CN115215869A

CN115215869A - Substituted tricyclic inhibitor and preparation method and application thereof

Info

Publication number: CN115215869A
Application number: CN202110432735.1A
Authority: CN
Inventors: 吕彬华; 崔大为
Original assignee: Zejing Pharmaceutical Zhejiang Co ltd; Suzhou Zelgen Biopharmaceutical Co Ltd
Current assignee: Zejing Pharmaceutical Zhejiang Co ltd; Suzhou Zelgen Biopharmaceutical Co Ltd
Priority date: 2021-04-21
Filing date: 2021-04-21
Publication date: 2022-10-21

Abstract

The invention relates to a substituted tricyclic 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

Substituted tricyclic inhibitor and preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a substituted tricyclic 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 for 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, icotininib, pyrotinib, rociletinib, osimertinib, etc.), ALK inhibitors (such as Ceritinib, alectoib, brigatinib, lorlatinib, ocatinib, etc.), and VEGFR inhibitors (Sorafenib, regrafenib, cabozantinib, sunitinib, doranib, etc.) (Current Medicinal Chemistry,2019,26, 1-39).

KRAS mutations occur in 20-40% of lung adenocarcinomas, this prevalence being higher in the western (vs Asia) population (26% vs 11%), higher 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 to KRAS mutation has been approved for marketing.

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 Activating 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 SOS2. Published data indicate that SOS1 plays a key role in mutant KRAS activation and oncogenic signaling. A reduction in SOS1 levels resulted in a reduction in proliferation and survival of tumor cells carrying KRAS mutations, 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 of SOS1 GEF activity in KRAS mutant cancer cells (see WO2019122129 A1).

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 SOS1 target proteins are pathologically associated with a variety of diseases, there is also a need for novel SOS1 inhibitors for clinical therapy. The highly selective and active SOS1 inhibitor can effectively treat diseases such as cancers caused by KRAS mutation and reduce the potential of off-target effect, thereby having more urgent clinical needs.

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

x and Y are independently selected from N or C;

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

the A ring is selected from: 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

ring B is selected from: a 6-membered heterocyclyl, phenyl ring, or 6-membered heteroaryl;

R ¹ the same or different, each independently selected from the group consisting of substituted or unsubstituted: 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; wherein said substitution is by R _m Substitution;

R ² the same or different, each independently selected from the group consisting of substituted or unsubstituted: 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; wherein said substitution is by R _m Substitution;

R ³ selected from the group consisting of substituted or unsubstituted: c ₃ -C ₁₈ Cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryl and 5-14 membered heteroaryl; wherein said substitution is by one or more R _m Substitution;

R ⁴ selected from the group consisting of substituted or unsubstituted: c ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl and 4-6 membered heterocyclyl; wherein said substitution is by one or more R _m Substitution;

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 (ii) a Wherein said substitution is by one or more R _m Substitution;

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 ⁹ And R ¹⁰ Is cyclized with its adjacent N atom to form a substituted or unsubstituted 4-8 membered heterocyclic group, or R ⁸ And R ⁹ Ring-closing with its adjacent atom to form a substituted or unsubstituted 4-8 membered heterocyclic group; wherein said substitution is by one or more R _m Substitution;

R ¹¹ each independently 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 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 _m Each independently 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 radicalBase, 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 independently 0, 1,2, 3, 4, 5 or 6;

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

q is independently 1 or 2;

u is independently 0, 1,2 or 3;

t is independently 0, 1,2, 3 or 4.

In another preferred embodiment, the 5-or 6-membered heterocyclic ring is a saturated or partially saturated ring.

In another preferred embodiment, R ⁴ Is a methyl group.

In another preferred embodiment, a 5-membered heterocyclyl or 5-membered heteroaryl.

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

in the formula, R ¹ 、R ² 、R ³ X, Y, ring A, ring B, u and t are as defined above.

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

selected from the group consisting of:

wherein R is ⁵ Independently selected from the group consisting of substituted or unsubstituted: hydrogen, - (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 ⁶ independently 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;

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 radical, deuteriumGeneration 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;

in the formula, R ⁸ 、R ⁹ 、R ¹⁰ M, p and q are as defined above.

In another preferred embodiment, R ⁵ Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, halogen, cyano, oxo, amino, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, hydroxy, mercapto, carboxyl, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, OC ₁ -C ₃ Alkylene radical C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkoxy, 4-8 membered heterocyclyloxy, R ¹¹ -(C ₃ -C ₈ Cycloalkylene radical C ₁ -C ₃ Alkylene) -, R ¹¹ - (4-to 8-membered heterocycloalkylene C) ₁ -C ₃ Alkylene) -, - (C) ₃ -C ₈ Cycloalkylene radical C ₁ -C ₃ Alkylene) -R ¹¹ - (4-to 8-membered heterocycloalkylene C) ₁ -C ₃ Alkylene) -R ¹¹ (ii) a Wherein said substitution is by one or more R _m Substitution;

