CN115043842A

CN115043842A - Amino-substituted bicyclic inhibitor and preparation method and application thereof

Info

Publication number: CN115043842A
Application number: CN202110257196.2A
Authority: CN
Inventors: 吕彬华; 崔大为
Original assignee: Suzhou Zelgen Biopharmaceutical Co Ltd; Shanghai Zelgen Pharmatech Co Ltd
Current assignee: Suzhou Zelgen Biopharmaceutical Co Ltd; Shanghai Zelgen Pharmatech Co Ltd
Priority date: 2021-03-09
Filing date: 2021-03-09
Publication date: 2022-09-13

Abstract

The invention relates to an amino-substituted bicyclic inhibitor and a preparation method and application thereof. The compound has a structure shown in a formula (I), and also discloses a preparation method of the compound and application of the compound as an SOS1 inhibitor, wherein the compound has a good selective inhibition effect on SOS1, and has better pharmacodynamics and pharmacokinetic properties and lower toxic and side effects.

Description

Amino-substituted bicyclic inhibitor and preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to an amino-substituted bicyclic inhibitor, and a preparation method and application thereof.

Background

Lung cancer is one of the leading causes of death in human cancers. Lung cancer can be divided into Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, with NSCLC accounting for 85% of all lung cancer patients. The market for NSCLC worldwide was statistically about $ 209 million in 2016, with the U.S. market half as much, followed by japan, germany, and china. From the current trend, the market for non-small cell lung cancer is continuing to grow, and the global market is expected to reach $ 540 billion in 2023 (Nature, 2018; 553(7689):446- > 454).

At present, the main therapeutic drugs of NSCLC include chemotherapeutic drugs, molecular targeted drugs, tumor immunotherapy and the like. The chemotherapy drugs mainly comprise gemcitabine, paclitaxel, platinum drugs and the like, but the drugs generally have poor selectivity and high toxicity, so that relatively strong toxic and side effects are caused. In recent years, molecular targeted drugs have become research hotspots due to the obvious advantages of high selectivity, relatively small toxic and side effects, accurate treatment and the like. Existing molecular targeted drugs for NSCLC include EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimetinib, etc.), ALK inhibitors (such as Ceritinib, Alectoib, Brigatinib, Lorlatinib, Ocatinib, etc.), and VEGFR inhibitors (Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Dunalinib, etc.) (Current medical Chemistry,2019,26, 1-39).

KRAS mutations occur in 20-40% of lung adenocarcinomas, with a higher prevalence in western (vs asia) populations (26% vs 11%) and in smokers (vs non-smokers) (30% vs 10%). The most common mutations occur in codons 12 and 13, the most common mutations include G12C, G12V, and G12D. To date, no drug against KRAS mutations has been approved for marketing in the market.

Within the cell, the KRAS protein transitions between an inactive and an active state, when KRAS is bound to Guanosine Diphosphate (GDP), it is in the inactive state, when it is bound to Guanosine Triphosphate (GTP), it is in the active state, and downstream signaling pathways can be activated. The transition of KRAS between inactive and active states is regulated by two types of factors. One class is guanine nucleotide exchange factor (GEF), which catalyzes the binding of KRAS to GTP, thereby promoting KRAS activation, including the SOS1 protein. Another class is the Gtpase Activator Proteins (GAPs), which promote the hydrolysis of KRAS-bound GTP to GDP, thereby inhibiting KRAS activity.

To date, three major RAS-specific GEFs have been identified, with SOS proteins being primarily found in tumors. SOS proteins are widely expressed in vivo and contain two isoforms SOS1 and SOS 2. Published data indicate that SOS1 plays a key role in mutant KRAS activation and oncogenic signaling. A decrease in the level of SOS1 resulted in a decrease in the proliferation and survival of tumor cells carrying the KRAS mutation, whereas KRAS wild-type cell lines were not affected. The effect of the loss of SOS1 could not be rescued by introducing a SOS1 mutated at the catalytic site, suggesting an important role for SOS1 GEF activity in KRAS mutant cancer cells (see WO2019122129a 1).

Since KRAS binding to GTP, whether mutated or wild-type, is dependent on SOS1, selective inhibition of SOS1, whether mutated or not, prevents interaction of SOS1 with KRAS and ultimately inhibits KRAS activation.

Since the SOS1 target protein is pathologically associated with a variety of diseases, there is also a need for novel SOS1 inhibitors for clinical therapy. The SOS1 inhibitor with high selectivity and high activity can be used for more effectively treating diseases such as cancers caused by KRAS mutation and reducing the potential of off-target effect, so that the clinical demand is more urgent.

Disclosure of Invention

The invention aims to provide a novel compound with selective SOS1 inhibition effect and/or better pharmacodynamic property and application thereof.

In a first aspect of the present invention, there is provided a compound having the structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:

in the formula:

ring A and ring B are each independently a 5-7 membered ring, and at least one ring atom in ring A or ring B is a heteroatom;

R ¹ selected from the group consisting of substituted or unsubstituted: c ₃ -C ₁₈ Cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl;

R ² selected from the group consisting of substituted or unsubstituted: c ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl or 4-6 membered heterocyclyl;

r and R', which are the same or different, are each independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, oxo, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which, CH ₂ H in (a) may be optionally substituted;

R ⁸ 、R ⁹ and R ¹⁰ Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, C ₁ -C ₁₈ Alkyl radical, C ₃ -C ₂₀ Cycloalkyl, 4-20 membered heterocyclyl, R ¹¹ -(C ₃ -C ₂₀ Cycloalkylene radical C ₁ -C ₁₈ Alkylene) -, R ¹¹ - (4-to 20-membered heterocycloalkylene C) ₁ -C ₁₈ Alkylene) -, - (C) ₃ -C ₂₀ Cycloalkylene radical C ₁ -C ₁₈ Alkylene) -R ¹¹ - (4-to 20-membered heterocycloalkylene C) ₁ -C ₁₈ Alkylene) -R ¹¹ ；

Or in- (CH) ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ In, R ⁸ And R ⁹ And the adjacent N atom thereof form a substituted or unsubstituted 4-8 membered heterocyclic group; or in- (CH) ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In, R ⁸ And R ⁹ Is cyclized with its adjacent N atom to form a substituted or unsubstituted 4-8 membered heterocyclic group, or R ⁸ And R ¹⁰ Ring-closing with its adjacent atom to form a substituted or unsubstituted 4-8 membered heterocyclic group;

R ¹¹ selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₃ -C ₂₀ Cycloalkyl oxy, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryloxy, 5-14 membered heteroaryloxy, 4-20 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

wherein the above substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl radicalHydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₃ -C ₂₀ Cycloalkyloxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryloxy, 5-14 membered heteroaryloxy, 4-20 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

m is 0, 1,2,3,4, 5 or 6;

p is 0, 1,2,3,4, 5 or 6;

q is 1 or 2;

u is 0, 1,2 or 3;

t is 0, 1,2,3 or 4;

the limiting conditions are:

is partially not

In another preferred embodiment, at least one ring atom of ring a or ring B is N.

In another preferred embodiment, 1 to 5 (i.e., 1,2,3,4, 5) ring atoms in ring a or ring B are N.

In another preferred embodiment, the 5-7 membered ring is selected from: 5-7 membered heterocyclic group, 5-7 membered heteroaryl group, C ₅ -C ₇ And (4) an aryl group.

In another preferred embodiment, ring a and ring B are each independently 6-membered heterocyclyl, 6-membered heteroaryl, phenyl.

In another preferred embodiment, R ⁸ 、R ⁹ And R ¹⁰ Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, R ¹¹ -(C ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -, R ¹¹ - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -, - (C) ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -R ¹¹ - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -R ¹¹ ；

R ¹¹ Selected from: hydrogen, deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl oxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-to 10-membered heteroaryloxy, 4-to 6-membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has the structure shown in formula (I'):

in the formula:

the same or different, each independently is a single bond or a double bond;

X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ and X ⁹ Each independently selected from: C. CR ³ 、CO、N、NR ⁴ 、SO ₂ Or CR ³ R ⁵ (ii) a Wherein X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ At least one of which contains a heteroatom;

R ³ identical or different, each independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which, CH ₂ H in (a) may be optionally substituted;

R ⁵ the same or different, each independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which, CH ₂ H in (a) may be optionally substituted;

R ⁴ identical or different, each independently selected from the group consisting of: hydrogen, deuterium, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which, CH ₂ H in (a) may be optionally substituted;

Or in- (CH) ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ In, R ⁸ And R ⁹ And the adjacent N atom thereof form a substituted or unsubstituted 4-8 membered heterocyclic group; or in- (CH) ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In, R ⁸ And R ⁹ Is cyclized with its adjacent N atom to form a substituted or unsubstituted 4-8 membered heterocyclic group, or R ⁸ And R ¹⁰ And the adjacent atoms are cyclized to form a substituted or unsubstituted 4-8 membered heterocyclic group;

R ¹¹ selected from: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₃ -C ₂₀ Cycloalkyloxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryloxy, 5-14 membered heteroaryloxy, 4-20 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

wherein the above substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterationC ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₃ -C ₂₀ Cycloalkyl oxy, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryloxy, 5-14 membered heteroaryloxy, 4-20 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

m is 0, 1,2,3,4, 5 or 6;

p is 0, 1,2,3,4, 5 or 6;

q is 1 or 2;

the limiting conditions are:

part is not

Wherein R is as defined above.

