WO2019233456A1 - Erk inhibitor and use thereof - Google Patents

Abstract

The present invention relates to a compound (as shown in formula I) as an extracellular signal-regulated kinase (ERK) inhibitor, a pharmaceutical composition thereof, a preparation method therefor, and use thereof in treating ERK-mediated diseases. Said compound of the present invention plays a role by regulating a plurality of processes such as cell proliferation, apoptosis, migration and angiogenesis.

Description

ERK inhibitor and its application Technical field

The invention relates to a series of compounds as extracellular signal-regulated kinase (ERK) inhibitors, a preparation method thereof, and a pharmaceutical composition. The present invention also relates to the use of the above compound or a pharmaceutical composition thereof in the treatment of ERK-mediated diseases.

Background technique

Cells have extremely complex life activities, and these life activities must be strictly regulated. As an open system, it not only needs to communicate information with the external environment, but also communicate information between cells. In the process of long-term evolutionary development and natural selection, a complex signal transduction network has been gradually established. It is formed by the interconnection and interaction of different signal transmission pathways, that is, different signal transduction pathways exist. " cross-talking ". In the signal network, the mitogen-activated protein kinase (MAPK) signaling pathway plays an extremely important role and controls various physiological processes of cells, such as cell growth, development, division, and death.

Extracellular signal-regulated kinase (ERK) is a member of the MAPK family. Its signal transmission pathway is the core of the signal network involved in regulating cell growth, development, and division. From extracellular stimulation to cells, to Corresponding biological effects of cells must pass through the three-stage kinase cascade of the MAPK signal transduction pathway, that is, upstream activation protein → MAPK kinase kinase (MAPKKK) → MAPK kinase (MAP-KK) → MAPK. In the transmission pathway of ERKs, Ras acts as an upstream activator protein, Raf acts as MAPKKK, MAPK / ERK kinase (MEK) acts as MAPKK, ERK is MAPK, and Ras-Raf-MEK-ERK pathway. MAPKKK phosphorylates MAPKK's serine and threonine sites and activates them, which in turn causes MAPKK to phosphorylate threonine and serine sites of MAPK. Phosphorylated activated ERK1 / 2 is translocated from the cytoplasm into the nucleus, which then mediates the activation of multiple transcription factors and genes such as Elk-1, ATF, NF-κB, Ap-1, c-fos, and c-Jun And transcription, participate in a variety of biological responses such as cell proliferation and differentiation, maintenance of cell morphology, cytoskeleton construction, apoptosis and canceration of cells.

ERK includes ERK1 and ERK2 and is the key to transmitting signals from surface receptors to the nucleus. The MAPK kinases ERK1 and ERK2 are widely expressed and participate in the RAS-RAF-MEK-ERK signaling cascade. They both contain unique N- and C-termini that provide signal specificity. The kinase domain also contains a residue of 31 amino acids, making It is functionally specific. In multiple cell types, multiple mitogens or other stimuli can activate multiple subtypes of RAS (HRAS, NRAS, and KRAS), and activated RAS can recruit and activate various RAF subunits (including ARAF, BRAF, and CRAF) Thus, the cascade activates MEK1 / 2, mediates the phosphorylation of downstream ERK1 and ERK2, thereby activating ERK1 / 2, regulates the activation and transcription of hundreds of its cytoplasmic and nuclear substrates, and the occurrence of related biological effects. (Refer to Yoon S, Seger R. The extracellular signal-regulatedkinases: multiple substrates and regulatory cellular functions; Growth Factors 2006, 24, 21-44).

The RAS-RAF-MEK-ERK signaling cascade plays a key role in the occurrence and development of various diseases, including brain injury, cancer, cardiac hypertrophy, diabetes, and inflammation. Especially in cancer, about 98% of pancreatic cancer, 52% of colorectal cancer, and 32% of lung adenocarcinoma have KRAS mutations, and 28% of melanomas have NRAS gene mutations. In addition, about 40-60% of melanomas, 40% of thyroid cancers and 20% of colorectal cancers have BRAF mutations (see Vakiani E, solit DB. KRAS and BrAF; KRAS and BRAF; drug targets and predictive biomarkers; Journal of Pathology 2011, 223, 219-29). Mutations in the RAS and RAF genes cause ERK in tumor cells to be continuously activated, causing excessive cell proliferation. Therefore, for a wide range of human tumors, the RAS-RAF-MEK-ERK signaling pathway is a very attractive anti-tumor therapy approach.

ERK inhibitors currently in clinical development include BVD-523, GDC-0994, KO-947, LY-3214996, and LTT462, etc., but they are all in the early stage of clinical development of Phase I / II. There are currently no drugs on the market and they need to be developed. Effective ERK inhibitor.

We have discovered a series of new compounds that can selectively inhibit ERK in the same signal cascade. The ERK inhibitor described in the present invention should be understood as being capable of inhibiting ERK1 and / or ERK2.

Summary of the Invention

The present invention relates to a compound as an inhibitor of extracellular signal-regulated kinase (ERK), or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof. The structure of the compound of the present invention is represented by formula (I):

among them,

X or Y is arbitrarily selected from N or CH;

Z or U is arbitrarily selected from N or CR ₁₀ , and R _{10 is} arbitrarily selected from H or unsubstituted or optionally substituted C _1-8 alkyl;

V is arbitrarily selected from O or S;

R _{1 is} arbitrarily selected from H, halogen, hydroxyl, CN, C _1-8 alkyl,-(C = O) OC _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, C _5-10 heteroaryl or C _3-10 heterocyclyl, said C _1-8 alkyl,-(C = O) OC _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, C _5-10 Heteroaryl or C _3-10 heterocyclyl is unsubstituted or optionally substituted with halogen, hydroxyl, C _1-8 alkyl, C _1-8 alkoxy or -C _1-8 alkoxy-C _1-8 alkane Oxo substitution

R _{2 is} arbitrarily selected from halogen, hydroxy, CN, C _1-8 alkyl,-(C = O) OC _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _{2- 8} alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, C _5-10 heteroaryl or C _3-10 heterocyclyl, said C _1-8 alkyl,-(C = O) OC _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, C _5-10 heteroaryl Or C _3-10 heterocyclyl is unsubstituted or optionally substituted by halogen, hydroxy, C _1-8 alkyl, C _1-8 alkoxy or -C _1-8 alkoxy-C _1-8 alkoxy Replace; or

R ₁ and R ₂ together with the C atom to which they are attached form a C _3-10 cycloalkyl or C _3-10 heterocyclyl, said C _3-10 cycloalkyl or C _3-10 heterocyclyl being unsubstituted or Optionally substituted with halogen, hydroxy, oxo, C _1-8 alkyl or C _1-8 alkyl-C _5-10 aryl;

