TW202227429A - P300 inhibitors and use thereof in medicine - Google Patents

Abstract

The present invention relates to compounds which have cancer treatment activity, and also relates to a preparation method for such compounds and a pharmaceutical composition comprising same.

Description

P300 inhibitors, pharmaceutical compositions containing the same, uses thereof, and methods of making the same

The present invention relates to a novel compound having cancer therapeutic activity. The present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing them.

Post-translational acetylation of histones has important biological functions in gene transcription regulation, cell differentiation, cell proliferation, cell cycle regulation, and apoptosis. Acetylation of histones is accomplished by histone acetyltransferases (HATs), which catalyze the acetyltransferase reaction from acetyl-CoA to specific lysines. p300 is the major cellular histone acetyltransferase. High levels of p300 were observed in some tumors, and when the p300 gene was knocked out, tumor cell proliferation was inhibited.

At present, there are few studies on histone acetyltransferase inhibitors, and the inhibitors under investigation such as C646 have the characteristics of weak inhibitory activity and strong in vivo toxicity. Therefore, the development of potent and highly selective histone acetyltransferase inhibitors is of great significance for the treatment of cancer.

(I) 其中， R ¹選自C _6-10芳基或5-10員雜芳基，R ¹任選地進一步被一個或多個R ⁵所取代； R ⁵獨立地選自H、氧代、醯基、氰基、鹵素、氧代基、C _1-6烷基、-C _0-3亞烷基-OR ^a、-C _0-3亞烷基-O-C(O)N(R ^a) ₂、-C _0-3亞烷基-N（R ^a） ₂、-C _0-3亞烷基-NR _aC(O)R _a、-C _0-3亞烷基-NR _aC(O)N（R ^a） ₂、-C _0-6亞烷基-NR _aS(O)R ^a、-C _0-3亞烷基-NR _aS(O) ₂R ^a、-C _0-3亞烷基-S(O)R ^a、-C _0-3亞烷基-S(O) ₂R ^a、-C _0-3亞烷基-S(O) ₂N(R ^a) ₂、-C _0-3亞烷基-S(O)N(R ^a) ₂、-C _0-3亞烷基SR ^a、-C _0-3亞烷基-S(R ^a) ₅、-C _0-3亞烷基-C(O)R ^a、-C _0-3亞烷基-C(O)OR ^a、-C _0-3亞烷基-C(=O)N（R ^a） ₂、-C(O)NHOR ^b、C _2-6烯基、C _2-6炔基、

、

、

、

、-C _0-3亞烷基-C _3-14環烷基、-C _0-3亞烷基-（3-14員雜環烷基）、-C _0-3亞烷基-C _6-14芳基或-C _0-3亞烷基-(5-14員雜芳基)；所述C _1-6烷基、C _2-6烯基、C _2-6炔基、-C _0-3亞烷基-C _3-14環烷基、-C _0-3亞烷基-（3-14員雜環烷基）、-C _0-3亞烷基-C _6-14芳基或-C _0-3亞烷基-(5-14員雜芳基)任選地進一步被一個或多個選自H、氧代、醯基、氰基、鹵素、氧代基、C _1-6烷基、C _1-6烷氧基、C _1-6鹵代烷基、C _1-6羥基烷基、-C _0-3亞烷基-OR ^a、-C _0-3亞烷基-O-C(O)N(R ^a) ₂、-C _0-3亞烷基-O-S(O) ₂OR ^a、-C _0-3亞烷基-OS(O) ₂R ^a、-C _0-3亞烷基-N（R ^a） ₂、-C _0-3亞烷基-NR _aC(O)R ^a、-C _0-3亞烷基-NR _aC(O)N（R ^a） ₂、-C _0-6亞烷基-NR ^aS(O)R ^a、-C _0-3亞烷基-NR ^aS(O) ₂R ^a、-C _0-3亞烷基-S(O)R ^a、-C _0-3亞烷基-S(O) ₂R ^a、-C _0-3亞烷基-S(O) ₂N(R ^a) ₂、-C _0-3亞烷基-S(O)N(R ^a) ₂、-C _0-3亞烷基SR ^a、-C _0-3亞烷基-S(R ^a) ₅、-C _0-3亞烷基-S(O)(NH)R ^a、-C _0-3亞烷基-C(O)R ^a、-C _0-3亞烷基-C(O)OR ^a、-C _0-3亞烷基-C(=O)N（R ^a） ₂、-C(O)NHOR ^b、-C _0-3亞烷基-C(S)N(R ^b) ₂、-P(O)(OR ^b) ₂、-P(O)(R ^b) ₂、C _2-6烯基、C _2-6炔基、-C _0-6亞烷基-C _3-14環烷基、-C _0-6亞烷基-(3-14員雜環基)、-C _0-6亞烷基-C _6-14芳基或-C _0-6亞烷基-(5-14員雜芳基)的取代基所取代；所述R _a各自獨立地選自H、鹵素、羥基、氨基、氧代基、硝基、氰基、羧基、C _1-6烷基、C _1-6羥基烷基、C _1-6氨基烷基、C _1-6鹵代烷基、C _1-6烷氧基、C _1-6鹵代烷氧基、C _1-6雜烷基、C _3-8環烷基、3-8員雜環基、C _6-14芳基或5-14員雜芳基； X選自鍵、O、S、NR ⁶、C _1-3亞烷基，所述C _1-3亞烷基任選地進一步被一個或多個R ⁶所取代，R ⁶選自羥基、氧代基、鹵素或C _1-6烷基；較佳X為鍵； R ²選自C _3-10環烷基、3-10員雜環基、C _6-10芳基或6-10員雜芳基，R ²任選地進一步被一個或多個R ⁷所取代； R ⁷獨立地選自氧代、醯基、氰基、鹵素、C _1-6烷基、C _1-6鹵代烷基、C _1-6醛基、-C _0-3亞烷基-OR ^b、-C _0-3亞烷基-N（R ^b） ₂、-C _0-3亞烷基-S(=O)R ^b、-C _0-3亞烷基-S(=O) ₂R ^b、-(CH ₂) _0-3-SR ^b、-(CH ₂) _0-3-S(R ^b) ₅、-C(=O)N（R ^b） ₂、C _2-6烯基、C _2-6炔基、-C _0-3亞烷基-C _3-14環烷基、-C _0-3亞烷基-（3-14員雜環烷基）、-C _0-3亞烷基-C _6-14芳基或-C _0-3亞烷基-(5-14員雜芳基)，所述-C _0-3亞烷基-C _3-14環烷基、-C _0-3亞烷基-（3-14員雜環烷基）、-C _0-3亞烷基-C _6-14芳基或-C _0-3亞烷基-(5-14員雜芳基)任選未取代或進一步被一個或多個R ^b取代基所取代，且每個R ^b獨立地為H、鹵素、C _1-6烷基、C _1-6鹵代烷基、C _3-14環烷基、3-14員雜環烷基、C _2-3烯基、C _2-3炔基、芳基或雜芳基； R ³選自

或

，所述R ⁸或R ⁹各自獨立地選自H或C _1-6烷基，所述C _1-6烷基任選地進一步被一個或多個選自-OH、C _1-6烷氧基、-OC(=O)-C _1-6烷基的取代基所取代； R ⁴獨立地選自H、鹵素、羥基、C _1-3烷基、C _1-3烷氧基或C _1-3鹵代烷基。 The present invention provides a compound represented by general formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt:

(1) wherein, R ¹ is selected from C _6-10 aryl or 5-10 membered heteroaryl, R ¹ is optionally further substituted by one or more R ⁵ ; R ⁵ is independently selected from H, oxo , acyl, cyano, halogen, oxo, C _1-6 alkyl, -C _0-3 alkylene-OR ^a , -C _0-3 alkylene-OC(O)N(R ^a ) ₂ , -C _0-3 alkylene-N(R ^a ) ₂ , -C _0-3 alkylene-NR _a C(O)R _a , -C _0-3 alkylene-NR _a C(O )N(R ^a ) ₂ , -C _0-6 alkylene-NR _a S(O)R ^a , -C _0-3 alkylene-NR _a S(O) ₂ R ^a , -C _0-3 Alkylene-S(O)R ^a , -C _0-3 alkylene-S(O) ₂ R ^a , -C _0-3 alkylene-S(O) ₂ N(R ^a ) ₂ , - C _0-3 alkylene-S(O)N(R ^a ) ₂ , -C _0-3 alkylene SR ^a , -C _0-3 alkylene-S(R ^a ) ₅ , -C _{0- 3} alkylene-C(O)R ^a , -C _0-3 alkylene-C(O)OR ^a , -C _0-3 alkylene-C(=O)N(R ^a ) ₂ , - C(O)NHOR ^b , C _2-6 alkenyl, C _2-6 alkynyl,

,

,

,

, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14-membered heterocycloalkyl), -C _0-3 alkylene-C _{6- 14} aryl or -C _0-3 alkylene-(5-14 membered heteroaryl); the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _{0- 3} alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocycloalkyl), -C _0-3 alkylene-C _6-14 aryl or - C _0-3 alkylene-(5-14 membered heteroaryl) is optionally further substituted by one or more selected from H, oxo, acyl, cyano, halogen, oxo, C _1-6 alkane group, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, -C _0-3 alkylene-OR ^a , -C _0-3 alkylene-OC(O) N(R ^a ) ₂ , -C _0-3 alkylene-OS(O) ₂ OR ^a , -C _0-3 alkylene-OS(O) ₂ R ^a , -C _0-3 alkylene- N(R ^a ) ₂ , -C _0-3 alkylene-NR _a C(O)R ^a , -C _0-3 alkylene-NR _a C(O)N(R ^a ) ₂ , -C _{0 -6} alkylene-NR ^a S(O)R ^a , -C _0-3 alkylene-NR ^a S(O) ₂ R ^a , -C _0-3 alkylene-S(O)R ^a , -C _0-3 alkylene-S(O) ₂ R ^a , -C _0-3 alkylene-S(O) ₂ N(R ^a ) ₂ , -C _0-3 alkylene-S(O )N(R ^a ) ₂ , -C _0-3 alkylene SR ^a , -C _0-3 alkylene-S(R ^a ) ₅ , -C _0-3 alkylene-S(O)(NH )R ^a , -C _0-3 alkylene-C(O)R ^a , -C _0-3 alkylene-C(O)OR ^a , -C _0-3 alkylene-C(=O) N(R ^a ) ₂ , -C(O)NHOR ^b , -C _0-3 alkylene-C(S)N(R ^b ) ₂ , -P(O)(OR ^b ) ₂ , -P(O )(R ^b ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, -C _0-6 alkylene-C _3-14 cycloalkyl, -C _0-6 alkylene-(3- 14-membered heterocyclyl), -C _0-6 alkylene-C _6-14 aryl or -C _0-6 alkylene-(5-14-membered heteroaryl) substituents; the R _a is each independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-14 Aryl or 5-14 member hetero Aryl; X is selected from bond, O, S, NR ⁶ , C _1-3 alkylene optionally further _substituted by one or more R ^{6 selected} from Hydroxyl, oxo, halogen or C _1-6 alkyl; preferably X is a bond; R ² is selected from C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 6- 10-membered heteroaryl, R ² is optionally further substituted by one or more R ⁷ ; R ⁷ is independently selected from oxo, acyl, cyano, halogen, C _1-6 alkyl, C _1-6 Haloalkyl, C _1-6 aldehyde group, -C _0-3 alkylene-OR ^b , -C _0-3 alkylene-N(R ^b ) ₂ , -C _0-3 alkylene-S(= O)R ^b , -C _0-3 alkylene-S(=O) ₂ R ^b , -(CH ₂ ) _0-3 -SR ^b , -(CH ₂ ) _0-3 -S(R ^b ) ₅ , -C(=O)N(R ^b ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 Alkylene-(3-14-membered heterocycloalkyl), -C _0-3 alkylene-C _6-14 aryl or -C _0-3 alkylene-(5-14-membered heteroaryl), The -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocycloalkyl), -C _0-3 alkylene-C _{6 -14} aryl or -C _0-3 alkylene-(5-14 membered heteroaryl ⁾ optionally unsubstituted or further substituted with one or more R substituents, and each R ^is independently H , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, 3-14 membered heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl or heteroaryl; ^R is selected from

or

, the R ⁸ or R ⁹ are each independently selected from H or C _1-6 alkyl, the C _1-6 alkyl is optionally further selected from -OH, C _1-6 alkoxy substituted by substituents of -OC(=O)-C _1-6 alkyl; R ⁴ is independently selected from H, halogen, hydroxyl, C _1-3 alkyl, C _1-3 alkoxy or C _{1 -3} haloalkyl.

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

，R ¹任選地進一步被一個或多個R ⁵所取代。 In some embodiments, the substituent of R ¹ described in formula (I) is selected from

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

, R ¹ is optionally further substituted by one or more R ⁵ .

、

、

、

、雜環基、氧代雜環基、苯基或吡啶基，所述C _2-6炔基、苯基或吡啶基任選地進一步被一個或多個選自鹵素、羥基、C _1-6烷基、C _1-6烷氧基、C _1-6羥基烷基、-C _0-3亞烷基-C(O)OR ^a、-C _0-3亞烷基-C(O)N(R ^a) ₂、-C _0-3亞烷基-C(S)N(R ^a) ₂、-C _0-3亞烷基-O-S(O) ₂OR ^a、-C _0-3亞烷基-OS(O) ₂R ^a、-C _0-3亞烷基-S(O) ₂R ^a、-C _0-3亞烷基-S(O)R ^a、-C _0-3亞烷基-S(O) ₂N(R ^a) ₂、-C _0-3亞烷基-S(O)(NH)R ^a、-C _0-3亞烷基-N(R ^a) ₂、-C _0-3亞烷基-NHS(O) ₂R ^a、-C _0-3亞烷基-NHC(O)R ^a、-C _0-3亞烷基-P(O)(OR ^a) ₂、-C _0-3亞烷基-P(O)(R ^a) ₂的取代基所取代；所述R ^a選自H、C _1-6烷基或環丙基。 In some embodiments, R ⁵ described in formula (I) is independently selected from H, hydroxyl, halogen, cyano, oxo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 hydroxyalkane base, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkoxy, -C _0-3 alkylene-C(O)OR ^a , -C _0-3 alkylene- C(O)N(R ^a ) ₂ , -C _0-3 alkylene-C(O)NHOR ^a , -C _0-3 alkylene-S(O) ₂ R ^a , -C _0-3 alkylene Alkyl-S(O) ₂ N(R ^a ) ₂ , -C _0-3 alkylene-N(R ^a ) ₂ , -C _0-3 alkylene-OC(O)N(R ^a ) ₂ ,

,

,

,

, heterocyclyl, oxoheterocyclyl, phenyl or pyridyl, said C _2-6 alkynyl, phenyl or pyridyl optionally further selected by one or more selected from halogen, hydroxy, C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, -C _0-3 alkylene-C(O)OR ^a , -C _0-3 alkylene-C(O)N( R ^a ) ₂ , -C _0-3 alkylene-C(S)N(R ^a ) ₂ , -C _0-3 alkylene-OS(O) ₂ OR ^a , -C _0-3 alkylene -OS(O) ₂ R ^a , -C _0-3 alkylene-S(O) ₂ R ^a , -C _0-3 alkylene-S(O)R ^a , -C _0-3 alkylene -S(O) ₂ N(R ^a ) ₂ , -C _0-3 alkylene-S(O)(NH)R ^a , -C _0-3 alkylene-N(R ^a ) ₂ , -C _0-3 alkylene-NHS(O) ₂ R ^a , -C _0-3 alkylene-NHC(O)R ^a , -C _0-3 alkylene-P(O)(OR ^a ) ₂ , -C _0-3 alkylene-P(O)(R ^a ) ₂ substituents; the R ^a is selected from H, C _1-6 alkyl or cyclopropyl.

。 In some embodiments, the substituent of R ¹ described in formula (I) is selected from

.

或

，較佳為

。 In some embodiments, the substituent of R ² described in formula (I) is selected from

or

, preferably

.

或

，較佳為

。 In some embodiments, the substituent of R ³ described in formula (I) is selected from

or

, preferably

.

In some embodiments, R ⁴ of formula (I) is H.

(I-1)                       (I-2)                        (I-3) 其中，取代基如式（I）所定義。 In some embodiments, formula (I) is selected from compounds of formula:

(I-1) (I-2) (I-3) wherein the substituents are as defined in formula (I).

。

。 In some embodiments, the compound of formula (I) is selected from:

.

.

化合物（IB）與化合物

發生偶聯反應，得到化合物（IC）, 其中R ₁-R ₉的定義如式（I）所述。 In some embodiments, methods of preparing compounds of general formula (IC), tautomers, deuterated compounds or pharmaceutically acceptable salts thereof comprise:

Compounds (IB) and Compounds

A coupling reaction occurs to give compound (IC), wherein R ₁ -R ₉ are as defined in formula (I).

The present invention also provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by formula (I) and at least one pharmaceutically acceptable excipient.

The present invention further provides a pharmaceutical composition, characterized in that the mass percentage of the therapeutically effective amount of at least one compound represented by formula (I) and pharmaceutically acceptable excipients is 0.0001:1-10.

The present invention provides the application of the compound represented by the structural formula (I) or the pharmaceutical composition in the preparation of medicine.

The present invention further provides a better technical solution for the application.

Preferably, the application is in the preparation of a drug for treating and/or preventing cancer.

Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, Esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, Lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

The present invention also provides a method for treating and/or preventing a disease, comprising administering a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.