In another preferred embodiment, X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ At least one of which is N.

In another preferred embodiment, R ² Is methyl.

In another preferred embodiment, in formulas I and I', the compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof has the structure shown in formula (II):

in the formula, R ¹ 、X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ Is as defined above.

In another preferred embodiment, R ¹ Selected from the group consisting of substituted or unsubstituted: c ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-10 membered heteroaryl;

wherein, the substitution refers to the substitution by one or more (such as 2,3, 4) groups selected from the following group: hydrogen, deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyloxy, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, phenyloxy, 5-6 membered heteroaryloxy, 4-6 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein,

moieties are selected from:

in the formula (I), the compound is shown in the specification,

R ^3a -R ^3f the same or different, each independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which CH ₂ H in (a) may be optionally substituted;

R ^4a -R ^4b the same or different, each independently selected from the group consisting of: hydrogen, deuterium, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which CH ₂ H in (a) may be optionally substituted;

R ^5b -R ^5c the same or different, each independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which CH ₂ H in (a) may be optionally substituted;

wherein the above substitution means substitution by a group selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₃ -C ₂₀ Cycloalkyloxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryloxy, 5-14 membered heteroaryloxy, 4-20 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

wherein R is ⁸ 、R ⁹ 、R ¹⁰ M, p and q are as defined above.

In a further preferred embodiment of the method,

moieties are selected from:

in the formula (I), the compound is shown in the specification,

R ^5d selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, halogen, cyano, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which, CH ₂ H in (b) may be optionally substituted, said substitution being with a group selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₃ -C ₂₀ Cycloalkyl oxy, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryloxy, 5-14 membered heteroaryloxy, 4-20 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

R ^3a -R ^3f 、R ^4a -R ^4b 、R ^5b -R ^5c 、R ⁸ 、R ⁹ 、R ¹⁰ m, p and q are as defined above.

In a further preferred embodiment of the method,

moieties are selected from:

in the formula, R ^3a -R ^3f 、R ^4a -R ^4b Is as defined above.

In a further preferred embodiment of the present invention,

moieties are selected from:

in the formula, R ^3a -R ^3f 、R ^4a -R ^4b Is as defined above.

In another preferred embodiment, R ^3a -R ^3f Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₃ -C ₆ Cycloalkyl radical C ₁ -C ₆ Alkylene, 4-to 6-membered heterocycloalkyl C ₁ -C ₆ Alkylene, -O-C ₁ -C ₆ Alkyl, -O-C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl-O-, C ₃ -C ₆ Cycloalkyl radical C ₁ -C ₆ alkylene-O-, 4-6 membered heterocycloalkyl C ₁ -C ₆ alkylene-O-, -O- (CH) ₂ ) _w C ₁ -C ₆ Alkoxy radical, R ¹² -(C ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -, R ¹² - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -, - (C) ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -R ¹² - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -R ¹² (ii) a Wherein w is 1,2,3 or 4;

wherein R is ¹² Selected from: hydrogen, deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl oxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy, 4-6 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

wherein said substitution means substitution by one or more groups selected from the group consisting of: deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide, or urea groups.

In another preferred embodiment, R ^4a -R ^4b Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₃ -C ₆ Cycloalkyl radical C ₁ -C ₆ Alkylene, 4-to 6-membered heterocycloalkyl C ₁ -C ₆ An alkylene group; wherein said substitution is by one or more groups selected from the group consisting of: deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, R ¹² -(C ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -, R ¹² - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -, - (C) ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -R ¹² - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -R ¹² Halogen, oxo, nitro, hydroxyl, cyano, ester, amino, amido, sulfonamide, or ureido;

wherein R is ¹² Selected from: hydrogen, deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl oxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy, 4-6 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea; .

In another preferred embodiment, R ^5b -R ^5c Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₃ -C ₆ Cycloalkyl radical C ₁ -C ₆ Alkylene, 4-to 6-membered heterocycloalkyl C ₁ -C ₆ Alkylene, -O-C ₁ -C ₆ Alkyl, -O-C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl-O-, C ₃ -C ₆ Cycloalkyl radical C ₁ -C ₆ alkylene-O-, 4-6 membered heterocycloalkyl C ₁ -C ₆ alkylene-O-, -O- (CH) ₂ ) _w C ₁ -C ₆ Alkoxy radical, R ¹² -(C ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -, R ¹² - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -, - (C) ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -R ¹² - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -R ¹² (ii) a Wherein w is 1,2,3 or 4;

wherein said substitution is by one or more groups selected from the group consisting of: deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea groups.

In another preferred embodiment, R ¹ Selected from the group consisting of substituted or unsubstituted: phenyl, pyridyl, pyrimidinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl,

Wherein said substitution means substitution by one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea groups.

In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is provided, wherein R is ¹ Selected from the group consisting of:

in another preferred embodiment, ring A, ring B, R, R', R ¹ 、R ² 、X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ 、X ⁹ 、R ^3a -R ^3f 、R ^4a -R ^4b 、R ^5b -R ^5c 、R ⁸ 、R ⁹ 、R ¹⁰ T, u, m, p and q correspond to the groups shown for each specific compound in the examples.

In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is selected from the group consisting of:

in another preferred embodiment, the compound is selected from the compounds shown in the examples.

In a second aspect of the present invention, there is provided a process for preparing a compound having a structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to the first aspect, comprising the steps of:

(i) reacting a compound of formula V-1 with a compound of formula V-2 in an inert solvent in the presence of a base, a condensing agent or a Pd catalyst to obtain a compound of formula (I);

in the formula (I), the compound is shown in the specification,

x is selected from: halogen, OH, O, OTf, OTs, Oms;

is a single bond or a double bond;

R ¹ 、R ² r, R', Ring A, Ring B, u and t are as defined above.

In a third aspect of the invention, there is provided a pharmaceutical composition comprising i) one or more compounds according to the first aspect, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and ii) a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition further comprises one or more therapeutic agents selected from the group consisting of: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemipimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009, or biologically similar drugs thereof), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, A167, F520, GR1405, MSB2311, or biologically similar drugs thereof), CD20 antibodies (e.g., rituximab, obizumab, ofatumumab, tositumomab, MSB 131, tositumomab, TSB 90, TSH-55, TSB-35, TSB-102, TSB-35, TSB-52, TSB-35, TSC-35, TSB-35, TSC-35, TSB-55, TSB-D-35, TSB-D2, TSB-D, Alectonib, Brigatinib, Lorlatinib, Ocatinib), PI3K inhibitors (e.g., Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipaliib, Buparlisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabutinib, Acalburtinib, Zanburtinib, Vecabbrutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlottinib, Lapatitinib, Dacomitinib, Icotinza, Canertinib, Sapititinib, Nakutinib, Pyratinib, Rocilitinib, Osimetinib, etc.), inhibitors (e.g., Sorafenib, Pazotinib, Zoletatinib, Entinosib, Ile, Nonacitinib, Picatinib, Spinosib, Spinostinib, Spinosib, Spinosi.

In a fourth aspect of the present invention, there is provided a use of a compound of the first aspect, a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, or a pharmaceutical composition of the third aspect, for the preparation of a medicament for the prevention and/or treatment of a disease associated with i) an activity or an expression amount of SOS 1; and/or ii) SOS1 downstream signal pathway related diseases.

In another preferred embodiment, the disease is cancer.

In another preferred embodiment, the cancer is selected from: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, leukemia, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, and skin cancer.

In a fifth aspect of the present invention, there is provided a method for inhibiting SOS1 activity in vitro, comprising the steps of: contacting a compound of the first aspect, a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, or a pharmaceutical composition of the third aspect, with a protein or a cell, thereby inhibiting SOS1 activity.

In another preferred embodiment, the cell is selected from the group consisting of: macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or a combination thereof.

In another preferred embodiment, the cell is from a rodent (e.g., mouse, rat), or primate (e.g., human).

In a sixth aspect of the invention, there is provided a method for non-diagnostic, non-therapeutic inhibition of SOS1, comprising the steps of: administering to a subject in need thereof an effective amount of a compound of the first aspect, a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or administering a pharmaceutical composition of the third aspect.