R _{3 is} arbitrarily selected from H, halogen, hydroxyl, CN, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, or C _2-8 alkynyl, said C _1-8 alkynyl Group, C _1-8 alkoxy, C _2-8 alkenyl or C _2-8 alkynyl is unsubstituted or optionally substituted with halogen, hydroxyl or C _1-8 alkyl;

R _{4 is} optionally selected from C _3-10 heterocyclyl, C _6-10 aryl, or C _5-10 heteroaryl, said C _3-10 heterocyclyl, C _6-10 aryl, or C _5-10 Heteroaryl is unsubstituted or optionally substituted by halogen, hydroxy, cyano, C _1-8 alkyl, C _1-8 alkoxy, C _3-10 cycloalkyl, -C _3-10 heteroaryl, C _{1 -8} alkylcarbonyl or-(C = O) NHR ₁₁ substitution, said C _1-8 alkyl, C _1-8 alkoxy, C _3-10 cycloalkyl, -C _3-10 heteroaryl or -(C = O) NHR ₁₁ is unsubstituted or arbitrarily substituted by hydroxyl, halogen, C _1-8 alkyl, C _3-10 heterocyclyl, C _1-8 alkoxy, -O (C = O) (CH ₂ ) _p R ₁₁ , -sulfonyl-C _1-8 alkyl, halogen-substituted C _1-8 alkoxy, or -C _1-8 alkoxy-C _1-8 alkoxy; R _{11 is} optionally Selected from amino or C _1-8 alkyl;

R _{5 is} arbitrarily selected from H, halogen, hydroxyl, CN, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl , C _6-10 aryl, C _5-10 heteroaryl or C _3-10 heterocyclyl, said C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _{2 -8} alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, C _5-10 heteroaryl or C _3-10 heterocyclyl is unsubstituted or optionally substituted with halogen, hydroxyl or C _1-8 alkane Radical substitution

R _{6 is} optionally selected from halogen, hydroxy, amino, CN, C _1-8 alkyl or NR ₇ R ₈ ;

R ₇ or R _{8 is} arbitrarily selected from H, halogen, hydroxyl, CN, C _1-8 alkyl,-(C = O) C _1-8 alkyl, C _3-10 cycloalkyl, C _6-10 aromatic Group,-(C = O) _p -C _5-10 heteroaryl or C _3-10 heterocyclyl, the C _1-8 alkyl group,-(C = O) C _1-8 alkyl group, C _{3 -10} cycloalkyl, C _6-10 aryl,-(C = O) _p -C _5-10 heteroaryl or C _3-10 heterocyclyl is unsubstituted or optionally substituted by halogen, hydroxyl, amino, CN, C _1-8 alkyl, C _1-8 alkoxy, halogen-substituted C _1-8 alkyl, C _3-10 heterocyclyl, -C _3-10 heteroaryl-C _1-8 alkyl, C _3-10 heteroaryl or-(C = O) C _1-8 alkyl substituted;

R _{9 is} arbitrarily selected from H, halogen, hydroxy, C _1-8 alkyl or C _1-8 alkoxy, said C _1-8 alkyl or C _1-8 alkoxy being unsubstituted or optionally halogen , Hydroxy or C _1-8 alkyl substitution;

The above heterocyclic or heteroaryl ring group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O or S;

m, n or p is arbitrarily selected from 0, 1 or 2.

With regard to the compound represented by formula (I), the present invention further provides some preferred technical solutions:

In some embodiments, X and Y in formula (I) are both N.

In some embodiments, Z in formula (I) is N, U is CH or Z is CH, and U is N.

In some embodiments, both Z and U in formula (I) are CH.

In some embodiments, V in Formula (I) is O.

In some embodiments, R ₁ in formula (I) is H, and R ₂ is hydroxy, C _1-6 alkyl, C _1-6 alkoxy, -C _1-6 alkylhydroxy, -C _1-6 Alkyl-C _1-6 alkoxy, -C _1-6 alkyl-C _1-6 alkoxy-C _1-6 alkoxy, or-(C = O) OC _1-6 alkyl.

In some embodiments, R ₁ in formula (I) is H, and R ₂ is hydroxy, methyl, methoxy, hydroxy-substituted methoxy, hydroxy-substituted methyl, methoxy-substituted methyl,- (C = O) OCH ₃ or -CH ₂ OCH ₂ OCH ₃ .

In some embodiments, R ₁ in formula (I) is H, and R ₂ is

In some embodiments, R ₁ or R ₂ in formula (I) is arbitrarily selected from halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, -C _1-6 alkylhydroxy, -C _1-6 alkyl-C _1-6 alkoxy or halogen-substituted C _1-6 alkyl.

In some embodiments, R ₁ or R ₂ in formula (I) is arbitrarily selected from F, Cl, hydroxy, methyl, methoxy, hydroxy-substituted methyl, methoxy-substituted methyl, or halogen-substituted methyl.

In some embodiments, R ₁ and R ₂ in formula (I) together with the C atom to which they are attached form a C _3-8 cycloalkyl or C _3-8 heterocyclyl, said C _3-8 heterocyclyl Optionally contains 1 or 2 heteroatoms independently selected from N, O or S, the C _3-8 cycloalkyl or C _3-8 heterocyclyl is unsubstituted or arbitrarily substituted by halogen, hydroxyl, oxo , C _1-6 alkyl or C _1-6 alkyl-phenyl.

In some embodiments, R ₁ and R ₂ in formula (I) together with the C atom to which they are attached form the following substituents:

In some embodiments, R ₃ in formula (I) is arbitrarily selected from H, hydroxy, halogen, or -C _1-6 alkyl-hydroxy.

In some embodiments, R ₃ in formula (I) is selected from H.

In some embodiments, R ₄ in formula (I) is selected from C _3-10 heterocyclyl, C _6-10 aryl, or C _5-10 heteroaryl, wherein C _3-10 heterocyclyl, C _{6 -10} aryl or C _5-10 heteroaryl is unsubstituted or optionally substituted by halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, -C _3-10 Heteroaryl-C _1-6 alkyl, C _1-8 alkylcarbonyl or-(C = O) NHR ₁₁ substitution, said C _1-6 alkyl, C _1-6 alkoxy, C _3-10 Cycloalkyl, -C _3-10 heteroaryl-C _1-6 alkyl, or-(C = O) NHR ₁₁ is unsubstituted or arbitrarily substituted by hydroxyl, halogen, C _3-6 heterocyclyl, C _1-8 Alkoxy, -O (C = O) (CH ₂ ) _p R ₁₁ , -sulfonyl-C _1-6 alkyl, halogen-substituted C _1-6 alkoxy, or -C _1-6 alkoxy- C _1-6 alkoxy substitution; R _{11 is} optionally selected from amino or C _1-3 alkyl, p is selected from 0 or 1; the C _5-10 heteroaryl or C _3-10 heterocyclyl is optionally Contains 1 or 2 heteroatoms selected from N, O or S.