R ¹¹ each independently 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 ₈ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyl oxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, C ₆ -C ₁₀ An aryloxy group 5-10 membered heteroaryloxy,4-8 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

wherein R is _m Each independently selected from: 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 ₈ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyl oxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, the compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is shown in the specification, wherein R is ³ Selected from the group consisting of substituted or unsubstituted: phenyl and 5-6 membered heteroaryl; 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 ₃ -C ₆ Cycloalkyl radical, 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 ³ Selected from the group consisting of substituted or unsubstituted: phenyl, pyridyl and pyrimidinyl; 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 (e.g. CH) ₂ F、CHF ₂ 、CF ₃ 、CH ₂ CH ₂ F、CH ₂ CHF ₂ ) Halogen substituted C ₁ -C ₆ Alkylhydroxy (e.g., -CHFCH) ₂ OH、-CF ₂ CH ₂ OH、-CF ₂ CH(OH)CH ₃ 、-CF ₂ C(OH)CH ₃ CH ₃ )、C ₃ -C ₆ Cycloalkyl radical, 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 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 ₈ Cycloalkyl, 4-8 membered heterocyclyl, R ¹¹ -(C ₃ -C ₈ Cycloalkylene radical C ₁ -C ₃ Alkylene) -, R ¹¹ - (4-to 8-membered heterocycloalkylene C) ₁ -C ₃ Alkylene) -, - (C) ₃ -C ₈ Cycloalkylene radical C ₁ -C ₃ Alkylene) -R ¹¹ - (4-to 8-membered heterocycloalkylene C) ₁ -C ₃ Alkylene) -R ¹¹ ；

R ¹¹ Each independently 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 ₈ Cycloalkyl, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyl oxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-to 10-membered heteroaryloxy, 4-to 8-membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, the compound, a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, wherein the compound has the structure shown in formula (III-a) and formula (III-B):

in the formula, R ¹ 、R ² 、R ³ 、R ⁵ X, Y, ring A, u and t are as defined above.

In another preferred embodiment, ring a is a 5-membered heteroaromatic ring; preferably the a ring is selected from: pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, triazolyl.

In another preferred embodiment, Y is N.

In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is provided, wherein R is ³ Selected from the group consisting of:

in another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is provided, wherein R is ² Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, halogen, cyano, oxo, C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₈ Cycloalkyl, 4-8 membered heterocyclyl, OR ¹² 、-(CH ₂ )OR ¹² 、-(CH ₂ ) ₂ OR ¹² 、-O(CH ₂ )R ¹³ 、-O(CH ₂ ) ₂ R ¹³ 、-(CH ₂ )O(CH ₂ )R ¹³ 、-(CH ₂ )O(CH ₂ ) ₂ R ¹³ 、-(CH ₂ ) ₂ O(CH ₂ ) ₂ R ¹³ 、COR ¹² 、C(O)OR ¹² 、S(O)R ¹⁷ 、S(O) ₂ R ¹⁷ 、NR ¹⁴ R ¹⁵ 、C(O)NR ¹⁴ R ¹⁵ 、NR ¹⁶ C(O)R ¹² 、NR ¹⁶ C(O)NR ¹⁴ R ¹⁵ 、S(O)NR ¹⁴ R ¹⁵ 、S(O) ₂ NR ¹⁴ R ¹⁵ 、NR ¹⁶ S(O)R ¹⁷ 、NR ¹⁶ S(O) ₂ R ¹⁷ 、NR ¹⁶ S(O)NR ¹⁴ R ¹⁵ 、NR ¹⁶ S(O) ₂ NR ¹⁴ R ¹⁵ (ii) a Wherein said substitution is by one or more R _m Substitution;

wherein R is ¹² 、R ¹⁴ 、R ¹⁵ And R ¹⁶ Each independently selected from the group consisting of substituted or unsubstituted: H. c ₁ -C ₆ Alkyl radical, C ₃ -C ₈ Cycloalkyl, 4-8 membered heterocyclyl, R ¹¹ -(C ₃ -C ₈ Cycloalkylene radical C ₁ -C ₃ Alkylene) -, R ¹¹ - (4-to 8-membered heterocycloalkylene C) ₁ -C ₃ Alkylene) -, - (C) ₃ -C ₈ Cycloalkylene radical C ₁ -C ₃ Alkylene) -R ¹¹ - (4-to 8-membered heterocycloalkylene C) ₁ -C ₆ Alkylene) -R ¹¹ (ii) a Wherein said substitution is by one or more R _m Substitution;

R ¹⁷ and R ¹³ Each independently selected from the group consisting of substituted or unsubstituted: H. c ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyl, 4-8 membered heterocyclyl, R ¹¹ -(C ₃ -C ₈ Cycloalkylene radical C ₁ -C ₃ Alkylene) -, R ¹¹ - (4-to 8-membered heterocycloalkylene C) ₁ -C ₃ Alkylene) -, - (C) ₃ -C ₈ Cycloalkylene radical C ₁ -C ₃ Alkylene) -R ¹¹ - (4-to 8-membered heterocycloalkylene C) ₁ -C ₃ Alkylene) -R ¹¹ (ii) a Wherein said substitution is by one or more R _m Substitution;

or at NR ¹⁴ R ¹⁵ 、C(O)NR ¹⁴ R ¹⁵ 、S(O)NR ¹⁴ R ¹⁵ 、S(O) ₂ NR ¹⁴ R ¹⁵ In, R ¹⁴ And R ¹⁵ And the adjacent N atom thereof form a substituted or unsubstituted 4-8 membered heterocyclic group; or at NR ¹⁶ C(O)R ¹² 、NR ¹⁶ C(O)NR ¹⁴ R ¹⁵ 、NR ¹⁶ S(O)R ¹⁷ 、NR ¹⁶ S(O) ₂ R ¹⁷ 、NR ¹⁶ S(O)NR ¹⁴ R ¹⁵ 、NR ¹⁶ S(O) ₂ NR ¹⁴ R ¹⁵ In, R ¹⁴ And R ¹⁵ Is cyclized with its adjacent N atom to form a substituted or unsubstituted 4-8 membered heterocyclic group, or R ¹⁶ And R ¹² With its adjacent atoms forming a substituted or unsubstituted 4-8 membered heterocyclic group, or R ¹⁶ And R ¹⁷ With its adjacent atoms forming a substituted or unsubstituted 4-8 membered heterocyclic group, or R ¹⁶ And R ¹⁴ And the adjacent atoms are cyclized to form a substituted or unsubstituted 4-8 membered heterocyclic group; wherein said substitution is by one or more R _m Substitution;