The present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any one compound represented by structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.

Unless otherwise indicated, general chemical terms used in the structural formulae have their ordinary meanings.

For example, unless otherwise specified, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, " _1-8 " in "base _1-8 alkyl" refers to a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in straight or branched chain form group.

"C _1-3 alkylene" refers to a linear or branched divalent saturated hydrocarbon group. For example, methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.

In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

The term "aryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted mono- or fused-ring aromatic group comprising atoms of a carbocyclic ring, having a fully conjugated pi-electron system. Preferred aryl groups are monocyclic or polycyclic aromatic ring groups of 6 to 14 members. Preferred are phenyl and naphthyl. The best is phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring.

The term "heterocyclyl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable monocyclic ring system consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S, which is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 14 carbon atoms, wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively replaced by quaternary ammonium change. The heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, oxidyl, oxazinyl, oxoxazinyl, oxoxaziridinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinylidene, thiomorpholinyl and tetrahydro oxadiazolyl. The heterocyclyl group can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl group.

The term "heteroaryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-, 10- or 14-membered A benzo-fused heteroaromatic ring system or a polycyclic heteroaromatic ring system consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may be Selectively oxidized, the nitrogen heteroatoms can be selectively quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene thiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.

The term "cycloalkyl" refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 14 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl . The cycloalkyl group can be fused to an aryl, heterocyclyl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl group.

、

、

、

、-C _0-3亞烷基-C _3-14環烷基、-C _0-3亞烷基-（3-14員雜環烷基）、-C _0-3亞烷基-C _6-14芳基或-C _0-3亞烷基-(5-14員雜芳基)；所述C _1-6烷基、C _2-6烯基、C _2-6炔基、-C _0-3亞烷基-C _3-14環烷基、-C _0-3亞烷基-（3-14員雜環烷基）、-C _0-3亞烷基-C _6-14芳基或-C _0-3亞烷基-(5-14員雜芳基)任選地進一步被一個或多個選自H、氧代、醯基、氰基、鹵素、氧代基、C _1-6烷基、C _1-6烷氧基、C _1-6鹵代烷基、C _1-6羥基烷基、-C _0-3亞烷基-OR ^a、-C _0-3亞烷基-O-C(O)N(R ^a) ₂、-C _0-3亞烷基-O-S(O) ₂OR ^a、-C _0-3亞烷基-OS(O) ₂R ^a、-C _0-3亞烷基-N（R ^a） ₂、-C _0-3亞烷基-NR _aC(O)R ^a、-C _0-3亞烷基-NR _aC(O)N（R ^a） ₂、-C _0-6亞烷基-NR ^aS(O)R ^a、-C _0-3亞烷基-NR ^aS(O) ₂R ^a、-C _0-3亞烷基-S(O)R ^a、-C _0-3亞烷基-S(O) ₂R ^a、-C _0-3亞烷基-S(O) ₂N(R ^a) ₂、-C _0-3亞烷基-S(O)N(R ^a) ₂、-C _0-3亞烷基SR ^a、-C _0-3亞烷基-S(R ^a) ₅、-C _0-3亞烷基-S(O)(NH)R ^a、-C _0-3亞烷基-C(O)R ^a、-C _0-3亞烷基-C(O)OR ^a、-C _0-3亞烷基-C(=O)N（R ^a） ₂、-C(O)NHOR ^b、-C _0-3亞烷基-C(S)N(R ^b) ₂、-P(O)(OR ^b) ₂、-P(O)(R ^b) ₂、C _2-6烯基、C _2-6炔基、-C _0-6亞烷基-C _3-14環烷基、-C _0-6亞烷基-(3-14員雜環基)、-C _0-6亞烷基-C _6-14芳基或-C _0-6亞烷基-(5-14員雜芳基)的取代基所取代；所述R _a各自獨立地選自H、鹵素、羥基、氨基、氧代基、硝基、氰基、羧基、C _1-6烷基、C _1-6羥基烷基、C _1-6氨基烷基、C _1-6鹵代烷基、C _1-6烷氧基、C _1-6鹵代烷氧基、C _1-6雜烷基、C _3-8環烷基、3-8員雜環基、C _6-14芳基或5-14員雜芳基。在一些實施例中，取代基獨立地選自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、叔丁氧基、-SCH ₃、-SC ₂H ₅、甲醛基、-C(OCH ₃)、氰基、硝基、-CF ₃、-OCF ₃、氨基、二甲基氨基、甲硫基、磺醯基和乙醯基的基團。 The term "substituted" refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively. Typical substituents include, but are not limited to, H, oxo, acyl, cyano, halogen, oxo, C _1-6 alkyl, -C _0-3 alkylene-OR ^a , -C _0-3 alkylene Alkyl-OC(O)N(R ^a ) ₂ , -C _0-3 alkylene-N(R ^a ) ₂ , -C _0-3 alkylene-NR _a C(O)R _a , -C _0-3 alkylene-NR _a C(O)N(R ^a ) ₂ , -C _0-6 alkylene-NR _a S(O)R ^a , -C _0-3 alkylene-NR _a S (O) ₂ R ^a , -C _0-3 alkylene-S(O)R ^a , -C _0-3 alkylene-S(O) ₂ R ^a , -C _0-3 alkylene-S (O) ₂ N(R ^a ) ₂ , -C _0-3 alkylene-S(O)N(R ^a ) ₂ , -C _0-3 alkylene SR ^a , -C _0-3 alkylene -S(R ^a ) ₅ , -C _0-3 alkylene-C(O)R ^a , -C _0-3 alkylene-C(O)OR ^a , -C _0-3 alkylene-C (=O)N(R ^a ) ₂ , -C(O)NHOR ^b , C _2-6 alkenyl, C _2-6 alkynyl,

,

,

,

, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14-membered heterocycloalkyl), -C _0-3 alkylene-C _{6- 14} aryl or -C _0-3 alkylene-(5-14 membered heteroaryl); the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _{0- 3} alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocycloalkyl), -C _0-3 alkylene-C _6-14 aryl or - C _0-3 alkylene-(5-14 membered heteroaryl) is optionally further substituted by one or more selected from H, oxo, acyl, cyano, halogen, oxo, C _1-6 alkane group, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, -C _0-3 alkylene-OR ^a , -C _0-3 alkylene-OC(O) N(R ^a ) ₂ , -C _0-3 alkylene-OS(O) ₂ OR ^a , -C _0-3 alkylene-OS(O) ₂ R ^a , -C _0-3 alkylene- N(R ^a ) ₂ , -C _0-3 alkylene-NR _a C(O)R ^a , -C _0-3 alkylene-NR _a C(O)N(R ^a ) ₂ , -C _{0 -6} alkylene-NR ^a S(O)R ^a , -C _0-3 alkylene-NR ^a S(O) ₂ R ^a , -C _0-3 alkylene-S(O)R ^a , -C _0-3 alkylene-S(O) ₂ R ^a , -C _0-3 alkylene-S(O) ₂ N(R ^a ) ₂ , -C _0-3 alkylene-S(O )N(R ^a ) ₂ , -C _0-3 alkylene SR ^a , -C _0-3 alkylene-S(R ^a ) ₅ , -C _0-3 alkylene-S(O)(NH )R ^a , -C _0-3 alkylene-C(O)R ^a , -C _0-3 alkylene-C(O)OR ^a , -C _0-3 alkylene-C(=O) N(R ^a ) ₂ , -C(O)NHOR ^b , -C _0-3 alkylene-C(S)N(R ^b ) ₂ , -P(O)(OR ^b ) ₂ , -P(O )(R ^b ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, -C _0-6 alkylene-C _3-14 cycloalkyl, -C _0-6 alkylene-(3- 14-membered heterocyclyl), -C _0-6 alkylene-C _6-14 aryl or -C _0-6 alkylene-(5-14-membered heteroaryl) substituents; the R _a is each independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-14 Aryl or 5-14 member hetero Aryl. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH ₃ , -SC ₂ H ₅ , carboxaldehyde, -C(OCH ₃ ), cyano, nitro, -CF ₃ , -OCF ₃ , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.

Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxinylmethyl and oxazinylmethyl.

Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxy.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic phosphoniums or acids.

Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).

Prodrugs of the compounds of the present invention are included within the scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or a pharmaceutically active metabolite thereof or Residues. Particularly preferred derivatives or prodrugs are those that increase the bioavailability of the compounds of the present invention when administered to a patient (eg, make orally administered compounds more readily absorbed into the bloodstream), or promote the delivery of the parent compound to a biological organ or those compounds delivered to the site of action (eg, the brain or lymphatic system). Therefore, the term "administration" in the treatment methods provided by the present invention refers to the administration of the compounds disclosed in the present invention that can treat different diseases, or, although not explicitly disclosed, can be transformed into the disclosed compounds in vivo after administration to a subject compounds of compounds.

The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.

When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

Substitution of compounds of formula (I) with heavier isotopes such as deuterium may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

When the compounds of formula (I) and their pharmaceutically acceptable salts exist as solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.

The term "composition", in the present invention, refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of this invention.

The pharmaceutical composition provided by the present invention includes the compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or excipients . Although in any given situation, the most appropriate mode of administration of the active ingredient will depend on the particular subject to be administered, the nature of the subject and the severity of the condition. The pharmaceutical compositions of the present invention may conveniently be presented in unit dosage form and prepared by any of the methods of preparation well known in the art of pharmacy.

Synthesis scheme:

Step A: Compound I-1 and compound I-2 are subjected to substitution reaction under basic conditions such as Cs ₂ CO ₃ to introduce R ¹ group to synthesize compound I-3.

Step B: The nitro group in compound I-3 is reduced to amino group by Pd/C to obtain compound I-4.

Step C: The carboxyl group in compound I-5 and the amino group in compound I-4 are condensed with ammonium acid under the action of a condensing agent to obtain compound I-6.

Step D: Compound I-6 is subjected to self-ring closure reaction under acidic conditions such as acetic acid to synthesize compound I-7.

Step E: Compound I-7 and compound I-8 are subjected to a Buchwald coupling reaction under the action of a Cu catalyst to introduce an R ₈ group to obtain the target compound I.

In order to make the above content clearer and clearer, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention, so that those skilled in the art can understand the present invention, but are not intended to limit the protection scope of the present invention. In the specific embodiments of the present invention, the technical means or methods that are not specifically described are conventional technical means or methods in the field. The chiral molecules of the present invention can be obtained by stereosynthesis or conventional chiral resolution techniques.

All parts and percentages herein are by weight and all temperatures are in degrees Celsius unless otherwise indicated.

The following abbreviations are used in the examples: DCM: dichloromethane; DIEA: diisopropylethylamine; DME: dimethyl ether; DMF: N,N-dimethylformamide; DMSO: dimethylsulfoxide; EA: ethyl acetate; MeOH: methanol; PE: petroleum ether; Pd/C: palladium carbon: THF: tetrahydrofuran; TFA: trifluoroacetic acid; NIS: N-iodobutanediimide; CDI: N,N'-carbonyldiimidazole; T3P: propylphosphoric anhydride; Pd(dppf) _{Cl 2} : 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; T3P: 2,4,6- Tripropyl-1,3,5,2,4,6-trihydroxymethyltriphosphine 2,4,6-trioxide pre-TLC: Preparative thin layer chromatography on silica gel plates; pre-HPLC: Preparative high efficiency Liquid Chromatography.

Synthesis of Intermediate M:

Step 1: Synthesis of Compound M-1

Compound 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.5 g) was dissolved in DMSO (20 mL) at room temperature, 4-bromothiazole was added -2-amine (1.59 g), NaOH (762.01 mg), and the reaction was stirred at room temperature for 4 h. 20 mL of water and 20 mL of EA were added to the reaction solution, and the layers were stirred and separated. The aqueous phase was extracted with EA, and the organic phases were combined, washed, dried, and concentrated. The concentrate was separated and purified by silica gel column (PE:EA=3:1 to PE:EA=1:3) to obtain the product M-1 (943 mg, 38.95% yield) as a yellow solid. ESI-MS m/z: 381.2 [M+H] ⁺ .

Step 2: Synthesis of Compound M-2

At room temperature, compound M-1 (943 mg) was dissolved in THF (10 mL), water (10 mL), ammonia water (2 mL), Na ₂ S ₂ O ₄ (4.15 g) were added, and at room temperature The reaction was stirred for 2 h. 20 mL of EA was added to the reaction solution, the layers were stirred and separated, the aqueous phase was extracted with EA, the organic phases were combined, and the organic phases were concentrated. The concentrate was separated and purified by silica gel column (PE:EA=1:1 to MeOH:DCM=1:10) to obtain the product M-2 (744 mg, 85.37% yield) as a yellow solid. ESI-MS m/z: 365.3 [M+H] ⁺ .

Step 3: Synthesis of Compound M-3

At room temperature, compound M-2 (432 mg) was dissolved in DCM (10 mL), (2S)-6-oxadiazine-2-carboxylic acid (203.16 mg, 1.42 mmol), N-ethyl was added -N-Isopropyl-2-amine (305.73 mg, 412.03 uL), 2,4,6-tripropyl-1,3,5,2,4,6-trihydroxymethyltriphosphane 2,4 , 6-trioxide (564.50 mg), and the reaction was stirred at room temperature for 4 h. 10 mL of water and 10 mL of DCM were added to the reaction solution, and the layers were stirred and separated. The aqueous phase was extracted with DCM, and the organic phases were combined, washed, dried, and concentrated. The concentrate was separated and purified by silica gel column (DCM:MeOH=10:1) to obtain the product M-3 as a yellow solid (388 mg, 66.90% yield). ESI-MS m/z: 490.4 [M+H] ⁺ .

Step 4: Synthesis of Compound M-4

Compound M-3 (388 mg) was dissolved in CH ₃ COOH (10 mL) at room temperature, and the reaction was stirred at 100 °C for 4 h. The heating was stopped, the reaction solution was concentrated, and the concentrate was separated and purified by Pre-TLC to obtain the product M-4 as a yellow solid (177 mg, 47.36% yield). ESI-MS m/z: 472.4 [M+H] ⁺ .

Step 5: Synthesis of Compound M

Compound M-4 (177 mg) was dissolved in DCM (5 mL) at room temperature, (3,4-difluorophenyl)boronic acid (177.51 mg), Cu(OAc) ₂ (97.26 mg) were added, Pyridine (1 mL), and the reaction was stirred at room temperature overnight. 10 mL of DCM and 10 mL of water were added to the reaction solution, and the layers were stirred and separated. The aqueous phase was extracted with DCM, and the organic phases were combined, washed, dried, and concentrated. The concentrate was separated and purified by Pre-TLC to give product M (122 mg, 55.71% yield) as a pale yellow solid. ESI-MS m/z: 584.4 [M+H] ⁺ .

Example 1: Compound 1 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4 Synthesis of -(4-methoxyphenyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one)

Step 1: Synthesis of Compound 1-1

Compound 2-bromo-1-(4-methoxyphenyl)ethan-1-one (5 g), thiourea (1.71 g) was dissolved in ethanol (20 mL) at room temperature, 80°C React for 1 hour. The ethanol was evaporated to obtain a white solid residue, to which was added water, saturated sodium bicarbonate solution, suction filtration, and the filter cake was washed with water and dried. Crude 1-1 (4.6 g) was obtained as a white solid. ESI-MS m/z: 207.1 [M+H] ⁺ .

Step 2: Synthesis of Compounds 1-2

At room temperature, compound 1-1 (192.12 mg), 4-(4-fluoro-3-nitro-phenyl)-3,5-dimethyl-isoxazole (200 mg), potassium carbonate ( 350.55 mg) was successively added to acetonitrile (10 mL), protected by _N2 , and reacted at 80 °C overnight. After direct concentration, the concentrate was separated and purified by silica gel column to obtain the product 1-2 as a brick-red solid (275 mg, 76.88% yield). ESI-MS m/z: 423.1 [M+H] ⁺ .

Step 3: Synthesis of Compounds 1-3

At room temperature, compound 1-2 (200 mg), ammonia water (0.3 mL) were added to water (4 mL) and THF (4 mL) successively, and the reaction was performed at 25° C. for 5 min, followed by the addition of Na ₂ S ₂ O ₄ (823.75 mg,), and the reaction was continued for 2 hours. The reaction solution was left to stand for layers, the aqueous layer was extracted twice with EA, the organic phase was washed with water, washed with saturated brine, and evaporated to dryness. The crude 1-3 was obtained as a reddish-brown solid (160 mg, 86.11% yield). ESI-MS m/z: 393.1 [M+H] ⁺ .

Step 4: Synthesis of Compounds 1-4

Compound 1-3 (100 mg), (2S)-6-oxoxidine-2-carboxylic acid (47.41 mg), DIEA (42.81 mg, 57.69 uL) were sequentially added to DCM (5 mL) at room temperature , react at 25°C for 10min, then add 2,4,6-tripropyl-1,3,5,2,4,6 trioxatriphosphine 2,4,6-trioxide (0.3 mL), The reaction was continued for 2 hours. DCM was added to the reaction solution to dilute, and the organic phase was washed once with water, twice with saturated sodium bicarbonate solution, once with water, washed with saturated brine, and evaporated to dryness. The crude product 1-4 was obtained as a brick red solid (120 mg, 90.99% yield). ESI-MS m/z: 518.2[M+H] ⁺ .