所述苯基、吡啶基或

未取代或任意地被F、Cl、甲基、羟基、羟基取代的甲基、羟基取代的乙基、羟基取代的异丙基、一氟甲基、三氟甲基、-CH ₂O(C＝O)CH ₂NH ₂、-CH ₂O(C＝O)CH ₃、-亚甲基-磺酰基-甲基、-(C＝O)NHCH ₃、羟基取代的环丙基、羟基取代的环丁基、甲氧基、甲氧基取代的甲基、二氟甲氧基取代的甲基、甲酰基、-CH ₂OCH ₂OCH ₃、乙酰基、CN或

取代。 In some embodiments, R ₄ in formula (I) is selected from phenyl, pyridyl,

The phenyl, pyridyl or

Unsubstituted or arbitrarily substituted with F, Cl, methyl, hydroxy, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted isopropyl, monofluoromethyl, trifluoromethyl, -CH ₂ O (C = O) CH ₂ NH ₂ , -CH ₂ O (C = O) CH ₃ , -methylene-sulfonyl-methyl,-(C = O) NHCH ₃ , hydroxy-substituted cyclopropyl, hydroxy-substituted Cyclobutyl, methoxy, methoxy-substituted methyl, difluoromethoxy-substituted methyl, formyl, -CH ₂ OCH ₂ OCH ₃ , acetyl, CN or

To replace.

In some embodiments, R ₅ in formula (I) is arbitrarily selected from H, halogen, hydroxyl, amino, CN, or C _1-6 alkyl, said C _1-6 alkyl being unsubstituted or optionally substituted with halogen .

In some embodiments, R ₅ in formula (I) is arbitrarily selected from H, F, Cl, hydroxyl, amino, CN or C _1-3 alkyl, said C _1-3 alkyl being unsubstituted or arbitrarily Halogen substitution.

In some embodiments, R ₅ in formula (I) is H, F, Cl, -CF ₃ , CN, or methyl.

In some embodiments, R ₆ in formula (I) is arbitrarily selected from halogen, hydroxy, C _1-6 alkyl, or NR ₇ R ₈ .

In some embodiments, R ₆ in formula (I) is NR ₇ R ₈ , and R ₇ or R _{8 is} arbitrarily selected from H, halogen, hydroxyl, C _1-6 alkyl,-(C = O) -C _{1 -6} alkyl, C _3-7 cycloalkyl, phenyl,-(C = O) C _5-6 heteroaryl or C _3-10 heterocyclyl, said C _1-6 alkyl, C _{3- 7} cycloalkyl, phenyl,-(C = O) C _5-6 heteroaryl or C _3-10 heterocyclyl is unsubstituted or optionally substituted with halogen, hydroxyl, amino, C _1-6 alkyl, C _{1 -6} alkoxy, halogen-substituted C _1-6 alkyl, C _3-10 heterocyclyl, -C _3-10 heteroaryl-C _1-6 alkyl, C _3-10 heteroaryl, _or- (C = O) C _1-6 alkyl substitution.

In some embodiments, R ₆ in formula (I) is NR ₇ R ₈ , and R ₇ or R _{8 is} arbitrarily selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Hydroxyl-substituted isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl-substituted cyclohexyl, acetyl,

In some embodiments, R ₆ in formula (I) is NR ₇ R ₈ , R ₇ is H, and R ₈ is isopropyl or

In some embodiments, it is characterized in formula (I) that R ₉ is H or F.

In some embodiments, m or n in formula (I) is arbitrarily selected from the following group:

(i) m and n are both 1;

(ii) m is 0 and n is 1;

(iii) m is 1, n is 0.

The invention further provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

1) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -4,4-difluoro-2,3,4,5- Tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

2) 7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -3- (hydroxymethyl) -3,4-dihydropyrrole And [1,2-a] pyrazine-1 (2H) -one;

3) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(2- (hydroxymethyl) benzyl) -2 ′, 3′-dihydro-1 'H, 5'H-spiro [oxetane-3,4'-pyrrolo [1,2-a] [1,4] diazepine] -1'-one;

4) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(3-chlorobenzyl) -2 ′, 3′-dihydro-1′H, 5 'H-spiro [azetidine-3,4'-pyrrolo [1,2-a] [1,4] diazalide] -1'-one;

5) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -4,4-bis (hydroxymethyl) -2,3, 4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

6) 2 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -5 ′-(2- (hydroxymethyl) benzyl) -5 ′, 6, -dihydro-4 'H, 8'H-spiro [oxetane-3,7'-pyrazolo [1,5-a] [1,4] diazepine] -4'-one;

7) 2- (5-chloro-2- (isopropylamino) pyridin-4-yl) -7- (chloromethyl) -7- (hydroxymethyl) -5- (2- (hydroxymethyl) Benzyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1,4] diazepine-4-one;

8) 2- (5-chloro-2- (isopropylamino) pyridin-4-yl) -8- (3-chlorobenzyl) -7,8-dihydro-5H, 9H-spiro [imidazo [ 1,2-a] [1,4] diazepine-6,3'-oxetane] -9-one;

9) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(3-chlorobenzyl) -1- (2,4-dimethoxybenzyl) -2 ′, 3′-dihydro-1′H, 5′H-spiro [azetidin-3,4′-pyrrolo [1,2-a] [1,4] diazalide] -1′-one;

10) (S) -8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(1- (3-chlorophenyl) -2-hydroxyethyl)- 2 ′, 3′-dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine]- 1′-one;

11) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -4,4-dimethyl-2,3,4,5 -Tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

12) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(3-chlorobenzyl) -2 ′, 3′-dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazalide] -1′-one;

13) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -1-oxo-2,3,4,5-tetrahydro- 1H-pyrrolo [1,2-a] [1,4] diazepine-4-carboxylic acid methyl ester;

14) (S) -7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -3-methyl-3,4-dihydro Pyrrolo [1,2-a] pyrazine-1 (2H) -one;

15) 2 ′-(4-chloro-2- (hydroxymethyl) benzyl) -8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′, 3′- Dihydro-1′H, 5′H-spiro [cyclopropane-1,4′-pyrrolo [1,2-a] [1,4] diazalide] -1′-one;

16) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -4-hydroxy-2,3,4,5-tetrahydro- 1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

17) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(pyridin-2-ylmethyl) -2 ′, 3′-dihydro-1′H , 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one;

18) 2 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -5 ′-(3-chlorobenzyl) -5 ′, 6′-dihydro-4′H, 8′H-spiro [oxetane-3,7′-pyrazolo [1,5-a] [1,4] diazepine] -4′-one;

19) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(5-fluoro-2- (hydroxymethyl) benzyl) -2 ′, 3′- Dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one;

20) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(2- (morpholinemethyl) benzyl) -2 ′, 3′-dihydro- 1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one;

