WO2014190949A1

WO2014190949A1 - Quadri-fused cyclic anaplastic lymphoma kinase inhibitor

Info

Publication number: WO2014190949A1
Application number: PCT/CN2014/079072
Authority: WO
Inventors: 吴永谦
Original assignee: 山东轩竹医药科技有限公司
Priority date: 2013-06-01
Filing date: 2014-06-03
Publication date: 2014-12-04
Also published as: CN105579459A; CN105579459B

Abstract

Provided are the compounds as shown by formula (I) or the stereoisomers thereof, or the pharmaceutically acceptable salts, esters, or solvates thereof, wherein A₁, A₂, A₃, M, Y, X, R³, R⁵, R⁶, R⁷, Q and n are as defined in the description, the preparation method of these compounds, pharmaceutical preparations and pharmaceutical compositions containing these compounds, and the use of the compounds or the stereoisomers thereof, or the pharmaceutically acceptable salts, esters, or solvates thereof in the preparation of drugs for the treatment and/or prevention of diseases associated with cancers mediated by ALK.

Description

Tetracyclic anaplastic lymphoma kinase inhibitor

Technical field

The present invention relates to the field of medical technology, and particularly relates to a tetracyclic anaplastic lymphoma kinase inhibitor or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, and a method for preparing the same, which comprises the compound Pharmaceutical preparations and pharmaceutical compositions, and the compounds or stereoisomers thereof, or pharmaceutically acceptable salts, esters or solvates thereof, in the manufacture of a medicament for the treatment and/or prevention of ALK-mediated cancer-related diseases application. Background technique

Anaplastic lymphoma kinase (ALK), a member of the receptor acid kinase family, recruits downstream proteins through autophosphorylation to express specific genes and regulate cell metabolism and growth. The anaplastic lymphoma kinase was first discovered in Anaplastic large cell lymphoma (ALCL) and was later found to be highly expressed in non-small cell lung cancer (NSCLC).

ALK's small molecule inhibitors can affect the growth of tumor cells and play an anti-tumor role. However, a large number of clinically proven ALK inhibitors, crizotinib (developed by Pfizer Inc.), are prone to drug resistance. The design and screening of second-generation ALK inhibitors with good efficacy in patients with resistance to Crizotinib has significant clinical significance.

Currently known ALK inhibitors include CH5424802 (Roche), LDK378 (Norartis), and

Therefore, the structure of the compound is modified to find a new compound structure, and efforts are made to improve the rationality of the compound. The nature of the drug, such as increasing the exposure or bioavailability of the compound, to find small molecule inhibitors with high activity on ALK mutations, is of great significance for the clinical treatment of diseases caused by ALK mutations. Summary of the invention

The present invention aims to develop a small molecule inhibitor against ALK, and has invented a tetracyclic anaplastic lymphoma kinase inhibitor which has a good effect on the treatment and/or prevention of ALK-mediated cancer-related diseases. The specific technical solutions are as follows:

A compound represented by the formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof, or

among them,

Selected from C-R ¹ or N;

A _{2 is} selected from 1 ² or

A _{3 is} selected from C-R ⁴ or N, and Ai, A ₂ and A _{3 are} not N at the same time;

R ¹ , R ² and R ⁴ are each independently selected from the group consisting of hydrogen, hydroxy, carboxy, nitro, halogen atom, amino, (C _1-6 alkyl) ₂ amino, cyano, C _1-6 alkyl, C _{1 -6} alkoxy, C _2-6 alkenyl, C _2-6 alkynyl or 3 to 14 membered cycloalkyl;

R ^{3 is} selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl, alicyclic, CL ₆ alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl or a 14-membered cycloalkyl group, the C _1-6 alkyl group, the C _1-6 alkoxy group, the C _2-6 alkenyl group, the C _2-6 alkynyl group and the 3 to 14 membered cycloalkyl group may be independently Optionally substituted by one or more of the following substituents: hydroxy, carboxy, amino, cyano, halo, nitro or 3 to 14 membered heterocyclyl;

M is selected from 0, S or NR ⁸ and R ^{8 is} selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl or C _2-6 alkynyl, said C _{1 -6} alkyl, C _2-6 alkenyl and C _2-6 alkynyl may be independently optionally substituted by C _1-6 alkoxy;

R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, and a hydroxyl group C _1-6

3⁄4^3⁄4, C2-6 women or. 2-6 fast

Or R ⁵ and R ⁶ are bonded to each other to form a 3 to 14 membered heterocyclic group or a 3 to 14 membered cycloalkyl group together with the carbon atom to which they are attached;

Y is selected from N or CR ⁹ ; X is selected from 0, S or NR ⁹ ;

. R ⁹ is selected from hydrogen, CL ₆ alkyl, C ₂ ₆ alkynyl, or 3~8-membered cycloalkyl group;

Q is selected from the following groups:

(1) 3 to 8 membered heterocyclic group,

(2) a 3 to 14 membered cycloalkyl group or a 6 to 14 membered heterocyclic group optionally substituted by one to three identical or different R ^1Q groups, and

(3) a 6 to 12 membered bridged ring group or a 6 to 12 membered spirocyclic group optionally substituted with one to three identical or different R ^1Q groups,

R ^{1Q is} selected from the group consisting of amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, CL ₆ alkylaminocarbonyl, hydroxy CL ₆ Alkyl, hydroxy CL ₆ alkylamino, substituted CL ₆ alkyl, d. ₆ alkylsulfonyl, C alkylsulfonylamino, aminosulfonyl, aminosulfonylamino, alkenyl,

. 2-6 blocks;

R ^{7 is} selected from a 6 to 12 membered bridged ring group, a 6 to 12 membered spirocyclic group, a 3 to 8 membered heterocyclic group or a 6 to 14 membered heterocyclic group which is optionally substituted with a substituent selected from the group consisting of Amino, hydroxy, nitro, alkane, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, 3 to 8 membered heterocyclic or 3 ~8-membered cycloalkyl;

n is selected from 0, 1, 2, 3, 4, 5 or 6,

requirement is:

When n is 0, R ⁷ does not exist.

When 1 ≥ 2, R ⁷ may be the same or different, and

When Q is selected from a 3 to 8 membered heterocyclic group, n cannot be 0, and R ⁷ cannot be selected from a 3 to 8 membered heterocyclic group.

2. A compound of the formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof:

Selected from C-R ¹ or N;

A _{2 is} selected from 1 ² or

R ¹ , R ² and R ⁴ are each independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, nitro, halogen atom, amino group, (C _1-6 alkyl) 2 amino, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl or 3 to 14 membered cycloalkyl ;

R ^{3 is} selected from the group consisting of hydrogen, cyano, hydroxy, amino, halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl or 3 to 14 membered ring The alkyl group, the C _1-6 alkyl group, the C _1-6 alkoxy group, the C _2-6 alkenyl group, the C ₂ alkynyl group and the 3 to 14 membered cycloalkyl group may be independently optionally one or more of the following Substituent substitution: a hydroxyl group, a carboxyl group, an amino group, a cyano group, a halogen atom, a nitro group or a 3 to 14 membered heterocyclic group;

3⁄4^3⁄4, C2-6 women or. 2-6 fast

Y is selected from N or CR ⁹ ;

X is selected from 0, S or NR ⁹ ;

Q is selected from the following groups:

(1) 3 to 8 membered heterocyclic group,

(2) a 6 to 14-membered heterocyclic group optionally substituted by one to three identical or different R ^1Q groups,

. 2-6 fast base;

R ^{7 is} selected from a 6 to 12 membered bridged ring group or a 6 to 12 membered spirocyclic group optionally substituted by a substituent selected from the group consisting of an amino group, a hydroxyl group, a nitro group, a halogen atom, a carboxyl group, and a C _1-6 alkane group. a group, a C _1-6 alkoxy group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a 3 to 8 membered heterocyclic group or a 3 to 8 membered cycloalkyl group;

n is 1.

3. A compound of the formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof:

Selected from C-R ¹ or N;

A _{2 is} selected from 1 ² or

3⁄4^3⁄4, C2-6 women or. 2-6 fast

Y is selected from N or CR ⁹ ;

X is selected from 0, S or NR ⁹ ;

Q is selected from the following groups:

(1) a 6 to 12 membered bridged ring group or a 6 to 12 membered spirocyclic group optionally substituted with one to three identical or different R ^1Q groups,

. 2-6 fast base;

R ^{7 is} selected from a 6 to 12 membered bridged ring group optionally substituted with a substituent, a 6 to 12 membered spirocyclic group or a 3 to 8 membered hetero a cyclic group, the substituent is selected from the group consisting of an amino group, a hydroxyl group, a nitro group, a halogen atom, a carboxyl group, a ^ ₆ alkyl group, an alkoxy group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, and a 3 to 8 membered heterocyclic ring. Base or 3 to 8 membered cycloalkyl;

n is selected from 0, 1, 2, 3, 4, 5 or 6,

requirement is:

When n is 0, R ⁷ does not exist.

When 1 ≥ 2, R ⁷ may be the same or different.

4. A compound according to any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof,

Wherein formula (I) is of formula (II):

among them,

R ¹ , R ² and R ⁴ are each independently selected from hydrogen, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or a 3 to 8 Metacycloalkyl;

R ^{3 is} selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl, alicyclic, CL ₆ alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl or ～8-membered cycloalkyl, the C _1-6 alkyl group, C _1-6 alkoxy group, C _2-6 alkenyl group, C _2-6 alkynyl group and 3 to 8 membered cycloalkyl group may be independently Substituted by one to three substituents: a hydroxyl group, a carboxyl group, an amino group, a cyano group, a halogen atom, a nitro group or a 3 to 8 membered heterocyclic group;

3⁄4^3⁄4, C2-6 women or. 2-6 fast

Or R ⁵ and R ⁶ are bonded to each other to form a 5- to 10-membered heterocyclic group or a 3- to 8-membered cycloalkyl group together with the carbon atom to which they are attached;

Y is selected from N or CR ⁹ ;

X is selected from 0, S or NR ⁹ ;

Q is selected from the following groups: (1) 4 to ⁷ membered heterocyclic group,

(2) a 3 to 8 membered cycloalkyl group or a 6 to 12 membered heterocyclic group optionally substituted by one to three identical or different R ^1Q groups, and

(3) a 7 to 10 membered bridged ring group or a 6 to 12 membered spirocyclic group optionally substituted by one to three identical or different R ^1Q groups,

R ^{1Q is} selected from the group consisting of amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, CL ₆ alkylaminocarbonyl, hydroxy CL ₆ Alkyl, hydroxy CL ₆ alkylamino, substituted CL ₄ alkyl, C _M alkylsulfonyl, C alkylsulfonylamino, aminosulfonyl, aminosulfonylamino, alkenyl,

. 2-6 blocks;

R ^{7 is} selected from a 6 to 10 membered bridged ring group, a 6 to 12 membered spirocyclic group, a 4 to 7 membered heterocyclic group or a 6 to 12 membered heterocyclic group which is optionally substituted with a substituent selected from the group consisting of Amino group, hydroxyl group, halogen atom, ^ ₆ alkyl group,

C 6 3⁄4* base, . 2-6 women's base or. 2-6 fast base;

n is selected from 0, 1, 2 or 3

requirement is:

When n is 0, R ⁷ does not exist.

When 1 ≥ 2, R ⁷ may be the same or different, and

When Q is selected from a 4 to 7 membered heterocyclic group, n cannot be 0, and R ⁷ cannot be selected from a 4 to ⁷ membered heterocyclic group.

5. A compound according to any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof,

among them,

_{ι ι} , A ₂ and A ₃ are each independently selected from CH;

R ^{3 is} selected from hydrogen or cyano;

M is selected from Li;

R ⁵ and R ⁶ are each independently selected from hydrogen or C _1-6 alkyl;

Y is selected from N;

X is selected from S.

6. A compound according to any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof,

among them,

R ¹ , R ² and R ⁴ are each independently selected from hydrogen, a halogen atom, a C _1-6 alkyl group or a 3 to 8 membered cycloalkyl group; and R ^{3 is} selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl Acyl, alkene, CL ₆ alkyl or 3 to 8 membered cycloalkyl;

M is selected from 0, S or NR ⁸ , R ^{8 is} selected from hydrogen, C _1-6 alkyl or C _1-6 alkoxy, and the C _1-6 alkyl may be optionally substituted by ^ ₆ alkoxy ;

R ⁵ and R ⁶ are each independently selected from hydrogen, a halogen atom, a ^ ₆ alkyl group, a ^ ₆ alkoxy group or a hydroxy C _1-6 alkyl group.

Or R ⁵ and R ⁶ are bonded to each other to form a 5- to 6-membered heterocyclic group or a 3- to 8-membered cycloalkyl group together with the carbon atom to which they are attached;

Y is selected from N or CR ⁹ ;

X is selected from 0, S or NR ⁹ ;

Q is selected from the following groups:

(1) 5 to 6 membered heterocyclic group,

(2) a 3 to 8 membered cycloalkyl group or a 6 to 10 membered heterocyclic group optionally substituted by one to three identical or different R ^1Q groups, and

(3) a 7- to 9-membered bridged ring group or a 7 to 11-membered spiro ring group optionally substituted with one to three identical or different R ^1Q groups,

R ^{1Q is} selected from the group consisting of amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylaminocarbonyl, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkylamino, C _M alkyl, methylsulfonyl, methylsulfonylamino, aminosulfonyl, aminosulfonylamino, C _2-6 alkenyl, C _2-6 alkynyl;

R ^{7 is} selected from a ⁷ to 10 membered bridged ring group optionally substituted with a substituent, a 7 to 11 membered spirocyclic group, a 5 to 6 membered heterocyclic group or a 6 to 10 membered heterocyclic group, and the substituent is selected from the group consisting of Amino group, hydroxyl group, halogen atom, ^ ₆ alkyl group,

C 6 3⁄4* base, . 2-6 women's base or. 2-6 fast base,

n is selected from 0, 1, 2 or 3

requirement is:

When n is 0, R ⁷ does not exist.

When 1 ≥ 2, R ⁷ may be the same or different, and

When Q is selected from a 5- to 6-membered heterocyclic group, n cannot be 0, and R ⁷ cannot be selected from a 5- to 6-membered heterocyclic group.

7. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof,

among them,

R ¹ , R ² and R ⁴ are each independently selected from hydrogen, methyl or ethyl; R ^{3 is} selected from the group consisting of hydrogen, cyano, hydroxy, amino, fluorine, chlorine, methyl or ethyl;

M is selected from NR ⁸ and R ^{8 is} selected from hydrogen or CL ₄ alkyl;

R ⁵ and R ⁶ are each independently selected from C _1-4 alkyl;

Y is selected from N or CR ⁹ ;

X is selected from S or NR ⁹ ;

R ^{9 is} selected from the group consisting of hydrogen, methyl, ethyl or n-propyl;

Q is selected from

(1) 5-6 membered heterocyclic group,

(2) a 6 to 10 membered heterocyclic group optionally substituted by one to two identical or different R ^1Q groups, and

(3) a 7- to 9-membered bridged ring group or a 7 to 11-membered spiro ring group optionally substituted with one to two identical or different R ^1Q groups,

R ^{1Q is} selected from amino or CL ₄ alkyl;

R ^{7 is} selected from the group consisting of 7 to 9 membered bridged ring groups, 7 to 11 membered spirocyclic groups or 5 to 6 membered heterocyclic groups.

n is selected from 0 or 1

requirement is:

When n is 0, R ⁷ does not exist, and

8. The compound of any one of the preceding claims 1-7, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof,

among them,

Q is selected from a 4 to 7 membered heterocyclic group, preferably having 1 or 2 nitrogen atoms as a ring atom, more preferably saturated;

R ^{7 is} selected from ^{7 to} 8 membered bridged ring groups, preferably containing 1 or 2 ring atoms selected from oxygen and nitrogen, more preferably saturated;

η is selected from 1.

9. The compound of the above aspect 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof,

among them,

:

n selected from 1

10. The compound of any one of the preceding claims 1-7, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof,

among them,

Q is selected from optionally substituted with one to two identical or different substituents R ^1Q of 7~8 membered bridged ring group, preferably containing 1 or 2 nitrogen atoms as ring atoms, more preferably a saturated,

R ^{1Q is} selected from amino or CL ₆ alkyl;

R ^{7 is} selected from a 4 to ⁷ membered heterocyclic group, preferably contains 1 or 2 ring atoms selected from oxygen and nitrogen, more preferably saturated;

n is selected from 0 or 1, and when n is 0, R ⁷ is absent.

The compound according to the above aspect 10 or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof,

among them,

n is selected from 0 or 1, and when n is 0, R ⁷ is absent.

12. The compound of any one of the preceding claims 1-11, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof,

Wherein at least one of Q and R ⁷ is a bridged ring group, the bridged ring group containing at least one nitrogen atom as a ring member, and the bridge is bridged by two ring atoms (such as carbon atoms) adjacent to the nitrogen atom. forming atoms, Q is selected from, for example, "optionally substituted alkyl CL ₄ - ^ - one,

⁵ Vy_/ i" and

s ^ \TJ R ⁷ does not exist or is selected from

The compound of any one of the preceding claims 1-7, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof,

among them,

Q is selected from 7 to 11 membered spirocyclic groups optionally substituted by one to two identical or different R ^1Q groups, preferably a spirocyclic group having 1 to 3 hetero atoms, more preferably the spiro group The cyclic group contains 7 to 11 ring atoms, wherein 1 or 2 ring atoms are nitrogen atoms, the remaining ring atoms are carbon atoms, and still more preferably, the spiro group is a saturated group,

R ^{1Q is} selected from amino or CL ₄ alkyl;

R ⁷ does not exist.

14. The compound of any one of the preceding claims 1-7, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof,

among them,

Q is selected from 6 to 10 membered heterocyclic groups optionally substituted by one to two identical or different R ^1Q , and the heterocyclic group is preferably a heterocyclic group having 1 to 3 hetero atoms, more preferably The heterocyclic group contains 6 to 10 ring atoms, wherein 1 to 3 ring atoms are hetero atoms selected from nitrogen and oxygen, and the remaining ring atoms are carbon atoms, still more preferably, the heterocyclic group Is a saturated group,

R ^{1Q is} selected from amino or CL ₄ alkyl;

R ⁷ does not exist.

15. A compound or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof,

16. A compound or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, selected from the group consisting of:

18. A pharmaceutical composition comprising the compound of any one of the preceding claims 1-17, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, and one or more A pharmaceutically acceptable carrier and/or diluent.

19. The pharmaceutical composition according to claim 18, characterized in that it further comprises one or more antitumor agents and immunosuppressive agents, said antitumor agent and immunosuppressive agent being selected from the group consisting of methotrexate and card Training Hebin, gemcitabine, deoxyfluorouridine, pemetrexed disodium, pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib, hersay Tet, bevacizumab, rituximab, trastuzumab, paclitaxel, vinorelbine, docetaxel, doxorubicin, hydroxycamptothecin, mitomycin, epirubicin, Pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, triclinin, flutamide, leuprolide, anastrozole, ifosfamide, busulfan, Cyclophosphamide, carmustine, nimustine, semustine, nitrogen mustard, melphalan, cyclamate, carboplatin, cisplatin, oxaliplatin, platinic, topotecan, camptothecin , topotecan, everolimus, sirolimus, dexamethasone, 6-mercaptopurine, 6-gram guanine, gram azole, bacteriocin D, daunorubicin, doxorubicin, Mitoxantrone, bleomycin, pucamycin or aminoglutethimide.

The compound according to any one of claims 1 to 17, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, for use in the treatment and/or prevention of ALK-mediated cancer The use of a drug related to a disease selected from the group consisting of a brain tumor, a non-small cell lung cancer, a squamous cell carcinoma, a bladder cancer, a stomach cancer, an ovarian cancer, a peritoneal cancer, a pancreatic cancer, a breast cancer, a head and neck cancer , cervical cancer, endometrial cancer, rectal cancer, liver cancer, hepatoblastoma, papillary renal cell tumor, head and neck squamous cell tumor, nephroblastoma, renal cancer, esophageal adenocarcinoma, esophageal squamous cell Cancer, glioma, prostate cancer, thyroid cancer, female genital tract cancer, carcinoma in situ, lymphoma, neuroblastoma, neurofibromatosis, bone cancer, skin cancer, colon cancer, testicular cancer, small cell lung cancer , gastrointestinal stromal tumors, prostate tumors, mast cell tumors, multiple myeloma or melanoma. A method of preparing a compound of the following formula (Γ),

Halogen and! ! ^, ! ^ in the presence of a base in a solvent

React under heating

or H-(R ⁷ ) _{n is present} in the solvent in the presence of indium trichloride

Reacting at room temperature, then adding a reducing agent,

Wherein A ₂ , A ₃ , M, Y, X, R ³ , R ⁵ , R ⁶ , R ⁷ , Q and n are as defined in the technical scheme 1-17, and Q' is as in the technical scheme 1-17 The defined Q or Q, R ⁷ ' as defined in Technical Schemes 1-17 protected by a protecting group (PG) is protected by R ⁷ or protected group (PG ) as defined in Technical Schemes 1-17 R ⁷ as defined in Technical Schemes 1-17. Detailed description of the invention

I, definition

The "prime atom" as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.

The "^ ₆ alkyl group" of the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms, and includes, for example, "C _1-4 alkyl group", "C _1-3 alkyl group" and the like. Such as methyl, ethyl, propyl, butyl, pentyl, hexyl and the like. The alkyl group "the present invention" refers to a specific example in which the number of carbon atoms is 1-4 in the above "C _1-6 alkyl group".

The "C _2-6 alkenyl group" of the present invention means a linear or branched or cyclic alkenyl group having 2 to 6 carbon atoms containing at least one of the bonds, including, for example, "C _2-4 alkenyl group". ", "C _2-3 alkenyl", "C _3-6 cycloalkenyl", etc., such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl And hexadienyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl and the like. The joy keys can optionally be cis and trans.

The "^ ₆ alkynyl group" of the present invention means a linear or branched alkynyl group having 2 to 6 carbon atoms containing at least one triple bond, and includes, for example, "C _2-6 alkynyl group", "C" _2-4 alkynyl", "C _2-3 alkynyl" and the like, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

The "C _1-6 alkylthio group", "C _1-6 alkoxy group", "C _1-6 alkylaminocarbonyl group", "C _1-6 alkylsulfonyl group", " ₆ " of the present invention The "alkylsulfonylamino group" means a group in which the above " ₆ alkyl group" is bonded to another structure through a thio group, an oxy group, an aminocarbonyl group, a sulfonyl group or a sulfonylamino group, respectively. The term "C _M alkylsulfonyl" and "C _1-4 alkylsulfonylamino" refer to a group in which the above " ₄ alkyl group" is bonded to another structure through a sulfonyl group and a sulfonylamino group, respectively.

The "hydroxy ₆ alkyl group" and "halogenated ₆ alkyl group" of the present invention respectively mean that a hydroxyl group or a halogen atom replaces one or more hydrogen atoms on the above "d. ₆ alkyl group", and passes through an alkyl group and other structures. Connected base Mission. The terms "hydroxyl. ₁₄ alkyl" and "halo < ₁₄ alkyl" mean, respectively, a hydroxy group, a halogen atom substituted for one or more hydrogen atoms on the above "C _M alkyl group", and which are bonded to other structures through an alkyl group. a group, wherein "halogen atom" is as described above.

The "hydroxy c _1-6 alkoxy group", "amino c _1-6 alkoxy group", "carbonyl c _1-6 alkoxy group" of the present invention respectively mean a hydroxyl group, an amino group or a carbonyl group to replace the above "^ ₆ alkane" One or more hydrogen atoms on the oxy group, and a group attached to the other structure through an alkoxy group.

The "hydroxy C _1-6 alkylamino group" as used in the present invention means a group in which an atom which can be substituted by any one of the amino groups is substituted by the above-mentioned "hydroxyl ₆ alkyl group" and which is bonded to another structure through an amino group.

The present invention "(^ ₆ alkyl) ₂ amino" and _"6 alkylamino" refer to an amino group and any two atoms of a substituent can be substituted with the aforementioned ".6 alkyl group", and by A group in which an amino group is bonded to other structures.

The "3- to 14-membered cycloalkyl group" as used in the present invention means that the alkane moiety of 3 to 14 carbon atoms is removed by a hydrogen atom-derived cyclic alkyl group, including a 3- to 8-membered cycloalkyl group (monocyclic ring), 6 -14 membered cyclocycloalkyl (bicyclic or polycyclic).

The 3- to 8-membered cycloalkyl group means that the alkane moiety of 3 to 8 carbon atoms is removed by a hydrogen atom-derived cyclic alkyl group, and examples thereof include, but are not limited to, cyclopropyl group, cyclobutylalkyl group, cyclopentyl group. , cyclohexane, cycloheptyl, cyclooctyl, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentanyl , dimethylcyclopentyl, methylcyclohexane, dimethylcyclohexane, and the like.

The 6- to 14-membered cyclocycloalkyl group refers to a 6- to 14-membered cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms, and examples thereof include, but are not limited to: Bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexane, bicyclo[3.2.0]heptyl, bicyclo[4.2.0 Octyl, octahydrocyclopentadienyl, octahydro-1/7-fluorenyl, decahydronaphthyl, tetradecafluorophenanyl, re-cyclo[3.1.0]hex-2-enyl, bicyclo [4.1.0]Hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, bicyclo[4.2.0]oct-3-enyl, 1,2,3,3-tetrahydrocyclo Pentadienyl, 2,3,3,4,7,7-hexahydro-1/7-fluorenyl, 1,2,3,4,4,5,6,8-octahydronaphthyl, 1, 2,4,5,6,8-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9,10-decahydrophenanyl and the like.

The "hetero atom" as used in the present invention means Ν, 0, C(0), S, SO and/or S0 ₂ and the like, preferably N, 0, S, more preferably N, 0.

The "3- to 14-membered heterocyclic group" of the present invention means a 3- to 14-membered cyclic group containing one to more hetero atoms, including a 3 to 8 membered heterocyclic group (monocyclic) and 6 to 14 members. Heterocyclic group (bicyclic or polycyclic). Heterocyclyl groups can be saturated, partially unsaturated or fully unsaturated.

a 3 to 8 membered heterocyclic group, which means having 3 to 8 ring atoms (having at least one hetero atom) Monocyclic heterocyclic group. Specific examples include, but are not limited to, 2,5-dihydrothiophenyl, 4,5-dihydropyrazolyl, 3,4-dihydro-2/7-pyranyl, 5,6-dihydro-4/7 -1,3-oxazinyl, aziridine, azetidinyl, s-heterocyclobutane, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, 1,4-dioxanyl group, 1,3-dioxanyl group, 1,3-dithiacyclohexane group, morpholinyl group, piperazinyl group and the like.

The 4- to 7-membered heterocyclic group of the present invention and the "5-6-membered heterocyclic group" refer to a specific example in which the number of ring atoms in the above "3 to 8 membered heterocyclic group" is 4 to 7 members and 5 to 6 members.

6-14-membered heterocyclic group means a fused ring containing 6 to 14 ring atoms (having at least one hetero atom) joined by two or more ring structures sharing two adjacent atoms with each other. a structure, such as a benzo 3 to 8 to 8 membered heterocyclic group and a 3 to 8 membered heterocyclic group

An isocyclic structure replaces a group formed by any substitutable hydrogen atom. The "6- to 12-membered heterocyclic group" and the "6- to 10-membered heterocyclic group" of the present invention mean that the above-mentioned "6- to 14-membered heterocyclic group" has a ring number of 6 to 12, 6 to 10 Specific examples of yuan.

The "5- to 10-membered heterocyclic group" as used in the present invention refers to a specific example in which the number of ring atoms in the above "3 to 14-membered heterocyclic group" is 5 to 10 members, and for example, a 5- to 10-membered heterocyclic group includes 5 to 6 members. Heterocyclyl (monocyclic) and 6 to 10 membered heterocyclic (heterocyclic or polycyclic).