Step 5: Synthesis of Compounds 1-5

Compound 1-4 (120 mgl) was dissolved in acetic acid (3 mL) at room temperature and reacted at 80°C for 3 hours. It was directly concentrated, and the concentrate was separated and purified by silica gel column to obtain the product 1-5 as a brown solid (80 mg, 69.07% yield). ESI-MS m/z: 500.2 [M+H] ⁺ .

Step 6: Synthesis of Compound 1

At room temperature, compound 1-5 (60.00 mg) and pyridine (0.15 mL) were added to DCM (5 mL), stirred at 25°C for 5 minutes, then added copper acetate monohydrate (31.23 mg), and continued stirring for 15 min After that, (3,4-difluorophenyl)boronic acid (70.17 mg) was added, and the reaction was continued. DCM was added to the reaction solution to dilute, the organic phase was washed twice with 2M hydrochloric acid, twice with water, and directly concentrated. The concentrate was separated and purified by silica gel column to obtain product 1 (50 mg, 68.06% yield) as a light gray solid. ESI-MS m/z: 612.2[M+H] ⁺ .

Example 2: ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-( Synthesis of 4-hydroxyphenyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one)

At room temperature, compound 1 (40 mg) was dissolved in DCM (5 mL), BBr ₃ (65.40 mg, ) was added dropwise under an ice bath, the dropping was completed, and the reaction was carried out for 30 min, monitored by LCMS. The reaction solution was quenched by adding water, extracted with DCM:MeOH=10:1, directly concentrated, and the concentrate was separated and purified by silica gel column to obtain pale yellow solid product 2 (16 mg, 40.94% yield). ESI-MS m/z: 598.2 [M+H] ⁺ .

Example 3: Compound 3 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5 - Synthesis of (hydroxymethyl)-4-(trifluoromethyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)guaidin-2-one)

For specific steps, refer to Example 1. ESI-MS m/z of target product 3: 603.6 [M+H] ⁺ .

Example 4: Compound 4((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4) Synthesis of -(4-(Methylsulfonyl)phenyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one)

For specific steps, refer to Example 1. ESI-MS m/z of target product 4: 660.2 [M+H] ⁺ .

Example 5: Compound 5 ((S)-4-(2-(2-(1-(1-(3,4-difluorophenyl)-6)-oxoxiridin-2-yl)-5- Synthesis of (3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)phenyl hydrogen sulfate)

At room temperature, 1,2-dichloroethane (2 mL) was added to compound 8 (50 mg), pyridine (132.36 mg) was added, and chlorosulfonic acid (48.74 mg) was added dropwise, followed by stirring at room temperature for 2 hs . The reaction solution was quenched by adding 15 ml of ice water, diluted by adding 10 ml of DCM, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was separated and purified by Pre-HPLC to give the product 5 as a white solid (1.3 mg, 2.29% yield). ESI-MS m/z: 677.7 [M+H] ⁺ .

Example 6: Compound 6 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4) -(2,2-Dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridine- 2-keto) synthesis

Step 1: Synthesis of Compound 6-1

To Na ₂ S⸱9H ₂ O (1.68 g) was added EtOH (113.4 mL) at room temperature, and a solution containing 4-bromo-1,2-bis(bromomethyl)benzene (2 g) was added dropwise with stirring EtOH (28 mL) solution, then reacted at 20°C for 20hs. The reaction solution was filtered, the filtrate was concentrated under reduced pressure to 30 mL, 30 mL of EA was added, washed with water (3*15 mL), washed with saturated brine (1*15 mL), the organic phase was dried, filtered, and concentrated under reduced pressure. The product 6-1 was obtained as a brown solid (1.2 g, 95.63% yield). ESI-MS m/z: 215.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 6-2

To a solution of compound 6-1 (1.2 g) in DCM (60 mL) at -25 °C, 3-chloroperoxybenzoic acid (3.85 g, ) was added, and then the temperature was slowly raised to 20 °C for reaction for 4 hs. The reaction solution was washed with 10% sodium hydroxide (1*40ml), washed with water (1*30ml), washed with saturated brine (1*30ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to directly obtain a white solid product 6 -2 (1.35 g, 97.93% yield). ESI-MS m/z: 247.1 [M+H] ⁺ .

Step 3: Synthesis of Compound 6-3

To a solution of compound 6-2 (1.35 g) in THF (70 mL) at room temperature was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaboran-2-yl)-1,3,2-dioxaborane (2.88 g), KOAc (1.67 g), PdCl ₂ (dppf).DCM (462.67 mg) then The temperature was raised to 70°C for 15hs. The reaction solution was cooled to room temperature, 98 mL of anhydrous tetrahydrofuran was added, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column (EA:PE=1% to 25%) to give the desired product 6-3 as a white solid (0.85 g, 51.00% yield). ESI-MS m/z: 294.2[M+H] ⁺ .

Step 4: Synthesis of Compound 6

To intermediate M (10 mg), compound 6-3 (15.10 mg) in Dioxane (1.4 mL) and _H2O (0.2 mL) at ₂₀ °C was added K2CO3 (9.45 mg), Pd( _{PPh3 )} ) ₄ (3.95 mg), under nitrogen protection, then warmed to 90 °C and stirred for 1 h. The reaction solution was cooled to room temperature, 10 mL of EA and 10 mL of water were added, the organic phase was separated, washed with saturated sodium chloride (2*10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by Pre-TLC (EA) to give the desired product 6 as a white solid (7.3 mg, 63.51% yield). ESI-MS m/z: 671.7[M+H] ⁺ .

Example 7: Compound 7((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5 Synthesis of -(Hydroxymethyl)-4-methylthiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one)

Refer to Example 1 for the specific reaction steps of compound 7-1. ESI-MS m/z: 592.6 [M+H] ⁺ .

At room temperature, compound 7-1 (25.00 mg), NaBH ₄ (10.60 mg) were sequentially added to THF (2 mL), under nitrogen protection, the reaction solution was heated to 50 °C, and MeOH (0.2 mg) was added dropwise to the reaction solution. mL), the dripping was completed, and the reaction was continued for 2 hours. Methanol was added dropwise to the reaction solution to quench the reaction, and the reaction solution was directly concentrated. The concentrate was purified by Pre-TLC to give product 7 as a white solid (14 mg, 60.28% yield). ESI-MS m/z: 550.0 [M+H] ⁺ .

Example 8: Compound 8((S)-N-(4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-( Synthesis of 3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)phenyl)methanesulfonamide)

Step 1: Synthesis of Compound 8-1

Compound 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (525.65 mg) was dissolved in MeCN (20 mL) at room temperature, 4-(4 -iodophenyl)thiazol-2-amine (672.39 mg), Cs ₂ CO ₃ (2.19 g), and the reaction was stirred at 80 °C for 6 h. Cool to room temperature, add 15 mL of water and 20 mL of EA to the reaction solution, stir to separate layers, extract the aqueous phase with EA, combine the organic phases, wash the organic phases, dry and concentrate. The concentrate was separated and purified by silica gel column (PE:EA=3:1-1:3) to obtain the product 8-1 as a brown solid (380 mg, 32.94% yield). ESI-MS m/z: 518.3 [M+H] ⁺ .

Step 2: Synthesis of Compound 8-2

At room temperature, compound 8-1 (380.00 mg) was dissolved in THF (10 mL), Na ₂ S ₂ O ₄ (1.28 g), ammonia water (2 mL), water (10 mL) were added, and at room temperature The reaction was stirred for 2 h. 20 mL of EA and 10 mL of water were added to the reaction solution, and the layers were stirred and separated. The aqueous phase was extracted with EA, and the organic phases were combined, washed, dried, and concentrated. The concentrate was separated and purified by silica gel column (PE:EA=1:3) to obtain the product 8-2 as a yellow solid (320 mg, 89.38% yield). ESI-MS m/z: 488.3 [M+H] ⁺ .

Step 3: Synthesis of Compound 8-3

At room temperature, compound 8-2 (320 mg) was dissolved in DCM (10 mL), (2S)-6-oxadiazine-2-carboxylic acid (121.94 mg), T ₃ P (312.74 mg) were added , DIEA (169.38 mg), stirred at room temperature for 2 h. 10 mL of water and 10 mL of DCM were added to the reaction solution, and the layers were stirred and separated. The aqueous phase was extracted with DCM (10 mL), and the organic phases were combined, washed, dried, and concentrated. The concentrate was purified by Pre-TLC (MeOH:DCM=15:1) to give the product 8-3 as a brown solid (190 mg, 47.26% yield). ESI-MS m/z: 613.5[M+H] ⁺ .

Step 4: Synthesis of Compounds 8-4

Compound 8-3 (190.00 mg) was dissolved in acetic acid (10 mL) at room temperature, and the reaction was stirred at 80 °C for 4 h. Heating was stopped, and the reaction solution was concentrated. The concentrate was purified by Pre-TLC (MeOH:DCM=1:10) to give the product 8-4 as a yellow solid (168 mg, 91.10% yield). ESI-MS m/z: 595.5 [M+H] ⁺ .

Step 5: Synthesis of Compounds 8-5

Compound 8-4 (168 mg) was dissolved in DCM (5 mL) at room temperature, 3,4-difluorophenylboronic acid (164.84 mg), Cu(OAc) ₂ (76.87 mg), pyridine (1 mL), and the reaction was stirred at room temperature for 5 h. 20 mL of 1 N HCl and 15 mL of DCM were added to the reaction solution, the layers were stirred, and the aqueous phase was extracted with DCM (10 mL). The organic phases were combined, washed, dried, and concentrated. The concentrate was purified by Pre-TLC (PE:EA=1:1) to give the product 8-5 as a white solid (80 mg, 40.08% yield). ESI-MS m/z: 707.5 [M+H] ⁺ .

Step 6: Synthesis of Compound 8

Compound 8-5 (40 mg) was dissolved in DMF (10 mL) at room temperature, methanesulfonamide (6.45 mg), CuI (538.35 ug), 2-(methylamino)acetic acid (1.01 mg) were added, K ₃ PO ₄ (30.01 mg), replaced the air with nitrogen three times, then protected with nitrogen, and stirred the reaction at 100 °C for 16 h. The heating was stopped, cooled to room temperature, 15 mL of EA and 20 mL of water were added to the reaction solution, the layers were stirred and separated, the aqueous phase was extracted with EA, the organic phases were combined, the organic phases were washed, dried, and concentrated. The concentrate was purified by Pre-HPLC to give product 8 as a white solid (9.2 mg, 24.12% yield). ESI-MS m/z: 674.7[M+H] ⁺ .

Example 9: Compound 9 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5 Synthesis of -Hydroxybenzo[d]thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one)

For specific steps, refer to Example 1. ESI-MS m/z of target product 9: 572.2 [M+H] ⁺ .

Example 10: Compound 10 ((S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5 - Synthesis of dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)phenylmethanesulfonate)

For specific steps, refer to Example 1. ESI-MS m/z of target product 10: 676.1 [M+H] ⁺ .

Example 11: Compound 11 ((S)-(4-(2-(2-(1-(3,4-difluorophenyl)-6-oxaperidin-2-yl)-5-(3, Synthesis of 5-dimethylisoxazol-4-yl)-1H benzo[d]imidazol-1-yl)thiazol-4-yl)phenyl)phosphonic acid diethyl ester)

At room temperature, compound 8-5 (40 mg) was dissolved in toluene (5 mL), triethyl phosphite (9.39 mg), Cs ₂ CO ₃ (73.68 mg), CuI (1.08 mg) were added with After nitrogen replacement three times, nitrogen protection was carried out, and the mixture was stirred at 130°C overnight. The concentrate was purified by Pre-HPLC to give product 11 as a white solid (12 mg, 29.57% yield). ESI-MS m/z: 718.2[M+H] ⁺ .

Example 12: Compound 12 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4) - Synthesis of (4-((methylsulfonyl)methyl)phenyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)quaridin-2-one)

Step 1: Synthesis of Compound 12-1

At room temperature, compound 1-bromo-4-(bromomethyl)benzene (1.0 g) was dissolved in DMF (20 mL), sodium methanesulfinate (816.95 mg) was added, and the reaction was stirred at 60 °C 2 hours. Heating was stopped, cooled to room temperature, 20 mL of water was added to the reaction solution, a solid was precipitated, filtered, and the filter cake was the product. The filter cake was purified by silica gel column (PE:EA=3:1 to DCM:MeOH=10:1) to give the product 12-1 (580 mg, 58.19% yield) as a white solid. ESI-MS m/z: 249.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 12-2

Compound 12-1 (200 mg) was dissolved in dioxane (10 mL) at room temperature, and 4,4,5,5-tetramethyl-2-(4,4,5,5- Tetramethyl-1,3,2-dioxolan-2-yl)-1,3,2-dioxolane (407.73 mg), KOAc (157.58 mg), Pd(dppf)Cl ₂ (65.51 mg), replaced the air with nitrogen three times, then protected with nitrogen, and stirred the reaction at 90 °C for 5 h. Stop heating, cool down to room temperature, add 10 mL of water and 10 mL of EA to the reaction solution, stir to separate layers, extract the aqueous phase with EA, combine the organic phases, wash the organic phases, dry and concentrate. The concentrate was purified by Pre-TLC (DCM:MeOH=10:1) to give the product 12-2 as a brown solid (112 mg, 47.10% yield). ESI-MS m/z: 296.2[M+H] ⁺ .

Step 3: Synthesis of Compound 12

Compound 12-2 (20.27 mg) was dissolved in dioxane (4 mL) at room temperature, Intermediate M, Pd(pph ₃ ) ₄ (3.95 mg), K ₂ CO ₃ (14.19 mg) were added , was replaced with nitrogen three times, and the reaction was stirred at 90 °C for 1 h under nitrogen protection. The heating was stopped, cooled to room temperature, 10 mL of DCM and 10 mL of water were added to the reaction solution, the layers were stirred and separated, the aqueous phase was extracted with DCM, the organic phases were combined, washed, dried and concentrated. The concentrate was purified by Pre-HPLC to give the product 12 as a white solid (4.9 mg, 21.25% yield). ESI-MS m/z: 673.8 [M+H] ⁺ .

Example 13: Compound 13 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4) - Synthesis of (dimethylphosphoryl)phenyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one)

Step 1: Synthesis of Compound 13-1

Compound 1-bromo-4-iodobenzene (1.0 g) was dissolved in dioxane (5 mL) at room temperature, methylphosphonomethane (331.07 mg), 4,5-bis-dioxane was added Phenylphosphine-9,9-dimethylxanthene (204.53 mg), Pd ₂ (dba) ₃ (323.69 mg ), under nitrogen protection, the reaction was stirred at 70° C. for 2 h. The heating was stopped, cooled to room temperature, 10 mL of water and 20 mL of EA were added to the reaction solution, the layers were stirred and separated, the aqueous phase was extracted with EA, and the organic phases were combined, washed, dried, and concentrated. The concentrate was purified by silica gel column (DCM:MeOH=10:1) to give the product 13-1 as a brown oil (620 mg, 75.27% yield). ESI-MS m/z: 233.0 [M+H] ⁺ .

Step 2: Synthesis of Compound 13-2

Compound 13-1 (200 mg) was dissolved in dioxane (5 mL) at room temperature, and 4,4,5,5-tetramethyl-2-(4,4,5,5- Tetramethyl-1,3,2-dioxolan-2-yl)-1,3,2-dioxolane (435.87 mg), KOAc (168.45 mg), Pd(dppf)Cl ₂ (70.03 mg) was replaced with nitrogen three times, and the reaction was stirred at 100 °C for 5 h under nitrogen protection. The heating was stopped, cooled to room temperature, 10 mL of water and 20 mL of EA were added, and the layers were stirred and separated. The aqueous phase was extracted with EA, and the organic phases were combined, washed, dried, and concentrated. The concentrate was purified by Pre-TLC (DCM:MeOH=10:1) to give the product 13-2 as a brown oil (94 mg, 39.10% yield). ESI-MS m/z: 280.1 [M+H] ⁺ .

Step 3: Synthesis of Compound 13

Intermediate M (20 mg) was dissolved in dioxane (2 mL) at room temperature, compound 13-2 (9.59 mg), Pd(pph ₃ ) ₄ (3.95 mg), K ₂ CO ₃ were added (9.46 mg), water (0.5 mL), replaced with nitrogen three times, nitrogen protection, and stirred for 1 h at 90 °C. Stop heating, cool down to room temperature, add 10 mL of EA and 5 mL of water to the reaction solution, stir to separate layers, extract the aqueous phase with EA, combine the organic phases, wash the organic phases, dry, and concentrate to dryness. The concentrate was purified by Pre-HPLC to give the product 13 as a white solid (6.6 mg, 29.33% yield). ESI-MS m/z: 657.7 [M+H] ⁺ .

Example 14: Compound 14 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4) Synthesis of -(3-hydroxyphenyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one)

For specific steps, refer to Example 1. ESI-MS m/z of target product 14: 598.2 [M+H] ⁺ .

Example 15: Compound 15 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4) Synthesis of -(3-methoxyphenyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one)

For specific steps, refer to Example 1. ESI-MS m/z of target product 15: 612.2 [M+H] ⁺ .

Example 16: Compound 16 ((S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5 - Synthesis of methylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)benzoate)

For specific steps, refer to Example 1. ESI-MS m/z of target product 16: 640.2 [M+H] ⁺ .

Example 17: Compound 17 ((S)-N-(4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-( Synthesis of 3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)phenyl)acetamide)

For specific steps, refer to Example 1. ESI-MS m/z of target product 17: 639.2 [M+H] ⁺ .