21) 2- (5-chloro-2- (isopropylamino) pyridin-4-yl) -8- (2- (hydroxymethyl) benzyl) -7,8-dihydro-5H, 9H-spiro [Imidazo [1,2-a] [1,4] diaza-6,3′-oxetane] -9-one;

22) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(3-fluoro-2- (hydroxymethyl) benzyl) -2 ′, 3′- Dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one;

23) (S) -8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(1- (3-fluorophenyl) -2-hydroxyethyl)- 2 ′, 3′-dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine]- 1′-one;

24) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(4-fluoro-2- (hydroxymethyl) benzyl) -2 ′, 3′- Dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one;

25) (S) -2 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -5 ′-(1- (3-fluorophenyl) -2-hydroxyethyl)- 5 ′, 6′-dihydro-4′H, 8′H-spiro [oxetane-3,7′-pyrazolo [1,5-a] [1,4] diazalide] -4′-one;

26) (S) -8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(1- (3,4-difluorophenyl) -2-hydroxyethyl Group) -2 ′, 3′-dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diaza Zhuo] -1′-one;

27) (S) -2 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -5 ′-(1- (3,4-difluorophenyl) -2-hydroxyethyl Group) -5 ′, 6′-dihydro-4′H, 8′H-spiro [oxetane-3,7′-pyrazolo [1,5-a] [1,4] diaze Hetero] -4′-one;

28) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(2- (hydroxymethyl) benzyl) -2 ′, 3′-dihydro-1 ′ H, 5′H-spiro [azetidin-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one;

29) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(4,5-difluoro-2- (hydroxymethyl) benzyl) -2 ′, 3′-dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine-1′-one ;

30) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (2- (hydroxymethyl) benzyl) -2 ′, 2′-dimethyl-2, 3-dihydro-1H, 5H-spiro [pyrrolo [1,2-a] [1,4] diazepine-4,5 '-[1,3] dioxane] -1-one;

31) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -4,4-bis (hydroxymethyl) -2- (2- (hydroxymethyl) benzyl) -2 , 3,4,5-tetrahydro-1H pyrrolo [1,2-a] [1,4] diazalide-1-one;

32) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4-hydroxy-2,3, 4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

33) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -2 ′, 2′-dimethyl -2,3-dihydro-1H, 5H-spiro [pyrrolo [1,2-a] [1,4] diazepine-4,5 '-[1,3] dioxane] -1 -ketone;

34) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4,4-bis (hydroxymethyl ) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazazol-1-one;

35) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(2- (hydroxymethyl) benzyl) -1-methyl-2 ′, 3 ′ -Dihydro-1′H, 5′H-spiro [azetidin-3,4′-pyrrolo [1,2-a] [1,4] diazalide] -1′-one;

36) (R) -7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (formaldehyde (Oxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

37) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4- (hydroxymethyl)- 2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

38) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -2,3-dihydro-1H , 5H-spiro [pyrrolo [1,2-a] [1,4] diazepine-4,5 '-[1,3] dioxane] -1-one;

39) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4,4-bis (methoxy Methyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

40) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

41) (R) -2- (5-chloro-2- (isopropylamino) pyridin-4-yl) -7- (5-fluoro-2- (hydroxymethyl) benzyl) -6- (formaldehyde (Oxymethyl) -6,7-dihydroimidazo [1,2-a] pyrazine-8- (5H) -one;

42) (R) -7- (5-chloro-3-fluoro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

43) (3R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( 1-hydroxyethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

44) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( 2-hydroxypropyl-2-yl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

45) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( Fluoromethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

46) (R) -7- (5-chloro-2-((4-fluoro-1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5- Fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

47) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (3-hydroxyphenyl)- 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

48) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (2-hydroxyphenyl)- 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

49) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((2-hydroxypyridine-3 -Yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

50) (R) -7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -3- (methoxymethyl) -2- (2-((methylsulfonyl) (Methyl) benzyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

51) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (2- (1-hydroxycyclobutyl) benzyl) -4,4-bis (hydroxymethyl ) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazalide-1-one;

52) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2-methoxybenzyl) -4,4-bis (hydroxymethyl)- 2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

53) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (2-((difluoromethoxy) methyl) -5-fluorobenzyl) -4, 4-bis (hydroxymethyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

54) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( Hydroxymethyl) benzyl) -3-((methoxymethoxy) methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

55) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (2- (1-hydroxy ring Propyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

56) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( (Methoxymethoxy) methyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

57) (R) -7- (5-chloro-2-((1- (difluoromethyl) -1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

58) (R) -7- (5-chloro-2-((1-ethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

59) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4-methoxy-2, 3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

60) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4- (hydroxymethyl)- 4- (methoxymethyl) -2,3,4,5-4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

61) 7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -1-oxo-1,2 , 3,4-tetrahydropyrrolo [1,2-a] pyrazine-3-carboxylic acid ethyl ester;

62) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (trifluoromethyl) benzyl) -4,4-bis (hydroxyl (Methyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

63) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (4-chloro-5-fluoro-2- (hydroxymethyl) benzyl) -4,4- Bis (hydroxymethyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one;

64) (R) -7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (hydroxyl (Methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

65) (R) -7- (5-chloro-2- (oxetan-3-ylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl ) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

66) (3R) -7- (5-chloro-2-((tetrahydrofuran-3-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl)- 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

67) (R) -7- (5-chloro-2-((tetrahydro-2H-pyran-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Group) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

68) (R) -7- (5-chloro-2-((3,3-difluorocyclobutyl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

69) (R) -7- (2- (tert-butylamino) -5-chloropyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (formaldehyde (Oxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

70) (R) -7- (5-chloro-2-((2-hydroxy-2-methylpropyl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl ) Benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

71) (R) -7- (5-chloro-2-((1-methylpiperidin-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl ) Benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

72) (R) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -7- (2-((tetrahydro-2H-pyran-4) -Yl) amino) pyridin-4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

73) (R) -7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-fluorobenzyl) -3- (methoxymethyl) -3, 4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

74) (R) -7- (5-chloro-2-((4,4-difluorocyclohexyl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl ) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

75) (R) -7- (5-chloro-2-((4-methyltetrahydro-2H-pyran-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2 -(Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

76) (R) -7- (5-chloro-2- (cyclobutylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (formaldehyde (Oxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

77) (R) -7- (5-chloro-2-((((1R, 4R) -4-hydroxycyclohexyl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl Group) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

78) (R) -7- (5-chloro-2- (cyclohexylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxy Methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

79) 7- (5-chloro-2-((1-isopropylpiperidin-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl ) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

80) (R) -7- (5-chloro-2- (cyclopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (formaldehyde (Oxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

81) (R) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -7- (5-fluoro-2- (isopropylamino) pyridin-4-yl) -3- (formaldehyde (Oxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

