Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof

1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein the compound has the structure of Formula (I):

wherein:

X and Y are each independently selected from the group consisting of a direct bond, C(═O), O, S(═O) i and NR, provided that at least one of X and Y is not a direct bond;

R is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl, and at most 2 ring members in the cyclic hydrocarbyl and heterocyclyl are C(═O);

ring A and ring B are each independently selected from the group consisting of saturated or partially unsaturated C 3-10 hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocycle, C 6-10 aromatic ring and 5- to 14-membered heteroaromatic ring, and at most 2 ring members in the hydrocarbon ring and heterocycle are C(═O); provided that when ring B is a heterocycle containing a nitrogen atom, ring B is not attached to X via the nitrogen atom;

ring C is selected from the group consisting of saturated or partially unsaturated C 3-10 hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocycle, C 6-10 aromatic ring and 5- to 14-membered heteroaromatic ring, and at most 2 ring members in the hydrocarbon ring and heterocycle are C(═O);

ring D is absent, or is selected from the group consisting of saturated or partially unsaturated C 3-10 hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocycle, C 6-10 aromatic ring and 5- to 14-membered heteroaromatic ring, and at most 2 ring members in the hydrocarbon ring and heterocycle are C(═O);

ring E is selected from the group consisting of

ring F is selected from the group consisting of saturated or partially unsaturated C 3-10 hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocycle, C 6-10 aromatic ring and 5- to 14-membered heteroaromatic ring, and at most 2 ring members in the hydrocarbon ring and heterocycle are C(═O);

R 1 is selected from the group consisting of H, C 1-6 alkyl, N-methylpyrrolidinyl, N-methylpiperidinyl, acetyl, —C(═O)—C 1-6 alkylene-N(C 1-6 alkyl) 2 , N-methylpiperazine substituted acetyl, —S(═O) 2 R 1a , —P(═O)R 1a R 1b ,

provided that when one of R 1 and R 10 is C 1-6 alkyl, and the other is H or C 3-10 cyclic hydrocarbyl, at least one of X and Y is a direct bond, and ring C is not a 5-membered heteroaromatic ring; when one of R 1 and R 10 is H, and the other is

ring C is not a 5-membered heteroaromatic ring; when both R 1 and R 10 are H, ring A contains at least one nitrogen atom, and is not a 5- or 6-membered ring; when one of R 1 and R 10 is H, and the other is

ring C is not a 5-membered heteroaromatic ring; and when one of R 1 and R 10 is H, and the other is H or acetyl, ring D is absent;

R 1a and R 1b are each independently selected from the group consisting of H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R 5 , —OC(═O)R 5 , —C(═O)OR 5 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —S(═O) 2 NR 5 R 6 , —NR 5 R 6 , —C(═O)NR 5 R 6 , —NR 5 —C(═O)R 6 , —NR 5 —C(═O)OR 6 , —NR 5 —S(═O) 2 —R 6 , —NR 5 —C(═O)—NR 5 R 6 , —C 1-6 alkylene-NR 5 R 6 , —C 1-6 alkylene-OR 5 and —O—C 1-6 alkylene-NR 5 R 6 , provided that when one of R 1a and R 1b is n-propyl, the other is not H; or R 1a and R 1b together with the atom to which they are attached form a 3- to 12-membered heterocycle or heteroaromatic ring;

R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10 , at each occurrence, are each independently selected from the group consisting of H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R 5 , —OC(═O)R 5 , —C(═O)OR 5 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —S(═O) 2 NR 5 R 6 , —NR 5 R 6 , —C(═O)NR 5 R 6 , —NR 5 —C(═O)R 6 , —NR 5 —C(═O)OR 6 , —NR 5 —S(═O) 2 —R 6 , —NR 5 —C(═O)—NR 5 R 6 , —C 1-6 alkylene-NR 5 R 6 and —O—C 1-6 alkylene-NR 5 R 6 ;

R 5 and R 6 , at each occurrence, are each independently selected from the group consisting of H, C 1-6 alkyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl;

the above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl, at each occurrence, are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R 5 , —OC(═O)R 5 , —C(═O)OR 5 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —S(═O) 2 NR 5 R 6 , —NR 5 R 6 , —C(═O)NR 5 R 6 , —NR 5 —C(═O)R 6 , —NR 5 —C(═O)OR 6 , —NR 5 —S(═O) 2 —R 6 , —NR 5 —C(═O)—NR 5 R 6 , —C 1-6 alkylene-NR 5 R 6 and —O—C 1-6 alkylene-NR 5 R 6 , and the alkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl;

m, at each occurrence, is each independently an integer of 0, 1, 2 or 3;

n is an integer of 0, 1 or 2;

i is an integer of 0, 1 or 2; and

g is an integer of 0, 1, 2, 3 or 4.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein X and Y are each independently selected from the group consisting of a direct bond, C(═O), O, S, S(═O), S(═O) 2 and NH, and at least one of X and Y is a direct bond, provided that at least one of X and Y is not a direct bond.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein

is

the above group is attached to X at either of the two positions labeled # or ##, and is attached to R 1 at the other position, wherein:

represents either a single or a double bond, and the adjacent bonds are not double bonds simultaneously;

Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 , at each occurrence, are each independently selected from the group consisting of C, CR 9 , C(R 9 ) 2 , CR 10 , C(R 10 ) 2 , C(═O), N, NR 9 , NR 10 , O and S; and

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

provided that at most two groups among Z 1 -Z 9 are simultaneously C(═O), and the atom attached to X is not a nitrogen atom;

R 9 and R 10 , at each occurrence, are each independently selected from the group consisting of halogen, methyl, ethyl, propyl and —CH 2 CH 2 —N(CH 3 ) 2 .

4. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein

is

wherein:

R 7 and R 8 , at each occurrence, are each independently selected from the group consisting of F, Cl, Br, I, cyano, methyl, ethyl, propyl, methoxy, trifluoromethyl, phenyl, —O—CH 2 CH 2 —N(CH 3 ) 2 and —CH 2 CH 2 —N(CH 3 ) 2 .

5. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein ring E is

R 3 and R 4 , at each occurrence, are each independently selected from the group consisting of H, F, Cl, Br, I, methyl, ethyl, propyl, methoxy, —O-ethylene-N(CH 3 ) 2 .

6. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein R 1 is methyl, —C(═O)CH 2 N(CH 3 ) 2 ,

wherein R 11 is H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R 5 , —OC(═O)R 5 , —C(═O)OR 5 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —S(═O) 2 NR 5 R 6 , —NR 5 R 6 , —C(═O)NR 5 R 6 , —NR 5 —C(═O)R 6 , —NR 5 —C(═O)OR 6 , —NR 5 —S(═O) 2 —R 6 , —NR 5 —C(═O)—NR 5 R 6 , —C 1-6 alkylene-NR 5 R 6 or —O—C 1-6 alkylene-NR 5 R 6 .

7. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein R 1a and R 1b are each independently selected from the group consisting of H, methyl, —CF 3 , ethyl, —CH 2 CF 3 , n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -ethylene-O-methyl, —CH 2 CN, —CH 2 CH 2 CN, —CH 2 CH 2 OH,

or R 1a and R 1b together with the atom to which they are attached form the following group:

8. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein the compound has the structure of any of the following formulae:

wherein:

Z is selected from the group consisting of O, S(═O) i and NR;

each of the remaining groups is as defined in claim 1 .

9. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein the compound has the following structure:

No.