In another preferred embodiment, the subject is a mammal, preferably a human.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The present inventors have conducted extensive and intensive studies for a long time and have unexpectedly found a novel class of compounds which selectively inhibit SOS1 and/or exhibit improved pharmacodynamic properties. On this basis, the inventors have completed the present invention.

Term(s) for

In the present invention, unless otherwise specified, the terms used have the ordinary meanings well known to those skilled in the art.

The term "alkyl" refers to straight or branched chain or cyclic alkyl groups containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, and,

Pentyl, isopentyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like.

The term "C ₁ -C ₁₈ Alkyl "refers to straight or branched chain or cyclic alkyl groups including from 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl (C) ((R))

) N-butyl, t-butyl, isobutyl (e.g. butyl, isobutyl)

) N-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl. "substituted alkyl" means an alkyl group which is substituted at one or more positions, especially 1 to 4 substituents, and may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. mono-or polyhalo-substituents, the latter being e.g. trifluoromethyl or containing Cl ₃ Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, OR _a 、SR _a 、S(＝O)R _e 、S(＝O) ₂ R _e 、P(＝O) ₂ R _e 、S(＝O) ₂ OR _e ,P(＝O) ₂ OR _e 、NR _b R _c 、NR _b S(＝O) ₂ R _e 、NR _b P(＝O) ₂ R _e 、S(＝O) ₂ NR _b R _c 、P(＝O) ₂ NR _b R _c 、C(＝O)OR _d 、C(＝O)R _a 、C(＝O)NR _b R _c 、OC(＝O)R _a 、OC(＝O)NR _b R _c 、NR _b C(＝O)OR _e ,NR _d C(＝O)NR _b R _c 、NR _d S(＝O) ₂ NR _b R _c 、NR _d P(＝O) ₂ NR _b R _c 、NR _b C(＝O)R _a Or NR _b P(＝O) ₂ R _e Wherein R is present therein _a May independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R _b 、R _c And R _d May independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R _b And R _c Together with the N atom may form a heterocyclic ring; r _e May independently represent hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. Typical substituents as mentioned above, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, may be optionally substitutedAnd (4) generation.

The term "alkylene" refers to a group formed by removing a hydrogen atom from an "alkyl" group, such as methylene, ethylene, propylene, isopropylene (e.g.

) Butylene (e.g. butyl oxide)

Or

) Pentylene (e.g. ethylene)

) Hexamethylene (e.g. hexamethylene)

) Heptylene (e.g. as

) And the like.

The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group comprising 1 to 4 rings containing 3 to 8 carbon atoms in each ring. "substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1 to 4 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. mono-or polyhalo-substituents, the latter being e.g. trifluoromethyl or containing Cl ₃ Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, OR _a 、SR _a 、S(＝O)R _e 、S(＝O) ₂ R _e 、P(＝O) ₂ R _e 、S(＝O) ₂ OR _e ,P(＝O) ₂ OR _e 、NR _b R _c 、NR _b S(＝O) ₂ R _e 、NR _b P(＝O) ₂ R _e 、S(＝O) ₂ NR _b R _c 、P(＝O) ₂ NR _b R _c 、C(＝O)OR _d 、C(＝O)R _a 、C(＝O)NR _b R _c 、OC(＝O)R _a 、OC(＝O)NR _b R _c 、NR _b C(＝O)OR _e ,NR _d C(＝O)NR _b R _c 、NR _d S(＝O) ₂ NR _b R _c 、NR _d P(＝O) ₂ NR _b R _c 、NR _b C(＝O)R _a Or NR _b P(＝O) ₂ R _e Wherein R is present therein _a May independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R _b 、R _c And R _d May independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R _b And R _c Together with the N atom may form a heterocyclic ring; r is _e May independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include spirocyclic, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocyclic (excluding heteroaromatic rings), bridged cycloalkyl, bridged alkenyl, bridged heterocyclic (excluding heteroaromatic rings), fused cycloalkyl, fused alkenyl, fused heterocyclyl or fused aromatic ring groups, which may be optionally substituted. Any two or more atoms on the ring may be further ring-connected with other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

The term "cycloalkylene" refers to a group formed by a cycloalkyl group minus two hydrogen atoms, such as:

and the like.

The term "cycloalkylene" refers to a cycloalkylalkyl or alkylcycloalkyl group as defined above, wherein two hydrogen atoms have been removed, and wherein "C" is ₁ -C ₁₈ Alkylene radical C ₃ -C ₂₀ Cycloalkylene "or" C ₃ -C ₂₀ Cycloalkylene radical C ₁ -C ₁₈ Alkylene "has the same meaning, including but not limited to:

etc., preferably, the alkylenecycloalkylene is C ₁ -C ₆ Alkylene radical C ₃ -C ₁₂ Cycloalkylene, more preferably C ₁ -C ₆ Alkylene radical C ₃ -C ₆ Cycloalkylene radicals.

The term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, e.g., 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic ring systems) in which at least one heteroatom is present in the ring having at least one carbon atom. Each heteroatom-containing heterocyclic ring may carry 1,2,3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein the nitrogen or sulfur atoms may be oxidized and the nitrogen atoms may also be quaternized. The heterocyclic group may be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule. Exemplary monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidinonyl, tetrahydropyranyl, morphinyl, thiomorpholinyl, thiomorpholino sulfoxide, thiomorpholino sulfone, 1, 3-dioxanyl, and tetrahydro-1, 1-dioxythiophene, and the like. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or are further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate groups, wherein any two or more atoms on the ring may be further ring-connected to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

The term "heterocyclylene" refers to a group formed by removing two hydrogen atoms from the above-mentioned heterocyclic group, and includes, but is not limited to:

and the like.

The term "heterocycloalkylenealkylene" refers to a cycloalkylalkyl or alkylcycloalkyl group in which two hydrogen atoms have been removed, wherein "4-to 20-membered heterocycloalkylene C ₁ -C ₁₈ Alkylene "or" C ₁ -C ₁₈ Alkylene 4-20 membered heterocycloalkylene "has the same meaning, including but not limited to:

etc., heterocycloalkylene is preferably 4-12 membered heterocycloalkylene C _1-6 Alkylene, more preferably 4-6 membered heterocycloalkylene C _1-6 An alkylene group.

The term "aryl" refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, in particularRefers to monocyclic and bicyclic groups such as phenyl, biphenyl, or naphthyl. Where the aromatic ring contains two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be linked by a single bond (e.g., biphenyl), or fused (e.g., naphthalene, anthracene, etc.). "substituted aryl" means that one or more positions in the aryl group are substituted, especially 1 to 3 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. mono-or polyhalo-substituents, the latter being e.g. trifluoromethyl or containing Cl ₃ Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, OR _a 、SR _a 、S(＝O)R _e 、S(＝O) ₂ R _e 、P(＝O) ₂ R _e 、S(＝O) ₂ OR _e ,P(＝O) ₂ OR _e 、NR _b R _c 、NR _b S(＝O) ₂ R _e 、NR _b P(＝O) ₂ R _e 、S(＝O) ₂ NR _b R _c 、P(＝O) ₂ NR _b R _c 、C(＝O)OR _d 、C(＝O)R _a 、C(＝O)NR _b R _c 、OC(＝O)R _a 、OC(＝O)NR _b R _c 、NR _b C(＝O)OR _e ,NR _d C(＝O)NR _b R _c 、NR _d S(＝O) ₂ NR _b R _c 、NR _d P(＝O) ₂ NR _b R _c 、NR _b C(＝O)R _a Or NR _b P(＝O) ₂ R _e Wherein R is present therein _a May independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R _b 、R _c And R _d May independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R _b And R _c Together with the N atom may form a heterocyclic ring; r _e May independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include fused ring substituents, especially fusedCycloalkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aryl group may be optionally substituted.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. The heteroaryl group is preferably a 5-to 10-membered ring, more preferably a 5-or 6-membered ring, for example, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl and the like. "heteroaryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate.

The term "alkoxy" refers to a straight or branched chain or cyclic alkoxy group having 1 to 18 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like. Preferably C ₁ -C ₈ Alkoxy, more preferably C ₁ -C ₆ An alkoxy group.

The term "oxo" refers to an ═ O group.

The term "alkyleneoxy" means "C ₁ -C ₁₈ An alkoxy group "one hydrogen atom off" is a group.

The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.

The term "halo" means substituted with halogen.

The term "deuterated" refers to a substitution by deuterium.

The term "hydroxyl" refers to a group with the structure OH.

The term "nitro" refers to a group with the structure NO ₂ A group of (1).

The term "cyano" refers to a group with the structure CN.

The term "ester group" refers to a group with the structure-COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.

The term "amine" refers to a group having the structure-NRR ', where R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' may be the same or different in the dialkylamine fragment.

The term "amido" refers to a group with the structure-CONRR ', where R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle as defined above. R and R' may be the same or different in the dialkylamine fragment.