82) (R) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -7- (2- (isopropylamino) -5- (trifluoromethyl) pyridin-4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

83) (R) -7- (5-chloro-2- (cyclopentylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (formaldehyde (Oxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

84) (3R) -7- (5-chloro-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl) amino) pyridin-4-yl) -2- (5- Fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

85) (3R) -7- (5-chloro-2-((5,5-dimethyltetrahydrofuran-3-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxyl (Methyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

86) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((2- (hydroxymethyl ) Pyridin-3-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

87) (R) -7- (5-chloro-2-((5-methylisoxazol-3-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Group) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

88) (R) -7- (5-chloro-3-methyl-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5- Fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

89) (R) -7- (5-chloro-2-((3,5-dimethylisoxazol-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

90) (R) -7- (5-chloro-2- (oxazol-2-ylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3 -(Methoxymethyl) -3,4 dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

91) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl)- 2-((1-methyl-1H-indazol-6-yl) methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

92) (R) -7- (5-chloro-2-((3-methylisoxazol-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Group) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

93) (R) -7- (5-chloro-2- (thiazol-2-ylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (Methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

94) (R) -7- (5-chloro-2-((5-methylthiazol-2-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

95) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-3-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

96) (R) -7- (5-chloro-2-((3-methylisoxazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Group) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

97) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

98) (R) -7- (5-chloro-2-((1,3-dimethyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -2- (5-fluoro- 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

99) (R) -7- (5-chloro-2-((4,5-dimethylthiazol-2-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxyl (Methyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

100) (R) -7- (5-chloro-2-((4-methylthiazol-2-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

101) (R) -7- (5-chloro-2- (isoxazol-3-ylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl)- 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

102) (R) -7- (5-chloro-2- (isoxazol-5-ylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl)- 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

103) (R) -7- (5-chloro-2-((6,7-dihydro-4H-pyrano [4,3-d] thiazol-2-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H )-ketone;

104) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl)- 2-((1-methyl-1H-indazol-7-yl) methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

105) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl)- 2-((1-methyl-1H-indazol-4-yl) methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

106) (R) -2-((1H-indazol-4-yl) methyl) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) Pyridin-4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

107) (R) -2-((1H-benzo [d] imidazol-4-yl) methyl) -7- (5-chloro-2-((1-methyl-1H-pyrazole-5- Yl) amino) pyridin-4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

108) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (4,5-difluoro- 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

109) (R) -7- (5-chloro-2-((1,3-dimethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro- 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

110) (R) -7- (5-chloro-2-((1,4-dimethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro- 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

111) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( Trifluoromethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

112) (R) -2- (Benzo [d] oxazole-4-methylene) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino ) Pyridin-4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

113) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (3-fluoro-2- ( (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

114) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (4-fluoro-2- ( (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

115) (R) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -7- (2-((1-methyl-1H-pyrazole -5-yl) amino) -5- (trifluoromethyl) pyridin-4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

116) (R) -4- (2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -1-oxo-1,2,3,4- Tetrahydropyrrolo [1,2-a] pyrazine-7-yl) -6-((1-methyl-1H-pyrazol-5-yl) amino) nicotinonitrile;

117) (R) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -7- (5-methyl-2-((1-methyl -1H-pyrazol-5-yl) amino) pyridin-4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

118) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (2- (hydroxymethyl) -5- (trifluoromethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

119) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((3- (hydroxymethyl ) -6-methylpyridin-2-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one ;

120) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((4- (hydroxymethyl ) -6-methylpyridin-3-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one ;

121) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((2- (hydroxymethyl ) -6- (trifluoromethyl) pyridin-3-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 ( 2H) -one;

122) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((3- (hydroxymethyl ) Pyridin-2-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

123) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((4- (hydroxymethyl ) Pyridin-3-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

124) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((6-hydroxypyridine-2 -Yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

125) (R) -7- (5-chloro-3-fluoro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl)- 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

126) 2-((8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -4,4-bis (hydroxymethyl) -1-oxo-4,5-dihydro- 1H-pyrrolo [1,2-a] [1,4] diazepine-2 (3H) -yl) methyl) -4-fluorobenzyl glycine ester;

127) 2-((8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -4,4-bis (hydroxymethyl) -1-oxo-4,5-dihydro -1H-pyrrolo [1,2-a] [1,4] diazepine-2 (3H) -yl) methyl) -4-fluorobenzyl acetate;

128) 7- (2-((1-acetylpiperidin-4-yl) amino) -5-chloropyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

129) (R) -2-((7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxy (Methyl) -1-oxo-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) methyl) -4-fluoro-N-methylbenzamide;

130) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (2-((difluoromethyl (Oxy) methyl) -5-fluorobenzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

131) (R) -7- (5-chloro-2-((4-methoxycyclohexyl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl ) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

132) (R) -N- (5-chloro-4- (2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -1-oxo-1 , 2,3,4-tetrahydropyrrolo [1,2-a] pyrazin-7-yl) pyridin-2-yl) acetamide;

133) (R) -7- (5-chloro-2-((((1-methyl-1H-pyrazol-5-yl) methyl) amino) pyridin-4-yl) -2- (5-fluoro 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

134) (R) -7- (5-chloro-2-((1- (2,2-difluoroethyl) -1H-pyrazol-3-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one ;

135) (R) -7- (5-chloro-2-((1- (2,2-difluoroethyl) -1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one ;

136) (R) -7- (5-chloro-2-((oxazole-4-methylene) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl Yl) -3- (methoxymethyl) -3,4-dihydropyrrole [1,2-a] pyrazine-1 (2H) -one;

137) (R) -N- (5-chloro-4- (2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -1-oxo-1 , 2,3,4-tetrahydropyrrolo [1,2-a] pyrazin-7-yl) pyridin-2-yl) -2-methylthiazole-4-carboxamide;

138) (R) -2- (Benzo [d] [1,3] dioxolane-4-methylene) -7- (5-chloro-2-((1-methyl-1H -Pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H)- ketone;

139) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl)- 2- (2- (1-methyl-1H-1,2,4-triazol-3-yl) benzyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 ( 2H) -one;

140) (R) -2- (2-acetyl-5-fluorobenzyl) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridine- 4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

141) (R) -2- (Benzo [d] [1,3] dioxol-5-ylmethyl) -7- (5-chloro-2-((1-methyl-1H -Pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H)- ketone;

142) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (3-methoxybenzyl ) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

143) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( Methoxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

144) (R) -7- (5-chloro-2-((1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) amino) pyridin-4-yl) -2 -(5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H)- ketone;

145) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2-methyl (Oxybenzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one;

146) (R) -3-((7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxy (Methyl) -1-oxo-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) methyl) -4- (hydroxymethyl) benzonitrile;

147) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((2,3-dihydro Benzo [b] [1,4] dioxane-5-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] Pyrazine-1 (2H) -one;

148) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl)- 2- (3,4,5-trifluoro-2- (hydroxymethyl) benzyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; or

149) (R) -2-((7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxy (Methyl) -1-oxo 3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) methyl) -4-fluorobenzaldehyde.