The "6- to 12-membered bridged ring group" as used in the present invention means that any two rings share two non-adjacent ring atoms and have 6 to 12 ring atoms (including carbon atoms and optional hetero atoms). structure. The bridged ring group can be saturated, partially unsaturated or completely unsaturated. These include, for example, "6 to 10 yuan bridge carbon ring group", "6 to 8 yuan bridge carbon ring group", "7-10 yuan bridge carbon ring group", "7 to 9 yuan bridge carbon ring group", "7~ 8-membered bridge carbocyclic group, "8-membered bridged carbocyclic group", "6- to 12-membered bridged heterocyclic group", "6- to 10-membered bridged heterocyclic group", "6- to 8-membered bridged heterocyclic group", "7 to 10 membered bridged heterocyclic group", "7 to 9 membered bridged heterocyclic group", "7 to 8 membered bridged heterocyclic group" and "8-membered bridged heterocyclic group" and the like. Examples include, but are not limited to:

The "6 12-membered spirocyclic group" as used in the present invention means a structure having at least two rings sharing a ring atom and having 6 to 12 ring atoms including a carbon atom and optionally a hetero atom. The spiro group can be saturated, partially unsaturated or completely unsaturated. These include, for example, "7 12-membered spirocarbocyclyl", "7 11-membered spirocarbocyclyl", "7-10-membered spirocarbocyclyl", "79-membered spirocarbocyclyl", and "7-eight-membered spiro carbon" "Cycloalkyl", "8-membered spirocarbocyclyl", "6 12-membered spiroheterocyclyl", "7 12-membered spiroheterocyclyl", "7-11-membered spiroheterocyclyl", "7-10-membered snail" Heterocyclic group", "7 9-membered spiroheterocyclyl", "7-membered spiroheterocyclyl" and "8-membered spiroheterocyclyl"

II, compound

The present invention provides a compound represented by the formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof:

(I)

Selected from CR ¹ or N;

A _{2 is} selected from CR ² or N;

A _{3 is} selected from CR ⁴ or N, and Ai, A ₂ and A _{3 are} not N at the same time;

3⁄4^3⁄4, C2-6 women or. 2-6 fast

Y is selected from N or CR ⁹ ;

X is selected from 0, S or NR ⁹ ;

Q is selected from the following groups:

(1) a 3-8 membered heterocyclic group (or a 3 to 8 membered monocyclic heterocyclic group),

(3) a 6 to 12 membered bridged ring group or a 6 to 12 membered spirocyclic group optionally substituted by one to three identical or different R ^1Q groups,

. 2-6 blocks;

R ^{7 is} selected from a 6 to 12 membered bridged ring group, a 6 to 12 membered spirocyclic group, a 3 to 8 membered heterocyclic group or a 6 to 14 membered heterocyclic group which is optionally substituted with a substituent selected from the group consisting of Amino, hydroxy, nitro, alkane, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, 3 to 8 membered heterocyclic or 3 ~8 yuan naphthenic Base

n is selected from 0, 1, 2, 3, 4, 5 or 6,

requirement is:

When n is 0, R ⁷ does not exist.

When 1 ≥ 2, R ⁷ may be the same or different, and

When Q is selected from a 3 to 8 membered heterocyclic group, n cannot be 0, and R ⁷ cannot be selected from a 3 to 8 membered heterocyclic group. In one embodiment, ₁ is 1 ¹ .

In one embodiment, A ₂ is CR ² .

In one embodiment, A ₃ is CR ⁴ .

In one embodiment, R ¹ , R ² and R ⁴ are each independently selected from the group consisting of hydrogen, halogen atom, ^ ₆ alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkyne Base or 3 to 8 membered cycloalkyl. In a preferred embodiment, R ¹ , R ² and R ⁴ are each independently selected from hydrogen, a halogen atom, a C _1-6 alkyl group or a 3 to 8 membered cycloalkyl group. In a preferred embodiment, RR ² and R ⁴ are each independently selected from hydrogen, methyl or ethyl.

In one embodiment, R ^{3 is} selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl , C _2-6 alkynyl or 3 to 8 membered cycloalkyl, said C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl and 3~ The 8-membered cycloalkyl group may be independently optionally substituted with one to three of the following substituents: a hydroxyl group, a carboxyl group, an amino group, a cyano group, a sulfonic acid atom, a nitro group or a 3 to 8 membered heterocyclic group. In a preferred embodiment, R ^{3 is} selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl, halogen atom, ^ ₆ alkyl or 3 to 8 membered cycloalkyl. In a preferred embodiment, R ^{3 is} selected from the group consisting of hydrogen, cyano, hydroxy, amino, fluoro, chloro, methyl or ethyl.

In one embodiment, M is selected from 0, S or NR ⁸ and R ^{8 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl or C _2-6 alkyne The C _1-6 alkyl group, the C _2-6 alkenyl group and the C _2-6 alkynyl group may be independently optionally substituted by a ₆ alkoxy group. In a preferred embodiment, M is selected from 0, S or NR ⁸ , R ^{8 is} selected from hydrogen, C alkyl or C alkoxy, and said C alkyl group may be optionally substituted by C alkoxy. In a preferred embodiment, M is selected from NR ⁸ and R ^{8 is} selected from hydrogen or C _1-4 alkyl.

In one embodiment, R ⁵ and R ⁶ are each independently selected from hydrogen, a halogen atom, ^ ₆ alkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, C _2-6 alkenyl or The C _2-6 alkynyl group, or R ⁵ and R ⁶ are bonded to each other to form a 5- to 10-membered heterocyclic group or a 3- to 8-membered cycloalkyl group together with the carbon atom to which they are attached. In a preferred embodiment, R ⁵ and R ⁶ are each independently selected from hydrogen, a halogen atom, a ^ ₆ alkyl group, a ^ ₆ alkoxy group or a hydroxy group . 6 alkyl group, or R ⁵ and R ⁶ are bonded to each other, Together with the carbon atom to which they are attached, a 5- to 6-membered heterocyclic group or a 3- to 8-membered cycloalkyl group is formed. In a preferred embodiment, R ⁵ and R ⁶ independently independently select a Ci_4 3⁄4* group.

In one embodiment, the oxime is selected from ruthenium or CR ⁹ , X is selected from 0, S or NR ⁹ ; R ^{9 is} selected from hydrogen, C _1-6 alkyl, CM alkynyl or 3 to 8 membered cycloalkyl. In one preferred embodiment, Y is selected from N or CR ^9, X is selected from S or NR ^{^9,} R ⁹ is selected from hydrogen, methyl, ethyl or n-propyl.

In one embodiment, Q is selected from the group consisting of: (1) a 4 to 7 membered heterocyclic group (or a 4 to 7 membered monocyclic heterocyclic group), (2) optionally being one to three identical or different R ^1Q substituted 3 to 8 membered cycloalkyl or 6 to 12 membered heterocyclic group, and (3) optionally 7 to 10 membered bridged or substituted by 1 to 3 identical or different R ^1Q A spiro ring group; R ^{1Q is} selected from the group consisting of amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, ^ ₆ alkylamino Carbonyl, hydroxy- ₆ alkyl, hydroxy- ₆ alkylamino, halogenated CL ₄ alkyl, CL ₄ alkylsulfonyl, CL ₄ alkylsulfonylamino, aminosulfonyl, aminosulfonylamino, C _2-6 Alkenyl, C _2-6 alkynyl. In a preferred embodiment, Q is selected from the group consisting of: (1) a 5- to 6-membered heterocyclic group (or a 5- to 6-membered monocyclic heterocyclic group), (2) optionally being one to three identical Or a different R ^1Q substituted 3 to 8 membered cycloalkyl or 6 to 10 membered heterocyclic group, and ( 3 ) a 7 to 9 membered bridged ring group optionally substituted by one to three identical or different R ^1Q or 7 to 11 membered spiro group, R ^{1Q is} selected from amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _{1 -6} alkylaminocarbonyl group, a hydroxyl CL ₆ alkyl, hydroxy ^ ₆ alkylamino, C _M substituting group, methylsulfonyl group, methylsulfonyl group, sulfamoyl group, sulfamoyl group, C _2-6 Alkenyl, C _2-6 alkynyl. In a preferred embodiment, Q is selected from the group consisting of (1) 5 to 6 membered heterocyclic groups (or 5 to 6 membered monocyclic heterocyclic groups), (2) optionally being one to two identical or different R ^{a 1Q-} substituted 6- to 10-membered heterocyclic group, and (3) a 7- to 9-membered bridged ring group or a 7- to 11-membered spirocyclic group optionally substituted by one or two identical or different R ^1Q , and R ^{1Q is} selected from the group consisting of Amino or C _M alkyl. In a preferred embodiment, Q is selected from a 4 to 7 membered heterocyclic group (or a 4 to 7 membered monocyclic heterocyclic group), preferably having 1 or 2 nitrogen atoms as a ring atom, more preferably _ν selected. The ground is saturated. In a preferred

Y / ~ \ , , , + ^NN — In the scheme, Q is selected from one to two

The same or different R ^{1 (J} substituted 7 to 8 membered bridged ring group, preferably having 1 or 2 nitrogen atoms as a ring atom, more preferably saturated, wherein R ^{1Q is} selected from an amino group or a ₆ alkyl group .In a

Wherein Q is selected from a 7 to 11-membered spiro group optionally substituted by one to two identical or different R ^1Q , and the spiro group is preferably a spiro group having 1 to 3 hetero atoms, more preferably The spiro group contains 7 to 11 ring atoms, wherein 1 or 2 ring atoms are nitrogen atoms, the remaining ring atoms are carbon atoms, and still more preferably, The spiro group is a saturated group wherein R ^{1Q is} selected from an amino group or a C _M alkyl group. In a preferred embodiment, Q is selected from 6 to 10 membered heterocyclyl optionally substituted with one to two identical or different R ^1Q groups, preferably having from 1 to 3 heteroatoms And a heterocyclic group, more preferably the heterocyclic group contains 6 to 10 ring atoms, wherein 1 to 3 ring atoms are hetero atoms selected from nitrogen and oxygen, and the remaining ring atoms are carbon atoms, and still more Preferably, the heterocyclic group is a saturated group, wherein R ^{1Q is} selected from an amino group or an alkyl group. In a preferred embodiment, 10

Q is selected from one to two identical or different

Ci_4 3⁄4*^- o

In one embodiment, R ^{7 is} selected from a 6 to 10 membered bridged ring group optionally substituted with a substituent, a 6 to 12 membered spirocyclic group, a 4 to 7 membered heterocyclic group or a 6 to 12 membered heterocyclic group. The substituent is selected from the group consisting of an amino group, a hydroxyl group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _2-6 alkenyl group or a C _2-6 alkynyl group. In a preferred embodiment, R ^{7 is} selected from the group consisting of a ⁷ to 10 membered bridged ring group optionally substituted with a substituent, a 7 to 11 membered spirocyclic group, a 5 to 6 membered heterocyclic group or a 6 to 10 membered heterocyclic group. a ring group, the substituent being selected from the group consisting of an amino group, a hydroxyl group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _2-6 alkenyl group or a C _2-6 alkynyl group. In a preferred embodiment, R ^{7 is} selected from the group consisting of 7 to 9 membered bridged ring groups, 7 to 11 membered spirocyclic groups or 5 to 6 membered heterocyclic groups. In a preferred embodiment, R ^{7 is} selected from the group consisting of ^{7 to} 8 membered bridged ring groups, preferably containing 1 or 2 selected from the group, more preferably

~7

The heterocyclic group preferably contains 1 or 2 ring atoms selected from oxygen and nitrogen, more preferably saturated.

In one embodiment, n is selected from 0, 1, 2 or 3. In a preferred embodiment, n Selected from 0 or 1. In a preferred embodiment, n is selected from zero. In a preferred embodiment, n is selected from 1.

In one embodiment, Α ₂ and Α ₃ are each independently selected from CH; R ^{3 is} selected from hydrogen or cyano; Μ is selected from NH; and R ⁵ and R ⁶ are each independently selected from hydrogen or C _1-6 Alkyl; Y is selected from N; X is selected from S.

In one embodiment, at least one of Q and R ⁷ is a bridged ring group containing at least one nitrogen atom as a ring member, the bridge passing through two ring atoms adjacent to the nitrogen atom (eg, carbon atom) is formed as a bridgehead atom, Q is selected from, for example, "optionally substituted C _M alkyl † N ^^ H" and ^N fT -, R ⁷ is absent or is selected from ^ "and a + N ^ yo. In one embodiment, Q is a bridged ring group containing at least one nitrogen atom as a ring member, and the bridge is formed as a bridgehead atom by two rings (such as carbon atoms) adjacent to the nitrogen atom, for example Q is selected from "optionally (^. ₄ alkyl substituted) and tenth Ν 1-.

In one embodiment, R ⁷ is a bridged ring group containing at least one nitrogen atom as two adjacent ring atoms (eg, carbon atoms) as a bridgehead

The present invention also includes any one of the embodiments obtained by combining the above embodiments and two or more of the above preferred embodiments.

The pharmaceutically acceptable salt of any one of the compounds of the formula (I) of the present invention means a salt prepared from a pharmaceutically acceptable, non-toxic base or acid, including an organic acid salt, a mineral acid salt, an organic alkali salt. , inorganic alkali salt. Organic acid salts include formic acid, acetic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, fumaric acid, gluconic acid, glutamic acid , salts of isethionate, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, and the like. The inorganic acid salt includes a salt of hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid or the like.

The organic base salts include primary, secondary and tertiary amines, and the substituted amines include naturally occurring substituted amines, cyclic amines and alkali ion exchange resins selected from the group consisting of betaines, caffeine, choline, N,N,-dibenzylethylene. Amine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, Haibamin, isopropylamine, methyl glucosamine, morpholine, piperazine, piperidine, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. salt. Natural amino acid salts such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyguanidine Salts of acid, histidine, ornithine, lysine, arginine, serine, and the like. Inorganic alkali salts include ammonium and 4 liters, sodium, potassium, Salts of calcium, magnesium, zinc, strontium, aluminum, iron, ketone, ferrous, manganese, divalent manganese, and the like.

The present invention claims that the "stereoisomer" of the compound of formula (I) refers to all stereoisomers, including enantiomers, which are produced when a compound of formula (I) has a chiral center, a bond or the like. Diastereomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of the invention.

The chromatographic method (such as high pressure liquid phase preparation, supercritical fluid chromatography) which is obtained by synthesizing any of the compounds represented by the formula (I) of the present invention as a racemate. Chiral fillers include, but are not limited to:

Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.

The "ester" of the compound of the formula (I) of the present invention includes an ester which can be formed by esterification reaction with an alcohol when a compound of the formula (I) is present, and an organic acid or an inorganic group when the compound of the formula (I) has a hydroxyl group. An ester formed by an esterification reaction of an acid or an organic acid salt. The ester can be hydrolyzed to form the corresponding acid or alcohol in the presence of an acid or a base.

The compound represented by the formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof may be in the form of a "solvate", and the solvent may be water, methanol, ethanol or the like. For example, the hygroscopicity of the solvate product proceeds gradually.

III. Composition

The present invention provides a pharmaceutical composition comprising a compound of the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, together with one or more pharmaceutically acceptable carriers and/or diluents .