The term "sulfonamide" refers to a sulfonamide group having the structure-SO ₂ NRR 'wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic as hereinbefore defined. R and R' may be the same or different in the dialkylamine fragment.

The term "ureido" refers to a group having the structure — NRCONR 'R ", where R, R' and R" may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.

The term "alkylaminoalkyl" refers to a group having the structure-RNHR ', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle as defined above. R and R' may be the same or different.

The term "dialkylaminoalkyl" refers to a group having the structure-RNHR 'R ", where R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, a heterocycle or a substituted heterocycle, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.

The term "heterocyclylalkyl" refers to a group having the structure-RR', wherein R may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; r' represents a heterocycle or a substituted heterocycle.

In the present invention, the term "substituted" means that one or more hydrogen atoms on a specified group are replaced with a specified substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such substituents are for example (but not limited to): halogen, hydroxy, cyano, carboxy (-COOH), C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₈ Cycloalkyl, 3-12 membered heterocyclyl, aryl, heteroaryl, C ₁ -C ₈ Aldehyde group, C ₂ -C ₁₀ Acyl radical, C ₂ -C ₁₀ Ester group, amino group, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₁₀ Sulfonyl, and C ₁ -C ₆ Urea groups, and the like.

Unless otherwise stated, it is assumed that any heteroatom that is not in a valence state has sufficient hydrogen to replenish its valence state.

When the substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to alkyleneoxy, and the like.

Active ingredient

As used herein, "compounds of the invention" refers to compounds of formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compounds of formula I.

In the present invention, the compound represented by formula I has the following structure

Wherein, ring A, ring B, R, R' and R ¹ 、R ² T and u are as defined above.

Preferably, at least one ring atom in ring a or ring B is N; more preferably, 1 to 5 (i.e., 1,2,3,4, 5) ring atoms in ring a or ring B are N; more preferably, ring a and ring B are each independently 6-membered heterocyclyl, 6-membered heteroaryl, phenyl.

Preferably, the compound has the structure shown in formula I

In the formula, R ¹ 、R ² 、X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ 、X ⁹ Is as defined above.

Preferably, X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ At least one of which is N.

Preferably, in the formulae I and I', R ² Is methyl.

Preferably, the compound has the structure shown in formula (II):

Preferably, in each of the above formulae, R ¹ Selected from the group consisting of substituted or unsubstituted: c ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-10 membered heteroaryl; preferably, R ¹ Selected from the group consisting of substituted or unsubstituted: phenyl, pyridyl, pyrimidinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl,

Wherein said substitution is by one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea groups.

Preferably, the first and second liquid crystal display panels are,

moieties are selected from:

in the formula, R ^3a -R ^3f 、R ^4a -R ^4b 、R ^5b -R ^5c Is as defined above.

Preferably, in the present invention, R ^3a -R ^3f Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₃ -C ₆ Cycloalkyl radical C ₁ -C ₆ Alkylene, 4-to 6-membered heterocycloalkyl C ₁ -C ₆ Alkylene, -O-C ₁ -C ₆ Alkyl, -O-C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl-O-, C ₃ -C ₆ Cycloalkyl radical C ₁ -C ₆ alkylene-O-, 4-6 membered heterocycloalkyl C ₁ -C ₆ alkylene-O-, -O- (CH) ₂ ) _w C ₁ -C ₆ Alkoxy radical, R ¹² -(C ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -, R ¹² - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -, - (C) ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -R ¹² - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -R ¹² (ii) a Wherein w is 1,2,3 or 4;

R ¹² selected from: hydrogen, deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyloxy radical, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy, 4-6 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

R ^4a -R ^4b each independently selected from the group consisting of substituted or unsubstituted: hydrogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₃ -C ₆ Cycloalkyl radical C ₁ -C ₆ Alkylene, 4-to 6-membered heterocycloalkyl C ₁ -C ₆ An alkylene group; wherein said substitution is by one or more groups selected from the group consisting of: deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, R ¹² -(C ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -, R ¹² - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -, - (C) ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -R ¹² - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -R ¹² Halogen, oxo, nitro, hydroxyl, cyano, ester, amino, amido, sulfonamide, or ureido;

R ^5b -R ^5c each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₃ -C ₆ Cycloalkyl radical C ₁ -C ₆ Alkylene, 4-to 6-membered heterocycloalkyl C ₁ -C ₆ Alkylene, -O-C ₁ -C ₆ Alkyl, -O-C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl-O-, C ₃ -C ₆ Cycloalkyl radical C ₁ -C ₆ alkylene-O-, 4-6 membered heterocycloalkyl C ₁ -C ₆ alkylene-O-, -O- (CH) ₂ ) _w C ₁ -C ₆ Alkoxy radical, R ¹² -(C ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -, R ¹² - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -, - (C) ₃ -C ₆ Cycloalkylene radical C ₁ -C ₆ Alkylene) -R ¹² - (4-to 6-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -R ¹² (ii) a Wherein w is 1,2,3 or 4;

wherein said substitution is by one or more groups selected from the group consisting of: deuterium, C ₁ -C ₆ Alkyl, aryl, heteroaryl, and heteroaryl,Deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea groups.

Preferably, in the present invention, R ^3a -R ^3f Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₃ -C ₆ Cycloalkyl-methylene-, 4-6 membered heterocycloalkyl-methylene-, -O-C ₁ -C ₆ Alkyl, -O-C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl-O-, C ₃ -C ₆ cycloalkyl-methylene-O-, 4-6 membered heterocycloalkyl-methylene-O-, -O- (CH) ₂ ) _w C ₁ -C ₆ Alkoxy radical, R ¹² -(C ₃ -C ₆ Cycloalkylene-methylene) -, R ¹² - (4-6 membered heterocycloalkylene-methylene) -, - (C) ₃ -C ₆ Cycloalkylene-methylene) -R ¹² - (4-6 membered heterocycloalkylene-methylene) -R ¹² (ii) a Wherein w is 1,2,3 or 4;

R ¹² selected from: hydrogen, deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl oxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy, 4-6 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

R ^4a -R ^4b each independently selected from substituted or unsubstitutedSubstituted groups of the following group: hydrogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₃ -C ₆ Cycloalkyl radical C ₁ -C ₆ Alkylene, 4-to 6-membered heterocycloalkyl C ₁ -C ₆ An alkylene group; wherein said substitution is by one or more groups selected from the group consisting of: deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, R ¹² -(C ₃ -C ₆ Cycloalkylene-methylene) -, R ¹² - (4-6 membered heterocycloalkylene-methylene) -, - (C) ₃ -C ₆ Cycloalkylene-methylene) -R ¹² - (4-to 6-membered heterocycloalkylene-methylene) -R ¹² Halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

R ^5b -R ^5c each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₃ -C ₆ Cycloalkyl-methylene-, 4-6 membered heterocycloalkyl-methylene-, -O-C ₁ -C ₆ Alkyl, -O-C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl-O-, C ₃ -C ₆ cycloalkyl-methylene-O-, 4-6 membered heterocycloalkyl-methylene-O-, -O- (CH) ₂ ) _w C ₁ -C ₆ Alkoxy radical, R ¹² -(C ₃ -C ₆ Cycloalkylene-methylene) -, R ¹² - (4-6 membered heterocycloalkylene-methylene) -, - (C) ₃ -C ₆ Cycloalkylene-methylene) -R ¹² - (4-to 6-membered heterocycloalkylene-methylene) -R ¹² (ii) a Wherein w is 1,2,3 or 4;

Preferably, unless otherwise specified, said substitution means substitution by one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl hydroxy, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl oxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy, 4-6 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

The salts which the compounds of the invention may form are also within the scope of the invention. Unless otherwise indicated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in either an acidic or basic form. Furthermore, when a compound of the present invention contains a basic moiety, including but not limited to pyridine or imidazole, and an acidic moiety, including but not limited to carboxylic acid, zwitterions ("inner salts") that may form are included within the scope of the term "salt(s)". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are useful, e.g., in isolation or purification steps of the preparation. The compounds of the invention may form salts, for example, by reacting compound I with an amount of acid or base, e.g. an equivalent amount, and then precipitating out in a medium, or by lyophilization in aqueous solution.

The compounds of the invention may contain basic moieties, including but not limited to amine or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids which may form salts include acetates (e.g. with acetic acid or trihaloacetic acid such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, diglycolates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptonates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g. 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g. 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g. 3-phenylpropionates), phosphates, propionates, citrates, and the like, Picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates, e.g., p-toluenesulfonate, dodecanoate, and the like

Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical salts with bases include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine (salt with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, and salts with amino acids such as arginine, lysine, and the like. The basic nitrogen-containing groups may be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenyl bromides), and the like.

Prodrugs and solvates of the compounds of the invention are also contemplated. The term "prodrug" as used herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to yield a compound, salt, or solvate of the present invention when used in the treatment of a related disease. The compounds of the present invention include solvates, such as hydrates.