Example 18: Compound 18 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4) - Synthesis of (4-(hydroxymethyl)phenyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one)

Step 1: Synthesis of Compound 18-1

Compound 16 (200 mg) was dissolved in MeOH (7.0 mL) at room temperature, an aqueous solution of sodium hydroxide (125.06 mg) in H ₂ O (1.5 mL) was added, and the mixture was stirred at 50° C. for 3 hours. After returning to room temperature, spin to dry methanol, add 5 mL of water to dilute, adjust pH=5 with 1N HCl solution, extract three times with EA (10 mL), dry the organic phase and concentrate in vacuo, and pass the concentrate through Pre-TLC (DCM:MeOH=10:1 ) was purified to give the product 18-1 as a white solid (120 mg, 61.35% yield). ESI-MS m/z: 625.6[M+H] ⁺ .

Step 2: Synthesis of Compound 18

At room temperature, compound 18-1 (50 mg), NaBH ₄ (5.91 mg) was dissolved in THF (1.5 mL), under nitrogen protection, methanol (0.5 mL) was added dropwise to the reaction solution at 55°C, keeping the The temperature continued to stir overnight. After returning to room temperature, the reaction solution was added to ice water to quench, and EA (10 mL) was extracted three times. The organic phase was dried and concentrated in vacuo. The concentrate was purified by Pre-TLC (DCM:MeOH=10:1) and Pre-HPLC to give the product 18 as a white solid (2.3 mg, 4.81% yield). ESI-MS m/z: 611.2[M+H] ⁺ .

Example 19: Compound 19 ((S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5 - Synthesis of dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)benzamide)

Compound 18-1 (20 mg) was dissolved in THF (1.0 mL) at room temperature, thorium chloride (19.02 mg) was added at room temperature, stirred at 50°C for 1 hour, cooled to 0°C, and ammonia water was slowly added (0.5 mL), and stirred in an ice bath for 0.5 h. The reaction solution was directly extracted three times with DCM (10 mL), and the organic phase was dried and concentrated in vacuo. The concentrate was purified by Pre-HPLC to give the product 19 as a white solid (11.4 mg, 56.49% yield). ESI-MS m/z: 624.7[M+H] ⁺ .

Example 20: Compound 20 ((S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5 - Synthesis of dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)-N-methylbenzamide)

Compound 18-1 (75 mg) was dissolved in THF (4.0 mL) at room temperature, under nitrogen protection, thionite chloride (142.62 mg) was added at room temperature, and the mixture was stirred at 50°C for 1 hour. After returning to room temperature, the solution was concentrated under reduced pressure, the solid was dissolved in THF (4.0 mL), under nitrogen protection, 1.2 mL of methylamine (74.46 mg) in THF solution was slowly added dropwise in an ice bath, and the solution was stirred in an ice bath for 1 hour. It was quenched by adding water, extracted three times with EA (10 mL), the organic phase was dried and concentrated in vacuo, and the concentrate was purified by Pre-HPLC to obtain the product 20 as a white solid (22.6 mg, 29.52% yield). ESI-MS m/z: 638.7[M+H] ⁺ .

Example 21: Compound 21 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4) - Synthesis of -(4-(Methylsulfonyl)phenyl)oxazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one)

For specific steps, refer to Example 1. ESI-MS m/z of target product 21: 644.2 [M+H] ⁺ .

Example 22: Compound 22 ((S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5 - Synthesis of dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)benzenesulfonamide)

Intermediate M (20.00 mg), (4-sulfamonophenyl)boronic acid (8.25 mg), K ₂ CO ₃ (9.45 mg ), Pd(PPh ₃ ) ₄ (3.95 mg) were dissolved at room temperature Dioxane (0.5 mL) and water (0.1 mL) were replaced with nitrogen, followed by stirring at 90°C for 2 hours. Return to room temperature, add 5 ml of water to quench, and extract three times with EA (10 mL). The organic phase is dried and concentrated in vacuo. The concentrate is purified by Pre-TLC to obtain product 22 (11.5 mg, 50.86% yield) as a yellow solid. ESI-MS m/z: 660.7[M+H] ⁺ .

Example 23: Compound 23 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4) Synthesis of -(4-hydroxyphenyl)oxazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one)

For specific steps, refer to Example 1. ESI-MS m/z of target product 23: 582.2 [M+H] ⁺ .

Example 24: Compound 24 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4) Synthesis of -(4-Methoxyphenyl)oxazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one)

For specific steps, refer to Example 1. ESI-MS m/z of target product 24: 596.2 [M+H] ⁺ .

Example 25: Compound 25 ((S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(6) - Synthesis of (methylsulfonyl)benzo[d]thiazol-2-yl)-1H benzo[d]imidazol-2-yl)pyridin-2-one)

For specific steps, refer to Example 1. ESI-MS m/z of target product 25: 634.1 [M+H] ⁺ .

Example 26: Compound 26 ((S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5 - Synthesis of dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)-N,N-dimethylbenzenesulfonamide)

Step 1: Synthesis of Compound 26-1

The compound 4-acetyl-N,N-dimethylbenzenesulfonamide (970 mg) was dissolved in THF (20.0 mL) at room temperature, and trimethyl(phenyl)ammonium (1.76 g) was added , and stirred at room temperature for 1 hour. Return to room temperature, concentrate under reduced pressure, dilute with water, adjust pH to 8 with ammonia water, extract three times with EA, dry the organic phase and concentrate in vacuo. The concentrate was purified by silica gel column to give the product 26-1 as a white solid (1.0 g, 76.53% yield). ESI-MS m/z: 306.2[M+H] ⁺ .

Step 2: Synthesis of Compound 26-2

At room temperature, compound 26-1 (970 mg) was dissolved in dioxane (10.0 mL), thiourea (1.21 g) was added at room temperature, and the mixture was stirred at 80°C for 1 hour. Return to room temperature, add an appropriate amount of water to dissolve the solid, add saturated sodium bicarbonate solution under stirring, a yellow solid is precipitated, filter, wash with water, and dry the solid to obtain a yellow solid product 26-2 (850 mg, 94.68% Yield). ESI-MS m/z: 283.4 [M+H] ⁺ .

Refer to Example 1 for the specific steps of the subsequent reaction. ESI-MS m/z of target product 40: 689.2 [M+H] ⁺ .

Example 27: Compound 27 ((6S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4 -(4-(Methylsulfonyl)cyclohex-1-en-1-yl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one) synthesis

Step 1: Synthesis of Compound 27-1

To 4-methylsulfonylcyclohexanone (0.5 g) was added DCM (10 mL) at 20°C, 2,6-di-tert-butyl-4-methylpyridine (1.28 g), Tf ₂ O (1.60 g), nitrogen protection, and then reflux reaction at 40°C for 12hs. The reaction solution was cooled to room temperature, added to 75 ml of ether, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column (EA:PE=1% to 60%) to obtain the target product 27-1 as a tan solid (784 mg, 89.63% yield).

Step 2: Synthesis of Compound 27-2

To compound 27-1 (784 mg), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxane) at 20°C Pentan-2-yl)-1,3,2-dioxolane (774.92 mg) was added DMSO (7.8 mL), KOAc (748.72 mg), PdCl ₂ (dppf).DCM (207.67 mg) , nitrogen protection, and then react at 70 ℃ for 12hs. The reaction solution was cooled to room temperature, 50 ml of ether and 20 ml of saturated brine were added, the organic phase was separated, washed with saturated brine (1*20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column (EA:PE=50%) to obtain the target product 27-2 as a colorless semi-solid (500 mg, 68.70% yield).

Step 3: Synthesis of Compound 27

At room temperature, compound 27-2 (10 mg), 4,4,5,5-tetramethyl-2-(4-methylsulfonylcyclohexen-1-yl)-1,3,2 -Dioxolane (14.69 mg) in dioxane (1.5 mL) and H ₂ O (0.2 mL) was added K ₂ CO ₃ (9.45 mg ), Pd(PPh ₃ ) ₄ (3.95 mg), Under nitrogen protection, the temperature was raised to 90 °C and stirred for 0.5 hs. The concentrate was purified by Pre-TLC to give the product 27 as a light brown solid (6.1 mg, 53.71% yield). ESI-MS m/z: 663.8[M+H] ⁺ .

Example 28: Compound 28 ((6S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4 Synthesis of -(S-methylsulfonimido)phenyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)quaridin-2-one)

Step 1: Synthesis of Compound 28-1

Compound 1-bromo-4-methylsulfonamidobenzene (1.8 g) was dissolved in EtOH (90 mL) at room temperature, PhI(OAc) ₂ (8.56 g) and NH ₄ OAc (10.92 g) were added at room temperature , and stirred at room temperature for 2 hours. After returning to room temperature, the solvent was spin-dried, concentrated, and the concentrate was purified by silica gel column to obtain the product 28-1 as a white solid (2.0 g, 96.39% yield). ESI-MS m/z: 234.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 28-2

At room temperature, compound 28-1 (1.0 g), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxo cyclopentan-2-yl)-1,3,2-dioxolane (1.30 g), Pd(dppf)Cl2 ( _348.82 mg), KOAc (837.20 mg) dissolved in dioxane ( 10 mL), nitrogen was replaced, and the mixture was stirred at 80°C for 2 hours. After returning to room temperature, diatomaceous earth was filtered, the filtrate was diluted with water, extracted with EA three times, backwashed with saturated brine, and the organic phase was dried and concentrated in vacuo to obtain the product 28-2 as a tan solid (1.2 g, 99.91% yield). ESI-MS m/z: 281.2[M+H] ⁺ .

Step 3: Synthesis of Compound 28

Intermediate M (10 mg), compound 42-2 (14.43 _mg ), K2CO3 (7.08 mg), Pd( _{PPh3 )4 (} 1.98 mg) were dissolved in dioxane (499.98 mg) at room temperature uL) and H ₂ O (100.02 uL), after nitrogen substitution, and stirring at 80° C. for 2 hours. Return to room temperature, dilute with water, extract three times with EA, backwash with saturated brine, dry the organic phase, and concentrate in vacuo. 75.70% yield, 98.07% purity). ESI-MS m/z: 658.7[M+H] ⁺ .

Example 29: Compound 29 ((S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5 - Synthesis of dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)-N-methylbenzenesulfonamide)

For specific steps, refer to Example 1. ESI-MS m/z of target product 29: 675.2 [M+H] ⁺ .

Example 30: Compound 4-(6-(3,5-Dimethylisoxazol-4-yl)-2-(methylamino) -1H -benzo[d]imidazol-1-yl)benzene Synthesis of Formic Acid

Step 1: Synthesis of Compound 30-1

At room temperature, compound 4-bromo-2-fluoro-1-nitrobenzene (5.0000 g), (3,5-dimethyl1,2-oxazol-4-yl)boronic acid (3.8437 g), Potassium carbonate (6.2824 g) and tetrakistriphenylphosphine palladium (1.3132 g) were dissolved in dioxane (50.0000 mL) and water (10.0000 mL), replaced with nitrogen, and stirred at 80 degrees for 4 hours. Return to room temperature, filter through celite, add 50 mL of water to dilute, extract three times with EA, backwash with saturated brine, dry the organic phase and concentrate in vacuo. The concentrate is purified by normal phase column (10% EA/PE) to obtain the yellow solid target Product 30-1 (3.8000 g, 70.7864% yield).

Step 2: Synthesis of Compound 30-2

At room temperature, compound 30-1 (2.9183 g), potassium tert-butoxide (2.7079 g) was dissolved in dimethyl sulfite (50.0000 mL), under nitrogen protection, and stirred at room temperature overnight. Add 100 mL of water to dilute, extract five times with EA, backwash with saturated brine, dry the organic phase and concentrate in vacuo. The concentrate was subjected to normal phase column (25% EA/PE) to remove part of impurities; reverse phase column (30%-80% acetonitrile/0.1% formic acid aqueous solution) was used to isolate target product 30-2 (1.7000 g, yield 28.7646%) Yellow solid. ESI-MS m/z: 368.1 [M+H] ⁺ .

Step 3: Synthesis of Compound 30-3

Compound 30-2 (0.8000 g) was dissolved in a mixed solution of methanol (10.0000 mL) and tetrahydrofuran (10.0000 mL) at room temperature, Pd/C (0.2318 g) was added, and after hydrogen replacement, the mixture was stirred at room temperature for 12 hours . Celite was filtered, and the filtrate was concentrated. The concentrate was purified by normal phase column (30% EA/PE) to obtain the target product 30-3 (0.4930 g, 67.1018% yield) as a white solid. ESI-MS m/z: 338.1 [M+H] ⁺ .

Step 4: Synthesis of Compound 30-4

Compound 30-3 (0.4930 g), N , N' -carbonyldiimidazole (0.3554 g) was dissolved in tetrahydrofuran (10.0000 mL) at room temperature, and stirred at 60 degrees for 2 hours. Return to room temperature, add 50 mL of water to dilute, and extract three times with EA (10 mL). Saturated brine was backwashed, and the organic phase was dried and concentrated in vacuo to obtain the target product 30-4 (0.4500 g, yield 84.7482%) as a white solid crude product, which was directly used in the next step. ESI-MS m/z: 364.1 [M+H] ⁺ .

Step 5: Synthesis of Compound 30-5

Compound 30-4 (0.2000 g) was dissolved in phosphorus oxychloride (5.000 mL) at room temperature and stirred at 110 degrees for 6 hours. Return to room temperature. The reaction night was slowly added to ice water, adjusted to pH=8 with 4N NaOH solution, a white solid was precipitated, the solid was filtered out, the EA was dissolved, dried, and concentrated in vacuo. The concentrate was passed through a normal phase column (20% EA/PE) to separate the target product 30-5 as a pale yellow solid (0.1300 g, 61.86% yield). ESI-MS m/z: 382.1 [M+H] ⁺ .

Step 6: Synthesis of Compound 30-6

At room temperature, compound 44-5 (0.0900 g) was placed in a microwave tube, methylamine (2M/THF) (2.0000 mL) was added, the tube was sealed at 100°C, stirred for 24 hours, returned to room temperature, and directly concentrated in vacuo. The concentrate was purified by Pre-TLC (50% EA/PE) to give the desired product 30-6 as a white solid (0.0570 g, 64.2424% yield). ESI-MS m/z: 377.2 [M+H] ⁺ .

Step 7: Synthesis of Compound 30

Compound 30-6 (0.0570 g) was dissolved in tetrahydrofuran (1.2000 mL) and water (0.3000 mL) at room temperature, lithium hydroxide monohydrate (0.0191 g) was added, and the mixture was stirred at room temperature for 3 hours. Spin dry THF, add 2 mL of water, adjust PH=3 with 3N HCl, a white solid is precipitated, filter, wash the solid with water several times, and dry with infrared light to obtain the target product 30 as a white solid (0.0443 g, yield 80.7276%) . ESI-MS m/z: 363.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 13.79-13.38 (m, 2H), 8.54 (s, 1H), 8.22 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 6.99 (s, 1H), 3.04-3.03 (m, 3H), 2.32 (s, 3H), 2.14 (s , 3H).

Example 31: Compound 31 Methyl( S )-2-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-difluorophenyl) Synthesis of methylisoxazol-4-yl) -1H -benzo[d]imidazol-1-yl)thiazole-5-carboxylate

Step 1: Synthesis of Compound 31-1

At room temperature, 4-(4-fluoro-3-nitrophenyl)-3,5-dimethyl-1,2-oxazole (1.00 g), 2-amino1,3-thiazole-5 - Methyl carboxylate (1.61 g) was added to DMF (10.00 mL) and the reaction was warmed to 70°C and the substrate until all dissolved. Cesium carbonate (2.76 g) was added in portions, and the mixture was stirred at 70°C for 5 hours. Water (15 mL) was added, followed by extraction with EA (30 mL)*2, the organic layer was washed with saturated brine*3 and dried over anhydrous sodium sulfate. Purification by column chromatography (DCM/MeOH, 3% MeOH eluted the product) gave the desired product 31-1 (1.04 g, 65.62% yield) as a yellow solid. ESI-MS m/z: 375.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 31-2

The above compound 31-1 (487.00 mg), Pd/C (201.36 mg) were added to tetrahydrofuran (25.00 mL) and methanol (20.00 mL) at room temperature. _H2 was replaced three times and stirred at room temperature for 12 h under _H2 atmosphere. Filtration (Celite), the filter cake was washed with MeOH (10 mL), and the filtrate was concentrated under reduced pressure to obtain crude product 31-2 as a pale gray solid (383.00 mg, yield 82.29%). ESI-MS m/z: 345.1 [M+H] ⁺ .

Step 3: Synthesis of Compound 31-3

At room temperature, the above crude product 31-2 (100.00 mg), ( 2R )-6-oxazidine-2-carboxylic acid (45.72 mg) was dissolved in dichloromethane (3.00 mL), and N was added. N -diisopropylethylamine (0.10 mL) was stirred at room temperature for 10 minutes, then T ₃ P (0.26 mL) was added, and the mixture was stirred at room temperature for 0.5 hour. A small amount of water (5 mL) was added, and DCM (10 mL)*2 was added for extraction. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography (DCM/MeOH, product eluted with 5% MeOH) afforded the desired product 31-3 as a pale yellow solid (102.00 mg, 74.81% yield). ESI-MS m/z: 470.1 [M+H] ⁺ .