R ¹¹ each independently 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 ₈ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyloxy radical, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

wherein R is _m Each independently selected from: deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ An alkyl group,Halogen substituted C ₁ -C ₆ Alkyl hydroxy, C ₃ -C ₈ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyloxy radical, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, R ² Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, halogen, cyano, oxo, amino, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, hydroxy, mercapto, carboxyl, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, OC ₁ -C ₃ Alkylene radical C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkoxy, 4-to 8-membered heterocyclyloxy, R ¹¹ -(C ₃ -C ₈ Cycloalkylene radical C ₁ -C ₃ Alkylene) -, R ¹¹ - (4-to 8-membered heterocycloalkylene C) ₁ -C ₃ Alkylene) -, - (C) ₃ -C ₈ Cycloalkylene radical C ₁ -C ₃ Alkylene) -R ¹¹ - (4-to 8-membered heterocycloalkylene C) ₁ -C ₃ Alkylene) -R ¹¹ (ii) a Wherein said substitution is by one or more R _m Substitution;

R ¹¹ each independently 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 ₈ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyl oxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy, 4-8-membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide or urea;

In another preferred embodiment, the compound has the structure shown in formula IV

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

R ² 、R ³ 、R ⁴ and t is as defined above.

In another preferred embodiment, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ X, Y, ring A, ring B, u and t are each a group corresponding to 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 a compound 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 the compound of formula (V-1) with the compound of formula (V-2) in an inert solvent in the presence of a base (such as DIPEA, TEA, DBU, or DMAP, etc.), a condensing agent (such as BOP, pyBOP, or EDC, etc.) or a Pd catalyst to obtain a compound of formula (V-3);

(ii) In an inert solvent, in a base (such as DIPEA, TEA, DBU, or DMAP, etc.), or in a Pd catalyst (such as Pd (OAc) ₂ 、Pd ₂ (dba) ₃ 、Pd(PPh ₃ ) ₄ Or Pd (dppf) Cl ₂ Etc.) in the presence of a compound of formula (V-3) and a compound of formula (V-4); then dehydrating agent (such as HCl, H) ₂ SO ₄ 、POCl ₃ 、PCl ₅ Polyphosphoric acid, msOH or TsOH) to generate ring closing reaction to obtain a compound shown in a formula (I);

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

P ₁ selected from: halogen, OH, O, OTf, OTs, OMs, etc.;

P ₂ 、P ₃ each independently selected from: none, H, halogen, OH, O, OTf, OTs, OMs, etc.;

Q ₁ and Q ₂ Are leaving groups, each independently selected from: H. halogen, OH, O, OMe, OEt, OTf, OTs, OMs, B (OH) ₂ 、

Sn( ⁿ Bu) ₃ Zn or ZnBr, etc.;

is a single bond or a double bond;

R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ x, Y, ring A, ring B, u and t are as defined above.

In another preferred embodiment, compound V-4 is 2, 2-dimethoxyethylamine.

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, HLXL10, BAT 1306, AK105, LZM 009, or biologically similar drugs thereof, etc.), PD-L1 inhibitors (e.g., durvalizumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, A167, F520, GRGW1405, MSB2311, or biologically similar drugs thereof, etc.), CD20 antibodies (e.g., rituximab, obizumab, ofatumumab, veltuzumab, tutumumab, tosimimab, 131I-tuzumab, humumab, huumumab 90, U-5-F47, etc.), CD-5-T-5 antibodies (e.g., CD47, 5-T-5, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (e.g., ceritinib, alectoib, brigatinib, lorlatinib, ocatinib), PI3K inhibitors (e.g., idelalisib, duvelisib, dactolisib, taselisib, bimiralisib, omipalisib, icpalisib, etc.), BTK inhibitors (e.g., ibrutinib, tirabutynib, acablutinib, zanbutinib, vecautibinib, etc.), EGFR inhibitors (e.g., afatinib, geqtinib, erlofibiib, lapatinib, daitatinib, canertinotitinib, saertinib, oslium, etc.), etc VEGFR inhibitors (e.g., sorafenib, pazopanib, regorafenib, sitravatinib, nigertinib, cabozantinib, sunitinib, dunalinib, etc.), HDAC inhibitors (e.g., givinostat, tucidinostat, vorinostat, fimepinostat, droxinostat, entinostat, dacinostat, quisinostat, tacedinaline, etc.), CDK inhibitors (e.g., palbociclib, ribociclib, abeciclib, milciclib, trilaciclib, lerociclib, etc.), MEK inhibitors (e.g., selumetiib (AZD 6244), trametinib (GSK 1120212), PD0325901, U0126, pimasertib (PD-703026), mTOR (mTOR) inhibitors (CI), mTOR (CI), etc.), SHP2 inhibitor (such as RMC-4630, JAB-3068, TNO155, etc.) or their combination.