Structural Formula

TDI01102

TDI01103

TDI01104

TDI01105

TDI01106

TDI01107

TDI01108

TDI01109

TDI01110

TDI01111

TDI01112

TDI01113

TDI01114

TDI01115

TDI01116

TDI01117

TDI01118

TDI01119

TDI01120

TDI01121

TDI01122

TDI01127

TDI01128

TDI01129

TDI01130

TDI01131

TDI01132

TDI01133

TDI01134

TDI01135

TDI01136

TDI01139

TDI01140

TDI01141

TDI01142

TDI01143

TDI01144

TDI01145

TDI01146

TDI01147

TDI01148

TDI01149

TDI01150

TDI01151

TDI01152

TDI01153

TDI01154

TDI01155

TDI01156

TDI01157

TDI01158

TDI01159

TDI01160

TDI01161

TDI01162

TDI01163

TDI01164

TDI01165

TDI01166

TDI01167

TDI01168

TDI01169

TDI01171

TDI01172

TDI01173

TDI01174

TDI01175

TDI01176

TDI01177

TDI01178

TDI01179

TDI01180

TDI01181

TDI01182

TDI01183

TDI01184

TDI01185

TDI01186

TDI01187

TDI01188

TDI01189

TDI01190

TDI01191

TDI01192

TDI01193

TDI01194

TDI01195

TDI01196

TDI01197

TDI01198

TDI01199

TDI01200

TDI01201

TDI01209

TDI01211

TDI01212

TDI01213

TDI01214

TDI01215

TDI01216

TDI01217

TDI01218

TDI01219

TDI01220

TDI01221

TDI01222

TDI01223

TDI01224

TDI01225

TDI01226

TDI01227

TDI01228

TDI01229

TDI01230

TDI01231

TDI01232

TDI01233

TDI01234

TDI01235

TDI01236

TDI01237

TDI01238

TDI01239

TDI01240

TDI01241

TDI01242

TDI01243

TDI01244

TDI01245

TDI01246

TDI01247

TDI01248

TDI01249

TDI01250

TDI01251

TDI01253

TDI01254

TDI01255

TDI01256

TDI01257

TDI01258

TDI01259

TDI01260

TDI01261

TDI01262

TDI01263

TDI01264

TDI01265

TDI01266

TDI01267

TDI01268

TDI01271

TDI01272

TDI01273

TDI01274

TDI01275

TDI01276

TDI01277

TDI01278

TDI01280

TDI01281

TDI01282

TDI01283

TDI01285

TDI01286

TDI01287

TDI01288

TDI01289

TDI01290

TDI01291

TDI01292

TDI01294

TDI01295

TDI01296

TDI01297

TDI01298

TDI01299

TDI01300

TDI01310

TDI01311

TDI01312

TDI01314

TDI01315

TDI01316

TDI01317

TDI01318

TDI01319

TDI01320

TDI01321

TDI01323

TDI01324

TDI01325

TDI01326

TDI01327

TDI01329

TDI01330

TDI01331

TDI01332

TDI01333

TDI01334

TDI01335

TDI01336

TDI01337

TDI01338

TDI01339

TDI01340

TDI01341

TDI01342

TDI01343

TDI01344

TDI01345

TDI01346

TDI01347

TDI01348

TDI01348P-2

TDI01350

TDI01351

TDI01354

TDI01355

TDI01362

TDI01363

TDI01366

TDI01369

TDI01370

TDI01379

TDI01381

TDI01388

TDI01393

TDI01397

TDI01398

TDI01402

TDI01344-2A

TDI01408

TDI01410

TDI01411

TDI01415

TDI01416

TDI01418

TDI01419

TDI01420

TDI01421

TDI01422

TDI01423

TDI01424

TDI01425

TDI01426

TDI01427

TDI01428

TDI01429

TDI01430

TDI01431

TDI01432

TDI01433

TDI01434

TDI01435

TDI01436

TDI01437

TDI01438

TDI01439

TDI01440

TDI01441

TDI01442

TDI01443

TDI01818

TDI01819

TDI01820

TDI01821

TDI01822

TDI01823

TDI01829B

TDI01829C

TDI01832

TDI01833

TDI01837

TDI01838

TDI01842

TDI01845

TDI01846

TDI01847B

TDI01849B

TDI01851

TDI01852

TDI01853

TDI01854

TDI01855

TDI01856

TDI01861

TDI01862

TDI01864

TDI01865

TDI01867

TDI01868

TDI01872

TDI01878

TDI01879

TDI01880

TDI01882

TDI01883

10. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, and a pharmaceutically acceptable carrier.

11. A method for the preparation of a compound of Formula (II) according to claim 8 , wherein the method comprises the following steps:

wherein:

R 2 is H;

Hal 1 and Hal 2 are same or different halogens;

PG 1 is a carboxy protecting group;

PG 2 is H or an amino protecting group;

R a and R a′ , at each occurrence, are each independently selected from the group consisting of H and C 1-6 alkyl; or R a and R a′ together with the group to which they are attached form a 5- to 10-membered ring system;

the remaining groups are as defined in claim 8 ;

the reaction conditions for each step are as follows:

step 1: reacting compound a-1 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound b-1;

step 2: reacting compound b-1 with compound REG-1 under the catalysis of a palladium catalyst, to obtain compound c-1; and

step 3: reacting compound c-1 with compound REG-2, to obtain the compound of Formula (II);

alternatively, the method comprises the following steps:

wherein each of the groups is as defined above;

the reaction conditions for each step are as follows:

step 1: reacting compound a-2 with compound REG-2, to obtain compound b-2;

step 2: reacting compound b-2 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound c-2; and

step 3: reacting compound c-2 with compound REG-1 under the catalysis of a palladium catalyst, to obtain the compound of Formula (II);

alternatively, the method comprises the following steps:

wherein each of the groups is as defined above;

the reaction conditions for each step are as follows:

step 1: reacting compound a-1 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound b-1;

step 2: deprotecting compound b-1 under a condition corresponding to PG 1 , to obtain compound c-3;

step 3: reacting compound c-3 with compound REG-2, to obtain compound d-3; and

step 4: reacting compound d-3 with compound REG-1 under the catalysis of a palladium catalyst, to obtain the compound of Formula (II).