Step 4: Synthesis of Compound 31-4

At room temperature, compound 31-3 (102.00 mg) was added to glacial acetic acid (5.00 mL), and the temperature was raised to 100°C and stirred overnight. Concentrated under reduced pressure, and purified by column chromatography (DCM/MeOH, 5% MeOH washed out the product) to obtain the target product 31-4 (105.00 mg, yield 107.07%) as pale yellow oil. ESI-MS m/z: 452.1 [M+H] ⁺ .

Step 5: Synthesis of Compound 31

At room temperature, compound 31-4 (105.00 mg), 3,4-difluorophenylboronic acid (110.19 mg) and Cu(OAc) _2. H ₂ O

(60.37 mg) was added to dichloromethane (3.00 mL) and pyridine (0.60 mL). Oxygen exchange was performed twice, and the mixture was stirred overnight at room temperature under an oxygen atmosphere. LCMS showed 60% starting material and stirring was continued for 12 hours. Water (5 mL) was added, followed by extraction with DCM (15 mL)*2, the organic layer was washed with 1N HCl*2, then washed with saturated brine, and finally dried over anhydrous sodium sulfate. Purification by column chromatography (DCM/MeOH, product eluted with 4% MeOH) afforded the desired product 31 as a pale yellow solid (30.00 mg, 22.89% yield). ESI-MS m/z: 464.1 [M+H] ⁺ .

Example 32: Compound ( S )-2-(2-(1-(3,4-difluorophenyl)-6-oxopridin-2-yl)-5-(3,5-dimethyliso Synthesis of oxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazole-5-carboxylic acid

Compound 31 (30.00 mg) was dissolved in tetrahydrofuran (0.50 mL) at room temperature, and a solution of sodium hydroxide (6.38 mg) in water (0.50 mL) was added. Stir at room temperature for 0.5 hour. Water (2 mL) was added and back-extracted with EA (2 mL)*2. The aqueous layer was adjusted to PH=5 with 1N HCl, and then extracted with DCM (5 mL)*2. The organic layer was washed with a small amount of saturated brine and dried over anhydrous sodium sulfate. The crude product was prepared by Pre-HPLC to obtain the target product 32 as a white solid (8.60 mg, purity 98.26%, yield 28.90%). ESI-MS m/z: 550.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 8.36 (s, 1H), 8.14 (s, 1H), 7.92-7.77 (m, 1H), 7.40-7.31 (m, 3H), 7.05-7.03 (m, 1H) , 5.85-5.83 (m, 1H), 2.64-2.56 (m, 2H), 2.43 (s, 3H), 2.39-2.37 (m, 1H), 2.25 (s, 3H), 2.20-2.13 (m, 1H) , 2.01-1.99 (m, 1H), 1.79-1.76 (m, 1H).

Example 33: Compound ( S )-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5-( Synthesis of Hydroxymethyl)thiazol-2-yl) -1H -benzo[d]imidazol-2-yl)pyridin-2-one

Compound 32 (40.00 mg) was dissolved in tetrahydrofuran (2.00 mL), and lithium tetrahydroaluminum (4.04 mg) was added portionwise at 0°C. Stir at 0°C for 0.25 hours. A drop of water was added dropwise under the ice bath, then a drop of 15% NaOH aqueous solution was added, and finally 3 drops of water were added dropwise. Stir for five minutes, then add anhydrous sodium sulfate and stir for 5 minutes. After filtration, the filter cake was rinsed with DCM (5 mL), and the filtrate was concentrated under reduced pressure. The crude product was prepared by Pre-HPLC to obtain the target product 33 as a white solid (11.20 mg, purity 99.11%, yield 29.19%). ESI-MS m/z: 536.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 7.90 (s, 1H), 7.78 (s, 1H), 7.60-7.59 (m, 1H), 7.37-7.31 (m, 3H), 7.06-7.04 (m, 1H) , 5.85 (s, 1H), 5.69-5.67 (m, 1H), 4.78 (s, 2H), 2.64-2.56 (m, 2H), 2.43 (s, 3H), 2.39-3.34 (m, 1H), 2.26 (s, 3H), 2.13-2.11 (m, 1H), 2.01-1.99 (m, 1H), 1.79-1.76 (m, 1H).

Example 34: Compound 4-(6-(3,5-Dimethylisoxazol-4-yl)-2-((tetrahydro- 2H -pyran-4-yl)amino ) -1H- Synthesis of Benzo[d]imidazol-1-yl)benzoic acid

Refer to Example 30 for the specific synthesis steps of compound 34. Target product 34 ESI-MS m/z: 433.2 [M+H] ⁺ .

Example 35: Compound ( R )-2-(2-(1-(3,4-difluorophenyl)-6-oxoguaridin-2-yl)-5-(3,5-dimethyliso Synthesis of oxazol-4-yl)-1H-benzo[d]imidazol-1-yl) -N , N - dimethylthiazole -5-sulfonamide

The specific synthesis steps of compound 35 refer to Example 31. Target product 35 ESI-MS m/z: 613.1 [M+H] ⁺ .

Example 36: Compound Methyl( S )-2-(2-(2-(1-(3,4-difluorophenyl)-6-oxoxazidine-2-yl)-5-(3,5 - Synthesis of dimethylisoxazol-4-yl) -1H -benzo[d]imidazol-1-yl)thiazol-4-yl)acetate

The specific synthesis steps of compound 36 refer to Example 31. Target product 36 ESI-MS m/z: 578.2 [M+H] ⁺ .

Example 37: Compound ( S )-2-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5-difluorophenyl)- Synthesis of methylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)acetic acid

The specific synthesis steps of compound 37 refer to Example 32. Target product 37 ESI-MS m/z: 564.1 [M+H] ⁺ .

Example 38: Compound ( S )-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-( Synthesis of 2-Hydroxyethyl)thiazol-2-yl) -1H -benzo[d]imidazol-2-yl)pyridin-2-one

The specific synthesis steps of compound 38 refer to Example 33. Target product 38 ESI-MS m/z: 550.2 [M+H] ⁺ .

Example 39: Compound ( S )-2-(2-(2-(1-(3,4-difluorophenyl)-6-oxoxazidine-2-yl)-5-(3,5-difluorophenyl)- Synthesis of methylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl) -N , N - dimethylacetamide

Compound 37 (25.00 mg), N -methylmethanamine (7.19 mg) was dissolved in DMF (0.50 mL) at room temperature, 1-hydroxybenzotriazole (9.01 mg), 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.79 mg) and N , N -diisopropylethylamine (0.03 mL) were stirred at room temperature for 2 hours. The reaction mixture was directly concentrated, and the concentrate was prepared by Pre-HPLC to obtain the target product 39 as a white solid (5.00 mg, purity 97.71%, yield 18.63%). ESI-MS m/z: 591.2 [M+H] ⁺ .

Example 40: Compound ( S )-2-(2-(2-(1-(3,4-difluorophenyl)-6-oxoxazidine-2-yl)-5-(3,5-difluorophenyl)- Synthesis of methylisoxazol-4-yl) -1H -benzo[d]imidazol-1-yl)thiazol-4-yl) -N -methylacetamide

The specific synthesis steps of compound 40 refer to Example 39. Target product 40 ESI-MS m/z: 577.2 [M+H] ⁺ .

Example 41: Compound ( S )-2-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethyliso Synthesis of oxazol-4-yl) -1H -benzo[d]imidazol-1-yl) -N -methylthiazole-5-carboxamide

The specific synthesis steps of compound 41 refer to Example 39. Target product 41 ESI-MS m/z: 563.2 [M+H] ⁺ .

Example 42: Compound ( S )-2-(2-(1-(3,4-difluorophenyl)-6-oxopridin-2-yl)-5-(3,5-dimethyliso Synthesis of oxazol-4-yl)-1H-benzo[d]imidazol-1-yl) -N , N -dimethylthiazole-5-carboxamide

The specific synthetic procedure of compound 42 refers to Example 39. Target product 42 ESI-MS m/z: 577.2 [M+H] ⁺ .

Example 43: Compound (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-( Synthesis of Hydroxymethyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

The specific synthesis steps of compound 43 refer to Example 33. Target product 43 ESI-MS m/z: 536.2 [M+H] ⁺ .

Example 44: Compound (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-( Synthesis of (Methylsulfonyl)methyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

The specific synthesis steps of compound 44 refer to Example 27. Target product 44 ESI-MS m/z: 598.1 [M+H] ⁺ .

Example 45: Compound (R)-2-(2-(4-(3,4-difluorophenyl)-5-oxomorpholin-3-yl)-5-(3,5-dimethyl) Synthesis of isoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-5-carboxamide

The specific synthetic procedure of compound 45 refers to Example 39. Target product 45 ESI-MS m/z: 565.1 [M+H] ⁺ .

Example 46: Compound (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxopridin-2-yl)-5-(3,5-dimethyliso Synthesis of oxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-4-carboxamide

The specific synthetic procedure of compound 46 refers to Example 39. Target product 46ESI-MS m/z: 563.2 [M+H] ⁺ .

Example 47: Compound (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethyliso Synthesis of oxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-5-sulfonamide

The specific synthetic procedure of compound 47 refers to Example 26. Target product 47 ESI-MS m/z: 599.1 [M+H] ⁺ .

Example 48: Compound (S)-2-(2-(2-(1-(3,4-difluorophenyl)-6-oxopridin-2-yl)-5-(3,5-difluorophenyl) Synthesis of methylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-5-yl)-N-methylacetamide

The specific synthetic procedure of compound 48 refers to Example 39. Target product 48 ESI-MS m/z: 577.2 [M+H] ⁺ .

Example 49: Compound (S)-2-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5-difluorophenyl) Synthesis of methylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-5-yl)-N,N-dimethylacetamide

The specific synthetic procedure of compound 49 refers to Example 39. Target product 49 ESI-MS m/z: 591.2 [M+H] ⁺ .

Example 50: Compound (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopridin-2-yl)-5-(3,5-dimethyliso Synthesis of oxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methylisothiazole-3-carboxamide

The specific synthesis steps of compound 50 refer to Example 39. Target product 50 ESI-MS m/z: 563.2 [M+H] ⁺ .

Example 51: Compound (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopridin-2-yl)-5-(3,5-dimethyliso Synthesis of oxazol-4-yl)-1H-benzo[d]imidazol-1-yl)isothiazole-3-carboxylic acid

The specific synthesis steps of compound 51 refer to Example 37. Target product 51 ESI-MS m/z: 550.1 [M+H] ⁺ .

Example 52: Compound (S)-2-(5-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5-difluorophenyl)- Synthesis of methylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)isothiazol-3-yl)-N-methylacetamide

The specific synthetic procedure of compound 52 refers to Example 39. Target product 52 ESI-MS m/z: 577.2 [M+H] ⁺ .

Example 53: Compound (S)-2-(5-(2-(1-(3,4-difluorophenyl)-6-oxoxazidine-2-yl)-5-(3,5-difluorophenyl) Synthesis of methylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-1,2,4-thiadiazol-3-yl)-N-methylacetamide

The specific synthesis procedure of compound 53 refers to Example 39. Target product 53 ESI-MS m/z: 578.2 [M+H] ⁺ .

Example 54: Compound (S)-N-Cyclopropyl-2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3, Synthesis of 5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazole-5-carboxamide

The specific synthetic procedure of compound 54 refers to Example 39. Target product 54 ESI-MS m/z: 589.2 [M+H] ⁺ .

Example 55: Compound (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethyliso Synthesis of oxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methyl-1,2,4-thiadiazole-3-carboxamide

The specific synthesis procedure of compound 55 refers to Example 39. Target product 55 ESI-MS m/z: 564.2 [M+H] ⁺ .

Example 56: Compound (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopridin-2-yl)-5-(3,5-dimethyliso Synthesis of oxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methyl-1,3,4-thiadiazole-2-carboxamide

The specific synthetic procedure of compound 56 refers to Example 39. Target product 56 ESI-MS m/z: 564.2 [M+H] ⁺ .

Example 57: Compound (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxopridin-2-yl)-5-(3,5-dimethyliso Synthesis of oxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methyl-1H-imidazole-5-carboxamide

The specific synthetic procedure of compound 57 refers to Example 39. Target product 57 ESI-MS m/z: 546.2 [M+H] ⁺ .

Example 58: Compound (S)-2-(5-(3,5-Dimethylisoxazol-4-yl)-2-(1-(4-fluorophenyl)-6-oxoxazolidine- Synthesis of 2-yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-5-carboxamide

The specific synthetic procedure of compound 58 refers to Example 39. Target product 58 ESI-MS m/z: 545.2 [M+H] ⁺ .

Example 59: Compound (S)-2-(2-(1-(3-Chloro-4-fluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethyl Synthesis of isoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-5-carboxamide

The specific synthesis procedure of compound 59 refers to Example 39. Target product 59 ESI-MS m/z: 579.1 [M+H] ⁺ .

Example 60: Compound (S)-2-(5-(3,5-Dimethylisoxazol-4-yl)-2-(1-(4-methoxyphenyl)-6-oxogua) Synthesis of pyridin-2-yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-5-carboxamide

The specific synthesis steps of compound 60 refer to Example 39. Target product 60 ESI-MS m/z: 557.2 [M+H] ⁺ .

Example 61: Compound (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5-( Synthesis of (Methylsulfonyl)methyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

The specific synthesis steps of compound 61 refer to Example 27. Target product 61 ESI-MS m/z: 598.1 [M+H] ⁺ .

Example 62: Compound (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-methyl) Synthesis of Oxyphenyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

Step 1: Synthesis of Compound 62-1

At room temperature, compound tert-butyl N-(4-aminophenyl)carbamate (551.07 mg), (4-fluoro-3-nitrophenyl)-3,5-dimethyl-1 ,2-oxazole (500.00 mg) was added to DMSO (6.00 mL) followed by DIEA (1.05 mL). Raised to 100°C and stirred overnight. EA (25 mL)*2 and H ₂ O (30 mL) were added for extraction, the organic layer was washed with saturated brine, the organic phase was dried, and concentrated to obtain the crude product of target compound 62-1 (1.14 g) as a yellow oil. ESI-MS m/z: 425.2 [M+H] ⁺ .

Step 2: Synthesis of Compound 62-2

Compound 62-1 (1.04 g) was added to THF (50.00 mL) and methanol (50.00 mL), followed by Pd/C (0.21 g) at room temperature. _H2 was replaced three times and stirred at room temperature under _H2 atmosphere overnight. After filtration, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (DCM/MeOH=100:3) to obtain the target compound 62-2 as a yellow solid (0.75 g, yield 78.01%). ESI-MS m/z: 395.2 [M+H] ⁺ .

Step 3: Synthesis of Compound 62-3

At room temperature, compound 62-2 (700.00 mg), (2S)-6-oxoxidine-2-carboxylic acid (508.01 mg) was added to dichloromethane (14.00 mL) followed by DIEA (1.03 mL) After stirring at room temperature for 5 minutes, T3P (1.85 mL) was added. Stir at room temperature for 1 h. Water (10 ml) and DCM (20 ml)*2 were added for extraction, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (DCM/MeOH=100:5) to obtain the target compound 62-3 as a yellow solid (696.00 mg, yield 75.49%). ESI-MS m/z: 520.0 [M+H] ⁺ .

Step 4: Synthesis of Compound 62-4

At room temperature, compound 62-3 (676.00 mg) was added to dichloromethane (10.00 mL), then TFA (3.00 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain the crude product of 62-4 as a yellow oil (545.00 mg, yield 99.86%). ESI-MS m/z: 420.0 [M+H] ⁺ .

Step 5: Synthesis of Compound 62-5

At room temperature, compound 62-4 (545.00 mg) was added to trifluoroacetic acid (13.00 mL), and the mixture was heated to 80° C. and stirred for 4 h. The reaction solution was directly concentrated under reduced pressure, and then adjusted to pH=8 with saturated NaHCO ₃ solution. Extracted with DCM (15 mL)*2, the organic layer was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was separated and purified by column chromatography (DCM/MeOH=100:5) to obtain the target compound 62-5 as a pale yellow solid (340.00 mg, yield 65.19%). ESI-MS m/z: 402.2 [M+H] ⁺ . Step 6: Synthesis of Compound 62

Compound 62-5 (30.00 mg), (3,4-difluorophenyl)boronic acid (58.98 mg), Cu(OAc) dihydrate (22.38 _mg ) was added to DCM (1.50 mL) and pyridine at room temperature (0.30 mL). _O2 was replaced three times and stirred at room temperature under _O2 atmosphere for 2.5 h. DCM (20 mL*2) and H ₂ O (10 mL) were added for extraction, and the organic layer was washed with 1N HCl*2, then with saturated brine, finally dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (DCM/MeOH=100:3) and prepared by Pre-HPLC to obtain the target compound 62 (57.60 mg, purity 98.30%, yield 17.71%) as a white solid. ESI-MS m/z: 514.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 7.78 (d, J = 5.0 Hz, 1H), 7.37-7.22 (m, 1H), 7.17 (dt, J = 4.8, 2.4 Hz, 1H), 7.03-6.99 (m , 1H), 6.95-6.88 (m, 1H), 6.64 (d, J = 29.3 Hz, 1H), 6.33 (s, 1H), 5.57 (d, J = 7.0 Hz, 1H), 5.04 (d, J = 9.2 Hz, 1H), 2.57 (s, 1H), 2.48-2.43 (m, 1H), 2.41 (d, J = 4.5 Hz, 1H), 2.23 (d, J = 6.8 Hz, 1H), 2.07-1.98 ( m, 1H), 1.81-1.72 (m, 1H).