The compounds, salts or solvates of the invention, in tautomeric forms (for example amides and imine ethers) may be present. All of these tautomers are part of the present invention.

All stereoisomers of the compounds (e.g., those asymmetric carbon atoms that may exist due to various substitutions), including enantiomeric and diastereomeric forms thereof, are contemplated within the invention. The individual stereoisomers of the compounds of the invention may not be present in combination with the other isomers (e.g. as a pure or substantially pure optical isomer having a particular activity), or may be present as a mixture, e.g. as a racemate, or as a mixture with all or a portion of the other stereoisomers. The chiral center of the invention has two S or R configurations, and is defined by the International Union of theory and applied chemistry (IUPAC) proposed in 1974. Racemic forms can be resolved by physical methods such as fractional crystallization, or by separation of the crystals by derivatization into diastereomers, or by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including, but not limited to, conventional methods such as salt formation with an optically active acid followed by crystallization.

The compounds of the present invention, obtained by preparing, isolating and purifying the compound in sequence, have a weight content of 90% or more, for example, 95% or more, 99% or more ("very pure" compounds), as set forth in the text. Such "very pure" compounds of the invention are also part of the invention herein.

All configurational isomers of the compounds of the invention are within the scope of the invention, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

Specific functional groups and definitions of chemical terms are detailed below. For purposes of the present invention, the chemical Elements are compatible with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics,75 ^th D. as defined in. The definition of a particular functional group is also described herein. In addition, the basic principles of Organic Chemistry, as well as specific functional groups and reactivities are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, which is incorporated by reference in its entirety.

Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomer, (L) isomer, racemic mixtures and other mixtures thereof. Further the asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers, as well as mixtures thereof, are encompassed by the present invention.

According to the present invention, the mixture of isomers may contain a variety of isomer ratios. For example, in a mixture of only two isomers there may be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, all ratios of isomers are within the scope of the invention. Similar ratios, as well as ratios that are mixtures of more complex isomers, are readily understood by those of ordinary skill in the art to be within the scope of this invention.

The invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as the original compound. It will generally occur that in practice one or more atoms are replaced by an atom having a different atomic mass or mass number from the atomic mass or mass number. Examples of isotopes that can be listed as compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively ² H、 ³ H、 ¹³ C、 ¹¹ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and ³⁶ and (4) Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing those compounds are within the scope of the present invention. Certain isotopically-labelled compounds of the invention, e.g. ³ H and ¹⁴ among these, the radioactive isotope of C is useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. ³ H and carbon-14, i.e. ¹⁴ C, their preparation and detection are relatively easy. Is the first choice among isotopes. Furthermore, heavier isotopes such as deuterium are substituted, i.e. ² H, due to its good metabolic stability, may be advantageous in certain therapies, such as increased half-life in vivo or reduced dose, and therefore, may be preferred in certain circumstances. Isotopically labeled compounds can be prepared by conventional methods by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent using the protocols disclosed in the examples.

If it is desired to design the synthesis of a particular enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or derivatised with chiral auxiliary agents, the resulting diastereomeric mixtures separated and the chiral auxiliary removed to give the pure enantiomers. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed therewith with an appropriate optically active acid or base, and the isolated enantiomers can be obtained in pure form by conventional means such as fractional crystallization or chromatography.

As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to extend their inclusion range. In general, the term "substituted", whether occurring before or after the term "optional", in the formula of the present invention including substituents, means that the hydrogen radical is replaced with a substituent of the indicated structure. When a plurality of the specified structures are substituted at a position with a plurality of the specified substituents, each position of the substituents may be the same or different. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any permissible organic compound described hereinabove to supplement its valence state. Furthermore, the present invention is not intended to be limited in any way as to the permissible substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is excellent in the treatment of diseases, such as infectious diseases or proliferative diseases, in the form of stable compounds. The term "stable" as used herein refers to compounds that are stable enough to maintain the structural integrity of the compound when tested for a sufficient period of time, and preferably are effective for a sufficient period of time, and are used herein for the purposes described above.

Metabolites of the compounds referred to herein and pharmaceutically acceptable salts thereof, as well as prodrugs that are convertible in vivo into the structures of the compounds referred to herein and pharmaceutically acceptable salts thereof, are also encompassed by the claims herein.

Preparation method

The process for preparing the compounds of formula (I) according to the invention is described in more detail below, but these particular processes do not limit the invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.

Typically, the process for the preparation of the compounds of the present invention is as follows, wherein the starting materials and reagents used are commercially available without specific reference.

Preferably, the compounds of the present invention are prepared by the following method

(i) In an inert solvent, a base (e.g. TEA, DIPEA, DMAP or K) ₂ CO ₃ ) Reacting the compound of formula V-1 with the compound of formula V-2 in the presence of a condensing agent (such as BOP, PyBOP, HATU or DCC) or a Pd catalyst to obtain the compound of formula (I);

in the formula (I), the compound is shown in the specification,

x is selected from: halogen, OH, O, OTf, OTs, Oms, etc.;

is a single or double bond;

R ¹ 、R ² r, R', ring A, ring B, u and t are as defined above.

(i ') A compound of formula V' -1 in a base (e.g. TEA, DIPEA, DMAP or K) ₂ CO ₃ ) Reacting with the compound of formula V '-2 under the action of a condensing agent (such as BOP, PyBOP, HATU or DCC) or Pd catalyst to obtain the compound of formula (I');

in the formula (I), the compound is shown in the specification,

x is selected from: halogen, OH, O, OTf, OTs, Oms, etc.;

R ¹ 、R ² 、X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ and X ⁹ Is as defined above.

Pharmaceutical compositions and methods of administration

The pharmaceutical composition is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immunological disease, and metabolic disease.

The compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug may be maintained unchanged while the compound of formula I is administered simultaneously or subsequently. When the compound of the formula I is administered simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs together with the compound of the formula I can be preferably used. The pharmaceutical combination also includes administration of the compound of formula I in an overlapping time period with one or more other known drugs. When a compound of formula I is administered in a pharmaceutical combination with one or more other drugs, the dose of the compound of formula I or the known drug may be lower than the dose at which they are administered alone.

Drugs or active ingredients that may be used in combination with the compounds of formula (I) include, but are not limited to: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemipimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009, or biologically similar drugs thereof), PD-L1 inhibitors (e.g., durvalumab, atezolimab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, A167, F520, GR1405, MSB2311, or biologically similar drugs thereof), CD20 antibodies (e.g., rituximab, OBINzumamab, OFatumumab, IBtuzumab, tosummamab, TOSITUMOMAb, I131-itimumab, Hulmumab 90, ALOMIfK-90, ALOMIfI-35, SANtX 3978, ALOMIfI-35, SANtX-150, ESK-35, ESK-S-K-35, ESK-K-II, ESK-II, ESK-III, ESK-II, ESK-III, ESSES-III, ESK-III, ESP, ESSES-III, ESP-II, ESP-III, ESP-II, ESP, ESB, ES, Alectonib, Brigatinib, Lorlatinib, oxcarinib), PI3K inhibitors (e.g., Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipaliib, Buparlisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabutinib, Acalabastib, Zanbutrutinib, Vecabutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlottinib, Lapatinib, Dacomitib, Icotinib, Canertinib, Sapinotinib, Naquratinib, Pyrotinib, Rocilitiniib, Osimetiniib, etc.), inhibitors (e.g., Sorafenib, Parraertinib, Lorlatinib 6284, Lipocinib, etc.), inhibitors (e.g., Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib inhibitors (e, Lipocinib inhibitors, etc.), inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, etc.), etc. (e, VEGF-III inhibitors, etc.), and so AS inhibitors, VEGF-12, VEGF-inhibitors (e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, such AS inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, VEGF-12, Lipocinib inhibitors, e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, Lipocinib inhibitors, Lip.

Dosage forms of the pharmaceutical compositions of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, pellicle, dripping pill, topical liniment, controlled release type or delayed release type or nanometer preparation.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier in a safe and effective amount range. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-1000mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and between the compounds of the present invention without significantly diminishing the pharmaceutical effectiveness of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

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

Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if desired.

The therapeutic methods of the invention can be administered alone or in combination with other therapeutic means or agents.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 50 to 1000 mg. Of course, the particular dosage will also take into account such factors as the route of administration, the health of the patient, and the like, which are within the skill of the skilled practitioner.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: mixing a pharmaceutically acceptable carrier with the compound of the general formula (I) or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof to form the pharmaceutical composition.

The present invention also provides a method of treatment comprising the steps of: administering a compound of formula (I), or a crystalline form, a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, or a pharmaceutical composition as described herein, to a subject in need of such treatment, for selectively inhibiting SOS 1.