In a fourth aspect of the present invention, there is provided a use of a compound according to 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 according to the third aspect, for the preparation of a medicament for the prophylaxis 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, skin cancer.

In a fifth aspect of the invention, there is provided a method of inhibiting SOS1 activity in vitro comprising the steps of: contacting a compound as described above in 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 as described above in the third aspect, with a protein or a cell, thereby inhibiting SOS1 activity.

In another preferred embodiment, the cells are 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 of non-diagnostically, non-therapeutically inhibiting SOS1, comprising the steps of: administering to a subject in need thereof an effective amount 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. 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 repeated herein, depending on the 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 having selective SOS1 inhibitory effects and/or superior 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 meaning 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, and the like isopropyl, n-butyl, tert-butyl, isobutyl, tert-butyl,

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 comprising from 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl

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

) N-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl. "substituted alkyl" means that one or more positions in the alkyl 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. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl ₃ Alkyl of (e.g., = O), 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. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.

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

) Butylene (e.g. butyl oxide)

) Pentylene (e.g. ethylene)

) Hexamethylene (e.g. hexamethylene)

) Heptylene (e.g. ethylene)

) And the like.

The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group comprising 1 to 4 rings each containing 3 to 8 carbon atoms. "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., monohalogen substituents or polyhalo substituents, the latter such as trifluoromethyl or containing Cl ₃ Alkyl of (e.g., = O), 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 spiro, bridged or fused ring substituents, especially spirocycloalkyl, spiroalkenyl, spiroheterocycle (excluding heteroaromatic rings), bridged cycloalkyl, bridged alkenyl, bridged heterocycle (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 joined to 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 group formed by removing two hydrogen atoms from a cycloalkylalkyl or alkylcycloalkyl group as described above, wherein,“C 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 ₃ Alkylene radical C ₃ -C ₈ Cycloalkylene radicals, e.g. methylene C ₃ -C ₈ Cycloalkylene, ethylene C ₃ -C ₈ Cycloalkylene radical, methylene C ₃ -C ₆ A cycloalkylene group.

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 heterocycle containing a heteroatom may carry 1,2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, which nitrogen or sulfur atoms may be oxidized or quaternized. The heterocyclic group may be attached to any heteroatom or residue of a carbon atom of the ring or ring system molecule. The heterocyclyl group is preferably a 3-10 membered heterocyclyl group, more preferably a 4-8 (i.e. 4, 5, 6, 7 or 8) membered heterocyclyl group, more preferably a 4-6 membered heterocyclyl group. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidyl, tetrahydropyranyl, morphinyl, thiomorpholinyl sulfoxide, thiomorpholinyl 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 joined in ring-by-ring with 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 4-8 (i.e. 4, 5, 6, 7 or 8) membered heterocycloalkylene C _1-3 Alkylene groups, such as 4-6 membered heterocycloalkylene methylene, 4-6 membered heterocycloalkylene ethylene.

The term "aryl" refers to aromatic cyclic hydrocarbon groups having 1 to 5 rings, especially 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 an aryl group which is substituted at one or more positions, especially 1 to 3 substituents, and can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl ₃ Alkyl) 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 arylRing, 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 fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclyl or fused ring aromatic ring groups, which cycloalkyl, cycloalkenyl, heterocyclyl and heterocyclylaryl groups may be optionally substituted.

The term "heteroaryl" refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 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 "hydroxy" 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 having the structure-COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic (including heterocyclic and heteroaryl), or substituted heterocyclic.

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, heterocycle or substituted heterocycle 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 ", wherein R, R', and R" can independently represent 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 "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 heterocyclic ring or a substituted heterocyclic ring.

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 certain substituted group may have one substituent selected from a specific group at any substitutable site of the group, and the substituents 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 compounds of formula I have the following structure:

in the formula, R ¹ 、R ² 、R ³ 、R ⁴ X, Y, ring A, ring B, u and t are as defined above.

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

Preferably, the compound has a structure represented by formula (III-A) or formula (III-B):

Preferably, the compound has the structure shown in formula IV

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

R ² 、R ³ 、R ⁴ and t is as defined above.

Preferably, in the present invention, R ² Identical or different, each independently selected from: hydrogen, deuterium, halogen, cyano, oxo, amino, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, hydroxy, mercapto, carboxyl, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, OC ₁ -C ₃ Alkylene radical C ₁ -C ₆ Alkoxy, C3-C8 cycloalkoxy, 4-8 membered heterocyclyloxy, R ¹¹ -(C ₃ -C ₈ Cycloalkylene radical C ₁ -C ₃ Alkylene) -, R ¹¹ - (4-to 8-membered heterocycloalkylene C) ₁ -C ₃ Alkylene) -, - (C) ₃ -C ₈ Cycloalkylene radical C ₁ -C ₃ Alkylene) -R ¹¹ - (4-to 8-membered heterocycloalkylene C) ₁ -C ₃ Alkylene) -R ¹¹ ；

R ¹¹ Each independently 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 ₈ Cycloalkyl, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyloxy radical, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

R ³ selected from the group consisting of substituted or unsubstituted: phenyl radicalAnd 5-6 membered heteroaryl;

R ⁴ is methyl.

Preferably, in the present invention, R _m Each independently selected from: 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 ₈ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyl oxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-to 10-membered heteroaryloxy, 4-to 8-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 salts thereof. 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 salting out in a medium, or lyophilizing in an 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 be salified 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-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g. 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g. 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g. with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates such as p-toluenesulfonate, dodecanoate and the like

Acidic moieties that certain compounds of the present invention may contain, including but not limited to carboxylic acids, 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 form (for example amides and imino ethers) may be present. All of these tautomers are part of the present invention.