The present invention further claims any of the compounds of the above formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, and one or more pharmaceutically acceptable carriers and/or The pharmaceutical composition of the diluent or diluent can be formulated into any of the pharmaceutically acceptable dosage forms. It is administered to a patient in need of such treatment by oral, parenteral, rectal or pulmonary administration. For oral administration, it can be prepared into conventional solid preparations such as tablets, capsules, pills, granules, etc.; or can be prepared into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. . When the oral preparation is prepared, a suitable filler, a binder, a disintegrant, a lubricant or the like may be added. For parenteral administration, it can be prepared as an injection, including injection, sterile powder for injection and concentrated solution for injection. When the injection is prepared, it can be produced by a conventional method in the prior art pharmaceutical field, and when the injection is formulated, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug. When used for rectal administration, it can be made into a suppository or the like. For pulmonary administration, it can be made into an inhalant or a spray.

The invention also provides a pharmaceutical composition comprising a compound of the invention or a stereoisomer thereof Or a pharmaceutically acceptable salt, ester or solvate thereof, one or more pharmaceutically acceptable carriers and/or diluents, and one or more anti-tumor agents and immunosuppressive agents. The antitumor agent and immunosuppressive agent are selected from the group consisting of methotrexate, capecitabine, gemcitabine, deoxyfluorouridine, pemetrexed disodium, paclitaxil, imatinib, erlotidine Nipa, lapatinib, gefitinib, vandetanib, Herceptin, bevacizumab, rituximab, trastuzumab, paclitaxel, vinorelbine, docetaxel, multiple Spirulina, hydroxycamptothecin, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, lysine, flutamide , leuprolide, anastrozole, ifosfamide, busulfan, cyclophosphamide, carmustine, nimustine, semustine, nitrogen mustard, melphalan, cocoaine, carboplatin, Cisplatin, oxaliplatin, ruthenium platinum, topotecan, camptothecin, topotecan, everolimus, sirolimus, dexamethasone, 6-mercaptopurine, 6-thioguanine, Azathioprine, bacteriocin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, pucamycin or aminoglutethimide.

IV, preparation method

Method of compound,

And H-Q'-(R ⁷ ') _n in a solvent (eg N-methylpyrazine)

The reaction in the presence of a base (e.g., triethylamine) under heating (e.g., about 100-120 ° C) (e.g., at least 30 minutes, such as about 1-2 hours);

Or

And H-(R ⁷ ) _n in a solvent (eg Ν, Ν-dimethyl 甲

The amide) is reacted at room temperature (eg, 10-30 C) in the presence of indium trichloride (eg, at least 30 minutes, such as about 16 hours), followed by the addition of a reducing agent (eg, sodium cyanoborohydride) (eg, at least 30 Minutes, such as about 2 hours),

Wherein Ai, A ₂ , A ₃ , M, Y, X, R ³ , R ⁵ , R ⁶ , R ⁷ , Q and n are as defined above, and Q' is a Q or a protected group as defined above ( PG) protected hereinbefore defined Q, R ⁷ 'R is as hereinbefore defined hereinbefore ⁷ or a protected group (PG) as defined protected R ^7.

The protecting group (PG) is a commonly used protecting group in the field of organic synthesis, including but not limited to: -Bn (benzyl), -PMB (p-methoxybenzyl), -Tos (p-toluenesulfonyl), -Fmoc (fluorenylmethoxycarbonyl), -Ac (acetyl), -SEM (2-(trimethylsilyl)ethoxymethyl), -Pht (phthaloyl) and -Alloc (allyloxy) Carbonyl).

Further, the preparation method of the present invention further comprises the step of deprotecting the protected Q and/or protected R ⁷ , and optionally alkylating (eg, methylating) the deprotected H atom. step. The next method, the reaction equation is as follows:

Preparation method 1:

Intermediate 7 Compound of formula (I)

Step 1 Preparation of intermediate 1

The raw material 1 is dissolved in a solvent (for example, glacial acetic acid), and a 40% hydrobromic acid solution is added thereto. Under ice water bath, a glacial acetic acid solution in which an appropriate amount of bromine is dissolved is added dropwise, and the mixture is stirred until the raw material is consumed, and quenched by adding ice water. The organic solvent is extracted by an organic solvent (for example, ethyl acetate), and the combined organic phase is separated and purified by a suitable method (for example, silica gel column chromatography).

Step 2 Preparation of intermediate 2

The intermediate 1 and the starting material 2 are dissolved in a suitable solvent (e.g., tetrahydrofuran), and the mixture is heated to reflux until the reaction is completed, the solvent is removed, and the intermediate 2 is obtained by an appropriate method.

Step 3 Preparation of Intermediate 3 The intermediate 2 and the copper bromide are dissolved in an organic solvent (for example, acetonitrile), and the t-butyl nitrite is added dropwise in an ice water bath. After completion, the temperature is raised to room temperature, stirred (for example, 2 h), and the solvent is removed. Intermediate 3 was isolated.

Step 4 Preparation of intermediate 4

The intermediate 3, the starting material 3 or its hydrochloride (e.g., its hydrochloride) is dissolved in a suitable solvent (e.g., trifluoroacetic acid, acetic acid), heated to completion, cooled, concentrated, and isolated to afford intermediate 4 as appropriate.

Step 5 Preparation of intermediate 5

The intermediate 4 is placed in a suitable solvent, and an appropriate amount of an oxidizing agent (for example, DDQ (2,3-dichloro-5,6-dicyanio-p-benzoquinone) and methyl dichromate) is added, and the reaction is completed at room temperature, and a saturated aqueous solution of sodium hydrogencarbonate is added. It is quenched, extracted with an organic solvent (e.g., dichloromethane), and the organic phase is combined, and Intermediate 5 is isolated by an appropriate method.

Step 6 Preparation of intermediate 6

The intermediate 5 and the starting material 4 are dissolved in a suitable solvent (e.g., acetonitrile), and a base (e.g., methyl carbonate) is added. The reaction is completed by heating, the solid is filtered, and the filtrate is concentrated, and the intermediate 6 is isolated by an appropriate method.

Step 7 Preparation of intermediate 7

The intermediate 6 is dissolved in a suitable solvent (dimethyl sulfoxide and triethylamine), and a suitable oxidizing agent (for example, sulfur trioxide pyridine) is added thereto, and the mixture is stirred at room temperature until the reaction is completed, and the reaction liquid is concentrated, and the intermediate 7 is isolated by an appropriate method. .

Alternatively, the intermediate 6 is dissolved in a suitable solvent (dichloromethane), and a suitable oxidizing agent (for example, Dess-Martin reagent) is added thereto, and the mixture is stirred at room temperature until the reaction is completed, and the reaction is quenched (for example, with water), and the intermediate 7 is isolated by an appropriate method. .

Alternatively, the intermediate 5 and the starting material 4' are dissolved in a solvent (for example, N-methylpyrrolidone), a base (for example, triethylamine) is added, heated (for example, to 120 ° C), and the reaction is stirred (for example, 2 hours), and cooled ( For example, to room temperature, the reaction solution is poured into a solvent (for example, water), stirred (for example, for half an hour), filtered, and dried to give Intermediate 7.

Step 8 Preparation of the compound of the formula (I) of the present invention

Dissolve intermediate 7 and starting material 5 in a suitable solvent (such as N, N-dimethylformamide), add indium trichloride, stir at room temperature overnight, then add a reducing agent (such as sodium cyanoborohydride), complete the reaction, add water The mixture is quenched, extracted with an organic solvent (e.g., ethyl acetate), and the organic phase is combined and purified by an appropriate method to obtain the compound of the formula (I) of the present invention.

Preparation method 2:

Compound of formula (I)

Step 1 Preparation of intermediate 1

Step 2 Preparation of intermediate 2

Step 3 Preparation of intermediate 3

The intermediate 2 and the copper bromide are dissolved in an organic solvent (for example, acetonitrile), and the t-butyl nitrite is added dropwise in an ice water bath. After completion, the temperature is raised to room temperature, stirred (for example, 2 h), and the solvent is removed. Intermediate 3 was isolated.

Step 4 Preparation of intermediate 5

Intermediate 3, intermediate 4 or its hydrochloride (such as its hydrochloride) is dissolved in a suitable solvent (such as trifluoroacetic acid, acetic acid), heated to completion, cooled, concentrated, and separated by an appropriate method. Step 5 Preparation of Intermediate 6

The intermediate 5 is placed in a suitable solvent, and an appropriate amount of an oxidizing agent (for example, DDQ (2,3-dichloro-5,6-dicyanio-p-benzoquinone) and potassium dichromate) is added, and the reaction is completed at room temperature, and a saturated aqueous solution of sodium hydrogencarbonate is added. It is quenched, extracted with an organic solvent (e.g., dichloromethane), and the organic phase is combined, and Intermediate 6 is isolated by an appropriate method. Step 6 Preparation of the compound of the formula (I) of the present invention

Dissolve intermediate 6 and intermediate 7 in a suitable solvent (eg N-methylpyrrolidone), add a suitable base (eg triethylamine), heat (eg 120 ° C), stir the reaction (eg 2 hours), cool to room temperature The mixture of water is quenched, suction filtered, and the filter cake is isolated by a suitable method to obtain the compound of the formula (I) of the present invention.

In the reaction equation, AA ₂ , A ₃ , M, Y, X, R ³ , R ⁵ , R ⁶ , Q, R ⁷ and n are as defined above.

V. Treatment and pharmaceutical use

The present invention provides the use of a compound of the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, for the manufacture of a medicament for the treatment and/or prevention of an ALK-mediated cancer-related disease.

The invention also provides a method of treating and/or preventing an ALK-mediated cancer-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a stereoisomer thereof, or a pharmaceutically acceptable thereof Accepted salts, esters or solvates.

The invention also provides a compound of the invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, in combination with one or more antitumor agents and immunosuppressive agents, for use in therapy and / or use in drugs that prevent ALK-mediated cancer-related diseases.

The invention also provides a method of treating and/or preventing an ALK-mediated cancer-related disease comprising administering to a subject in need thereof a therapeutically effective amount of the combination in combination with one or more anti-tumor agents and an immunosuppressant A compound of the invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof.

The antitumor agent and immunosuppressive agent are selected from the group consisting of methotrexate, capecitabine, gemcitabine, deoxyfluorouridine, pemetrexed disodium, paclitaxil, imatinib, erlotidine Nipa, lapatinib, gefitinib, vandetanib, Herceptin, bevacizumab, rituximab, trastuzumab, paclitaxel, vinorelbine, docetaxel, multiple Spirulina, hydroxycamptothecin, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, lysine, flutamide , leuprolide, anastrozole, ifosfamide, busulfan, cyclophosphamide, carmustine, nimustine, Semustine, nitrogen mustard, melphalan, cyclamate, carboplatin, cisplatin, oxaliplatin, platinum, topotecan, camptothecin, topotecan, everolimus, sirmo , special cancer, 6-mercaptopurine, 6-thioguanine, azathioprine, bacteriocin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, pucamycin or ammonia Mitt.

The cancer-related diseases are selected from the group consisting of brain tumors, non-small cell lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrium. Cancer, rectal cancer, liver cancer, hepatoblastoma, papillary renal cell tumor, head and neck squamous cell tumor, nephroblastoma, renal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, glioma, prostate Cancer, thyroid cancer, female genital tract cancer, carcinoma in situ, lymphoma, neuroblastoma, neurofibromatosis, bone cancer, skin cancer, colon cancer, testicular cancer, small cell lung cancer, gastrointestinal stromal tumor, Prostate tumors, mast cell tumors, multiple myeloma or melanoma.

Preferably, the cancer-related disease is selected from the group consisting of lymphoma (e.g., anaplastic large cell lymphoma) and lung cancer (e.g., non-small cell lung cancer).

More preferably, the cancer-related disease is selected from the group consisting of lung cancer (e.g., non-small cell lung cancer).

VI. The compounds of the invention have the following advantages:

(1) The compound of the formula (I) of the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, has excellent ALK inhibitory activity;

(2) The compound of the formula (I) of the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof exhibits good biostability, is more durable, and has high bioavailability;

(3) The preparation process of the compound of the invention has a high purity and stable quality, and is easy to carry out large-scale industrial production.

VII. The beneficial effects of the compounds of the present invention are further illustrated by the in vitro enzymatic inhibitory activity assay and the in vivo pharmacokinetic assay in rats, but it should not be construed that the compounds of the present invention have only the following beneficial effects.

The following active experiments, pharmacokinetic experiments, and starting materials used in the preparation examples are commercially available. The nomenclature of the compounds in the preparation examples was obtained by Chemical Draw 13.0 software. The chemical structural formulae shown in Preparation Examples 10 and 12 and the related chemical structural formulae appearing in the specification and claims are intended only to illustrate the cis/trans configuration of the compound, rather than the absolute stereo configuration of the compound.

Experimental Example 1 In vitro enzymatic activity experiment of the compound of the present invention

Test Specimens: Compounds 1-6, 9, 10, 13, 14, 18, 24 and 26 of the present invention, the chemical names and preparation methods thereof, can be found in the preparation examples of the respective compounds. Control drug: CH5424802, it can be based on

Prepared by the method disclosed in CN102459172A.

DMSO: Dimethyl sulfoxide

DTT: Diphthylitol ( DL-Dithiothreitol )

SEB: Supplement Enzymatic buffer, available from Cisbio Bioassays, http:〃 www.htrf.com/htrf-kinease, HTRF® KinEASETM-TK 62TK0PEB

ATP: Adenosine Triphosphate

ALK: Analytical '1' Lymphoma Kinase

SA-XL665: Streptavidin-XL665, available from Streptavidin-XL665

Cisbio Bioassays, http:〃 www.htrf.com/htrf-kinease, HTRF® KinEASETM-TK

62TK0PEB )

2.5 χ, 5 χ, 10 x of "x": times Experimental method:

ALK Kinase Buffer Preparation:

Appropriate amount of 1000 mM MgCl ₂ , 2500 nM SEB, 100 mM DTT, 5 chymase buffer were added to the ultrapure water, so that the final concentrations were: 5 mM, 25 nM, 1 mM, 1 χEnzyme buffer, mix, stand by.

2.5 χ Preparation of test solution:

Prepare the 1 mM stock solution of the reference drug: Weigh 1.69 mg of the reference drug, dissolve it with appropriate amount of DMSO, mix it, and set aside.