Compared with the prior art, the invention has the following main advantages:

(1) the compound has good selective inhibition effect on SOS 1;

(2) the compound has better in vivo and in vitro pharmacodynamics and pharmacokinetic performance and lower toxic and side effects.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) and liquid mass chromatography (LC-MS).

NMR was detected using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the assay solvent contained deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated acetone (CD) ₃ COCD ₃ ) Deuterated chloroform (CDCl) ₃ ) And deuterated methanol (CD) ₃ OD), and internal standards are Tetramethylsilane (TMS), chemical shifts are measured in parts per million (ppm).

Liquid chromatography-mass spectrometry (LC-MS) was detected using a Waters SQD2 mass spectrometer. HPLC measurements were performed using an Agilent1100 high pressure chromatograph (Microsorb 5micron C18100 x 3.0.0 mm column).

Thin layer chromatography silica gel plate is blue island GF254 silica gel plate, TLC adopts 0.15-0.20mm, and preparative thin layer chromatography adopts 0.4-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available or may be used or synthesized according to literature reports in the art.

All reactions of the present invention are carried out under continuous magnetic stirring in a dry inert gas (e.g., nitrogen or argon) at temperatures in degrees celsius, unless otherwise specified.

Examples

Example 1 preparation of (R) -5- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -3-cyclopropyl-1, 7-dimethylpyrimidine [4,5-d ] pyrimidine-2, 4(1H,3H) -dione

The first step is as follows: (E) preparation of (E) -N, N-dimethyl-N' - (3-methyl-2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidin-4-yl) carboximide

To a solution of 6-amino-1-methylpyrimidine-2, 4(1H,3H) -dione (10.0g,70.8mmol,1.00eq) in DMF (50mL) was added DMF-DMA (16.8g,141mmol,18.8mL,2.00 eq). The reaction was stirred at 40 ℃ for 4h and then cooled to 0 ℃. The resulting mixture was filtered, and the filter cake was washed with MTBE (50mL) and dried to give the desired product (14.0g,64.2mmol, 90.6% yield).

LC-MS：m/z 197(M+H) ⁺ 。

The second step is that: (E) preparation of (E) -N' - (1-cyclopropyl-3-methyl-2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidin-4-yl) -N, N-dimethylformimide

(E) Na was added to a solution of (E) -N, N-dimethyl-N' - (3-methyl-2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidin-4-yl) carboximide (15.0g,76.4mmol,1.00eq) and cyclopropylboronic acid (7.88g,91.7mmol,1.20eq) in dimethyl carbonate (150mL) ₂ CO ₃ (16.2g,152mmol,2.00eq)、Cu(OAc) ₂ (2.78g15.3mmol,0.20eq) and 2- (2-pyridyl) pyridine (2.39g,15.3mmol,0.20 eq). The reaction was stirred at 75 ℃ for 16h and then cooled to room temperature. The resulting mixture was filtered through celite and the filter cake was washed with EtOAc (100 mL). Saturated NH for filtrate ₄ The Cl aqueous solution was washed (300mL), the aqueous phase was separated and extracted with EtOAc (3 x 500 mL). The combined organic phases were washed with saturated brine, dried and concentrated under reduced pressure. The residue was slurried with MTBE (150mL) to give the desired product (11.0g,46.5mmol, 60.9% yield).

LC-MS：m/z 237(M+H) ⁺ 。

The third step is the preparation of 6-amino-3-cyclopropyl-1-methylpyrimidine-2, 4(1H,3H) -dione

(E) To a solution of (E) -N' - (1-cyclopropyl-3-methyl-2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidin-4-yl) -N, N-dimethylformimide (6.00g,25.4mmol,1.00eq) in MeOH (40mL) was added NaOH (2M,25.4mL,2.00 eq). The reaction was stirred at 25 ℃ for 2h, then concentrated under reduced pressure to remove methanol. The residue was filtered and the filter cake was collected and dried to give the desired product (2.80g,14.7mmol, 57.8% yield).

LC-MS：m/z 182(M+H) ⁺ 。

The fourth step is the preparation of ethyl 6-amino-3-cyclopropyl-1-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylate

To a solution of 6-amino-3-cyclopropyl-1-methylpyrimidine-2, 4(1H,3H) -dione (4.50g,24.8mmol,1.00eq) in Py (88.2g,1.12mol,90.0mL,44.9eq) was added ethyl chloroformate (23.3g,214mmol,20.5mL,8.66eq) dropwise at 0 ℃. After the dropwise addition, the reaction mixture was stirred at 90 ℃ for 12h, then cooled to room temperature and then quenched with saturated NH at 0 ℃ ₄ Cl (200mL) was quenched, followed by extraction with DCM (300mL x 3). The combined organic phases were washed with saturated brine, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the objective product (3.5g,12.4mmol, 50.1% yield).

LC-MS：m/z 254(M+H) ⁺ 。

The fifth step is the preparation of 6-amino-3-cyclopropyl-1-methyl-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

6-amino-3-cyclopropyl-1-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester (1.70g,6.71mmol,1.00eq) in DMF (10mL) solutionAdding NH ₃ .H ₂ O (30.9g,265mmol,34.0mL, 30.0% purit, 39.5 eq). The reaction mixture was stirred at 130 ℃ for 16 hours in a sealed state, and then concentrated under reduced pressure. The residue was slurried with water to give the desired product (1.20g,5.08mmol, 75.7% yield).

LC-MS：m/z 225(M+H) ⁺ 。

The sixth step is the preparation of 3-cyclopropyl-1, 7-dimethylpyrimidine [4,5-d ] pyrimidine-2, 4,5(1H,3H,6H) -trione

Ac of 6-amino-3-cyclopropyl-1-methyl-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (600mg,2.68mmol,1.00eq) ₂ A solution of O (2.18g,21.3mmol,2.00mL,7.9. eq.) was stirred at 140 ℃ for 3h, then concentrated under reduced pressure. The residue was slurried with water to give the desired product (0.42g,1.61mmol, 60.1% yield).

LC-MS：m/z 249(M+H) ⁺ 。

The seventh step is the preparation of (R) -5- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -3-cyclopropyl-1, 7-dimethylpyrimidine [4,5-d ] pyrimidine-2, 4(1H,3H) -dione

3-cyclopropyl-1, 7-dimethylpyrimidine [4,5-d]To a solution of pyrimidine-2, 4,5(1H,3H,6H) -trione (0.20g,805umol,1.00eq) in DMF (2mL) was added PyBOP (838mg,1.61mmol,2.00eq) and TEA (407mg,4.03mmol,5601uL,5.00 eq). The reaction was stirred at room temperature for 30min, followed by addition of (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (246mg,1.21mmol,4.98uL,1.50 eq). The resulting reaction was stirred at room temperature for 30min, followed by EtOAc (20mL) and H ₂ Layers were separated between O (5 mL). The combined organic phases were washed with saturated brine, dried and concentrated under reduced pressure. The residue was separated by preparative chromatography to give the desired product (0.18g,414umol, 51.4% yield, 98.9% purity).

LC-MS：m/z 435(M+H) ⁺ 。 ¹ HNMR:(400MHz,DMSO-d6)δ9.29(d,J＝8.28Hz,1H)6.82(s,2H)6.74(s,1H)5.62(s,2H)5.37(quin,J＝7.15Hz,1H)3.40(s,3H)2.58-2.65(m,1H)2.39(s,3H)1.51(d,J＝7.03Hz,3H)0.96-1.06(m,2H)0.69-0.79(m,2H)。

Example 2 preparation of (R) -5- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -1-cyclopropyl-3, 7-dimethylpyrimidine [4,5-d ] pyrimidine-2, 4(1H,3H) -dione

The first step is as follows: preparation of 1-cyclopropyl-3-methylurea

Cyclopropylamine (8.00g,140mmol,9.71mL,1.00eq) and Et ₃ A solution of N (28.3g,280mmol,39.0mL,2.00eq) in DCM (100mL) was cooled to 0 deg.C, followed by dropwise addition of N-methyl-chloroformamide (13.1g,140mmol,1.00 eq). The reaction solution was reacted at 25 ℃ for 2 hours and then filtered. The filtrate was collected and concentrated under reduced pressure to give the desired product (16.0g,112mmol, 80.0% yield). The product is used for the next reaction without purification.

LC-MS：m/z 115(M+H) ⁺ 。

The second step is that: preparation of 2-cyano-N- (cyclopropylcarbamoyl) -N-methylacetamide

Under a nitrogen atmosphere, a solution of 1-cyclopropyl-3-methylurea (16.0g,140mmol,1.00eq) and cyanoacetic acid (23.8g,280mmol,2.00eq) in DMF (120mL) was added with Ms ₂ O (29.3g,168mmol,1.20 eq). The reaction solution is reacted for 4H at 25 ℃ and then is reacted with H ₂ O (200mL) diluted and extracted with EtOAc (100mL x 3). The combined organic phases were washed with saturated brine, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain the objective product (18.0g,89.4mmol, 63.8% yield).