The present invention also provides a pharmaceutical composition comprising an effective therapeutic dose of at least any one compound of the formula (I) of the present invention and at least one pharmaceutically acceptable excipient.

The invention further provides a pharmaceutical composition, wherein the weight ratio of the compound represented by the structural formula (I) to the excipient is 0.0001-10.

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

The present invention further provides a preferred technical solution for the application:

Advantageously, said application is to treat, prevent, delay or prevent the occurrence or progression of cancer or cancer metastasis.

Preferably, the application is to prepare a medicament for treating a disease mediated by ERK. Preferably, the disease is 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, polymorphous lung cancer, ovarian cancer, and esophagus Cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Cancer, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

Advantageously, said application is as an ERK inhibitor.

Advantageously, said use is as an ERK1 and / or ERK2 inhibitor.

The present invention also provides a method of administering a therapeutically effective amount of a compound or a pharmaceutical composition of at least any one of the formula (I) to a subject to treat and / or prevent a disease mediated by ERK.

Preferably, in the above method, the ERK includes ERK1 and / or ERK2.

Preferably, in the above method, the ERK-mediated disease is cancer.

Preferably, in the above method, the cancer is selected from the group consisting of breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, and pleomorphism. Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cells Tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, liposarcoma.

The present invention also provides a method for treating cancer, which comprises administering to a subject a therapeutically effective amount of at least any one compound represented by formula (I) or a pharmaceutical composition or a pharmaceutical composition, said cancer being 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, hepatocellular carcinoma, Head and neck cancer, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin Cancer, pancreatic cancer, testicular cancer, or liposarcoma.

Preferably, in the above method, the subject to be treated is a human.

The general chemical terms used in the above structural formulas have the usual meanings. For example, unless otherwise stated, the term "halogen" as used herein means fluorine, chlorine, bromine or iodine. Preferred halogen groups include fluorine, chlorine and bromine.

As used herein, unless stated otherwise, "alkyl" includes straight-chain 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 and the like. Similar, "C _1-8 alkyl""C_1-8" means comprising 7 or 8 carbon atoms, a straight-chain or branched-chain arranged in the form of Group.

Alkenyl and alkynyl include straight or branched chain alkenyl and alkynyl. Similarly, "C _2-8 alkenyl" and "C _2-8 alkynyl" refer to alkenyl groups containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched chain. Or alkynyl.

"Alkoxy" refers to the oxyether form of the aforementioned straight or branched chain alkyl group, ie, -O-alkyl.

As used herein, "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", as used herein, refers to an unsubstituted or substituted monocyclic or fused ring aromatic group including a carbon ring atom, unless otherwise specified. Preferred aryl groups are 6 to 10 membered monocyclic or bicyclic aromatic ring groups. Preferred are phenyl and naphthyl. Most preferred is phenyl.

The term "heterocyclyl", unless otherwise stated herein, refers to an unsubstituted or substituted 3-8 membered stable monocyclic ring consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S A system in which nitrogen or sulfur heteroatoms can be selectively oxidized and nitrogen heteroatoms can be selectively quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom to form a stable structure. Examples of these heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolane, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydro Oxadiazolyl.

The term "heteroaryl", as used herein, unless otherwise stated, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- or 10-membered benzocondensate Heteroaromatic ring system or bicyclic heteroaromatic ring system consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein said nitrogen or sulfur heteroatoms can be selectively oxidized The nitrogen heteroatom may 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, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, benzene Thiathiazolyl, benzotriazolyl adenine, quinolyl or isoquinolyl.

The term "cycloalkyl" refers to a cyclic saturated alkyl chain having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term "substituted" means that one or more hydrogen atoms in the group are replaced with the same or different substituents, respectively. Typical substituents include, but are not limited to, halogen (F, Cl, Br, or I), C _1-8 alkyl, C _3-12 cycloalkyl, -OR ₁ , -SR ₁ , = O, = S, -C (O) R ₁ , -C (S) R ₁ , = NR ₁ , -C (O) OR ₁ , -C (S) OR ₁ , -NR ₁ R ₂ , -C (O) NR ₁ R ₂ , Cyano, nitro, -S (O) ₂ R ₁ , -OS (O ₂ ) OR ₁ , -OS (O) ₂ R ₁ , -OP (O) (OR ₁ ) (OR ₂ ); where R ₁ And R _{2 are} independently selected from -H, C _1-6 alkyl, C _1-6 haloalkyl. In some embodiments, the substituent is 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 , formaldehyde, -C (OCH ₃ ), cyano, nitro, -CF ₃ , -OCF ₃ , amino, dimethyl Amino, methylthio, sulfonyl, and acetyl groups.

Examples of substituted alkyl include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.

Examples of substituted alkoxy include, but are not limited to, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts such as aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are the salts of ammonium, calcium, magnesium, potassium and sodium. Pharmaceutically acceptable non-toxic organic bases capable of deriving into salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N ′, N′-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, halamine, isopropylamine , Lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compound provided by the present invention is a base, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, isethionic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, Hydroiodic acid, perchloric acid, hydrochloric acid, isethionic acid, propionic acid, glycolic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, acetic acid, pantothenic acid, phosphoric acid , Succinic acid, sulfuric acid, 2-naphthalenesulfonic acid, cyclohexylaminesulfonic acid, salicylic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid.

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% purity, a more suitable purity is at least 75%, and a particularly suitable purity is at least 98% (% is weight ratio).

Prodrugs of the compounds of the invention are included within the scope of the invention. Generally, the prodrug refers to a functional derivative that is easily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present application, which is capable of directly or indirectly providing the compound of the present application or a pharmaceutically active metabolite thereof, or Residues. Particularly preferred derivatives or prodrugs are those compounds that, when administered to a patient, can increase the bioavailability of the compounds of the present application (e.g., can make the oral compound more easily absorbed into the blood), or promote the parent compound to a biological organ or Those compounds delivered by the site of action, such as the brain or lymphatic system. Therefore, the term "administration" in the treatment method provided by the present invention refers to the administration of a compound disclosed in the present invention that can treat different diseases, or, although not explicitly disclosed, can be converted into the present disclosure in vivo after administration to a subject Compound of compounds. Conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985).

Obviously, the definition of any substituent or specific position variable in a molecule is independent of other positions in the molecule. It is easy to understand that those skilled in the art can select the substituents or substituted forms of the compounds in the present invention through the prior art means and the methods described in the present invention to obtain chemically stable and easily synthesized compounds.

The compounds according to the invention may contain one or more asymmetric centers and may result in diastereomers and optical isomers. The invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.