31、32、33

3

34

4

35

6

36、37、38

7

39、42

8、11

40、41

9

43、46

10

44

12

45、54

13

47

14

48、49

15

50、51

16、18、19、20

52、53

17

55

21、23、24

56

22

57

25

58

26

59

27

60

28

61

29

62

30

      The corresponding synthetic intermediates are as follows: Example number Intermediate Example number Intermediate 1, 2, 5

31, 32, 33

3

34

4

35

6

36, 37, 38

7

39, 42

8, 11

40, 41

9

43, 46

10

44

12

45, 54

13

47

14

48, 49

15

50, 51

16, 18, 19, 20

52, 53

17

55

21, 23, 24

56

twenty two

57

25

58

26

59

27

60

28

61

29

62

30

563.2 64 （S） -5-（2-（1-（3,4-二氟苯基）-6-噁阿片呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H苯并[d]咪唑-1-基）-3-氟-N-甲基噻吩-2-羧醯胺

580.2 65 （S） -2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-5-碳腈

531.4 66 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（5-（甲磺醯基）噻唑-2-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

584.1 67 （S） -6-（1-（5-（氮雜環丁烷-1-羰基）噻唑-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

589.3 68 （S） -2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-7-羥基-1H-苯并[d]咪唑-1-基）-N-甲基噻唑-5-甲醯胺

579.2 69 （S） -2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-6-（3,5-二甲基異噁唑-4-基）-3H-咪唑并[4,5-b]吡啶-3-基）-N-甲基噻唑-5-甲醯胺

564.2 70 （S） -2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-咪唑并[4,5-b]吡啶-1-基）-N-甲基噻唑-5-甲醯胺

564.2 71 （S） -2-（5-（3,5-二甲基異噁唑-4-基）-2-（1-（3-氟-4-甲氧基苯基）-6-氧呱啶-2-基）-1H-苯并[d]咪唑-1-基）-N-甲基噻唑-5-甲醯胺

575.2 72 （S） -2-（2-（1-（2-氯吡啶-4-基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-N-甲基噻唑-5-甲醯胺

562.2 73 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（5-（2-羥基丙烷-2-基）噻唑-2-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

564.2 74 （S） -6-（1-（5-氨基噻唑-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

521.2 75 （S） -2-（2-（3-（3,4-二氟苯基）-2-氧代-1,3-噁嗪-4-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-N-甲基噻唑-5-甲醯胺

565.1 76 （S） -2-（2-（3-（3,4-二氟苯基）-2-氧代-1,3-噁嗪-4-基）-6-（3,5-二甲基異噁唑-4-基）-3H-咪唑并[4,5-b]吡啶-3-基）-N-甲基噻唑-5-甲醯胺

566.1 77 （S） -2-（2-（5-（3,5-二甲基異噁唑-4-基）-2-（1-（3-氟-4-甲氧基苯基）-6-氧呱啶-2-基）-1H-苯并[d]咪唑-1-基）噻唑-5-基）-N-甲基乙醯胺

589.2 78 （S） -2-（2-（1-（2-氯吡啶-4-基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-5-基）-N-甲基乙醯胺

576.2 79 2-（2-（（S）-1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-3a，7a-二氫-1H-苯并咪唑-1-基）-4,7-二氫噻唑[4,5-c]吡啶-6（5H）-酮

577.2 80 2-（2-（（S）-1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-3a，7a-二氫-1H-苯并咪唑-1-基）-4,6-二氫-5H-吡咯[2,3-d]噻唑-5-酮

563.2 81 2-（5-（3,5-二甲基異噁唑-4-基）-2-（（S）-1-（3-氟-4-甲氧基苯基）-6-氧呱啶-2-基）-3a，7a-二氫-1H-苯并[d]咪唑-1-基）-4,7-二氫噻唑[4,5-c]吡啶-6（5H）-酮

589.2 82 2-（5-（3,5-二甲基異噁唑-4-基）-2-（（S）-1-（3-氟-4-甲氧基苯基）-6-氧呱啶-2-基）-3a，7a-二氫-1H-苯并[d]咪唑-1-基）-4,6-二氫-5H-吡咯[2,3-d]噻唑-5-酮

575.2 83 2-（5-（3,5-二甲基異噁唑-4-基）-2-（（S）-1-（3-氟-4-甲氧基苯基）-6-噁阿片呱啶-2-基）-3a，7a-二氫-1H-苯并[d]咪唑-1-基）-6,7-二氫噻唑[5,4-c]吡啶-4（5H）-一

589.2 84 2-（5-（3,5-二甲基異噁唑-4-基）-2-（（S）-1-（3-氟-4-甲氧基苯基）-6-氧呱啶-2-基）-3a，7a-二氫-1H-苯并[d]咪唑-1-基）-4,5-二氫-6H-吡咯[3,4-d]噻唑-6-酮

575.2 85 2-（2-（（S）-1-（2-氯吡啶-4-基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-3a，7a-二氫-1H-苯并[d]咪唑-1-基）-6,7-二氫噻唑[5,4-c]吡啶-4（5H）-酮

576.2 86 2-（2-（（S）-1-（2-氯吡啶-4-基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-3a，7a-二氫-1H-苯并[d]咪唑-1-基）-4,5-二氫-6H-吡咯[3,4-d]噻唑-6-酮

562.1 87 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（甲胺基）苯基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

528.2 88 2-（2-（（S）-1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-3a，7a-二氫-1H-苯并咪唑-1-基）-6,7-二氫噻唑[5,4-c]吡啶-4（5H）-酮

577.2 89 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-甲氧基苯基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

529.2 90 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-羥基苯基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

515.2 91 （S） -4-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）苯甲醯胺

542.2 92 （S） -1-（3,4-二氟苯基）-6-（1-（4-（二甲氨基）苯基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

542.2 93 （S） -4-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-N-甲基苯甲醯胺

556.2 94 （S） -4-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-N，N-二甲基苯甲醯胺

570.2 95 （S） -6-（1-（4-（氮雜環丁烷-1-基）苯基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

554.2 96 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（2-氧代氮雜苯胺-1-基）苯基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

568.2 97 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（3-氧吡咯烷-1-基）苯基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

582.2 98 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（2-氧呱啶-1-基）苯基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

596.2 99 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（（甲基磺醯基）甲基）苯基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

591.2 100 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（甲磺醯基）苯基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

577.2 101 （S） -4-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）苯磺醯胺

578.2 102 （S） -（4-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）苯基）甲基磺醯胺

592.2 103 （S） -2-（4-（2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）苯基）乙醯胺

639.2 104 （S） -2-（4-（2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）苯基）-N-甲基乙醯胺

653.2 105 （S） -2-（4-（2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）苯基）-N，N-二甲基乙醯胺

667.2 106 （S） -2-（5-（2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）吡啶-2-基）乙醯胺

640.2 107 （S） -3-（4-（2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）苯基）丙胺

653.2 108 （S） -2-（4-（2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）苯基）乙硫醯胺

655.2 109 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（4-（（甲基磺醯基）甲基）苯基）噻唑-2-基）-1H-吡咯并[3,2-b]吡啶-2-基）呱啶-2-酮

674.2 110 （S） -2-（6-（2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）吡啶-3-基）乙醯胺

640.2 111 （S） -1-（3,4-二氟苯基）-6-（6-（3,5-二甲基異噁唑-4-基）-1-（4-（4-（（甲基磺醯基）甲基）苯基）噻唑-2-基）-1H-咪唑并[4,5-b]吡啶-2-基）呱啶-2-酮

675.2 112 （S） -2-（6-（2-（1-（3,4-二氟苯基）-6-噁呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）吡啶-3-基）-N-甲基乙醯胺

654.2 113 （S） -1-（3,4-二氟苯基）-6-（6-（3,5-二甲基異噁唑-4-基）-1-（4-（4-（（甲基磺醯基）甲基）苯基）噻唑-2-基）-1H-咪唑并[4,5-b]吡啶-2-基）呱啶-2-酮

675.2 114 （S） -4-（2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）苯并硫代醯胺

640.2 115 （S） -4-（2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）-N-甲基苯并硫醯胺

655.2 116 （S） -3-（4-（2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）苯基）丙硫醯胺

669.2 117 （S） -6-（1-（4-氨基-3-氟苯基）-5-（3,5-二甲基異噁唑-4-基）-1H苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

532.2 118 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（3-氟-4-（甲氨基）苯基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

546.2 119 （S） -1-（3,4-二氟苯基）-6-（1-（4-（二甲氨基）-3-氟苯基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

560.2 120 （S） -6-（1-（4-氨基-3-（三氟甲基）苯基）-5-（3,5-二甲基異噁唑-4-基）-1H苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

582.2 121 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（甲氨基）-3-（三氟甲基）苯基）-1H苯并[d]咪唑-2-基）呱啶-2-酮

596.2 122 （S） -1-（3,4-二氟苯基）-6-（1-（4-（二甲氨基）-3-（三氟甲基）苯基）-5-（3,5-二甲基異噁唑-4-基）-1H苯并[d]咪唑-2-基）呱啶-2-酮

610.2 123 （S） -2-氨基-5-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）苯腈

539.2 124 （S） -5-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-2-（甲氨基）苯腈

553.2 125 （S） -5-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-2-（二甲氨基）苯腈

567.2 126 （S） -6-（1-（6-氨基吡啶-3-基）-5-（3,5-二甲基異噁唑-4-基）-1H苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

515.2 127 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（6-（甲氨基）吡啶-3-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

529.2 128 （S） -1-（3,4-二氟苯基）-6-（1-（6-（二甲氨基）吡啶-3-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

543.2 129 （S） -6-（1-（4-氨基-3-（三氟甲氧基）苯基）-5-（3,5-二甲基異噁唑-4-基）-1H苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

598.2 130 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（甲氨基）-3-（三氟甲氧基）苯基）-1H苯并[d]咪唑-2-基）呱啶-2-酮

612.2 131 （S） -1-（3,4-二氟苯基）-6-（1-（4-（二甲氨基）-3-（三氟甲氧基）苯基）-5-（3,5-二甲基異噁唑-4-基）-1H苯并[d]咪唑-2-基）呱啶-2-酮

626.2 132 （S） -N-環丙基-2-（2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）乙醯胺

603.2 133 （S） -2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（1,5-二甲基-6-氧代-1,6-二氫吡啶-3-基）-1H-苯并[d]咪唑-1-基）-N-甲基噻唑-5-甲醯胺

589.2 134 （S） -5-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-N-甲基噻吩-2-甲醯胺

562.2 135 （S） -2-（2-（1-（4-氯-3-氟苯基）-6-噁呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-N-甲基噻唑-5-甲醯胺

579.2 136 （S） -2-（2-（3-（4-氯-3-氟苯基）-2-氧代-1,3-噁嗪南-4-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-N-甲基噻唑-5-甲醯胺

581.1 137 （S） -2-（2-（1-（3,4-二氟苯基）-6-噁呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-N-甲氧基噻唑-5-甲醯胺

579.2 138 （S） -2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-N-羥基噻唑-5-甲醯胺

565.1 139 （S） -2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-N-（2-羥乙基）噻唑-5-甲醯胺

593.2 140 （S） -2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-N-（2-甲氧基乙基）噻唑-5-甲醯胺

607.2 141 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（5-（甲磺醯基）苯并[d]噻唑-2-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

634.1 142 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（6-（（甲磺醯基）甲基）吡啶-3-基）噻唑-2-基）-1H苯并[d]咪唑-2-基）呱啶-2-酮

675.2 143 （S）-1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（4-（甲基亞碸基）甲基）苯基）噻唑-2-基）-1H苯并[d]咪唑-2-基）呱啶-2-酮

658.2 144 （S） -1-（3,4-二氟苯基）-6-（1-（4-（二甲氨基）甲基）苯基）噻唑-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

639.2 145 （S）-1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（甲基亞碸基）苯基）噻唑-2-基）-1H苯并[d]咪唑-2-基）呱啶-2-酮

644.2 146 （S） -4-（2-（2-（1-（3,4-二氟苯基）-6-噁呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）-2-氟苯甲醯胺

643.2 147 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（5-甲基-4-（4-（（甲磺醯基）甲基）苯基）噻唑-2-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

688.2 148 （S） -4-（5-（2-（1-（3,4-二氟苯基）-6-噁呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）-1,2,4-噻二唑-3-基）苯甲醯胺

626.2 149 （S） -5-（2-（2-（1-（3,4-二氟苯基）-6-噁呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）吡啶醯胺

626.2 150 （S） -4-（2-（2-（1-（3,4-二氟苯基）-6-噁呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）-3-甲氧基苯甲醯胺

655.2 151 （S） -2-（4-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）苯基）乙醯胺

556.2 152 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（（甲磺醯基）甲基）苯基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

591.2 153 （S） -（4-（2-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）苯基）甲磺醯亞胺

675.2 154 （S） -2-（2-（1-（3,4-二氟苯基）-6-噁呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-5-甲醯胺

549.1 155 （S） -2-（4-（2-（2-（1-（3,4-二氟苯基）-6-噁呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H苯并[d]咪唑-1-基）噻唑-4-基）-2-氟苯基）乙醯胺

657.2 156 （S） -4-（2-（2-（1-（3,4-二氟苯基）-6-噁呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）-2-甲氧基苯甲醯胺

655.2 157 （S） -4-（2-（2-（1-（3,4-二氟苯基）-6-噁呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）噻唑-4-基）-3-氟苯甲醯胺

643.2 158 （S） -4-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）苯基二甲基氨基甲酸酯

586.2 159 （S） -6-（1-（4-氨基-3,5-二氟苯基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

550.2 160 （S） -6-（1-（3,5-二氟-4-（甲氨基）苯基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

564.2 161 （S） -N-（5-（2-（1-（3,4-二氟苯基）-6-氧呱啶-2-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-1-基）吡啶-2-基）乙醯胺

557.2 162 （S） -6-（1-（6-（環丙基氨基）吡啶-3-基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

555.2 163 （S） -6-（1-（4-（氨基甲基）苯基）-5-（3,5-二甲基異噁唑-4-基）-1H苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

528.2 164 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（甲氨基）甲基）苯基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

542.2 165 （S） -1-（3,4-二氟苯基）-6-（1-（4-（二甲氨基）甲基）苯基）-5-（3,5-二甲基異噁唑-4-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

556.3 166 （S） -6-（1-（4-氨基-3-氯苯基）-5-（3,5-二甲基異噁唑-4-基）-1H苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

548.2 167 （S） -6-（1-（3-氯-4-（甲氨基）苯基）-5-（3,5-二甲基異噁唑-4-基）-1H苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

562.4 168 （S） -6-（1-（3-氯-4-（二甲氨基）苯基）-5-（3,5-二甲基異噁唑-4-基）-1H苯并[d]咪唑-2-基）-1-（3,4-二氟苯基）呱啶-2-酮

576.2 169 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-（甲氨基）噻唑-2-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

535.2 170 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（5-（甲氨基）噻唑-2-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

535.2 171 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-羥基噻唑-2-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

522.1 172 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（5-羥基噻唑-2-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

522.1 173 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-甲氧基噻唑-2-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

536.2 174 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（5-甲氧基噻唑-2-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

536.2 175 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（4-甲基噻唑-2-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

520.2 176 （S） -1-（3,4-二氟苯基）-6-（5-（3,5-二甲基異噁唑-4-基）-1-（5-甲基噻唑-2-基）-1H-苯并[d]咪唑-2-基）呱啶-2-酮

520.2 The following examples were synthesized using the methods described above, or analogously using the corresponding intermediates. Example Chemical Name structure ESI-MS [M+H] ⁺ 63 2-(2-((S)-1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-3a,7a-dihydro-1H-benzimidazol-1-yl)-4,5-dihydro-6H-pyrro[3,4-d]thiazol-6-one

563.2 64 (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopiaziridin-2-yl)-5-(3,5-dimethylisoxazole-4 -yl)-1Hbenzo[d]imidazol-1-yl)-3-fluoro-N-methylthiophene-2-carboxamide

580.2 65 (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)thiazole-5-carbonitrile

531.4 66 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5-(methylsulfonyl) Thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

584.1 67 (S)-6-(1-(5-(azetidine-1-carbonyl)thiazol-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H -Benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyridin-2-one

589.3 68 (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-7-hydroxy-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-5-carboxamide

579.2 69 (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-6-(3,5-dimethylisoxazole-4- yl)-3H-imidazo[4,5-b]pyridin-3-yl)-N-methylthiazole-5-carboxamide

564.2 70 (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-imidazo[4,5-b]pyridin-1-yl)-N-methylthiazole-5-carboxamide

564.2 71 (S)-2-(5-(3,5-Dimethylisoxazol-4-yl)-2-(1-(3-fluoro-4-methoxyphenyl)-6-oxapyridine -2-yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-5-carboxamide

575.2 72 (S)-2-(2-(1-(2-Chloropyridin-4-yl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-5-carboxamide

562.2 73 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5-(2-hydroxypropane- 2-yl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

564.2 74 (S)-6-(1-(5-Aminothiazol-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2- yl)-1-(3,4-difluorophenyl)pyridin-2-one

521.2 75 (S)-2-(2-(3-(3,4-difluorophenyl)-2-oxo-1,3-oxazin-4-yl)-5-(3,5-dimethyl) Isoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-5-carboxamide

565.1 76 (S)-2-(2-(3-(3,4-difluorophenyl)-2-oxo-1,3-oxazin-4-yl)-6-(3,5-dimethyl) Isoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-N-methylthiazole-5-carboxamide