Preparation of the compound's I mM stock solution: Weigh the appropriate amount of the compound (see the table below for the specific sample amount), add the appropriate amount of DMSO to dissolve, mix, and set aside. Compound No. Weighing Quantity (mg) Compound No. Weighing Quantity (mg)

1 1.71 9 1.6

2 1.69 10 1.5

3 1.46 13 1.49

4 1.56 14 1.44

5 1.46 18 1.48

6 1.75 24 1.47

26 1.59

A 1 mM stock solution was taken and diluted with DMSO to prepare a solution having a concentration of 200 μM as a mother liquor. The mother liquor was diluted three times in DMSO to prepare a series of solutions, and then each concentration was diluted 80 times with ALK kinase buffer to prepare 2.5 χ each test solution, the concentrations were: 2500 ηΜ, 833.33 ΜΜ, 277.78 ηΜ, 92.59 ηΜ, 30.86 ηΜ, 10.29 ηΜ, 3.43 ηΜ, 1.14 ηΜ, 0.38 ηΜ, 0.13 ηΜ, 0.04 ηΜ.

Various other reagents are formulated:

The required 5xALK kinase solution, 5 χ substrate solution, and 5 χΑΤΡ solution were separately prepared in ALK kinase buffer and used.

ALK enzymatic reaction:

1) Add 4 prepared 2.5 χ test solutions and 2 μΐ of prepared 5xALK kinase solution to the corresponding wells in a 384-well plate and incubate at 25 °C for 10 minutes.

2) Add 2 μL of the prepared 5x substrate solution and 2 μL of the prepared 5χΑΤΡ solution to the corresponding wells, start the enzyme reaction, and incubate at 25 °C for 30 minutes.

Enzymatic testing:

Prepare the desired concentration of SA-XL665 with detection buffer, then mix it with the equivalent tyrosine kinase antibody, and add 10 prepared antibody solution to the corresponding wells to stop the reaction. Incubate at 25 °C for 1 h.

Yeast meter 665nm/615nm reading board.

IC ₅₀ : Calculated inhibition rate (%) = (maximum - sample ratio) / (maximum - minimum value) χ ΐοο, curve fitting using Graph prisim software, resulting in IC ₅₀ values. Maximum: Positive control without compound, Minimum: Negative control without enzyme. Experimental results and conclusions:

Table 1: In vitro enzymatic inhibitory activity of the compounds of the invention

Compound 10

Compound 14

Compound 18

Compound 24

Compound 26 It can be seen from Table 1 that the compound of the present invention has a good inhibitory activity against ALK kinase and is comparable to the inhibitory activity of the reference drug, and can be used for the treatment of a kinase-related disease, particularly an ALK kinase-mediated disorder or condition, which is remarkable. Clinical significance. Experimental Example 2 Pharmacokinetic experiments in rats of the present invention

Test article: The compounds of the present invention 1 and 7, were prepared by themselves, and their chemical names and preparation methods are shown in the preparation examples of the respective compounds. Control drug: 5424802, which can be used as a basis

CN102459172A Compound 1 :

Compound 7:

: Test animals: male SD rats, 3 / route of administration / test article, weight 200-280g Preparation of test solution:

For the control drug, weigh 3.02 mg, add 0.592 mL DMSO (dimethyl sulfoxide), dissolve in a 50 V water bath, add 1. 184 mL PEG400 (polyethylene glycol 400), vortex and mix, 50 V water bath Insulation, add 4.144 mL of 28% captisol (sulfobutyl-β-cyclodextrin) ρΗ=3.0 hydrochloric acid solution, heat in a water bath at 50 °C for 20 min, and pass through a 0.22 μηη microporous membrane to obtain IV IV as a rat. For the reference drug, weigh 3.29 mg, add 0.1% Tween 80 + 2% HPC (hydroxypropyl cellulose) 6.45 mL, grind thoroughly with a tissue grinder 600 rpm, mix well, that is, as Rat PO administration drug solution.

For compound 1, weigh 3.70 mg, add DMA (N,N-dimethylacetamide) 0.717 mL, dissolve in the ultrasonic solution, add Solutol (polyethylene glycol stearate 15) 0.717 mL, vortex and mix, then Add 5.732 mL of sterile water for injection and vortex to obtain a clear transparent solution [as a rat IV/PO drug solution].

For compound 7, weigh 2.48 mg, add DMF (N,N-dimethylformamide) 482 L, dissolve in ultrasound, add PEG400 482 L vortex to mix, add 1.474 mL of sterile water for injection, vortex and mix Clear solution is clear, this solution is used as a rat IV drug solution; for compound 7, 6.29 mg is weighed, 0.1% Tween 80+2% HPC 6.116 mL is added to the tissue grinder, 1000 rpm , Disperse evenly, as a rat PO drug solution.

28% captisol pH=3.0 Hydrochloric acid solution preparation method: Firstly prepare pH3.0 hydrochloric acid solution, then weigh 28g captisol, slowly add 80mL pH3.0 hydrochloric acid solution, sonicate, vortex and mix, continue to add pH3.0 hydrochloric acid solution The volume is up to 100 mL, and the vortex is clarified to clear the clear solution.

Preparation method of 0.1% Tween 80+2% HPC: Weigh 2 g of HPC, slowly add to 80 mL of ultrapure water, stir thoroughly and dissolve thoroughly, add 0.1 mL of Tween 80, vortex and mix, continue to join The ultra-pure water is made up to a final volume of 100 mL, and vortexed and mixed.

Preparation method of 28% HP-P-CD: Weigh ΗΡ-β-CD 28 g, add 80 mL of sterile water for injection, dissolve in ultrasound, vortex and mix, continue to add sterile water for injection to a final volume of 100 In mL, vortex and mix to clear the clear solution.

experimental method

Dosing:

The test solution is administered according to the following method: experiment

Dosing dose Dosing concentration Dosing volume Test article Animal Administration route

Mg/kg mg/mL mL/kg

3 tail vein bolus ( IV ) 1 0.5 2 comparator

3 gavage (PO ) 2 0.5 4

3 tail vein bolus ( IV ) 1 0.5 2 compound 1

3 gavage (PO ) 2 0.5 4

3 tail vein bolus ( IV ) 2 1 2 compound 7

3 gavage (PO) 5 1 5 blood collection:

For the comparator, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 30, 48 h after IV administration, 0.167, 0.5, 1, 2, 4, 6, 8, 24 after PO administration 30, 48 h for tail vein blood collection; for compound 1, IV after administration 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h, PO after administration 0.167, 0.5, 1, 2, 4 Blood was collected from the tail vein at 6, 8 and 24 h;

For Compound 7, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 30 h after IV administration, 0.167, 0.5, 1, 2, 4, 6, 8, 24, 30 after PO administration h for tail vein blood collection,

At each time point, about 100 μΐ whole blood was taken, and the plasma was separated by centrifugation at 8000 rpm for 6 min in a high-speed centrifuge, and the plasma was frozen in a refrigerator at -80 °C. Plasma must be prepared within 30 minutes of blood collection.

Plasma sample analysis

For the control drug, the plasma sample was taken by liquid-liquid extraction method: 20 L of plasma was added, and a solution of 600 BEBE (tert-butyl methyl ether) containing internal standard (BEZ-235) (10 ng/mL) was added, and vortex was 1500 rpm. Min, then centrifuge at 12000 rpm for 5 min, take the supernatant 300 μΐ, blow dry under nitrogen, reconstitute with 300 acetonitrile: water (7:3, V/V), vortex and mix, LC-MS/ MS analysis.

For compound 1, plasma samples were taken by protein precipitation: 20 plasma, 200 μL of internal standard (CH5424802) in methanol (50 ng/mL), vortexed at 1500 rpm for 5 min, then centrifuged at 12,000 rpm for 5 min. Take the supernatant 100 μΐ^, add 100 μM water, vortex and mix, and analyze by LC-MS/MS.

For compound 7, plasma samples were taken by protein precipitation: 30 plasma was added, 200 μL of internal standard (CH5424802) in acetonitrile was added, vortexed at 1500 rpm, and then centrifuged at 4000 rpm for 20 min. After centrifugation, take 100 L of the supernatant, add 100 more water, vortex and mix, LC-MS/MS analysis.

Table 2.1: Rat PK evaluation results (IV)

Test sample dose (mg/kg) AUC _last (h*ng/mL) CL (L/h/kg) Control drug 1 1543 0.59 Compound 1 1 1431 0.69 Compound 7 2 7715 0.26 Table 2.2 Rat ΡΚ evaluation results ( ΡΟ )

Test sample dose (mg/kg) AUC _last (h*ng/mL) F (%) Control drug 2 1936 59.6 Compound 1 2 2053 72.2 Compound 7 5 9977 51.8

AUC _last : represents the area under the curve of the medicine 0→t

CL: represents the clearance rate

F%: represents absolute bioavailability

From the experimental results of Table 2.1 and Table 2.2, it is understood that the pharmacokinetic properties of the compound of the present invention are good as compared with the control drug.

VIII. Synthesis Example

The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. The techniques implemented based on the above aspects of the present invention are all within the scope of the present invention.

The definitions represented by the following abbreviations are as follows:

DMF: N,N-dimethylformamide

NBS: N-bromosuccinimide

TFA: trifluoroacetic acid

Cbz-Cl: benzyl chloroformate

THF: tetrahydrofuran

DDQ: 2,3-dichloro-5,6-dicyanide p-benzoquinone

Boc: tert-butoxycarbonyl

Cbz: benzyloxycarbonyl Example 1

2-(4-(3-oxa-8-azabicyclo[3.2.11 octane-8-yl)piperidin-1-yl)-4,4-dimethyl-10-oxo -5,1 Preparation of nitrile (Compound 1)

Preparation of 2-dimethylhexanedione

2-Methyl-1,3-cyclohexanedione (10.1 g, 80 mmol), methyl iodide (12.5 mL, 200 mmol), and methyl carbonate (22.1 g, 160 mmol) were dissolved in acetone (60 mL). The mixture was heated to reflux for 8 hrs, then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The product was obtained (7.7 g, yield 69%).

2) Preparation of 4-bromo-2,2-1,3-cyclohexanedione

2,2-Dimethyl-1,3-cyclohexanedione (6.4 g, 45.7 mmol) was dissolved in glacial acetic acid (100 mL), 40% hydrogen bromide solution (0.4 mL) was added and cooled in ice water bath , a solution of bromine (6.9 g, 43 mmol) in glacial acetic acid (25 mL) was added dropwise, stirred for 30 min, warmed to room temperature, stirred for 2 h, solvent was evaporated under reduced pressure, and ice water (100 mL), acetic acid Ethyl acetate (500 mL), EtOAc (EtOAc)EtOAc.

(3) Preparation of 2-amino-4,4-dimethyl-6,7-dihydrobenzo Mthiazole-5(4//)-one

4-Bromo-2,2-dimethyl-1,3-cyclohexanedione (4.4 g, 20 mmol), thiourea (1.83 g, 24 mmol) in tetrahydrofuran (50 mL), heated to reflux 4 The solvent was removed by rotary evaporation, and the residue was purified mjjjjjjj

(4) Preparation of 2-bromo-4,4-dimethyl-6,7-dihydrobenzo[ί]thiazol-5(4/7)-one

2-Amino-4,4-dimethyl-6,7-dihydrobenzothiazol-5(4/7)-one (1.55 g, 7.9 mmol), copper bromide (2.1 g, 9.4 mmol) Dissolve in acetonitrile (50 mL), cool to 0 ° C, add tert-butyl nitrite (1.22 g, 11.8 mmol) dropwise. After the addition is completed, warm to room temperature, stir for 2 hours, remove solvent by rotary evaporation, residue The product was isolated and purified (yield: EtOAc (EtOAc:EtOAc)

Preparation of carbazole-7-carbonitrile

2-Bromo-4,4-dimethyl-6,7-dihydrobenzothiazol-5(4/7)-one (1.56 g, 6 mmol), 3-mercaptobenzonitrile (1.6 g , 12 mmol) was dissolved in trifluoroacetic acid (20 mL), heated to 100 ° C, stirred for 6 h, cooled, evaporated, evaporated, evaporated. The organic layer was dried over anhydrous EtOAc (EtOAc) (EtOAc).

(6) Preparation of 2-bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile

Dissolving 2-bromo-4,4-dimethyl-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (537 mg, 1.5 mmol) in tetrahydrofuran (5 mL), cool to 0 ° C, add 2,3-dichloro-5,6-dicyan-p-benzoquinone (408 mg, 1.8 mmol) for 1.5 hours, then rise to 25 ° C, then stir 2 After 10 hours, 10% sodium hydroxide solution (25 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. (Dichloromethane: methanol = 20: 1) The product was isolated (293 mg, yield 49%).

(7) 2-(4-Hydroxypiperidin-1-yl)-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6] Preparation of carbazole-7-carbonitrile

2-Bromo-4,4-methyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (186 mg _; 0.5 mmol The 4-hydroxypiperidine (152 mg, 1.5 mmol) was dissolved in acetonitrile (10 mL), heated to 90 ° C, EtOAc (EtOAc) Methanol = 30: 1) The product was isolated and purified (151 mg, yield 77%).

(8) 4,4-Dimethyl-10-oxo-2-(4-oxopiperidin-1-yl)-5,10-dihydro-4/7-thiazolo[4,5-6 Carbazole

2-(4-Hydroxypiperidin-1-yl)-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]pyrene -7-carbonitrile (137 mg, 0.35 mmol) was dissolved in dichloromethane (10 mL). EtOAc (EtOAc) The mixture was extracted with EtOAc (EtOAc) (EtOAc)EtOAc.

(9) 2-(4-(3-Oxogold-8-azabicyclo[3.2.1]octane-8-yl)piperidin-1-yl)-4,4-dimethyl-10-oxo Preparation of di-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile

4,4-Dimethyl-10-oxo-2-(4-oxopiperidin-1-yl)-5,10-dihydro-4/7-thiazolo[4,5-6]indole Zylo-7-carbonitrile (117 mg, 0.3 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (89 mg, 0.6 mmol) dissolved in N, N-dimethyl Add indium trichloride (66 mg, 0.3 mmol) to formamide (10 mL), stir at room temperature overnight, add sodium cyanoborohydride (37 mg, 0.6 mmol), stir at room temperature for 2 h, add water (10 mL) The mixture was extracted with EtOAc (EtOAc) (EtOAc) ).

