by 1 to 4 selected from F, CHF 2 , CF 3 , OCHF 2 , OCF 3 , methyl, methoxy, =O, CH 2 OH, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 ; B选自表B-1、表B-2或表B-3所示的结构片段之一，其右侧与L连接，b1、b2各自独立地选自0、1或2；B is selected from one of the structural fragments shown in Table B-1, Table B-2 or Table B-3, the right side of which is connected to L, and b1 and b2 are each independently selected from 0, 1 or 2; K选自表K-2所示的结构片段之一。K is selected from one of the structural fragments shown in Table K-2. 根据权利要求7所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 7 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L选自键、-Ak1-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-；L is selected from a bond, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2- Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2- Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-C y3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2 -Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3 -Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3 -Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3- Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4- Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1- Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy 3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -A k1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1 -Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak 2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5- , -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-; Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、-C(＝O)NH-或-NHC(＝O)-；Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -O-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -CH=CH-, -CH=C(CN)-, -CH=C(F)-, -C(CN)=CH-, -C(F)=CH-, -C≡C-, -C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -N(CH 3 )-, -NH-, -CH 2 N(CH 3 )-, -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O)CH 2 NH-, -CH 2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-; V选自键、NH、NHC(CH3)2CH2、NHCH2C(CH3)2、CH2CH2、C(CH3)2CH2、CH2C(CH3)2、NHCH2CH2、NHCH2、OCH2、CH2NH、CH2O、NHC(CH3)2、OC(CH3)2、C(CH3)2NH、C(CH3)2O、N(CH3)CH2、N(CH3)C(CH3)2、C(CH3)2N(CH3)、CH2N(CH3)、N(CH3)、O、S。V is selected from the group consisting of bonds, NH, NHC(CH 3 ) 2 CH 2 , NHCH 2 C(CH 3 ) 2 , CH 2 CH 2 , C(CH 3 ) 2 CH 2 , CH 2 C(CH 3 ) 2 , NHCH 2 CH 2 , NHCH 2 , OCH 2 , CH 2 NH, CH 2 O, NHC(CH 3 ) 2 , OC(CH 3 ) 2 , C(CH 3 ) 2 NH, C(CH 3 ) 2 O, N(CH 3 )CH 2 , N(CH 3 )C(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ), CH 2 N(CH 3 ), N(CH 3 ), O, S. 根据权利要求8所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 8 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L选自键或表L-1、L-2或L-3所示的结构片段之一，其中基团左侧与B连接。 L is selected from a bond or one of the structural fragments shown in Table L-1, L-2 or L-3, wherein the left side of the group is connected to B. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自表E-1所示结构之一。The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E-1. 一种药物组合物，包括权利要求1-10任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体，优选地，药物组合物中包含1-1500mg权利要求1-10任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition comprises 1 to 1500 mg of a compound according to any one of claims 1 to 10 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof. 根据权利要求1-10任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或者权利要求10所述的药物组合物在用于制备治疗与AR或AR剪切突变体活性或表达量相关疾病的药物中的应用。Use of a compound according to any one of claims 1 to 10 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 10 in the preparation of a drug for treating a disease associated with the activity or expression of AR or an AR splicing mutant. 根据权利要求1-10任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或者权利要求10所述的药物组合物在用于制备治疗与抑制或降解AR或AR剪切突变体相关疾病的药物中的应用。Use of a compound according to any one of claims 1 to 10 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 10 in the preparation of a drug for treating a disease associated with the inhibition or degradation of AR or AR splicing mutants. 根据权利要求12或13所述的应用，其特征在于，所述的疾病选自前列腺癌。The use according to claim 12 or 13, characterized in that the disease is selected from prostate cancer. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-10任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选1-1500mg，所述的疾病优选AR或AR剪切突变体活性或表达量相关疾病。 A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 10 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease related to the activity or expression of AR or an AR splice mutant.
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