The above formula (I) does not precisely define the stereo structure of a certain position of the compound. The present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific stereoisomers isolated are also included in the present invention. In the synthesis of such compounds, or in the process of racemization or epimerization known to those skilled in the art, the product obtained may be a mixture of stereoisomers.

When a tautomer of a compound represented by the formula (I) exists, unless specifically stated, the present invention includes any possible tautomer and a pharmaceutically acceptable salt thereof, and mixtures thereof.

When a compound of formula (I) and a pharmaceutically acceptable salt thereof exist in a solvate or a polymorph, the present invention includes any possible solvate and polymorph. The type of the solvate-forming solvent is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone and the like can be used.

The term "composition" herein refers to a product including a specified amount of each specified ingredient, and any product produced directly or indirectly from a combination of specified amounts of each specified ingredient. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient and a method for preparing the compound of the present invention are also part of the present invention. In addition, some crystalline forms of the compound may exist in a polymorphic form, and this polymorphic form is included in the present invention. In addition, some compounds can form solvates with water (ie, hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention.

The pharmaceutical composition provided by the present invention comprises, as an active ingredient, a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable excipient, and other optional therapeutic components or Excipients. Although the most suitable way of administering the active ingredient in any given case depends on the particular subject, the nature of the subject, and the severity of the disease, the pharmaceutical composition of the present invention includes Pharmaceutical composition for parenteral (including subcutaneous, intramuscular, intravenous) administration. The pharmaceutical composition of the present invention can be conveniently prepared in the unit dosage form known in the art and any preparation method known in the pharmaceutical field.

In fact, according to the conventional drug mixing technology, the compound represented by formula (I), or a prodrug, or a metabolite, or a pharmaceutically acceptable salt of the present invention, can be mixed with a drug carrier to form a drug combination as an active ingredient. Thing. The pharmaceutical carrier can take a variety of forms, depending on the mode of administration desired, for example, oral or injection (including intravenous). Therefore, the pharmaceutical composition of the present invention can be used as a separate unit suitable for oral administration, such as a capsule, cachet, or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may be in the form of a powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition, in addition to the above-mentioned common dosage forms, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may also be administered by a controlled release manner and / or a delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with a carrier that makes up one or more of the necessary ingredients. Generally, the pharmaceutical composition is prepared by uniform and close mixing of the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two. In addition, the product can be easily prepared into a desired appearance.

Therefore, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I) or a stereoisomer, tautomer, polymorph, solvate, pharmaceutically acceptable Salt, its prodrug. Combinations of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof with one or more other compounds having therapeutic activity are also included in the pharmaceutical composition of the present invention.

The pharmaceutical carrier used in the present invention may be, for example, a solid carrier, a liquid carrier, or a gas carrier. Solid carriers include, but are not limited to, lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, and water. Gas carriers, including but not limited to carbon dioxide and nitrogen. When preparing pharmaceutical oral preparations, any pharmaceutically convenient medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants and the like can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starch, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used for oral solid preparations such as powders, capsules and tablets. In view of ease of administration, tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here. Alternatively, the tablet coating may use standard aqueous or non-aqueous formulation techniques.

The tablets containing the compound or pharmaceutical composition of the present invention can be formed by compression or molding, and optionally, can be made into tablets together with one or more auxiliary components or adjuvants. The active ingredients are mixed in a free-flowing form, such as powder or granules, with a binder, lubricant, inert diluent, surfactant or dispersant, and compressed tablets can be made by compression in a suitable machine. A powdered compound or pharmaceutical composition is wetted with an inert liquid diluent and then molded in a suitable machine by molding. Preferably, each tablet contains about 0.05 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of active ingredient. For example, a formulation intended for oral administration in humans contains from about 0.5 mg to about 5 g of active ingredient, compounded with a suitable and conveniently metered auxiliary material, the auxiliary material accounting for about 5% to 95% of the total pharmaceutical composition. Unit dosage forms generally contain about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared by adding the active ingredient to water to prepare an aqueous solution or suspension. A suitable surfactant such as hydroxypropyl cellulose may be included. Dispersions can also be made in glycerol, liquid polyethylene glycols, and their mixtures in oil. Further, a preservative may be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.

The invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersions. Further, the above pharmaceutical composition can be prepared into a sterile powder form for instant preparation of a sterile injection solution or dispersion. In any case, the final injection form must be sterile and, for easy injection, it must be easy to flow. In addition, the pharmaceutical composition must be stable during preparation and storage. Therefore, preferably, the pharmaceutical composition is stored under conditions that are resistant to contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical composition provided by the present invention may be in a form suitable for topical application, for example, an aerosol, an emulsion, an ointment, a lotion, dusting powder, or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention may be in a form suitable for use in a transdermal drug delivery device. These preparations can be prepared by a conventional processing method using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof. As an example, an emulsion or ointment is prepared by adding about 5 to 10% by weight of a hydrophilic material and water to produce an emulsion or ointment having a desired consistency.

The pharmaceutical composition provided by the present invention can be in a form suitable for rectal administration with a solid as a carrier. Unit-dose suppositories are the most typical dosage form. Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, then cooling and mold forming.

In addition to the excipient components mentioned above, the above formulation may also include, as appropriate, one or more additional excipient components such as a diluent, a buffer, a flavoring agent, a binder, a surfactant, a Thickeners, lubricants and preservatives (including antioxidants). Further, other adjuvants may also include penetration enhancers that regulate the isotonic pressure of the drug and blood. A pharmaceutical composition containing a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, can be prepared in the form of a powder or a concentrated solution.

In general, to treat the conditions or discomfort shown above, the dosage level of the drug is about 0.01 mg / kg body weight to 150 mg / kg body weight per day, or 0.5 mg to 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergies / asthma, diseases and discomforts of the immune system, diseases and discomforts of the central nervous system (CNS), effective dosages of drugs for treatment from 0.01 mg / kg body weight to 50 mg / kg body weight per day, or 0.5mg to 3.5g per patient per day.

It is understood, however, that lower or higher doses than those described above may be required. The specific dose level and treatment regimen for any particular patient will depend on a number of factors, including the activity of the specific compound used, age, weight, general health, gender, diet, time of administration, route of administration, excretion rate, combination of drugs The condition and severity of the particular disease being treated.

Detailed ways

To make the above content more clear and specific, the present invention will further illustrate the technical solution of the present invention by using the following examples. The following examples are only used to illustrate specific implementation manners of the present invention, so that those skilled in the art can understand the present invention, but are not used to limit the protection scope of the present invention. In the specific embodiments of the present invention, technical means or methods that are not specifically described are conventional technical means or methods in the art.

Unless otherwise stated, all parts and percentages of the present invention are by weight and all temperatures are in degrees Celsius.