Molecular formula: C ₂₇ H ₂₉ N ₅ 0 ₂ S; Molecular weight: 487.62; LC-MS (m/z): 488.0 [M+H] + 3⁄4-NMR (400MHz, DMSO-^) δ: 12.74 (s, 1H) , 8.20-8.18 (d, 1H, J = 8.4 Hz), 7.99 (s, 1 H), 7.56-7.53 (m, 1H), 4.12-4.04 (m, 2H), 3.77-3.60 (m, 2H), 3.58-3.45 (m, 4H), 3.32-3.24 (m, 3H), 2.00-1.74 (m, 6H), 1.66 (s, 6H), 1.53-1.36 (m, 2 H).

Example 2

2-(4-(8-oxa-3-azabicyclo[3.2.11 oct-3-yl)piperidin-1-yl)-4,4-dimethyl-10-oxo

Preparation of -5,10 (Compound 2)

(1) 2-(4-Hydroxypiperidin-1-yl)-4,4-methyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6] fluorene Azole

2-Bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (260 mg, 0.70) Methyl), 4-hydroxypiperidine (76 mg, 0.75 mmol) dissolved in acetonitrile (40 mL), added potassium carbonate (138 mg, 1 mmol), heated to 90 ° C, stirred for 14 hours, cooled to room temperature, rotating The solvent was evaporated, and the obtained crude material wasjjjjjjjj

(2) 4,4-Dimethyl-10-oxo-2-(4-oxopiperidin-1-yl)-5,10-dihydro-4/7-thiazolo[4,5-6 Carbazole

2-(4-Hydroxypiperidin-1-yl)-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole _7-carbonitrile (240 mg, 0.61 mmol) was dissolved in dimethyl sulfoxide (3 mL) and triethylamine (2 mL), and sulphur trioxide pyridine (500 mg, 3.14 mmol) was added with stirring. The reaction was stirred at room temperature for 2 hours. The reaction mixture was purified to mjjjjjjjjli

(3) 2-(4-(8-oxa-3-azacyclo[3.2.1]octane-3-yl)piperidin-1-yl)-4,4-dimethyl-10- Preparation of oxo-5, -7-carbonitrile

4,4-Dimethyl-10-oxo-2-(4-oxopiperidin-1-yl)-5,10-dihydro-4/7-thiazolo[4,5-6]indole Azole-7-carbonitrile (200 mg, 0.51 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (100 mg, 0.67 mmol) in N,N-dimethyl To the formic acid (5 mL), indium trichloride (221 mg, 1 mmol) was added, and the mixture was stirred at room temperature for 16 hours, sodium cyanoborohydride (30 mg, 0.48 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, EtOAc (EtOAc (EtOAc) 1) The final product (103 mg, yield 41%).

Molecular formula: C ₂₇ H ₂₉ N ₅ 0 ₂ S; Molecular weight: 487.62; LC-MS (m/z): 488.3 [M+H] ⁺ iH-NMR (400 MHz, DMSO-^) δ: 13.24 (s, 1H) , 8.18 (d, 1H, J = 8.4Hz), 7.97 (s, 1H), 7.53 (d, 1H, J = 8.4 Hz), 4.09-4.21 (m, 2H), 3.91-.3.93 (m, 2H) , 3.62-3.24 (m, 6H), 2.57-2.59 (m, 1H), 1.98-1.66 (m, 12H), 1.55-1.35 (2H, m).

Example 3

4,4-Dimethyl-2-(8-morpholino-3-azabicyclo[3.2.11 oct-3-yl)-10-oxo-5,10-dihydro-g-) Preparation

Preparation of t-butyl acid ester

8-Oxo-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (20.0 mg, 0.89 mmol) and morpholine (100 mg, 1.15 mmol) in acetonitrile (10 mL) 3 drops of acetic acid were added, and the mixture was stirred at room temperature for 16 hours, and then sodium triacetoxyborohydride (380 mg, 1.79 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) =1 : 1) The product was obtained (210 mg, yield 80%).

(2) Preparation of 4-(3-azacyclo-[3.2.1]octane-8-yl)morpholine

Boc-N Γ )-N O HN Γ )-N O

Dissolve 8-morpholino-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (210 mg, 0.71 mmol) in dichloromethane (5 mL). Acetic acid (3 mL) was stirred at room temperature for 16 hours. The reaction solution was evaporated to dryness to give crystals (yield: 130 mg, yield 93%).

(3) 4,4-dimethyl-2- (8-morpholino-3-aza and bicyclo [3.2.1] octan-3-yl) _ ^10-oxo-5, 10-dihydro- Preparation of -4/7-thiazolo[4,5-6]carbazole-7-carbonitrile

2-Bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (250 mg, 0.67 Methyl) and 4-(3-azabicyclo[3.2.1]octane-8yl)morpholine (130 mg, 0.66 mmol) were dissolved in N-methylpyrrolidone (10 mL). Mg, 1.98 mmol), heated to 120 ° C. Stirring for 2 hours, cooling to room temperature, pouring the reaction into water, stirring for half an hour, filtering, drying the filter cake, and purifying with silica gel to obtain the final product (130 mg , yield 40%).

Molecular formula: C ₂₇ H ₂₉ N ₅ 0 ₂ S; Molecular weight: 487.62; LC-MS (m/z): 488.3 [M+H] ⁺

3⁄4-NMR (400MHz, DMSO-^) δ: 13.12 (brs, 1H), 8.16 (d, 1H, J = 8.0Hz), 7.95 (s, 1H), 7.49 (d, 1H, J = 8.0Hz,) , 3.46-3.73 (m, 10H), 2.42-2.49 (m, 4H), 2.21-2.24 (m, 1H), 1.76-1.79 (m, 2H), 1.66-1.70 (m, 6 H), 1.53 -1.57 (m, 2H).

Example 4

4,4-Dimethyl-2-(3-morpholino-8-azabicyclo[3.2.11octane-8-yl)-10-oxo-5,10-dihydro-g-4) Preparation

4,4-Dimethyl-10-oxo-2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)-5,10-dihydro-4/7 -

2-Bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (250 mg, 0.67 Methyl), 8-azabicyclo[3.2.1]octane-3-one (150 mg, 1.2 mmol) dissolved in N-methylpyrrolidone (10 mL), triethylamine (150 mg, 1.5) (mmol), the reaction was stirred to 120 ° C for 2 hours, cooled to room temperature, the reaction solution was poured into water, stirred for half an hour, filtered, and the obtained cake was dried to give a product (210 mg, yield 75%).

(2) 4,4-Dimethyl-2-(3-morpholino-8-azacyclo[3.2.1]octane-8-yl)-10-oxo-5,10-dihydro Preparation of -4/7-thiazolo[4,5-6]carbazole-7-carbonitrile

4,4-Dimethyl-10-oxo-2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)-5,10-dihydro-4/ 7-thiazolo[4,5-6]carbazole-7-carbonitrile (210 mg, 0.5 mmol) and morpholine (500 mg, 5.74 mmol) in N,N-dimethylformamide (10 mL) Indium trichloride (1.3 g, 5.88 mmol) was added, and the mixture was stirred at room temperature for 16 hours, sodium cyanoborohydride (100 mg, 1.59 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, EtOAc (EtOAc (EtOAc) (EtOAc) The end product (110 mg, yield 45%).

Molecular formula: C ₂₇ H ₂₉ N ₅ 0 ₂ S; Molecular weight: 487.62; LC-MS (m/): 488.3 [M+H] ⁺ iH-NMR (400MHz, DMSO- ₆ ) δ: 13.13 (brs., 1H) , 8.17 (d, 1H, J= 8.0Hz), 7.96 (s, 1H), 7.51 (d, 1H, J = 8.4Hz), 4.38 (s, 2H), 3.57 (s, 4H), 2.70-2.75 ( m, 1H), 2.35 (s, 4H), 1.96-2.06 (m, 2H), 1.81-1.84 (m, 4H), 1.80 (s, 6H), 1.68-1.73 (m, 2H).

Example 5

4,4-Dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2.11octane-8-yl)-10-oxo-5,10-dihydro-^- Preparation of substance 5)

8-(7-Cyano-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]oxazol-2-yl)-3

2-Bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (250 mg, 0.67 Methyl) and 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (200 mg, 0.94 mmol) dissolved in N-methylpyrrolidone (10 mL), triethylamine (150 mg, 1.48 mmol), heating to 120 ° C, stirring the reaction for 2 hours, cooling to room temperature, pouring the reaction solution into water, stirring for half an hour, filtering, the resulting filter cake was dried to give the product (290 mg, yield 86%) .

(2) 2-(3,8-diazacyclo[3.2.1]octane-8-yl)-4,4-dimethyl-10-oxo-5,10-dihydro-4/ Preparation of 7-thiazolo[4,5-6]carbazole-7-carbonitrile

8-(7-Cyano-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]oxazol-2-yl) 3,8-diazacyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (290 mg, 0.58 mmol) was added to dichloromethane (10 mL). mL), after the addition was completed, the reaction was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness crystals crystals crystals crystals crystals

(3) 4,4-Dimethyl-2-(3-methyl-3,8-diazacyclo[3.2.1]octane-8-yl)-10-oxo_ ⁵ ,10- Preparation of dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile

2-(3,8-diazacyclo[3.2.1]octane-8-yl)-4,4-dimethyl-10-oxo-5,10-dihydro-4/7- Thiazolo[4,5-6]oxazol-7-carbonitrile (180 mg, 0.45 mmol) was dissolved in anhydrous formic acid (10 mL), then aq. Stir for 4 hours. The reaction mixture was evaporated to dryness crystals crystals crystals crystals crystals

Molecular formula: C ₂₃ H ₂₃ N ₅ OS; Molecular weight: 417.53; LC-MS (m/z): 418.2 [M+H] ⁺ iH-NMR (400MHz, -DMSO-^) δ: 12.90 (brs. , 1H) , 8.19 (d, 1H, J = 8.4Hz), 7.97 (s, 1H), 7.53 (d, 1H, J = 8.4Hz), 4.35 (s, 2H), 2.68 (d, 2H, J = 10.4Hz) , 2.29 (d, 2H, J = 10.8Hz), 2.15(s, 3H), 1.93 (s, 4H), 1.67 (s, 6H).

Example 6

4,4-Dimethyl-2-(8-methyl-3,8-diazabicyclo[3.2.11 oct-3-yl)-10-oxo-5,10-dihydro-^- Preparation of substance 6)

(1) Preparation of 8-methyl-3,8-diaza-cyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

^ HCHO ^

ΗΝ 1 N-Boc »► -N 1 N-Boc

3,8-Diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (200 mg, 0.94 mmol) and 37% aqueous formaldehyde (2 mL) were dissolved in ethanol (10 mL) and added The mixture was stirred at room temperature for 16 hours under reduced pressure of H.sub.2, filtered, and evaporated to give the product (190 mg, yield 89%).

(2) Methyl ⁸ _ _ ³ _ ⁸ and diaza ring. ^[3 ^2.1] octane

TFA

-Ν Ί N-Boc -Ν Ί Η Dissolve 8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (190 mg, 0.84 mmol) in dichloromethane (10 mL) and stir. Trifluoroacetic acid (5 mL) was added and the mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated to dryness to give crystals (yield: 100%, yield: 94%).

(3) 4,4-Dimethyl-2-(8-methyl-3,8-diazacyclo[3.2.1]octane-3-yl)-10-oxo_ ⁵ ,10- Preparation of dihydro-4/7-thiazole [4,5-6]carbazole-7-carbonitrile

2-Bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (250 mg, 0.67 Methyl) and 8-methyl-3,8-diazabicyclo[3.2.1]octane (100 mg, 0.79 mmol) dissolved in N-methylpyrrolidone (10 mL) with triethylamine (200 mg) , 1.98 mmol), heat to 120 ° C, stir the reaction for 2 hours, cool to room temperature, pour the reaction solution into water, stir for half an hour, filter, and the filter cake is dried, washed with methanol, and dried to give the final product (130 mg, Yield 46%).

Molecular formula: C ₂₃ H ₂₃ N ₅ OS; Molecular weight: 417.53; LC-MS (m/z): 418.2 [M+H] ⁺ iH-NMR (400MHz, DMSO-^) δ: 12.72 (s, 1H), 8.19 (d, 1H, J = 8.4Hz), 7.98 (s, 1H), 7.54 (d, 1H, J = 8.4Hz), 3.59 (brs., 2H), 3.15-3.29 (m, 4H), 2.24 (s , 3H), 1.97 (m, 2H), 1.65 (s, 6H), 1.54 (d, 2H, J = 7.6Hz).

Example 7

4,4-Dimethyl-2-(7-methyl-2,7-diazaspiro[3.51 decan-2-yl)-10-oxo-5,10-dihydro-g- 9) Preparation

(1) Preparation of 7-methyl-2,7-spiro[3.5]decane-2-carboxylic acid tert-butyl ester

2,7-diazaspiro[3.5]decane-2-carboxylic acid tert-butyl ester (200 mg, 0.88 mmol) and 37% aqueous solution of methyl ketone (2 mL) were dissolved in ethanol (10 mL) and palladium was added. The charcoal (50 mg) was stirred under a hydrogen atmosphere at room temperature for 16 hours, filtered, and the filtrate was evaporated to give the product (190 mg, yield 90%).

(2) Preparation of 7-methyl-2,7-diazaspiro[3.5]decane 7-Methyl-2,7-diazaspiro[3.5]decane-2-carboxylic acid tert-butyl ester (190 mg, 0.79 mmol) was dissolved in dichloromethane (5 mL). Acetic acid (3 mL) was added and the reaction was stirred at room temperature for 16 hours. The solvent was evaporated to dryness to give the product (l.

(3) 4,4-Dimethyl-2-(7-methyl-2,7-diazaspiro[3.5]decane-2-yl)-10-oxo-5,10-dihydro- 4/7-thiazolo[4,5-6]

2-Bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (250 mg, 0.67 Methyl) and 7-methyl-2,7-diazaspiro[3.5]decane (110 mg, 0.78 mmol) were dissolved in N-methylpyrrolidone (10 mL) and triethylamine (200 mg, 1.98) Ment), heating to 120 ° C, stirring the reaction for 1 hour, cooling to room temperature, pouring the reaction solution into water, stirring for half an hour, filtering, drying the filter cake, and purifying with silica gel to obtain the final product (130 mg, yield 45%).

Molecular formula: C ₂₄ H ₂₅ N ₅ OS; Molecular weight: 431.56; LC-MS (m/z): 432.2 [M+H] ⁺ iH-NMR (400 MHz, DMSO-^) δ: 12.85 (s, IH), 8.19 (d, IH, J = 8.4 Hz), 7.98 (s, IH), 7.54 (m, IH), 3.89 (s, 4H), 2.69 (m, 4H), 2.41 (s, 3H), 1.74 (m, 4H) _; 1.65 (s, 6H).