Stereoisomers of all compounds (e.g. those asymmetric carbon atoms which may exist due to various substitutions), including enantiomeric and diastereomeric forms, are contemplated within the scope of 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, such 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. The 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, which are obtained by preparing, isolating and purifying the compound in order to obtain the compound in an amount of 90% by weight or more, for example, 95% by weight or more, or 99% by weight or more ("very pure" compounds), are listed in the text description. 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 compounds in the present invention encompasses both cis (Z) and trans (E) olefin 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 the purposes of the present invention, the chemical Elements are combined with a 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, 60, 30, 80. Similar ratios, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention, as would be readily understood by one of ordinary skill in the art.

The invention also includes isotopically-labeled compounds, equivalent to those disclosed herein for the original compound. In practice, however, it will often occur that one or more atoms are replaced by an atom having a different atomic weight 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, such as 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. In the inventionCertain isotopically-labelled compounds, e.g. ³ H and ¹⁴ radioisotopes of C are also useful, among other things, 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 by derivatization with chiral auxiliary agents, separation of the resulting diastereomeric mixture and removal of the chiral auxiliary agent to give the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a diastereomeric salt thereof can be formed with an appropriate optically active acid or base, and the resulting salt can be separated by a conventional means such as fractional crystallization or chromatography to obtain a pure enantiomer.

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 and pharmaceutically acceptable salts thereof to which this application relates, and prodrugs that can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof to which this application relates, are also included in the claims of this application.

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 compounds of the present invention are prepared by the following procedures, 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

(ii) In an inert solvent, in a base (such as DIPEA, TEA, DBU, or DMAP, etc.), or in a Pd catalyst (such as Pd (OAc) ₂ 、Pd ₂ (dba) ₃ 、Pd(PPh ₃ ) ₄ Or Pd (dppf) Cl ₂ Etc.) in the presence of a catalyst of the formula (V-3)Reacting the compound with a compound of formula (V-4); then dehydrating agent (such as HCl, H) ₂ SO ₄ 、POCl ₃ 、PCl ₅ Polyphosphoric acid, msOH or TsOH) to generate a ring closing reaction to obtain a compound shown in a formula (I);

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

P ₁ selected from: halogen, OH, O, OTf, OTs, OMs, etc.;

Sn( ⁿ Bu) ₃ Zn or ZnBr, etc.;

is a single bond or a double bond;

(s 1) reacting the compound 1-1 with the compound (V-2) in an inert solvent such as isopropanol in the presence of a base such as DIPEA, TEA, DBU, or DMAP to give a compound of the formula 1-2;

(s 2) reacting compound 1-2 with compound 1-3 in an inert solvent (such as DMF) in the presence of a base (such as DIPEA, TEA, DBU, or DMAP, etc.) to give compound 1-4;

(s 3) in an inert solvent (e.g. toluene) in a dehydrating agent (e.g. HCl, H) ₂ SO ₄ 、POCl ₃ 、PCl ₅ Polyphosphoric acid, polyphosphoric acid,MsOH or TsOH) to generate ring closing reaction to obtain a compound V;

in the formula, R ² 、R ³ 、R ⁴ And t is as defined above.

Pharmaceutical compositions and methods of administration

The pharmaceutical composition of the invention 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 formula I is administered simultaneously with one or more other drugs, it may be preferable to use a pharmaceutical composition containing both one or more known drugs and the compound of formula I. 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 dosage of the compound of formula I or the known drugs may be lower than the dosage for their administration alone.

Drugs or active ingredients that may be used in combination with the compounds of formula (I) include, but are not limited to: <xnotran> PD-1 ( nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 ), PD-L1 ( durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 ), CD20 ( rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab,131I-tositumomab, ibritumomab,90Y-ibritumomab,90In-ibritumomab, ibritumomab tiuxetan ), CD47 ( Hu5F9-G4, CC-90002, TTI-621, TTI-622,OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM 01), ALK ( Ceritinib, alectinib, brigatinib, lorlatinib, ), PI3K ( Idelalisib, duvelisib, dactolisib, taselisib, bimiralisib, omipalisib, buparlisib ), BTK ( Ibrutinib, tirabrutinib, acalabrutinib, zanubrutinib, vecabrutinib ), EGFR ( Afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canertinib, sapitinib, naquotinib, pyrotinib, rociletinib, osimertinib ), VEGFR ( Sorafenib, pazopanib, regorafenib, sitravatinib, ningetinib, cabozantinib, sunitinib, ), HDAC ( Givinostat, tucidinostat, vorinostat, fimepinostat, droxinostat, entinostat, dacinostat, quisinostat, tacedinaline ), CDK ( Palbociclib, ribociclib, abemaciclib, milciclib, trilaciclib, lerociclib ), MEK ( Selumetinib (AZD 6244), trametinib (GSK 1120212), PD0325901, U0126, pimasertib (AS-703026), PD184352 (CI-1040) ), </xnotran> mTOR inhibitors (e.g., vissturtib, etc.), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), or combinations thereof.

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 in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. 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 "compatibility" is meant herein that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the compoundsHas medical effect. 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. propylene glycol, glycerol, mannitol, sorbitol, 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, especially 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 treatment methods of the present invention can be administered alone or in combination with other therapeutic means or agents.