566.1 77 (S)-2-(2-(5-(3,5-dimethylisoxazol-4-yl)-2-(1-(3-fluoro-4-methoxyphenyl)-6- Oxyridin-2-yl)-1H-benzo[d]imidazol-1-yl)thiazol-5-yl)-N-methylacetamide

589.2 78 (S)-2-(2-(1-(2-Chloropyridin-4-yl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)thiazol-5-yl)-N-methylacetamide

576.2 79 2-(2-((S)-1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-3a,7a-dihydro-1H-benzimidazol-1-yl)-4,7-dihydrothiazol[4,5-c]pyridin-6(5H)-one

577.2 80 2-(2-((S)-1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-3a,7a-dihydro-1H-benzimidazol-1-yl)-4,6-dihydro-5H-pyrro[2,3-d]thiazol-5-one

563.2 81 2-(5-(3,5-Dimethylisoxazol-4-yl)-2-((S)-1-(3-fluoro-4-methoxyphenyl)-6-oxopridine -2-yl)-3a,7a-dihydro-1H-benzo[d]imidazol-1-yl)-4,7-dihydrothiazol[4,5-c]pyridin-6(5H)-one

589.2 82 2-(5-(3,5-Dimethylisoxazol-4-yl)-2-((S)-1-(3-fluoro-4-methoxyphenyl)-6-oxopridine -2-yl)-3a,7a-dihydro-1H-benzo[d]imidazol-1-yl)-4,6-dihydro-5H-pyrro[2,3-d]thiazol-5-one

575.2 83 2-(5-(3,5-Dimethylisoxazol-4-yl)-2-((S)-1-(3-fluoro-4-methoxyphenyl)-6-oxopioid pyridin-2-yl)-3a,7a-dihydro-1H-benzo[d]imidazol-1-yl)-6,7-dihydrothiazol[5,4-c]pyridine-4(5H)-one

589.2 84 2-(5-(3,5-Dimethylisoxazol-4-yl)-2-((S)-1-(3-fluoro-4-methoxyphenyl)-6-oxopridine -2-yl)-3a,7a-dihydro-1H-benzo[d]imidazol-1-yl)-4,5-dihydro-6H-pyrro[3,4-d]thiazol-6-one

575.2 85 2-(2-((S)-1-(2-Chloropyridin-4-yl)-6-oxopridin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-3a,7a-dihydro-1H-benzo[d]imidazol-1-yl)-6,7-dihydrothiazol[5,4-c]pyridin-4(5H)-one

576.2 86 2-(2-((S)-1-(2-Chloropyridin-4-yl)-6-oxopridin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-3a,7a-dihydro-1H-benzo[d]imidazol-1-yl)-4,5-dihydro-6H-pyrro[3,4-d]thiazol-6-one

562.1 87 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(methylamino)benzene) yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

528.2 88 2-(2-((S)-1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-3a,7a-dihydro-1H-benzimidazol-1-yl)-6,7-dihydrothiazol[5,4-c]pyridin-4(5H)-one

577.2 89 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl) -1H-Benzo[d]imidazol-2-yl)pyridin-2-one

529.2 90 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H -Benzo[d]imidazol-2-yl)pyridin-2-one

515.2 91 (S)-4-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)benzamide

542.2 92 (S)-1-(3,4-Difluorophenyl)-6-(1-(4-(dimethylamino)phenyl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

542.2 93 (S)-4-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)-N-methylbenzamide

556.2 94 (S)-4-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)-N,N-dimethylbenzamide

570.2 95 (S)-6-(1-(4-(azetidin-1-yl)phenyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo [d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyridin-2-one

554.2 96 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(2-oxonitrogen) Heteroanilin-1-yl)phenyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

568.2 97 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(3-oxopyrrolidine) -1-yl)phenyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

582.2 98 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(2-oxazolidine) -1-yl)phenyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

596.2 99 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-((methylsulfonyl) yl)methyl)phenyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

591.2 100 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(methylsulfonyl) Phenyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

577.2 101 (S)-4-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)benzenesulfonamide

578.2 102 (S)-(4-(2-(1-(3,4-Difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4) -yl)-1H-benzo[d]imidazol-1-yl)phenyl)methylsulfonamide

592.2 103 (S)-2-(4-(2-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethyl) Isoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)phenyl)acetamide

639.2 104 (S)-2-(4-(2-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethyl) Isoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)phenyl)-N-methylacetamide

653.2 105 (S)-2-(4-(2-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethyl) Isoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)phenyl)-N,N-dimethylacetamide

667.2 106 (S)-2-(5-(2-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethyl) Isoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)pyridin-2-yl)acetamide

640.2 107 (S)-3-(4-(2-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethyl) Isoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)phenyl)propylamine

653.2 108 (S)-2-(4-(2-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethyl) Isoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)phenyl)ethionamide

655.2 109 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(4-((methyl) sulfonyl)methyl)phenyl)thiazol-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)quaridin-2-one

674.2 110 (S)-2-(6-(2-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethyl) Isoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)pyridin-3-yl)acetamide

640.2 111 (S)-1-(3,4-Difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-1-(4-(4-((methyl) sulfonyl)methyl)phenyl)thiazol-2-yl)-1H-imidazo[4,5-b]pyridin-2-yl)quaridin-2-one

675.2 112 (S)-2-(6-(2-(1-(3,4-difluorophenyl)-6-oxadiridin-2-yl)-5-(3,5-dimethylisoxazole) -4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)pyridin-3-yl)-N-methylacetamide

654.2 113 (S)-1-(3,4-Difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-1-(4-(4-((methyl) sulfonyl)methyl)phenyl)thiazol-2-yl)-1H-imidazo[4,5-b]pyridin-2-yl)quaridin-2-one

675.2 114 (S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxoguaridin-2-yl)-5-(3,5-dimethylisoxazole) -4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)benzothioamide

640.2 115 (S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxoguaridin-2-yl)-5-(3,5-dimethylisoxazole) -4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)-N-methylbenzothiamide

655.2 116 (S)-3-(4-(2-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethyl) Isoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)phenyl)propylthioamide

669.2 117 (S)-6-(1-(4-Amino-3-fluorophenyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazole-2- yl)-1-(3,4-difluorophenyl)pyridin-2-one

532.2 118 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-fluoro-4-(methyl) Amino)phenyl)-1H-benzo[d]imidazol-2-yl)quaridin-2-one

546.2 119 (S)-1-(3,4-Difluorophenyl)-6-(1-(4-(dimethylamino)-3-fluorophenyl)-5-(3,5-dimethylisoxanil) oxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

560.2 120 (S)-6-(1-(4-Amino-3-(trifluoromethyl)phenyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d ]imidazol-2-yl)-1-(3,4-difluorophenyl)pyridin-2-one

582.2 121 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(methylamino)-3 -(Trifluoromethyl)phenyl)-1Hbenzo[d]imidazol-2-yl)pyridin-2-one

596.2 122 (S)-1-(3,4-Difluorophenyl)-6-(1-(4-(dimethylamino)-3-(trifluoromethyl)phenyl)-5-(3,5- Dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)pyridin-2-one

610.2 123 (S)-2-Amino-5-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethylisoxanil) oxazol-4-yl)-1H-benzo[d]imidazol-1-yl)benzonitrile

539.2 124 (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)-2-(methylamino)benzonitrile

553.2 125 (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)-2-(dimethylamino)benzonitrile

567.2 126 (S)-6-(1-(6-Aminopyridin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl )-1-(3,4-difluorophenyl)pyridin-2-one

515.2 127 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(6-(methylamino)pyridine- 3-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

529.2 128 (S)-1-(3,4-Difluorophenyl)-6-(1-(6-(dimethylamino)pyridin-3-yl)-5-(3,5-dimethylisoxazole) -4-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

543.2 129 (S)-6-(1-(4-Amino-3-(trifluoromethoxy)phenyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[ d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyridin-2-one

598.2 130 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(methylamino)-3 -(Trifluoromethoxy)phenyl)-1Hbenzo[d]imidazol-2-yl)guaidin-2-one

612.2 131 (S)-1-(3,4-Difluorophenyl)-6-(1-(4-(dimethylamino)-3-(trifluoromethoxy)phenyl)-5-(3,5) -Dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)pyridin-2-one

626.2 132 (S)-N-Cyclopropyl-2-(2-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5- Dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)acetamide

603.2 133 (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(1,5-dimethyl-6-oxo- 1,6-Dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-5-carboxamide

589.2 134 (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiophene-2-carboxamide

562.2 135 (S)-2-(2-(1-(4-Chloro-3-fluorophenyl)-6-oxaziridin-2-yl)-5-(3,5-dimethylisoxazole-4 -yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-5-carboxamide

579.2 136 (S)-2-(2-(3-(4-Chloro-3-fluorophenyl)-2-oxo-1,3-oxazinan-4-yl)-5-(3,5-di Methylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methylthiazole-5-carboxamide

581.1 137 (S)-2-(2-(1-(3,4-Difluorophenyl)-6-oxadidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)-N-methoxythiazole-5-carboxamide

579.2 138 (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)-N-hydroxythiazole-5-carboxamide

565.1 139 (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)-N-(2-hydroxyethyl)thiazole-5-carboxamide

593.2 140 (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)-N-(2-methoxyethyl)thiazole-5-carboxamide

607.2 141 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5-(methylsulfonyl) Benzo[d]thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

634.1 142 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(6-((methyl) Sulfonyl)methyl)pyridin-3-yl)thiazol-2-yl)-1Hbenzo[d]imidazol-2-yl)quaridin-2-one

675.2 143 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(4-(methyl) selenidene)methyl)phenyl)thiazol-2-yl)-1H benzo[d]imidazol-2-yl)quaridin-2-one

658.2 144 (S)-1-(3,4-Difluorophenyl)-6-(1-(4-(dimethylamino)methyl)phenyl)thiazol-2-yl)-5-(3,5- Dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

639.2 145 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(methylsulfonylidene) ) phenyl)thiazol-2-yl)-1Hbenzo[d]imidazol-2-yl)pyridin-2-one

644.2 146 (S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5-dimethylisoxazole) -4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)-2-fluorobenzamide

643.2 147 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5-methyl-4-( 4-((Methylsulfonyl)methyl)phenyl)thiazol-2-yl)-1H-benzo[d]imidazol-2-yl)quaridin-2-one

688.2 148 (S)-4-(5-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5-dimethylisoxazole) -4-yl)-1H-benzo[d]imidazol-1-yl)-1,2,4-thiadiazol-3-yl)benzamide

626.2 149 (S)-5-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5-dimethylisoxazole) -4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)pyridinamide

626.2 150 (S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5-dimethylisoxazole) -4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)-3-methoxybenzamide

655.2 151 (S)-2-(4-(2-(1-(3,4-difluorophenyl)-6-oxoiridin-2-yl)-5-(3,5-dimethylisoxazole) -4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide

556.2 152 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-((methylsulfonyl) )methyl)phenyl)-1H-benzo[d]imidazol-2-yl)guaidin-2-one

591.2 153 (S)-(4-(2-(2-(1-(3,4-difluorophenyl)-6-oxoxazidine-2-yl)-5-(3,5-dimethylisoxanil) oxazol-4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)phenyl)methanesulfonimide

675.2 154 (S)-2-(2-(1-(3,4-Difluorophenyl)-6-oxadidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)thiazole-5-carboxamide

549.1 155 (S)-2-(4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5-dimethyl) Isoxazol-4-yl)-1Hbenzo[d]imidazol-1-yl)thiazol-4-yl)-2-fluorophenyl)acetamide

657.2 156 (S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5-dimethylisoxazole) -4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)-2-methoxybenzamide

655.2 157 (S)-4-(2-(2-(1-(3,4-difluorophenyl)-6-oxazidine-2-yl)-5-(3,5-dimethylisoxazole) -4-yl)-1H-benzo[d]imidazol-1-yl)thiazol-4-yl)-3-fluorobenzamide

643.2 158 (S)-4-(2-(1-(3,4-difluorophenyl)-6-oxoxidin-2-yl)-5-(3,5-dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-1-yl)phenyldimethylcarbamate

586.2 159 (S)-6-(1-(4-Amino-3,5-difluorophenyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d] imidazol-2-yl)-1-(3,4-difluorophenyl)pyridin-2-one

550.2 160 (S)-6-(1-(3,5-Difluoro-4-(methylamino)phenyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo [d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyridin-2-one

564.2 161 (S)-N-(5-(2-(1-(3,4-difluorophenyl)-6-oxoguaridin-2-yl)-5-(3,5-dimethylisoxazole) -4-yl)-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)acetamide

557.2 162 (S)-6-(1-(6-(Cyclopropylamino)pyridin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d ]imidazol-2-yl)-1-(3,4-difluorophenyl)pyridin-2-one

555.2 163 (S)-6-(1-(4-(Aminomethyl)phenyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazole-2- yl)-1-(3,4-difluorophenyl)pyridin-2-one

528.2 164 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(methylamino)methyl) ) phenyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

542.2 165 (S)-1-(3,4-Difluorophenyl)-6-(1-(4-(dimethylamino)methyl)phenyl)-5-(3,5-dimethylisoxazole -4-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

556.3 166 (S)-6-(1-(4-Amino-3-chlorophenyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazole-2- yl)-1-(3,4-difluorophenyl)pyridin-2-one

548.2 167 (S)-6-(1-(3-Chloro-4-(methylamino)phenyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazole -2-yl)-1-(3,4-difluorophenyl)pyridin-2-one

562.4 168 (S)-6-(1-(3-Chloro-4-(dimethylamino)phenyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d] imidazol-2-yl)-1-(3,4-difluorophenyl)pyridin-2-one

576.2 169 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-(methylamino)thiazole- 2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

535.2 170 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5-(methylamino)thiazole- 2-yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

535.2 171 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxythiazol-2-yl) )-1H-benzo[d]imidazol-2-yl)pyridin-2-one

522.1 172 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5-hydroxythiazol-2-yl) )-1H-benzo[d]imidazol-2-yl)pyridin-2-one

522.1 173 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxythiazole-2) -yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

536.2 174 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5-methoxythiazole-2) -yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

536.2 175 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-methylthiazole-2- yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

520.2 176 (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(5-methylthiazole-2- yl)-1H-benzo[d]imidazol-2-yl)pyridin-2-one

520.2

Example 177: Compound (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-( Synthesis of 3-(Methylsulfonyl)prop-1-yn-1-yl)thiazol-2-yl)-1H benzo[d]imidazol-2-yl)guaidin-2-one

Step 1: Synthesis of Compound 177-1

At room temperature, into a 1.50 mL single-necked flask, successively added Intermediate M (570.00 mg), CuI (18.57 mg), PdCl ₂ (PPh ₃ ) ₂ (34.25 mg), DMF (15.00 mL), and purged with nitrogen. Oxygen, then dimethylpropoxytert-butylsilane (830.59 mg), DIEA (1.29 mL) was added, the oxygen was deoxygenated by nitrogen bubbling, then capped, and the reaction was stirred at room temperature for about 2 days. The reaction solution was transferred to a separatory funnel with 100 mL of EA, then washed with 60 mL of water each time and separated, washed three times, and then washed with 50 mL of saturated aqueous sodium chloride solution and separated. The organic phase was dried over anhydrous sodium sulfate. Filter and concentrate. The concentrate was separated and purified by column chromatography (DCM/MeOH=500/15+2 mLTA) and Prep-HPLC to obtain the target compound 177-1 (94.00 mg, 14.30%) as a white solid powder. ESI-MS m/z: 674.2 [M+H] ⁺ .

Step 2: Synthesis of Compound 177-2

At room temperature, compound 177-1 (72.00 mg), THF (5.00 mL), and triethylamine trihydrofluoride (0.17 mL) were sequentially added to a 25 mL single-necked flask, and the reaction was stirred at room temperature. The reaction solution was diluted with 40 mL of ethyl acetate, washed with 20 mL of water each time and separated, and washed three times in total. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target compound 177-2 (62.00 mg, yield 92.18%) as a pale yellow foamy solid. ESI-MS m/z: 560.2 [M+H] ⁺ .

Step 3: Synthesis of Compound 177-3

In a 25 mL single-neck flask at room temperature, compound 177-2 (62.00 mg), DCM (3.00 mL), DIEA (0.09 mL) were sequentially added, and finally TosCl (31.69 mg) was added, and the reaction was stirred at room temperature overnight. The reaction solution was directly concentrated to obtain the crude product (172 mg) of the target compound 177-3 as pale yellow viscous, which was directly used in the next reaction. ESI-MS m/z: 714.2 [M+H] ⁺ .

Step 4: Synthesis of Compound 177

At room temperature, in a 25 mL single-necked flask, successively added the above crude product 177-3 (79.00 mg), DMF (2.00 mL), sodium methanesulfinate (22.60 mg), nitrogen protection, oil bath heating, and kept for 40 ~50°C reaction. The reaction solution was diluted with 30 mL of EA, then washed with 10 mL of water each time, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by Prep-HPLC to finally obtain the target compound 177 (4.29 mg, purity 92.76%, yield 5.78%) as a pale yellow solid powder. ESI-MS m/z: 622.1 [M+H] ⁺ .

Comparative Example: Synthesis of Comparative Compound D1

D1。 Comparative compound D1, CCS1477, was prepared according to Example 152 of WO2018073586A1.

D1.