Example 8

4,4-Dimethyl-2-(2-methyl-2,7-diazaspiro[3.51 dec-7-yl)-10-oxo-5,10-dihydro-g- 10) Preparation

(1) Preparation of 2-methyl-2,7-diazaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

2,7-diazaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (200 mg, 0.88 mmol) and 37% aqueous solution of methyl ketone (2 mL) were dissolved in ethanol (10 mL) and palladium was added. The charcoal (50 mg) was stirred at room temperature under reduced pressure of hydrogen for 16 hr, filtered and evaporated to give the product (195 mg, yield 92%).

(2) Preparation of 2-methyl-2,7-diazaspiro[3.5]decane 2-methyl-2,7-diazaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (195 mg, 0.81 mmol) was dissolved in dichloromethane (5 mL). Acetic acid (3 mL) was stirred at room temperature for 16 hours. The reaction solution was evaporated to dryness to give crystals (yield: 110 mg, yield 97%).

(3) 4,4-Dimethyl-2-(2-methyl-2,7-diazaspiro[3.5]decane-7-yl)-10-oxo-5,10-dihydro- 4/7-thiazolo[4,5-6]

2-Bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (250 mg, 0.67 Methyl) and 2-methyl-2,7-diazaspiro[3.5]decane (110 mg, 0.78 mmol) were dissolved in N-methylpyrrolidone (10 mL) and triethylamine (200 mg, 1.98) Ment), heating to 120 ° C, stirring the reaction for 1 hour, cooling to room temperature, pouring the reaction solution into water, stirring for half an hour, filtering, drying the filter cake, and purifying with silica gel to obtain the final product (78 mg, yield 27%).

Molecular formula: C ₂₄ H ₂₅ N ₅ OS; Molecular weight: 431.56; LC-MS (m/z): 432.2 [M+H] ⁺ iH-NMR (400 MHz, DMSO-^) δ: 13.19 (brs, 1H), 8.19 (d, 1H, J = 8.0Hz), 7.98 (s, 1H), 7.53 (d, 1H, J = 8.4Hz), 3.97 (s, 2H), 3.31 (s, 2H), 3,12-3.17 ( m, 7H), 1.94 (m, 2H), 1.85 (s, 8H).

Example 9

4,4-Dimethyl-2-(9-methyl-3,9-diazaspiro[5.51 undec-3-yl)-10-oxo-5,10-dihydro-g- 14 Preparation

(1) Preparation of 9-methyl-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (200 mg, 0.79 mmol) and 37% aqueous solution of methyl ketone (2 mL) were dissolved in ethanol (10 mL) and palladium was added. The charcoal (50 mg) was stirred at room temperature under reduced pressure of hydrogen for 16 hr, filtered, and the solvent was evaporated to give the product (192 mg, yield 91%).

(2) Preparation of 3-methyl-3,9-diazaspiro[5.5]undecane

9-methyl-3,9- It was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added with stirring, and the mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated to dryness to give crystals (yield:

(3) 4,4-Dimethyl-2-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-10-oxo-5,10-

2-Bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (250 mg, 0.67 Methyl) and 3-methyl-3,9-diazaspiro[5.5]undecane (120 mg, 0.71 mmol) were dissolved in N-methylpyrrolidone (10 mL), and triethylamine (200 mg, 1.98 mmol), heating to 120 ° C, stirring the reaction for 2 hours, cooling to room temperature, pouring the reaction solution into water, stirring for half an hour, filtering, drying the filter cake, washing with methanol, drying to obtain the product (150 mg, yield 49%).

Molecular formula: C ₂₆ H ₂₉ N ₅ OS; Molecular weight: 459.61 ; LC-MS (m/z): 460.3 [M+H] ⁺ iH-NMR (400MHz, DMSO- ₆ ) δ: 13,44 (brs., 1H ), 8.18 (d, lH, J = 8Hz), 7.97(s, 1H), 7.52 (m, 1H), 3.56 (s, 4H), 2.46-2.54 (m, 4H), 2.31 (s, 3H), 1.67 (s, 6H), 1.56 (s, 8H).

Example 10

Preparation of 4,4-dimethyl-2-(cis-5-methylhexahydropyrrolo[3,4-clpyrrole-2qg-yl)-10-oxo-5,10 (Compound 18)

Preparation of 5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1/7)-carboxylic acid tert-butyl ester

cis-Hexahydropyrrolo[3,4-c]pyrrole-2(1/7)-carboxylic acid tert-butyl ester (200 mg, 0.94 mmol) and 37% aqueous formaldehyde (2 mL) were dissolved in ethanol (10) In a solution of EtOAc, EtOAc (EtOAc)EtOAc.

(2) Preparation of cis-2-methyl-octahydropyrrolo[3,4-c]pyrrole

cis-5-Methylhexahydropyrrolo[3,4-c]pyrrole-2(1/7)-carboxylic acid tert-butyl ester (185 mg, 0.82 mmol) was dissolved in dichloromethane (5 mL) Trifluoroacetic acid (3 mL) was added with stirring. After the addition was completed, the reaction was stirred at room temperature for 16 hours. The reaction solution was evaporated to dryness to give crystals (yield: 100 mg, yield 97%).

(3) 4,4-Dimethyl-2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1/7)-yl)-10-oxo-5 10-dihydro-4/7

2-Bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (250 mg, 0.67 Methyl) and cis-2-methyl-octahydropyrrolo[3,4-c]pyrrole (100 mg, 0.79 mmol) were dissolved in N-methylpyrrolidone (10 mL), and triethylamine (200 mg, 1.98 mmol), heated to 120 ° C, stirred for 2 hours, cooled to room temperature, poured into the water, stirred for half an hour, filtered, the filter cake was dried, washed with methanol, dried to give the final product (150 mg, yield Rate 54%).

Molecular formula: C ₂₃ H ₂₃ N ₅ OS; Molecular weight: 417.53 ; LC-MS (m/z): 418.4 [M+H] ⁺ -NMR (400MHz, DMSO- ₆ ) δ: 12.86 (s, 1H), 8. 19 (d, 1H, J = 8.0Hz), 7.99(s, 1H), 7.54 (d, 1H, J = 8.0 Hz), 3.70-3.74 (m, 2H), 3.43-3.46 (m, 3H), 3.08 (s, 2H), 2.81 (s, 4H), 2.42 (s, 2H), 1.67 (s, 6H).

Example 11

Preparation of 2-(6-Amino-3-azabicyclo[3.1.01hexane-3-yl)-4,4-dimethyl-10-oxo-5,10-dihydro-^- 24)

- Preparation of ((; (benzyloxy)carbonyl)amino)-3-nitro-3-carboxylic acid tert-butyl ester

6-Amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) and triethylamine (170 mg, 1.68 mmol) were dissolved in dichloromethane (20) In mL), add benzyl chloroformate (175 mg,

The reaction was stirred at room temperature for 16 hr. EtOAc (EtOAc:EtOAc)

(2) Preparation of 3-azabicyclo[3.1.0]hexane-6-ylcarbamic acid benzyl ester

6-((; (Benzyloxy)carbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (270 mg, 0.81 mmol) was dissolved in dichloromethane. In 10 mL), trifluoroacetic acid (5 mL) was added with stirring. After the addition was completed, the reaction was stirred at room temperature for 16 hours. The reaction solution was rotary evaporated to remove the solvent to give product (180 mg, yield 95%).

(3) 3-(7-Cyano-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]oxazol-2-yl ) -3

2-Bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (250 mg, 0.67 Methyl) and 3-azabicyclo[3.1.0]hexane-6-ylcarbamic acid benzyl ester (180 mg, 0.77 mmol) dissolved in N-methylpyrrolidone (10 mL). Mg, 1.5 mmol), heated to 120 ° C, stirred for 1 hour, cooled to room temperature, poured into the water, stirred for half an hour, filtered, the filter cake was dried, washed with methanol, dried to give the product (250 mg, Yield 71%).

(4) 2- (6-amino-3-aza and bicyclo [3.1.0] hexane-3-yl) -4,4-dimethyl-10-oxo _ ^5, 10-dihydro-4 /7-

3-(7-Cyano-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]oxazol-2-yl) 3-Azacyclo[3.1.0]hexane-6-ylcarbamic acid benzyl ester (250 mg, 0.48 mmol) was dissolved in hydrogen bromide acetic acid solution (10 mL), and the reaction was stirred at room temperature for 5 hours. The liquid was poured into water, the pH was adjusted to 8 with aqueous ammonia, and filtered, and the obtained filter cake was dried and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) (96 mg, yield 52%).

Molecular formula: C ₂₁ H ₁₉ N ₅ OS; Molecular weight: 389.48; LC-MS (m/z): 390.2 [M+H] ⁺ -NMR (400MHz, DMSO-^) δ: 8.19 (d, 1H, J = 8.0 Hz), 7.97 (s, 1H), 7.53 (d, 1H, J= 8.4Hz), 3.51 (s, 4H), 2.03 (s, 1H), 1.65 (s, 8H).

Example 12

4,4-dimethyl-2-(trans-octahydropyridyl[3,4->lil,41oxazin-6-yl)-10-oxo-5.10-dihydro-g-thiazole Preparation of 4,5->1 carbazole-7-carbonitrile (Compound 26)

(1) trans-: hydrogen-1/7-pyrido[3,4->][1 ,4]oxazine-1,6(5/7)-dicarboxylic acid 1-benzyl 6-tert-butyl Preparation of ester

Trans-octahydro-6/7-pyrido[3,4-6][l,4]oxazine-6-carboxylic acid tert-butyl ester (200 mg, 0.83 mmol) and triethylamine (170 mg, 1.68 mmol) was dissolved in dichloromethane (20 mL), benzyl chloroformate (170 mg, 1 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The solvent was removed by rotary evaporation. Ethyl acetate = 5 : 1 ) purified product (250 mg, yield 80%).

(2) Preparation of trans-octahydro-1/7-pyrido[3,4-b][l,4]oxazine-1-carboxylic acid benzyl ester

Trans-hexahydropyrido[3,4-/)][l,4]oxazine-1,6(5//)-didecanoic acid 1-benzyl 6-tert-butyl ester (250 mg, 0.66 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added with stirring, and the mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated to dryness to give crystals (yield: 180 mg, yield 98%).

(3) 6-(7-Cyano-4,4-dimethyl-10-oxo-5, 10-dihydro-4//-thiazolo[4,5-6]oxazol-2-yl - Preparation of trans-octahydropyrido[3,4-indole][1,4]oxazine-1 -formic acid benzyl ester

2-Bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-b]carbazole-7-carbonitrile (200 mg, 0.54 Methyl) and trans-octahydro-1/7-pyrido[3,4-][1,4]oxazine-1 -decanoic acid benzyl ester (180 mg, 0.65 mmol) dissolved in N-A To the pyrrolidone (10 mL), add triethylamine (150 mg, 1.5 mmol), heat to 120 ° C, stir the reaction for 2 hours, cool to room temperature, pour the reaction into water, stir for half an hour, filter, filter cake dry The obtained crude product was washed with methanol and dried to give product (260 mg, yield: 85%).

(4) 4,4-Dimercapto-2-(trans-octahydro-6-pyrido[3,4-6][1 ,4]oxazin-6-yl)-10-oxo-5 Preparation of 10-Dihydro-4/7-thiazolo[4,5-6]carbazole-7-indolecarbonitrile

6-(7-Cyano-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]oxazol-2-yl) Trans-octahydropyrido[3,4-6][1,4]oxazine-1-carboxylic acid benzyl ester (190 mg, 0.33 mmol) dissolved in hydrogen bromide acetic acid solution (10 mL), stirred at room temperature After reacting for 5 hours, the reaction solution was poured into water, and the pH was adjusted to 8 with aqueous ammonia. After filtration, the obtained cake was dried and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the final product (76 mg , yield 53%).

Molecular formula: C ₂₃ H ₂₃ N ₅ 0 ₂ S; Molecular weight: 433.53 ; LC-MS (m/z): 434.2 [M+H] ⁺ iH-NMR (400MHz, DMSO- ₆ -) δ: 13. 15 (brs . , IH), 8. 18 (d, IH, J = 8.0Hz), 7.97 (s, IH), 7.53 (d, IH, J = 8.0Hz), 3.96-4.08 (m, 2H), 3.75-3.77 (m, IH), 3.48-3.51 (m, IH), 3.21-3.27 (m, IH), 3.12-3.16 (m, IH), 3.07-3.11 (m, IH), 2.96-3.02 (m, IH) , 2.73-2.84 (m, 2H), 1.74-1.77 (m, IH), 1.67 (s, 6H), 1.32-1.48 (m, IH).

Example 13

Preparation of 2-(3,8-diazabicyclo[3.2.11 Octane-8-yl)-4,4-dimethyl-10-oxo-5,10-dihydro-g-thiazole

(1) Preparation of 2,2-dimethylcyclohexane-1,3-dione

In a 10 L three-necked flask, add acetone (4.4 L), potassium carbonate (1.14 kg, 8.25 mol), and 2-methylcyclohexane-1,3-dione (700 g, 5.55 mol) at room temperature. Methyl iodide (1.17 kg, 8.24 mol) was added dropwise to the system, and the addition was completed in four hours. After the addition, the system was heated to 55 ° C and kept overnight. After completion of the reaction, the system was filtered, and the filter cake was washed three times with ethyl acetate (1 L); The solvent was removed by rotary evaporation, ethyl acetate (3 L) was evaporated,EtOAcEtOAcjjjjjjjjjjjjjjj The product was isolated (330 g, yield 42%) by crystallization.

(2) Preparation of 4-bromo-2,2-dimethylcyclohexane-1,3-dione

In a 10 L three-necked flask, acetic acid (2 L), 40% hydrobromic acid (20.6 mL), 2,2-dimethylcyclohexane-1,3-dione (330 g, 2.35 mol); Bromide (376 g, 2.35 mol) was dissolved in acetic acid (2.5 L), slowly added dropwise to the system at 0 ° C, and allowed to warm to room temperature overnight. The acetic acid was evaporated to dryness, taken-up ethyl acetate (3 L), and then extracted three times with a saturated aqueous sodium chloride aqueous solution and diluted with saturated aqueous sodium carbonate. The organic phase was dried and evaporated <RTI ID=0.0>

(3) Preparation of 2-amino-4,4-dimethyl-6,7-dihydrobenzothiazol-5(4/7)-one

The crude product (200 g) of 4-bromo-2,2-dimethylcyclohexyl-1,3-dione was dissolved in THF (1 L), and sulphonic acid (77.4 g, 1 mol) was added and heated to reflux. After overnight, the THF was evaporated to dryness and purified by column chromatography to afford product (50 g, 0.255 mol).