In the case of pharmaceutical compositions, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the administration is a pharmaceutically acceptable and effective dose, and the daily dose for a human of 60kg body weight is usually 1 to 2000mg, preferably 50 to 1000mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is 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 to a subject in need of treatment a compound of formula (I) as described herein, or a crystalline form, a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described herein, for selectively inhibiting SOS1.

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, pharmacokinetic performance and lower toxic and side effect.

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, generally following conventional conditions such as Sambrook et al, molecular cloning: 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. 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 chromatography-mass spectrometry (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), internal standard using 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 was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100x 3.0mm column).

Thin layer chromatography silica gel plate is blue island GF254 silica gel plate, TLC is 0.15-0.20mm, and preparative thin layer chromatography is 0.4-0.5 mm. Column chromatography is generally carried out by using Qingdao silica gel 200-300 mesh 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 N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -8-methoxy-7- (((S) -tetrahydrofuran-3-yl) oxy) imidazo [1,2-a ] quinazolin-5-amine

The first step is as follows: preparation of methyl (S) -4-methoxy-2-nitro-5- ((tetrahydrofuran-3-yl) oxy) benzoate

Methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (10.0g, 44.0mmol, 1.00eq) and (R) -tetrahydrofuranTo a solution of pyran-3-yl-4-methylbenzenesulfonate (13.9 g,57.2mmol, 1.30eq) in DMF (100 mL) was added Cs ₂ CO ₃ (43.0 g,132mmol, 3.00eq). The resulting reaction was allowed to react at 80 ℃ for 16h, then cooled to room temperature and quenched by addition of water (300 mL) and extracted with EtOAc (500 mL). The organic phase was separated, washed with saturated aqueous sodium carbonate (200 mL) and then anhydrous Na ₂ SO ₄ Dried and then filtered. The filtrate was concentrated under reduced pressure to give the desired product (7.00g, crop). The product was used in the next reaction without further purification.

¹ HNMR(400MHz,DMSO-d6)δ1.93-2.01(m,1H)2.22-2.33(m,1H)3.75(td,J＝8.38,4.75Hz,1H)3.81-3.93(m,7H)5.20-5.25(m,1H)7.32(s,1H)7.65(s,1H)。

The second step is that: preparation of methyl (S) -2-amino-4-methoxy-5- ((tetrahydrofuran-3-yl) oxy) benzoate

To a solution of methyl (S) -4-methoxy-2-nitro-5- ((tetrahydrofuran-3-yl) oxy) benzoate (7.00g, 23.6mmol, 1.00eq) in MeOH (100 mL) under nitrogen was added Pd/C (1.4 g, 10%). The resulting reaction solution was reacted at 25 ℃ for 16 hours under a hydrogen atmosphere (15 psi). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give the objective product (7.00g, crop). The product was used in the next reaction without further purification.

LC-MS：m/z 268(M+H) ⁺ 。

The third step is the preparation of (S) -7-methoxy-6- ((tetrahydrofuran-3-yl) oxy) quinazoline-2, 4 (1H, 3H) -dione

Under nitrogen, (S) -2-amino-4-methoxy-5- ((tetrahydrofuran-3-yl) oxy) benzoic acid methyl ester (7.00g, 26.2mmol, 1.00eq) and urea (31.5g, 523mmol,28.1mL, 20.0eq) were reacted at 180 ℃ for 3h, then diluted with water (500 mL). The resulting mixture was reacted at 25 ℃ for 30mins and then filtered. The filter cake was dried to give the desired product (6.00g, 21.6mmol,82.3% yield). The product was used in the next reaction without further purification.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.02(br s,2H),7.24(s,1H),6.70(s,1H),5.01(br dd,J＝4.4,5.7Hz,1H),3.88-3.79(m,5H),3.78-3.71(m,1H),3.75(dt,J＝4.5,8.3Hz,1H),2.28-2.11(m,1H),2.03-1.90(m,1H)

The fourth step is the preparation of (S) -2, 4-dichloro-7-methoxy-6- ((tetrahydrofuran-3-yl) oxy) quinazoline

(S) -7-methoxy-6- ((tetrahydrofuran-3-yl) oxy) quinazoline-2, 4 (1H, 3H) -dione (5.00g, 18.0mmol, 1.00eq) in POCl ₃ The solution (60 mL) was reacted at 130 ℃ for 2h and then concentrated under reduced pressure. The residue was diluted with EtOAc (500 mL) and then quenched with ice-water (300 mL). The organic phase was collected, washed with saturated brine (150ml × 2), and then dried over anhydrous Na ₂ SO ₄ Dried and then filtered. The filtrate was concentrated under reduced pressure in vacuo to give the objective product (2.60g, 8.25mmol,45.9% yield). The product was used in the next reaction without further purification.

LC-MS：m/z 315(M+H) ⁺ 。

The fifth step preparation of 2-chloro-7-methoxy-N- ((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine

DIEA (1.23g, 9.52mmol,1.66mL, 3.00eq) was added to a solution of (S) -2, 4-dichloro-7-methoxy-6- ((tetrahydrofuran-3-yl) oxy) quinazoline (1.00g, 3.17mmol, 1.00eq) and (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine (1.20g, 4.44mmol,1.40eq, HCl) in isopropanol (20.0 mL). The resulting reaction mixture was reacted at 80 ℃ for 16 hours. The same experiment was carried out in parallel 2 times, and the reaction solutions were combined and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain the objective product (2.90g, 5.65mmol,89.1% yield).