LC-MS：m/z 182(M+H) ⁺ 。

The third step: preparation of 6-amino-1-cyclopropyl-3-methylpyrimidine-2, 4(1H,3H) -dione

2-cyano-N- (cyclopropylcarbamoyl) -N-methylacetamide (16.0g,88.3mmol,1.00eq) and NaOH (706mg,17.7mmol,0.20eq) in H ₂ O (220mL) solution was reacted at 80 ℃ for 1h, then cooled to room temperature and stirred at room temperature for 2-3 h. The resulting mixture was filtered, and the filter cake was washed with water and collected and dried to give the desired product (11.5g,60.3mmol, 68.3% yield).

LC-MS：m/z 182(M+H) ⁺ 。

The fourth step: preparation of 6-amino-1-cyclopropyl-3-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester

At 0 ℃, 6-amino-1-Ethyl chloroformate (24.8g,229mmol,21.8mL,5.94eq) was added dropwise to a solution of cyclopropyl-3-methylpyrimidine-2, 4(1H,3H) -dione (7.00g,38.6mmol,1.00eq) in Py (137g,1.73mol,140mL,44.9 eq). After the dropwise addition, the reaction solution was stirred at 90 ℃ for 12 hours, then cooled to room temperature, and then saturated NH was added at 0 ℃ ₄ Cl (200mL) was quenched and then extracted with DCM (300mL × 3). The combined organic phases were washed with saturated brine, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the objective product (2.60g,9.75mmol, 25.2% yield).

LC-MS：m/z 254(M+H) ⁺ 。

The fifth step: preparation of 6-amino-1-cyclopropyl-3-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

To a solution of ethyl 6-amino-1-cyclopropyl-3-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylate (0.80g,3.16mmol,1.00eq) in DMF (10mL) was added NH ₃ .H ₂ O (14.5g,124mmol,16.0mL, 30.0% purit, 39.5 eq). The reaction solution was stirred at 130 ℃ for 16 hours in a sealed state and then concentrated under reduced pressure. The residue was slurried with water to give the title product (0.42g,1.69mmol, 53.4% yield).

LC-MS：m/z 225(M+H) ⁺ 。

And a sixth step: preparation of 1-cyclopropyl-3, 7-dimethylpyrimidine [4,5-d ] pyrimidine-2, 4,5(1H,3H,6H) -trione

Ac of 6-amino-1-cyclopropyl-3-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (0.40g,1.78mmol,1.00eq) ₂ A solution of O (2.18g,21.3mmol,2.00mL,11.9eq) was stirred at 140 ℃ for 16h, then concentrated under reduced pressure, and the residue was slurried with water to give the title product (0.20g,765umol, 42.9% yield).

LC-MS：m/z 249(M+H) ⁺ 。

The seventh step: preparation of (R) -5- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -1-cyclopropyl-3, 7-dimethylpyrimidine [4,5-d ] pyrimidine-2, 4(1H,3H) -dione

1-cyclopropyl-3, 7-dimethylpyrimidine [4,5-d ]]To a solution of pyrimidine-2, 4,5(1H,3H,6H) -trione (0.14g,564umol,1.00eq) in DMF (2mL) was added PyBOP (584mg,1.13mmol,2.00eq) and TEA (285mg,2.82mmol,392uL,5.00 eq). The reaction was stirred at room temperature for 30min, followed by addition of (R) -3- (1-Aminoethyl) -5- (trifluoromethyl) aniline (173mg,846umol,4.98uL,1.50 eq). The resulting reaction was stirred at room temperature for 30min, followed by EtOAc (20mL) and H ₂ Layers were separated between O (5 mL). The combined organic phases were washed with saturated brine, dried and concentrated under reduced pressure. The residue was separated by preparative chromatography to give the desired product (80.6mg,179umol, 31.9% yield).

LC-MS：m/z 435(M+H) ⁺ 。 ¹ HNMR:(400MHz,DMSO-d6)δ9.25(d,J＝8.19Hz,1H)6.81(s,2H)6.74(s,1H)5.61(s,2H)5.28-5.41(m,1H)3.22(s,3H)2.72-2.83(m,1H)2.41(s,3H)1.50(d,J＝6.85Hz,3H)1.01-1.15(m,2H)0.69-0.87(m,2H)。

EXAMPLE 34 preparation of- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2, 8-dimethyl-6- (((S) -tetrahydrofuran-3-yl) oxy) pyridin [2,3-d ] pyrimidin-7 (8H) -one

The first step is as follows: preparation of methyl 2-chloro-1-methyl-6-oxo-1, 6-dihydropyridine-3-carboxylate

LiH (0.900g,129mmol,1.10mL,2.50eq) was added to a solution of 2-chloro-1-methyl-6-oxo-1, 6-dihydropyridine-3-carboxylic acid (9.00g,51.9mmol,1.00eq) in DMF (150mL) at 0 ℃. The reaction solution is reacted for 0.5h at 0 ℃, and then CH is added ₃ I (16.2g,114mmol,7.10mL,2.20 eq). The resulting mixture was stirred at 25 ℃ for 1.5h, then quenched with 2M HCl (50mL) at 0 ℃. The resulting mixture was diluted with water (200mL) and extracted with EtOAc (400 mL). The combined organic phases were washed with saturated brine, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to isolate the objective product (7.00g,34.7mmol, 67.0% yield).

LC-MS：m/z 202(M+H) ⁺ 。

The second step is that: preparation of 4-hydroxy-2, 8-dimethylpyridin [2,3-d ] pyrimidin-7 (8H) -one

To a solution of methyl 2-chloro-1-methyl-6-oxo-1, 6-dihydropyridine-3-carboxylate (3.50g,17.4mmol,1.00eq) and glyoxaline hydrochloride (1.64g,17.4mmol,1.00eq) in EtOH (100mL) was added K ₂ CO ₃ (7.20g,52.1mmol,3.00eq). The reaction mixture was reacted at 90 ℃ for 16 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the objective product (500mg,2.48mmol, 14.3% yield).

LC-MS：m/z 192(M+H) ⁺ 。

The third step: preparation of 6-bromo-4-hydroxy-2, 8-dimethylpyridin [2,3-d ] pyrimidin-7 (8H) -one

4-hydroxy-2, 8-dimethylpyridine [2,3-d ] at 0 deg.C]To a solution of pyrimidin-7 (8H) -one (700mg,3.66mmol,1.00eq) in DCM (40mL) was added Br ₂ (643mg,4.03mmol,208uL,1.10 eq). The reaction mixture was reacted at 25 ℃ for 2 hours and then concentrated under reduced pressure to obtain the objective product (900mg,926umol, 25.3% yield). The product is used for the next reaction without purification.

LC-MS：m/z 270(M+H) ⁺ 。

The fourth step: preparation of 6-bromo-4-chloro-2, 8-dimethylpyridin [2,3-d ] pyrimidin-7 (8H) -one

6-bromo-4-hydroxy-2, 8-dimethylpyridine [2,3-d]Pyrimidin-7 (8H) -one (350mg,1.30mmol,1.00eq) in POCl ₃ (10mL) the solution was reacted at 110 ℃ for 3h, then concentrated under reduced pressure. The residue was quenched with water (50mL) and extracted with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine, dried and concentrated under reduced pressure to give the desired product (500mg, loud). The product is used in the next reaction without purification.

LC-MS：m/z 288(M+H) ⁺ 。

The fifth step: preparation of (R) -6-bromo-2, 8-dimethyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyridine [2,3-d ] pyrimidin-7 (8H) -one

To a solution of 6-bromo-4-chloro-2, 8-dimethylpyridin [2,3-d ] pyrimidin-7 (8H) -one (0.50g,1.21mmol,1.00eq) and (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine (328mg,1.21mmol,1.00eq, HCl) in i-PrOH (10mL) was added DIEA (784mg,6.07mmol,1.06mL,5.00 eq). The reaction solution is reacted for 16h at 80 ℃ and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain the objective product (0.40g,823umol, 67.8% yield).

LC-MS：m/z 486(M+H) ⁺ 。

And a sixth step: preparation of (R) -6-hydroxy-2, 8-dimethyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyridine [2,3-d ] pyrimidin-7 (8H) -one

(R) -6-bromo-2, 8-dimethyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyridine [2,3-d ] under nitrogen atmosphere]Dioxane (5mL) of pyrimidin-7 (8H) -one (0.40g,823umol,1.00eq) and H ₂ To a solution of O (1mL) were added t-BuXphos (34.9mg, 82.3. mu. mol,0.10eq), KOH (138mg,2.47mmol,3.00eq) and Pd ₂ (dba) ₃ (75.3mg,82.3umol,0.10 eq). The reaction was reacted at 100 ℃ for 2h and then diluted with water (50mL) and extracted with EtOAc (200 mL). The combined organic phases were washed with saturated brine, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain the objective product (200mg,472umol, 57.4% yield).