12. A method for the preparation of a compound of Formula (XII) according to claim 8 , wherein the method comprises the following steps:

wherein:

R 2 is H;

Hal 1 and Hal 2 are same or different halogens;

PG 1 is a carboxy protecting group;

PG 2 is H or an amino protecting group;

R a and R a′ , at each occurrence, are each independently selected from the group consisting of H and C 1-6 alkyl; or R a and R a′ together with the group to which they are attached form a 5- to 10-membered ring system;

the remaining groups are as defined in claim 8 ;

the reaction conditions for each step are as follows:

step 1: reacting compound a-1 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound b-1;

step 2: reacting compound b-1 with compound REG-1′ under the catalysis of a palladium catalyst, to obtain compound c-1′; and

step 3: reacting compound c-1′ with compound REG-2′, to obtain the compound of Formula (XII).

13. A method for the preparation of a compound of Formula (XIII) according to claim 8 , wherein the method comprises the following steps:

wherein:

R 2 is H;

Hal 1 and Hal 2 are same or different halogens;

PG 1 is a carboxy protecting group;

PG 2 is H or an amino protecting group;

R a and R a′ , at each occurrence, are each independently selected from the group consisting of H and C 1-6 alkyl; or R a and R a′ together with the group to which they are attached form a 5- to 10-membered ring system;

the remaining groups are as defined in claim 8 ;

the reaction conditions for each step are as follows:

step 1: reacting compound a-1 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound b-1;

step 2: reacting compound b-1 with compound REG-1 under the catalysis of a palladium catalyst, to obtain compound c-1; and

step 3: reacting compound c-1 with compound REG-2′, to obtain the compound of Formula (XIII).

14. A method for the preparation of a compound of Formula (XIV) according to claim 8 , wherein the method comprises the following steps:

wherein:

R 2 is H;

Hal 1 and Hal 2 are same or different halogens;

PG 1 is a carboxy protecting group;

PG 2 is H or an amino protecting group;

R a and R a′ , at each occurrence, are each independently selected from the group consisting of H and C 1-6 alkyl; or R a and R a′ together with the group to which they are attached form a 5- to 10-membered ring system;

the remaining groups are as defined in claim 8 ;

the reaction conditions for each step are as follows:

step 1: reacting compound a-1 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound b-1;

step 2: reacting compound b-1 with compound REG-1′ under the catalysis of a palladium catalyst, to obtain compound c-1′; and

step 3: reacting compound c-1′ with compound REG-2, to obtain the compound of Formula (XIV);

alternatively, the method comprises the following steps:

wherein each of the groups is as defined above;

the reaction conditions for each step are as follows:

step 1: reacting compound a-2 with compound REG-2, to obtain compound b-2;

step 2: reacting compound b-2 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound c-2; and

step 3: reacting compound c-2 with compound REG-1′ under the catalysis of a palladium catalyst, to obtain the compound of Formula (XIV);

alternatively, the method comprises the following steps:

wherein each of the groups is as defined above;

the reaction conditions for each step are as follows:

step 1: reacting compound a-1 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound b-1;

step 2: deprotecting compound b-1 under a condition corresponding to PG 1 , to obtain compound c-3;

step 3: reacting compound c-3 with compound REG-2, to obtain compound d-3; and

step 4: reacting compound d-3 with compound REG-1′ under the catalysis of a palladium catalyst, to obtain the compound of Formula (XIV).

15. The compound according to claim 3 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 , at each occurrence, are each independently selected from the group consisting of C, CH, CCl, CCH 3 , CH 2 , C(═O), N, NH, NCH 3 , NCH 2 CH 2 —N(CH 3 ) 2 , O and S.

16. The compound according to claim 3 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein

is

the above group is attached to X at either of the two positions labeled # or ##, and is attached to R 1 at the other position, wherein:

represents either a single or a double bond, and the adjacent bonds are not double bonds simultaneously;

Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 , at each occurrence, are each independently selected from the group consisting of C, CR 9 , C(R 9 ) 2 , CR 10 , C(R 10 ) 2 , C(═O), N, NR 9 , NR 10 , O and S; and

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

provided that at most two groups among Z 1 -Z 9 are simultaneously C(═O), and the atom attached to X is not a nitrogen atom.

17. The compound according to claim 16 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 , at each occurrence, are each independently selected from the group consisting of C, CH, CCl, CCH 3 , CH 2 , C(═O), N, NH, NCH 3 , NCH 2 CH 2 —N(CH 3 ) 2 , O and S.