Preparation of 5(4/7)-ketone

2-Amino-4,4-dimethyl-6,7-dihydrobenzothiazol-5(4/7)-one (50 g, 0.255 mol) dissolved in acetonitrile (1 L), added CuBr ₂ (68.3 g, 0.306 mol), diluted tert-butyl nitrite (36.4 g, 0.36 mol) was added dropwise to the reaction system at -10 ° C. After the addition, TLC was monitored, the reaction was completed, and the solvent was removed by rotary evaporation. The ethyl acetate and ethyl acetate phases were extracted three times with a saturated aqueous solution of sodium chloride, and the organic phase was combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation and purified by column chromatography (35 g, yield 53%) .

Preparation of oxazo[4,5-6]carbazole-7-carbonitrile

2-Bromo-4,4-dimethyl-6,7-dihydrobenzothiazol-5(4/7)-one (35 g, 0.135 mol) and 3-mercaptobenzonitrile hydrochloride ( 45.4 g, 0.269 mol) was dissolved in acetic acid (1 L). After heating at 100 ° C for 2 h, the reaction was completed, and the mixture was extracted with water and ethyl acetate. The ethyl acetate phase was combined, dried over anhydrous sodium sulfate, and evaporated. The solvent was removed and purified by column chromatography to yield (17.6 g, yield 42%).

(6-1) 2-Chloro-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile preparation

Dissolving 2-chloro-4,4-dimethyl-5,10-dihydro-4/7-thiazolo[4,5-b]carbazole-7-carbonitrile (3 g, 9.6 mmol) in THF In a mixed solution of water/V (V/V = 9:1) (50 mL), DDQ (3.81 g, 16.8 mmol) was added to the system and oxidized overnight. Extraction with ethyl acetate water, washing with water three times, ethyl acetate phase was combined, solvent was evaporated, and the residue was purified by column chromatography (127 mg, yield 4%).

Or

(6-2) 2-Chloro-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile preparation

Dissolving 2-chloro-4,4-dimethyl-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (7.6 g, 24.2 mmol) in acetone In a mixed solvent of acetic acid (V/V = 2: l) (220 mL), a solution of dichromate (15.7 g, 53.4 mmol) was added to the system, and oxidation was completed until the reaction was completed, and succinic acid was added to the system. Sodium, extracted with water and ethyl acetate. The ethyl acetate phase was washed three times with saturated aqueous sodium chloride, and the ethyl acetate phase was combined, and the solvent was removed by rotary evaporation. 66%).

(7) 8-(7-Cyano-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]oxazol-2-yl ) -

2-Chloro-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (300 mg, 0.92 Methyl) and 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (200 mg, 0.94 mmol) dissolved in N-methylpyrrolidone (10 mL), triethylamine (150 mg, 1.48 mmol), heated to 100 ° C, stirred for 1 hour, cooled to room temperature, poured into water, stirred for half an hour, filtered, and the obtained filter cake was dried and purified by silica gel column chromatography (dichloromethane: Methanol = 20: 1) Purification afforded the product (360 mg, yield 78%).

(8) 2-(3,8-diazacyclo[3.2.1]octane-8-yl)-4,4-dimethyl-10-oxo-5,10-dihydro-4/ 7- Preparation of [4,5-6]carbazole-7-carbonitrile

8-(7-Cyano-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]oxazol-2-yl) 3,8-Diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (360 mg, 0.71 mmol) was added to dichloromethane (10 mL). After the addition, the reaction was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness crystals crystals crystals crystals crystals crystals

Molecular formula: C ₂₂ H ₂₁ N ₅ OS; Molecular weight: 403.50; LC-MS (m/z): 404.2 [M+H] ⁺

-NMR (400MHz, DMSO- ₆ ) δ: 12.78 (s, 1H), 8.19 (d, 1H, J = 8.0 Hz), 7.99 (s, 1H), 7.55 (dd, 1H, J7=1.2Hz, J2 = 8.0 Hz), 4.38 (s, 2H), 3.11 (d, 2H, J = 12 Hz), 2.91 (d, 2H, J = 12.0 Hz), 2.00-2.07 (m, 4H), 1.67 (s, 6H) .

Example 14

4,4-Dimethyl-2-(6-methyl-2,6-diazaspiro[3.31heptan-2-yl)-10-oxo-5,10-dihydro-g- 13) Preparation

(1) 6-(7-Cyano-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]oxazol-2-yl ) -

2-Bromo-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]carbazole-7-carbonitrile (250 mg, 0.67 Methyl) and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) dissolved in N-methylpyrrolidone (10 mL) with triethylamine (150) Mg, 1.48 mmol), heated to 100 ° C, stirred for 1 hour, cooled to room temperature, poured into water, stirred for half an hour, filtered, and the obtained filter cake was dried to give product (280 mg, yield 85%).

(2) 4,4-Dimethyl-10-oxo-2-(2,6-diazaspiro[3.3]heptan-2-yl)-5,10-dihydro-4/7-thiazole And preparation of [4,5-6]carbazole-7-carbonitrile

6-(7-Cyano-4,4-dimethyl-10-oxo-5,10-dihydro-4/7-thiazolo[4,5-6]oxazol-2-yl) Add 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (280 mg, 0.57 mmol) to dichloromethane (10 mL). After the addition was completed, the reaction was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness crystals crystals crystals crystals crystals crystals

(3) 4,4-Dimethyl-2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-10-oxo-5,10-dihydro- 4/7-

4,4-Dimethyl-10-oxo-2-(2,6-diazaspiro[3.3]heptan-2-yl)-5,10-dihydro-4/7-thiazolo[ 4,5-6]carbazole-7-carbonitrile (220 mg, 0.56 mmol) was dissolved in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL), glacial acetic acid (1 mL), 37% formaldehyde Aqueous solution (2 mL) and palladium on carbon (50 mg) were stirred at room temperature under hydrogen pressure for 24 hours. Filtration, rotary evaporation of the filtrate to remove the solvent, add concentrated ammonia

(2 mL), stirring for 5 minutes, the solvent was removed by rotary evaporation, and a solvent mixture of dichloromethane (20 mL) and methanol (2 mL) was added, and the mixture was stirred and filtered. Mg _; yield 80%).

Molecular formula: C ₂₂ H ₂₁ N ₅ OS; Molecular weight: 403.50; LC-MS (m/z): 404.2 [M+H] ⁺ iH-NMR (400MHz, DMSO- ₆ ) δ: 13.09 (s, 1H), 8.18 (d, 1H, J = 8.0Hz),

7.98 (s, 1H), 7.54 (dd, 1H, J = 8.0Hz), 4.31 (s, 4H), 4.15 (brs., 4H), 2.69 (s, 3H),

1.66 (s, 6H).

According to the preparation method exemplified in the preparation method section, the following compounds were prepared in a manner similar to the above examples:

Claims

Rights request

A compound represented by the formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof or

among them,

Selected from C-R ¹ or N;

A _{2 is} selected from 1 ² or

3⁄4^3⁄4, C2-6 women or. 2-6 fast

Y is selected from N or CR ⁹ ;

X is selected from 0, S or NR ⁹ ;

Q is selected from the following groups:

(1) 3 to 8 membered heterocyclic group,

(2) a 3 to 14 membered cycloalkyl group or a 6 to 14 membered heterocyclic group optionally substituted by one to three identical or different R ^1Q groups, and (3) a 6 to 12 membered bridged ring group or a 6 to 12 membered spirocyclic group optionally substituted with one to three identical or different R ^1Q groups,

. 2-6 blocks;

n is selected from 0, 1, 2, 3, 4, 5 or 6,

requirement is:

When n is 0, R ⁷ does not exist.

When 1 ≥ 2, R ⁷ may be the same or different, and

The compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the formula (I) is a formula (II):

among them,

M is selected from 0, S or NR ⁸ and R ^{8 is} selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl or C _2-6 alkynyl, said C _{1 -6} alkyl, C _2-6 alkenyl and C _2-6 alkynyl may be independently optionally substituted by C _1-6 alkoxy; R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, and a hydroxyl group C _1-6

3⁄4^3⁄4, C2-6 women or. 2-6 fast

Y is selected from N or CR ⁹ ;

X is selected from 0, S or NR ⁹ ;

Q is selected from the following groups:

(1) 4 to ⁷ membered heterocyclic group,

. 2-6 blocks;

C 6 3⁄4* base, . 2-6 women's base or. 2-6 fast base;

n is selected from 0, 1, 2 or 3

requirement is:

When n is 0, R ⁷ does not exist.

When 1 ≥ 2, R ⁷ may be the same or different, and

3. A compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof:

among them,

_{ι ι} , A ₂ and A ₃ are each independently selected from CH;

R ^{3 is} selected from hydrogen or cyano;

M is selected from Li;

R ⁵ and R ⁶ are each independently selected from hydrogen or C _1-6 alkyl; Y is selected from N;

X is selected from S.

4. A compound according to claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof:

among them,

R ¹ , R ² and R ⁴ are each independently selected from hydrogen, a halogen atom, a C _1-6 alkyl group or a 3 to 8 membered cycloalkyl group; and R ^{3 is} selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl An acyl group, a phenol atom, a CL ₆ alkyl group or a 3 to 8 membered cycloalkyl group;

Y is selected from N or CR ⁹ ;

X is selected from 0, S or NR ⁹ ;

Q is selected from the following groups:

(1) 5 to 6 membered heterocyclic group,

C 6 3⁄4* base, . 2-6 women's base or. 2-6 fast base,

n is selected from 0, 1, 2 or 3

requirement is: When n is 0, R ⁷ does not exist.

When 1 ≥ 2, R ⁷ may be the same or different, and

5. A compound according to claim 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof:

among them,

R ¹ , R ² and R ⁴ are each independently selected from hydrogen, methyl or ethyl;

R ^{3 is} selected from the group consisting of hydrogen, cyano, hydroxy, amino, fluorine, chlorine, methyl or ethyl;

M is selected from NR ⁸ and R ^{8 is} selected from hydrogen or CL ₄ alkyl;

R ⁵ and R ⁶ are each independently selected from C _1-4 alkyl;

Y is selected from N or CR ⁹ ;

X is selected from S or NR ⁹ ;

Q is selected from

(1) 5-6 membered heterocyclic group,

R ^{1Q is} selected from amino or CL ₄ alkyl;

n is selected from 0 or 1

requirement is:

When n is 0, R ⁷ does not exist, and

6. A compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof:

among them,

R ^{7 is} selected from ^{7 to} 8 membered bridged ring groups, preferably containing 1 or 2 ring atoms selected from oxygen and nitrogen, more preferably saturated; n is selected from 1.

7. A compound according to claim 6 or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

among them,

η is selected from 1.

The compound of claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof:

among them,

R ^{1Q is} selected from amino or CL ₆ alkyl;

n is selected from 0 or 1, and when n is 0, R ⁷ is absent.

9. A compound according to claim 8 or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

among them,

Q is selected from the group consisting of one or two identical or different R ^1Q

Or - N, N- - R ^{1Q is} selected from amino or CL ₄ alkyl;

R is selected from ,

+Ν 0,

n is selected from 0 or 1, when n is 0, R ⁷ does not exist,

10. A compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof:

among them,

R ^{1Q is} selected from amino or CL ₄ alkyl;

R ⁷ does not exist.

11. A compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof:

among them,

R ^{1Q is} selected from amino or CL ₄ alkyl;

R ⁷ does not exist.

12. The compound of claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, selected from the group consisting of:

L9

6Ρ6

A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, and one or more drugs Use a carrier and / or a diluent.

The pharmaceutical composition according to claim 13, which may further comprise one or more antitumor agents and immunosuppressive agents, wherein said antitumor agent and immunosuppressive agent are selected from the group consisting of methotrexate and card Peitabin, gemcitabine, deoxyfluorouridine, pemetrexed disodium, pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib, hep Statin, bevacizumab, rituximab, trastuzumab, paclitaxel, vinorelbine, docetaxel, doxorubicin, hydroxycamptothecin, mitomycin, epirubicin , pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, triclinin, flutamide, leuprolide, anastrozole, ifosfamide, busulfan , cyclophosphamide, carmustine, nimustine, semustine, nitrogen mustard, melphalan, cyclamate, carboplatin, cisplatin, oxaliplatin, platinum, topotecan, hi-tree Alkali, Topotecan, Everolimus, Sirolimus, Tetracarcinoma, 6-mercaptopurine, 6-stone guanine, gramazole Methotrexate, streptozotocin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, mithramycin or aminoglutethimide.

15. A compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, for use in the manufacture and/or prevention of ALK-mediated cancer. The use of a disease-related disease selected from the group consisting of a brain tumor, a non-small cell lung cancer, a squamous cell carcinoma, a bladder cancer, a stomach cancer, an ovarian cancer, a peritoneal cancer, a pancreatic cancer, a breast cancer, a head and neck cancer, Cervical cancer, endometrial cancer, rectal cancer, liver cancer, hepatoblastoma, papillary renal cell tumor, head and neck squamous cell tumor, nephroblastoma, renal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma , glioma, prostate cancer, thyroid cancer, female genital tract cancer, carcinoma in situ, lymphoma, neuroblastoma, neurofibromatosis, bone cancer, skin cancer, colon cancer, testicular cancer, small cell lung cancer, Gastrointestinal stromal tumors, prostate tumors, mast cell tumors, multiple myeloma or melanoma.

16. A method of preparing a compound of the formula (Γ) described below,

It includes the following steps:

H-Q'-(R ⁷ ') _n in a solvent in the presence of a base

React under heating

Or

And H-(R ⁷ ) _n in the presence of indium trichloride in a solvent

Reacting at room temperature, then adding a reducing agent,

Wherein A ₂ , A ₃ , M, Y, X, R ³ , R ⁵ , R ⁶ , R ⁷ , Q and n are as defined in claim 1, Q' is Q as defined in claim 1 or Q, R ⁷ ' as defined in claim 1 protected by a protecting group (PG) is R ⁷ as defined in claim 1 or protected by a protecting group (PG) as defined in claim 1. R ⁷ .