LC-MS：m/z 424(M+H) ⁺ 。

The seventh step: preparation of 2, 8-dimethyl-4- (((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -6- (((S) -tetrahydrofuran-3-yl) oxy) pyridin [2,3-d ] pyrimidin-7 (8H) -one

(R) -6-hydroxy-2, 8-dimethyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyridine [2,3-d]To a solution of pyrimidin-7 (8H) -one (0.19g,449umol,1.00eq) and (R) -tetrahydrofuran-3-yl-4-methylbenzenesulfonate (163mg,673umol,1.50eq) in DMF (3mL) was added Cs ₂ CO ₃ (439mg,1.35mmol,3.00 eq). The reaction mixture was reacted at 80 ℃ for 2 hours. Then diluted with water (50mL) and extracted with EtOAc (200 mL). The combined organic phases were washed with saturated brine, dried and concentrated under reduced pressure to give the desired product (200mg, loud). The product is used in the next reaction without purification.

LC-MS：m/z 494(M+H) ⁺ 。

Eighth step: preparation of 4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2, 8-dimethyl-6- (((S) -tetrahydrofuran-3-yl) oxy) pyridin [2,3-d ] pyrimidin-7 (8H) -one

2, 8-dimethyl-4- (((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -6- (((S) -tetrahydrofuran-3-yl) oxy) pyridine [2,3-d]Pyrimidin-7 (8H) -one (200mg,405umol,1.00eq) in EtOH (5mL) and H ₂ To a solution of O (1mL) were added Fe (113mg,2.03mmol,5.00eq) and NH ₄ Cl (217mg,4.05mmol,10.0 eq). The reaction solution reacts for 1h at the temperature of 80 DEG CAnd (4) filtering. The filtrate was concentrated under reduced pressure, and the obtained residue was separated by preparative liquid phase to give the objective product (78.0mg,168umol, 41.5% yield).

LC-MS：m/z 464(M+H) ⁺ 。 ¹ HNMR:(400MHz,DMSO-d ₆ )δ12.68(br s,1H),7.87(d,J＝9.3Hz,1H),6.41(d,J＝9.3Hz,1H),3.54(s,3H),2.39(s,3H)。

Example 4 evaluation of biological assays

The following biological test examples further illustrate the present invention, but these examples are not meant to limit the scope of the present invention.

Compound pair KRAS ^G12C Inhibition assay for binding to SOS 1.

Experimental procedure

(1) Gradient dilution of test compound: 10mM stock solution (dissolved in 100% DMSO) was added to 384 well assay plates to a final DMSO content of 0.25%.

(2) 5ul of Tag1-SOS1 solution was added to the test plate and 5ul of dilution buffer was added to the control.

(4) 5ul of Tag2-KRAS was added to the test plate ^G12C And (3) solution.

(4) 10ul of Anti-Tag1-Tb3+ and Anti-Tag2-XL665 test solution were added to the test plate. Centrifuged at 1000rpm for 1 min and incubated at room temperature for 2 hr.

(5) Reading board

(6) Finally, IC of the compound was calculated using GraphPad Prism software ₅₀ And (5) obtaining values, and drawing a fitting curve.

KRAS-Compound pairs of examples of the invention ^G12C The inhibitory activity of the enzyme in combination with SOS1 is shown in Table 1.

Table 1 inhibitory Activity of the Compounds of the examples of the present invention

IC ₅₀	(nM)
		Example 1	>10000
Example 2	>10000
		Example 3	<100

As can be seen from table 1:

EXAMPLES OF THE INVENTION Compound 3 for KRAS ^G12C The combination with SOS1 showed good inhibitory activity.

Pharmacokinetic testing evaluation

Male SD rats weighing about 220g were fasted overnight and then gavaged with 10mg/kg of a solution of the compound of the present invention [ CMC/TW80 as vehicle ]. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 post administration of the compound of the invention, respectively, and the concentration of the compound of the invention in plasma was determined by LC/MS/MS.

The detection result shows that the compound of the invention has good pharmacokinetic property.

Evaluation of antitumor Effect

100uL of the solution containing 5x10 ⁶ The MIA PaCa-2 tumor cell suspension was subcutaneously inoculated into the right posterior abdomen of nude mice. Mice were monitored daily for health and measurements were started when tumors grew to reach. The formula for calculating the tumor volume is 0.5xLxW ² Wherein L, W represents tumor length and width, respectively. Tumor growth to 150mm ³ Mice were randomly grouped. Mice were gavaged daily with the corresponding dose (15, 50mg/Kg) of CMC-Na suspension of the compound while monitoring their general state. Tumors were measured 3 times per week and body weights were measured twice per week.

The detection result shows that the compound has good anti-tumor effect.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the appended claims of the present application.

Claims

1. A compound having the structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:

in the formula (I), the compound is shown in the specification,

r and R', which are identical or different, are each independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, oxo, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which CH ₂ H in (a) may be optionally substituted;

R ¹¹ selected from: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₃ -C ₂₀ Cycloalkyl oxy, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryloxy, 5-14 membered heteroaryloxy, 4-20 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

wherein the above substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₃ -C ₂₀ Cycloalkyloxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryloxy, 5-14 membered heteroaryloxy, 4-20 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

m is 0, 1,2,3,4, 5 or 6;

p is 0, 1,2,3,4, 5 or 6;

q is 1 or 2;

u is 0, 1,2 or 3;

t is 0, 1,2,3 or 4;

the limiting conditions are:

is partially not

2. The compound of claim 1, a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, having the structure of formula (Γ):

in the formula (I), the compound is shown in the specification,

the same or different, each independently is a single bond or a double bond;

X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ and X ⁹ Each independently selected from: C. CR ³ 、CO、N、NR ⁴ 、SO ₂ Or CR ³ R ⁵ (ii) a Wherein, X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ At least one of which contains a heteroatom;

R ³ the same or different, each independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which CH ₂ H in (a) may be optionally substituted;

R ⁴ the same or different, each independently selected from the group consisting of: hydrogen, deuterium, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which CH ₂ H in (a) may be optionally substituted;

R ¹¹ selected from: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₃ -C ₂₀ Cycloalkyl oxy, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryloxy, 5-14 membered heteroaryloxy, 4-20 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

wherein the above-mentioned substitution means substitution by one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₃ -C ₂₀ Cycloalkyl oxy, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryloxy, 5-14 membered heteroaryloxy, 4-20 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

m is 0, 1,2,3,4, 5 or 6;

p is 0, 1,2,3,4, 5 or 6;

q is 1 or 2;

the limiting conditions are that:

part is not

Wherein R is as defined in claim 1.

3. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof according to claim 1 or 2, having the structure of formula (II):

in the formula, R ¹ 、X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ Is defined as in claim 2.

4. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 2 to 3,

moieties are selected from:

in the formula (I), the compound is shown in the specification,

R ^4a -R ^4b identical or different, each independently selected from the group consisting of: hydrogen, deuterium, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which CH ₂ H in (a) may be optionally substituted;

R ^5b -R ^5c the same or different, each independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m (CH＝CH)R ⁸ 、-(CH ₂ ) _m (C≡C)R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which, CH ₂ H in (a) may be optionally substituted;

wherein the above substitution means substitution by a group selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₃ -C ₂₀ Cycloalkyloxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryloxy, 5-14 membered heteroarylAn acyloxy group, a 4-20 membered heterocyclyloxy group, a halogen, an oxo group, a nitro group, a hydroxyl group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group;

wherein R is ⁸ 、R ⁹ 、R ¹⁰ M, p and q are as defined in claim 1.

5. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 4, wherein R is ¹ Selected from the group consisting of:

6. the compound, its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof according to any one of claims 1-5, wherein said compound is selected from the group consisting of:

7. a process for the preparation of a compound of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to claim 1, characterized by the steps of:

in the formula (I), the compound is shown in the specification,

x is selected from: halogen, OH, O, OTf, OTs, Oms;

is a single bond or a double bond;

R ¹ 、R ² r, R', ring A, ring B, u and t are as defined in claim 1.

8. A pharmaceutical composition comprising i) one or more compounds of any one of claims 1-6, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof; and ii) a pharmaceutically acceptable carrier.

9. Use of a compound according to any one of claims 1 to 6, a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, or a pharmaceutical composition according to claim 8, for the preparation of a medicament for the prophylaxis and/or treatment of a disease associated with i) SOS1 activity or expression; and/or ii) SOS1 downstream signal pathway related diseases.

10. A method of inhibiting SOS1 activity in vitro comprising the steps of: contacting a compound of any one of claims 1-6, a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, or a pharmaceutical composition of claim 8, with a protein or a cell, thereby inhibiting SOS1 activity.