18. The compound according to claim 3 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein at least one of ring A and ring B is selected from the group consisting of saturated or partially unsaturated 3- to 10-membered heterocycle and 5- to 14-membered heteroaromatic ring, and at most 2 ring members in the heterocycle are C(═O).

19. The compound according to claim 3 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein

is

wherein ring A′ and ring B′ are each independently selected from the group consisting of saturated or partially unsaturated 3- to 10-membered heterocycle and 5- to 14-membered heteroaromatic ring, and at most 2 ring members in the heterocycle are C(═O); provided that when ring B′ is a heterocycle containing a nitrogen atom, ring B′ is not attached to X via the nitrogen atom.

20. The compound according to claim 19 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein

is

21. The compound according to claim 19 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein

is

22. The compound according to claim 3 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein

is selected from the group consisting of

the above group is attached to X at either of the two positions labeled # or ##, and is attached to R 1 at the other position, provided that the atom attached to X is not a nitrogen atom.

23. The compound according to claim 4 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein

is

the above group is attached to Y at either of the two positions labeled * or **, and is attached to X at the other position,

wherein:

represents either a single or a double bond, and the adjacent bonds are not double bonds simultaneously;

V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 and V 9 , at each occurrence, are each independently selected from the group consisting of C, CR 7 , C(R 7 ) 2 , CR 8 , C(R 8 ) 2 , C(═O), N, NR 7 , NR 8 , O and S; and

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

provided that at most two groups among V 1 -V 9 are simultaneously C(═O).

24. The compound according to claim 4 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein

is

the above group is attached to Y at either of the two positions labeled * or **, and is attached to X at the other position,

wherein:

represents either a single or a double bond, and the adjacent bonds are not double bonds simultaneously;

V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 and V 9 , at each occurrence, are each independently selected from the group consisting of C, CR 7 , C(R 7 ) 2 , CR 8 , C(R 8 ) 2 , C(═O), N, NR 7 , NR B , O and S; and

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

provided that at most two groups among V 1 -V 9 are simultaneously C(═O).

25. The compound according to claim 23 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 and V 9 , at each occurrence, are each independently selected from the group consisting of C, CH, CF, CCl, CCN, CCH 3 , C—OCH 3 , CCF 3 , —CO—CH 2 CH 2 —N(CH 3 ) 2 , CH 2 , C(═O), N, NH, NCH 3 , N-Ph, —N—CH 2 CH 2 —N(CH 3 ) 2 , O and S.

26. The compound according to claim 24 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 and V 9 , at each occurrence, are each independently selected from the group consisting of C, CH, CF, CCl, CCN, CCH 3 , C—OCH 3 , CCF 3 , —CO—CH 2 CH 2 —N(CH 3 ) 2 , CH 2 , C(═O), N, NH, NCH 3 , N-Ph, —N—CH 2 CH 2 —N(CH 3 ) 2 , O and S.

27. The compound according to claim 4 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein

is

28. The compound according to claim 4 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein

is

29. The compound according to claim 4 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein

the above group is attached to Y at either of the two positions labeled * or **, and is attached to X at the other position.

30. The compound according to claim 5 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein ring E is

31. The compound according to claim 5 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein ring E is

32. The compound according to claim 6 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, N-oxide, isotopically labeled compound, or metabolite thereof, wherein R 1 is

33. The pharmaceutical composition according to claim 10 , wherein the pharmaceutical composition is in the form of a solid, semi-solid, liquid, or gas preparation.

34. The method according to claim 11 , wherein Hal 1 and Hal 2 are each independently selected from F, Cl, Br and I.

35. The method according to claim 11 , wherein PG 1 is C 1-6 alkyl.

36. The method according to claim 11 , wherein PG 2 is tert-butyloxycarbonyl (Boc).

37. The method according to claim 12 , wherein Hal 1 and Hal 2 are each independently selected from F, Cl, Br and I.

38. The method according to claim 12 , wherein PG 1 is C 1-6 alkyl.

39. The method according to claim 12 , wherein PG 2 is tert-butyloxycarbonyl (Boc).

40. The method according to claim 13 , wherein Hal 1 and Hal 2 are each independently selected from F, Cl, Br and I.

41. The method according to claim 13 , wherein PG 1 is C 1-6 alkyl.

42. The method according to claim 13 , wherein PG 2 is tert-butyloxycarbonyl (Boc).

43. The method according to claim 14 , wherein Hal 1 and Hal 2 are each independently selected from F, Cl, Br and I.

44. The method according to claim 14 , wherein PG 1 is C 1-6 alkyl.

45. The method according to claim 14 , wherein PG 2 is tert-butyloxycarbonyl (Boc).