Comparative Example: Synthesis of Comparative Compound D2

D2。 Compound ( S )-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(thiazol-2-yl)- Refer to Example 45 for the specific synthesis procedure of 1 H -benzo[d]imidazol-2-yl)piperidin-2-one. Target product 46 ESI-MS m/z: 506.1 [M+H] ⁺ .

D2.

Comparative Example: Synthesis of Comparative Compound D3

D3。 Comparative compound D3 was prepared according to Example 126 of WO2018073586A1.

D3.

Pharmacological experiments

Example 1: EP300 BRD domain binding assay

Example 1A Alpha Screen method 1) Prepare 1× test buffer; 2) Preparation of compound concentration gradients: the compounds to be tested were all started at 1 μM, diluted 2 times, and 10 gradient concentrations were set, and each concentration was set up for duplicate well detection. The solution was serially diluted in 384-well Source plate to the corresponding 1000-fold final concentration, and then transferred 10 nL to 384-well reaction plate for testing. Transfer 10 nL of 100% DMSO in the min and max wells; 3) Prepare 2 × EP300 protein (BRD domain) solution with 1 × reaction solution; 4) Add 5 μL of 2 × EP300 protein solution to each well, add 5 μL of 1 × test buffer to the minimum well, and incubate at room temperature for 15 minutes; 5) Prepare 2 × acetylated histone polypeptide solution with 1 × reaction solution; 6) Add 5 μL of 2 × acetylated histone polypeptide solution to each well of the reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 60 min; 7) Add 15 μL of detection solution, centrifuge at 1000 rpm for 1 min, shake gently to mix, and incubate at room temperature for 60 min.

X 100 最大值：DMSO對照孔的讀值 最小值: 無蛋白孔讀值 Read with EnVision. Inhibition rate calculation formula: Inhibition rate (%) =

X 100 Max: reading in DMSO control wells Min: reading in no protein wells

Taking the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis, the 'log(inhibitor) vs. response -Variable slope' model of the analytical software GraphPad Prism was used to fit the dose-response curve, thereby obtaining the inhibitory effect of the compound on protein binding. The median inhibition ( _IC50 ) values (Table 1).

[Table 1] Compound name _IC50 (nM) D1 58 2 43 4 28 6 46 8 56 10 19 19 49 26 54 27 44

X 100 最大值：DMSO對照孔的讀值 最小值: 無蛋白孔讀值 Example 1B HTRF Method (1) 1 x Assay Buffer was prepared. (2) Preparation of compound concentration gradient: the compounds to be tested were all started at 1 μM, diluted 3 times, and 10 gradient concentrations were set, and each concentration was set up for duplicate well detection. The solution was serially diluted in 384-well Source plate to the corresponding 1000-fold final concentration, and then 20 nL was transferred to 384-well reaction plate for testing. Transfer 20 nL of 100% DMSO in the min and max wells. (3) Prepare 4 × EP300 protein (BRD domain) solution with 1 × reaction solution. (4) Add 5 μL of 4 × EP300 protein solution to each well, add 5 μL of 1 × test buffer to the minimum well, and incubate at room temperature for 15 min. (5) Prepare 4 × acetylated histone polypeptide solution with 1 × reaction solution. (6) Add 5 μL of 4× acetylated histone polypeptide solution to each well of the reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 15 min. (7) Add 10 μL of HTRF detection system, centrifuge at 1000 rpm for 1 min, gently shake and mix, and incubate at room temperature for 60 min. (8) Read with EnVision. Inhibition rate calculation formula: Inhibition rate (%) =

X 100 Max: reading in DMSO control wells Min: reading in no protein wells

Taking the log value of the concentration as the X-axis and the percentage inhibition rate on the Y-axis, the 'log(inhibitor) vs. response -Variable slope' model of the analytical software GraphPad Prism 5 was used to fit the dose-response curve to obtain the compound's inhibition of protein binding. The median inhibition rate (IC ₅₀ ) value (Table 2).

[Table 2] Compound name _IC50 (nM) Compound name _IC50 (nM) 32 4.6 133 3.6 33 4.5 134 2.7 36 9.0 135 16 37 6.9 136 10 38 4.2 137 19 39 6.4 138 13 40 6.1 139 6.1 41 4.8 140 11 42 8.0 141 17 44 7.1 142 2.7 50 15 143 7 54 19 144 7.2 56 16 145 5 59 14 146 1.3 61 6.5 147 8.5 62 3.0 148 4.4 87 12 149 2.0 88 16 150 2.0 89 7.4 151 2.1 90 7.9 152 2.0 91 4.7 153 10 93 2.4 154 7.7 94 5.0 155 5.2 103 2.7 156 2.3 104 7.4 157 3.6 106 4.1 158 3.0 107 15 160 9.4 121 7.2 161 7.3 126 9.4 162 8.2 127 5.7 163 6.9 128 7.8 177 2.5 132 12

Example 2: Cell proliferation inhibition assay (22Rv1)

The 22Rv1 cells were plated in a 96-well cell culture plate at 2000 cells and 180 μL/well. After overnight incubation, compound solutions with gradient concentrations were prepared, and 20 μL of DMSO solutions of the compounds to be tested were added to the cells in each well. , 0 nM (the final concentration of DMSO is 0.25%). Incubate for 120 h at 37°C, 5% CO ₂ . Add 50 μL of Cell-titer Glo working solution to each well, shake and mix well, incubate at room temperature for 10 min, read the Luminescence luminescence value on the multi-plate reader, and convert the luminescence value reading into the inhibition percentage: Inhibition percentage = (maximum value - Compound Well Readings)/(Max-Min)*100.

"Max" is the DMSO control; "Min" is the cell-free control.

Curve fitting was performed with Graphpad Prism software and _IC50 values were obtained.

See Table 3 for _IC50 data of the example compounds and comparative compound D1 for inhibition of 22Rv1 cells.

[table 3] Compound name _IC50 (nM) Compound name _IC50 (nM) D1 620 41 365 D2 3759 62 354 D3 >10000 103 304 4 135 121 138 8 379 135 472 10 98 145 273 12 194 146 282 16 493 148 239 19 175 149 259 20 609 150 291 twenty one 338 153 499 26 131 156 149 29 389 157 339 35 586

Example 3: Cell proliferation inhibition assay (PC3)

AR-Negative tumor cells PC3 (derived from the cell bank of the Chinese Academy of Sciences, Shanghai) were plated in a low-adsorption 96-well plate at a cell density of 1×10 ³ /well, and cultured in a cell incubator overnight. After the cells adhered, the compounds to be tested were added to the 96-well plate according to the final concentration of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, 0 nM (the final concentration of DMSO was 0.25%), and the temperature was 37 °C. After culturing for 120 h, 50 μL of Cell-titer GLO working solution was added to each well, shaken and mixed, and incubated at room temperature for 10 min. The Luminescence luminescence value was read on a multi-plate reader, and the luminescence value was calculated and converted into inhibition percentage. And according to the following formula, calculate the percentage of inhibition of cell proliferation: Inhibition percentage=(1-(measured value-minimum value)/(maximum value-minimum value))*100

("Max" from 0.25% DMSO control wells, "Min" from blank medium control wells, "Measured" from compound treated wells).

Curve fitting was performed using GraphPad Prism software and _IC50 values were obtained.

The compounds of the present invention have good selectivity. The example compounds have better selectivity than CCS1477.

[Table 4] Compound name 22Rv1 _IC50 (nM) PC3 _IC50 (nM) selective D1 620 4000 6.5 62 354 19648 55.5

Example 4: Permeability test

The bidirectional permeability and efflux rates of the example compounds and comparative compounds were determined using the Caco-2 monolayer cell model. In the experiment, 300 μL of 2×10 ⁵ cells/mL Caco-2 cells were seeded into a 24-well cell culture plate and used for the transport experiment after 21 days of continuous culture. The respective compounds were administered bidirectionally at a concentration of 5 μM in the presence or absence of verapamil, a P-glycoprotein (P-gp) inhibitor. Cell plates were placed at 37±1°C for 5 The samples were incubated for 120 minutes under the conditions of % CO ₂ and saturated humidity, and the samples at the apical and basal ends were collected, and the content of each compound in the samples was determined by liquid chromatography tandem mass spectrometry (LC/MS/MS).

See Table 4 for the permeability data of some compounds in the Examples. Compared with CCS1477, the compound of the example has significantly enhanced permeability and significantly decreased efflux rate, which enhances intestinal drug absorption.

[table 5] Compound name Verapamil (μM) Papp(A‐B) (10 ⁶ , cm/s) Papp(B‐A) (10 ⁶ , cm/s) RE (Efflux Ratio) 87 0 12.8 45.3 3.5 87 100 25.0 20.6 0.8 146 0 3.52 12.79 3.6 146 100 6.01 7.87 1.3 D1 0 0.78 68.5 87.4 D1 100 1.9 69.0 36.8

Although the present invention has been fully described in terms of its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims of the present invention.

none.

none.

none.

Claims (13)

A compound shown in general formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt,

(1) wherein, R ¹ is selected from C _6-10 aryl or 5-10 membered heteroaryl, R ¹ is optionally further substituted by one or more R ⁵ ; R ⁵ is independently selected from H, oxo , acyl, cyano, halogen, oxo, C _1-6 alkyl, -C _0-3 alkylene-OR ^a , -C _0-3 alkylene-OC(O)N(R ^a ) ₂ , -C _0-3 alkylene-N(R ^a ) ₂ , -C _0-3 alkylene-NR _a C(O)R _a , -C _0-3 alkylene-NR _a C(O )N(R ^a ) ₂ , -C _0-6 alkylene-NR _a S(O)R ^a , -C _0-3 alkylene-NR _a S(O) ₂ R ^a , -C _0-3 Alkylene-S(O)R ^a , -C _0-3 alkylene-S(O) ₂ R ^a , -C _0-3 alkylene-S(O) ₂ N(R ^a ) ₂ , - C _0-3 alkylene-S(O)N(R ^a ) ₂ , -C _0-3 alkylene SR ^a , -C _0-3 alkylene-S(R ^a ) ₅ , -C _{0- 3} alkylene-C(O)R ^a , -C _0-3 alkylene-C(O)OR ^a , -C _0-3 alkylene-C(=O)N(R ^a ) ₂ , - C(O)NHOR ^b , C _2-6 alkenyl, C _2-6 alkynyl,

,

,

,

, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14-membered heterocycloalkyl), -C _0-3 alkylene-C _{6- 14} aryl or -C _0-3 alkylene-(5-14 membered heteroaryl); the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _{0- 3} alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocycloalkyl), -C _0-3 alkylene-C _6-14 aryl or - C _0-3 alkylene-(5-14 membered heteroaryl) is optionally further substituted by one or more selected from H, oxo, acyl, cyano, halogen, oxo, C _1-6 alkane group, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, -C _0-3 alkylene-OR ^a , -C _0-3 alkylene-OC(O) N(R ^a ) ₂ , -C _0-3 alkylene-OS(O) ₂ OR ^a , -C _0-3 alkylene-OS(O) ₂ R ^a , -C _0-3 alkylene- N(R ^a ) ₂ , -C _0-3 alkylene-NR _a C(O)R ^a , -C _0-3 alkylene-NR _a C(O)N(R ^a ) ₂ , -C _{0 -6} alkylene-NR ^a S(O)R ^a , -C _0-3 alkylene-NR ^a S(O) ₂ R ^a , -C _0-3 alkylene-S(O)R ^a , -C _0-3 alkylene-S(O) ₂ R ^a , -C _0-3 alkylene-S(O) ₂ N(R ^a ) ₂ , -C _0-3 alkylene-S(O )N(R ^a ) ₂ , -C _0-3 alkylene SR ^a , -C _0-3 alkylene-S(R ^a ) ₅ , -C _0-3 alkylene-S(O)(NH )R ^a , -C _0-3 alkylene-C(O)R ^a , -C _0-3 alkylene-C(O)OR ^a , -C _0-3 alkylene-C(=O) N(R ^a ) ₂ , -C(O)NHOR ^b , -C _0-3 alkylene-C(S)N(R ^b ) ₂ , -P(O)(OR ^b ) ₂ , -P(O )(R ^b ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, -C _0-6 alkylene-C _3-14 cycloalkyl, -C _0-6 alkylene-(3- 14-membered heterocyclyl), -C _0-6 alkylene-C _6-14 aryl or -C _0-6 alkylene-(5-14-membered heteroaryl) substituents; the R _a is each independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-14 Aryl or 5-14 member hetero Aryl; X is selected from bond, O, S, NR ⁶ , C _1-3 alkylene optionally further _substituted by one or more R ^{6 selected} from Hydroxyl, oxo, halogen or C _1-6 alkyl; preferably X is a bond; R ² is selected from C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 6- 10-membered heteroaryl, R ² is optionally further substituted by one or more R ⁷ ; R ⁷ is independently selected from oxo, acyl, cyano, halogen, C _1-6 alkyl, C _1-6 Haloalkyl, C _1-6 aldehyde group, -C _0-3 alkylene-OR ^b , -C _0-3 alkylene-N(R ^b ) ₂ , -C _0-3 alkylene-S(= O)R ^b , -C _0-3 alkylene-S(=O) ₂ R ^b , -(CH ₂ ) _0-3 -SR ^b , -(CH ₂ ) _0-3 -S(R ^b ) ₅ , -C(=O)N(R ^b ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 Alkylene-(3-14-membered heterocycloalkyl), -C _0-3 alkylene-C _6-14 aryl or -C _0-3 alkylene-(5-14-membered heteroaryl), The -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocycloalkyl), -C _0-3 alkylene-C _{6 -14} aryl or -C _0-3 alkylene-(5-14 membered heteroaryl ⁾ optionally unsubstituted or further substituted with one or more R substituents, and each R ^is independently H , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, 3-14 membered heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl or heteroaryl; ^R is selected from

or

, the R ⁸ or R ⁹ are each independently selected from H or C _1-6 alkyl, the C _1-6 alkyl is optionally further selected from -OH, C _1-6 alkoxy substituted by substituents of -OC(=O)-C _1-6 alkyl; R ⁴ is independently selected from H, halogen, hydroxyl, C _1-3 alkyl, C _1-3 alkoxy or C _{1 -3} haloalkyl. The compound represented by the general formula (I), its tautomer, deuterated product or pharmaceutically acceptable salt according to claim 1, wherein the substituent of R ¹ is selected from the group consisting of

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

, R ¹ is optionally further substituted by one or more R ⁵ . The compound represented by the general formula (I), tautomer, deuterated product or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ⁵ is independently selected from H, hydroxyl, halogen, cyano , oxo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkoxy, -C _0-3 alkylene-C(O)OR ^a , -C _0-3 alkylene-C(O)N(R ^a ) ₂ , -C _0-3 alkylene-C(O)NHOR ^a , -C _0-3 alkylene-S(O) ₂ R ^a , -C _0-3 alkylene-S(O) ₂ N(R ^a ) ₂ , -C _0-3 alkylene-N (R ^a ) ₂ , -C _0-3 alkylene-OC(O)N(R ^a ) ₂ ,

,

,

,

, heterocyclyl, oxoheterocyclyl, phenyl or pyridyl, said C _2-6 alkynyl, phenyl or pyridyl optionally further selected by one or more selected from halogen, hydroxy, C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, -C _0-3 alkylene-C(O)OR ^a , -C _0-3 alkylene-C(O)N( R ^a ) ₂ , -C _0-3 alkylene-C(S)N(R ^a ) ₂ , -C _0-3 alkylene-OS(O) ₂ OR ^a , -C _0-3 alkylene -OS(O) ₂ R ^a , -C _0-3 alkylene-S(O) ₂ R ^a , -C _0-3 alkylene-S(O)R ^a , -C _0-3 alkylene -S(O) ₂ N(R ^a ) ₂ , -C _0-3 alkylene-S(O)(NH)R ^a , -C _0-3 alkylene-N(R ^a ) ₂ , -C _0-3 alkylene-NHS(O) ₂ R ^a , -C _0-3 alkylene-NHC(O)R ^a , -C _0-3 alkylene-P(O)(OR ^a ) ₂ , -C _0-3 alkylene-P(O)(R ^a ) ₂ substituents; the R ^a is selected from H, C _1-6 alkyl or cyclopropyl. The compound represented by general formula (I), its tautomer, deuterated product or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein the substituent of R ¹ is selected from the group consisting of

. The compound represented by general formula (I), its tautomer, deuterated product or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein the substituent of R ² is selected from the group consisting of

or

, preferably

. The compound represented by general formula (I), its tautomer, deuterated product or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein the substituent of R ³ is selected from the group consisting of

or

, preferably

. The compound represented by the general formula (I), its tautomer, deuterated product or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein said R ⁴ is H. The compound represented by the general formula (I) according to any one of claims 1 to 7, its tautomer, deuterated product or pharmaceutically acceptable salt, which is selected from the compounds of the following formula:

(I-1) (I-2) (I-3) wherein the substituent is as defined in claim 1. A compound, its tautomer, deuterated substance or a pharmaceutically acceptable salt, wherein the compound is selected from:

. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1 to 9; and at least one pharmaceutically acceptable adjuvant. A use of the compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 in the preparation of medicines. A method for preparing a compound of general formula (IC), its tautomer, deuterated substance or a pharmaceutically acceptable salt, the method comprising:

Compounds (IB) and Compounds

A coupling reaction occurs to give compound (IC), wherein R ₁ -R ₉ are as defined in claim 1. A compound of general formula (IB), its tautomer, deuterated substance or pharmaceutically acceptable salt,

(IB) wherein R1- _R9 are as defined in claim ₁ .