LC-MS：m/z 513(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.66(d,J＝7.3Hz,1H),8.58

(s,1H),8.38(s,1H),8.32(s,1H),7.76(s,1H),7.12(s,1H),5.66(quin,J＝7.0Hz,1H),5.28-5.11(m,1H),4.05-3.98(m,1H),3.95-3.78(m,1H),3.95-3.78(m,6H),2.42-2.29(m,1H),2.10-2.01(m,1H),1.70(d,J＝7.1Hz,3H).

Sixth step preparation of N2- (2, 2-Dimethoxyethyl) -7-methoxy-N4- ((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (((S) -tetrahydrofuran-3-yl) oxy) quinazoline-2, 4-diamine

To a solution of 2-chloro-7-methoxy-N- ((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine (0.60g, 1.17mmol, 1.00eq) and 2, 2-dimethoxyethylamine (369mg, 3.51mmol,382uL, 3.00eq) in DMF (8.00 mL) was added DIEA (756mg, 5.85mmol,1.02mL, 5.00eq). The resulting reaction mixture was reacted at 140 ℃ for 2 hours, followed by vacuum concentration under reduced pressure to obtain the objective product (700mg, crop). The product was used in the next reaction without further purification.

LC-MS：m/z 582(M+H) ⁺ 。

Seventh step preparation of 8-methoxy-N- ((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (((S) -tetrahydrofuran-3-yl) oxy) imidazo [1,2-a ] quinazolin-5-amine

A mixed solution of N2- (2, 2-dimethoxyethyl) -7-methoxy-N4- ((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (((S) -tetrahydrofuran-3-yl) oxy) quinazoline-2, 4-diamine (600mg, 1.03mmol, 1.00eq) in toluene (2.00 mL) and HCl (1.00 mL) was reacted at 110 ℃ for 2h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (15ml × 2). The combined organic phases were washed with saturated brine (150ml × 2) and then with anhydrous Na ₂ SO ₄ Dried and then filtered. And concentrating the filtrate under vacuum and reduced pressure to obtain a target product. The product was used in the next reaction without further purification.

LC-MS：m/z 518(M+H) ⁺ 。

Eighth step preparation of N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -8-methoxy-7- (((S) -tetrahydrofuran-3-yl) oxy) imidazo [1,2-a ] quinazolin-5-amine

8-methoxy-N- ((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (((S) -tetrahydrofuran-3-yl) oxy) imidazo [1,2-a]Quinazolin-5-amine (400mg, 773umol, 1.00eq) in EtOH (1.00 mL) and H ₂ To a mixed solution of O (0.20 mL) were added Fe (216mg, 3.87mmol, 5.00eq) and NH ₄ Cl (413mg, 7.73mmol, 10.0eq). The resulting reaction solution was reacted at 80 ℃ for 1 hour and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by prep-HPLC to give the desired product (50.2mg, 101umol,13.1% yield,98.4% yield by mass).

LC-MS：m/z 488(M+H) ⁺ 。 ¹ HNMR(400MHz,DMSO-d ₆ )δ8.08(br s,1H),7.95(br d,J＝2.8Hz,1H),7.88(br d,J＝5.4Hz,1H),7.61(br d,J＝3.4Hz,1H),7.14(br s,1H),6.87(br d,J＝8.7Hz,2H),6.70(br s,1H),5.66-5.41(m,3H),5.23(br s,1H),4.00(br d,J＝3.2Hz,3H),3.96-3.77(m,4H),2.36-2.17(m,1H),2.06(br s,1H),1.57(br d,J＝3.5Hz,3H).

The following compounds were synthesized as in example 1, starting from different starting materials:

EXAMPLE 2 preparation of N- ((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) -8-methoxy-7- (((S) -tetrahydrofuran-3-yl) oxy) imidazo [1,2-a ] quinazolin-5-amine

LC-MS：m/z 491(M+H) ⁺ 。

Example 3, 1-difluoro-1- (2-fluoro-3- ((R) -1- ((8-methoxy-7- (((S) -tetrahydrofuran-3-yl) oxy) imidazo [1,2-a ] quinazolin-5-yl) amino) ethyl) phenyl) -2-methylpropan-2-ol

LC-MS：m/z 531(M+H) ⁺ 。

Example 4 evaluation of biological tests

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 And inhibition of SOS1 binding.

Experimental procedure

(1) Gradient dilution of test compound: 10mM stock solution (dissolved in 100% DMSO) was added to the 384 well test plates, with 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 group.

(4) Add 5ul Tag2-KRAS to test plates ^G12C And (3) solution.

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

(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

As can be seen from table 1:

compounds of the examples of the invention for KRAS ^G12C The combination with SOS1 showed very good inhibitory activity.

Pharmacokinetic testing evaluation

Male SD rats, weighing around 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 after administration of the compound of the present invention, respectively, and the concentration of the compound of the present invention in plasma was determined by LC/MS/MS.

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

Evaluation of antitumor Effect

Make 100uL contain 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 and W represent the length and width of the tumor respectively. Tumor growth to 150mm ³ Mice were randomly grouped. Mice were gavaged daily with the corresponding dose (15, 50 mg/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 mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and 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 present invention as defined by the appended claims.

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,

x and Y are independently selected from N or C;

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

the B ring is selected from: a 6-membered heterocyclyl, phenyl ring, or 6-membered heteroaryl;

R ¹ the same or different, each independently selected from the group consisting of substituted or unsubstituted: 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; wherein said substitution is by R _m Substitution;

R ³ selected from the group consisting of substituted or unsubstituted: c ₃ -C ₁₈ Cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryl and 5-14 membered heteroaryl; wherein, theSubstituted means by one or more R _m Substitution;

R ¹¹ each independently 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 R is _m Each independently 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;

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

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

q is independently 1 or 2;

u is independently 0, 1,2 or 3;

t is independently 0, 1,2, 3 or 4.

2. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to claim 1, characterized in that it has the structure according to formula (II):

in the formula, R ¹ 、R ² 、R ³ X, Y, ring A, ring B, u and t are as defined in claim 1.

3. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to claim 1 or 2,

selected from the group consisting of:

wherein R is ⁵ Independently selected from the group consisting of substituted or unsubstituted: hydrogen, - (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 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 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;

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

4. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to any one of claims 1 to 3, wherein R is ³ Selected from the group consisting of substituted or unsubstituted: phenyl and 5-6 membered heteroaryl; 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 ₃ -C ₆ Cycloalkyl radical, 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.

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 said compound has the structure shown in formula (III-A) and formula (III-B):

in the formula, R ⁵ Selected from the group consisting of substituted or unsubstituted: hydrogen, - (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 ¹ 、R ² 、R ³ 、R ⁴ 、R ⁸ 、R ⁹ 、R ¹⁰ x, Y, ring A, u, t, m, q are as defined in claim 1.

6. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to any one of claims 1 to 5, wherein R is ³ Selected from the group consisting of:

7. the compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 6, wherein R is ² Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, halogen, cyano, oxo, C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₈ Cycloalkyl, 4-8 membered heterocyclyl, OR ¹² 、-(CH ₂ )OR ¹² 、-(CH ₂ ) ₂ OR ¹² 、-O(CH ₂ )R ¹³ 、-O(CH ₂ ) ₂ R ¹³ 、-(CH ₂ )O(CH ₂ )R ¹³ 、-(CH ₂ )O(CH ₂ ) ₂ R ¹³ 、-(CH ₂ ) ₂ O(CH ₂ ) ₂ R ¹³ 、COR ¹² 、C(O)OR ¹² 、S(O)R ¹⁷ 、S(O) ₂ R ¹⁷ 、NR ¹⁴ R ¹⁵ 、C(O)NR ¹⁴ R ¹⁵ 、NR ¹⁶ C(O)R ¹² 、NR ¹⁶ C(O)NR ¹⁴ R ¹⁵ 、S(O)NR ¹⁴ R ¹⁵ 、S(O) ₂ NR ¹⁴ R ¹⁵ 、NR ¹⁶ S(O)R ¹⁷ 、NR ¹⁶ S(O) ₂ R ¹⁷ 、NR ¹⁶ S(O)NR ¹⁴ R ¹⁵ 、NR ¹⁶ S(O) ₂ NR ¹⁴ R ¹⁵ (ii) a Wherein said substitution is by one or more R _m Substitution;

or at NR ¹⁴ R ¹⁵ 、C(O)NR ¹⁴ R ¹⁵ 、S(O)NR ¹⁴ R ¹⁵ 、S(O) ₂ NR ¹⁴ R ¹⁵ In, R ¹⁴ And R ¹⁵ And the adjacent N atom thereof form a substituted or unsubstituted 4-8 membered heterocyclic group; or at NR ¹⁶ C(O)R ¹² 、NR ¹⁶ C(O)NR ¹⁴ R ¹⁵ 、NR ¹⁶ S(O)R ¹⁷ 、NR ¹⁶ S(O) ₂ R ¹⁷ 、NR ¹⁶ S(O)NR ¹⁴ R ¹⁵ 、NR ¹⁶ S(O) ₂ NR ¹⁴ R ¹⁵ In, R ¹⁴ And R ¹⁵ Is cyclized with its adjacent N atom to form a substituted or unsubstituted 4-8 membered heterocyclic group, or R ¹⁶ And R ¹² With its adjacent atoms forming a substituted or unsubstituted 4-8 membered heterocyclic group, or R ¹⁶ And R ¹⁷ With its adjacent atoms forming a substituted or unsubstituted 4-8 membered heterocyclic group, or R ¹⁶ And R ¹⁴ Ring-closing with its adjacent atom to form a substituted or unsubstituted 4-8 membered heterocyclic group; wherein said substitution is by one or more R _m Substitution;

R ¹¹ each independently 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 ₈ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyl oxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyloxy, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

wherein R is _m Each independently selected from: 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 ₈ Cycloalkyl, C ₁ -C ₆ Alkoxy, deuterated C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyl oxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyloxy, haloAn 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.

8. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 7, characterized in that said compound is selected from the group consisting of:

9. a process for the preparation of a compound of formula (I), or 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:

(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 (V-3);

(ii) Reacting a compound of formula (V-3) with a compound of formula (V-4) in an inert solvent in the presence of a base or a Pd catalyst; then carrying out ring closing reaction under the action of a dehydrating agent to obtain a compound shown as a formula (I);

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

P ₁ selected from: halogen, OH, O, OTf, OTs, OMs;

P ₂ 、P ₃ each independently selected from: none, H, halogen, OH, O, OTf, OTs, OMs;

Sn( ⁿ Bu) ₃ Zn or ZnBr;

is a single or double bond;

R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ x, Y, ring A, ring B, u and t are as defined in claim 1.

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

11. Use of a compound according to any one of claims 1 to 8, 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 10, for the preparation of a medicament for the prophylaxis 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.