The following abbreviations are used in the examples:

ATP: adenosine triphosphate;

BINAP: binaphthyl diphenylphosphine;

Boc: tert-butoxycarbonyl;

(Boc) ₂ O: di-tert-butyl dicarbonate;

Bpd: bis (pinacol) diboron;

(BPIN) ₂ : pinacol diborate;

DBU: 1,8-diazabicycloundec-7-ene;

DCE: dichloroethane;

DCM: dichloromethane;

DIAD: diisopropyl azodicarboxylate;

DIBAl-H: diisobutylaluminum hydride;

DIEA or DIPEA: N, N-diisopropylethylamine;

DMA: N, N-dimethylacetamide;

DMAP: 4-dimethylaminopyridine;

DME: ethylene glycol dimethyl ether;

DMF: N, N-dimethylformamide;

DMSO: dimethyl sulfoxide;

EA: ethyl acrylate;

EDCI.HCl: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride;

Et ₃ N: triethylamine;

EtOAc: ethyl acetate;

EtOH: ethanol;

h or hrs: hour;

HATU: 2- (7-benzotriazole) -N, N, N ′, N′-tetramethylurea hexafluorophosphate;

HOBt: 1-hydroxybenzotriazole;

iprMgCl: isopropyl magnesium chloride;

KOAc: potassium acetate;

LAH: lithium tetrahydroaluminum;

LC-MS: liquid chromatography-mass spectrometry;

MeCN: acetonitrile;

MeMgBr: methyl magnesium bromide;

MeOH: methanol;

min: minutes;

MOMCl: chloromethyl methyl ether;

MTBE: methyl tert-butyl ether;

NEt ₃ : triethylamine;

NMM: N-methylmorpholine;

PBD: 2- (4-biphenyl) -5-phenyloxadiazole;

PCC: pyridinium chlorochromate;

Pd ₂ dba ₃ or Pd ₂ (dba) ₃ : tris (dibenzylideneacetone) dipalladium;

Pd (dppf) Cl ₂ : 1,1′-bisdiphenylphosphinoferrocene palladium dichloride;

Pd (PPh ₃ ) ₄ : tetrakis (triphenylphosphine) palladium;

Pd (PPh ₃ ) ₂ Cl ₂ : dichlorobis (triphenylphosphine) palladium;

PE: petroleum ether;

Pin ₂ B ₂ : pinacol biborate;

PPh ₃ : triphenylphosphine;

(PPh ₃ ) ₂ PdCl ₂ : bistriphenylphosphonium palladium dichloride;

Pre-TLC: preparative thin layer chromatography;

RT or rt: room temperature;

TBAI: tetrabutylammonium iodide;

TBDPSCl: tert-butyldiphenylchlorosilane;

TBSCl: tert-butyldimethylchlorosilane;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran;

TLC: thin layer chromatography;

TMSCF ₂ Br: triethyl (bromodifluoromethyl) silane;

xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene;

XPhos or Xphos: 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl.

Preparation of intermediate M1:

Step 1: Preparation of compound M1-2

Compound M1-1 (4.500 g) was dissolved in ethanol (20 mL), isopropylamine (5.200 g) was added, and the reaction was stirred at 80 ° C for 12 hrs. The reaction solution was concentrated under reduced pressure, 50 mL of water, 50 mL of ethyl acetate were added, and the layers were separated. The organic phase was washed again with 50 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 3.500 g of a pale yellow oily liquid. That is M1-2.

LC-MS [M + H] ⁺ = 297.0.

Step 2: Preparation of compound M1-3

Compound M1-2 (3.400 g) was dissolved in DME (20 mL), (5- (methoxycarbonyl) -1-toluenesulfonyl-1H-pyrrole-3-yl) boronic acid (5.600 g), and Pd ( PPh ₃ ) ₄ (1.300 g), sodium carbonate (2.400 g) was dissolved in water (3 mL) and added to the reaction solution, protected by nitrogen, and the reaction was stirred at 80 ° C. for 12 hrs. After filtration, the filter cake was washed twice with 10 mL of ethyl acetate, 50 mL of water was added to the mother liquor, 50 mL of ethyl acetate was separated, and the organic phase was washed once with 50 mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue It was separated and purified by column chromatography to obtain 3.700 g of a yellow solid. That is M1-3.

LC-MS [M + H] ⁺ = 448.1.

Step 3: Preparation of compound M1

Compound M1-3 (1.000 g) was dissolved in THF (20 mL), LiOH.H ₂ O (0.280 g) was dissolved in water (2 mL) and added to the reaction solution, and the reaction was stirred at 70 ° C. for 12 hrs. The reaction solution was directly concentrated under reduced pressure. The residue was just dissolved by adding 2 mL of water, and hydrochloric acid (6N) was slowly added to adjust the pH to 6-7. A large amount of white solids were precipitated, filtered, and the filter cake was washed twice with 2 mL of water. The filter cake Transfer to a 100 mL Erlenmeyer flask, add 10 mL of methanol to dissolve, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 0.700 g of off-white solid. That is M1.

LC-MS [M + H] ⁺ = 280.1.

Preparation of intermediate M2:

Step 1: Preparation of compound M2-2

In a 100 mL three-necked flask, add 1- (tert-butyl) -3,3-diethylazetidine-1,3,3-tricarboxylic acid ester (M2-1, 5.000 g) and 50 mL of methanol. After replacing with nitrogen three times, the temperature was lowered to 0 ° C, and sodium borohydride (1.300 g) was added in portions. After the addition was completed, the temperature was raised to room temperature and the reaction was held for 3 hrs. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (DCM: MeOH = 5: 1) to obtain 3.400 g of a white solid product.

LC-MS [M + H] ⁺ = 218.1.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 4.80 (t, J = 5.5 Hz, 2H), 3.55 (s, 2H), 3.50 (s, 2H), 3.44 (s, 2H), 3.43 (s, 2H), 1.37 (s, 9H).

Step 2: Preparation of compound M2

In a 100 ml three-necked flask, 3,3-bis (hydroxymethyl) azetidine-1-carboxylic acid tert-butyl ester (M2-2, 3.400 g) and triphenylphosphorus (9.100 g) were dissolved in 120 mL After the temperature was lowered to 0 ° C in anhydrous dichloromethane, carbon tetrabromide (11.500g) was added in batches under nitrogen protection, and the reaction was held for 5hrs. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (PE: EtOAc = 9: 1) to obtain 1.200 g of a white solid.

LC-MS [M + H] ⁺ = 342.0.

¹ H NMR (600 MHz, CDCl ₃ ) δ 3.77 (s, 4H), 3.76 (s, 4H), 1.47 (s, 9H).

Preparation of intermediate M3:

(S) -2-amino-2- (3-chlorophenyl) ethan-1-ol (M3-1, 2.000 g) was dissolved in DCM (40 mL), and DMAP (0.285 g) and triethylamine ( 2.353 g), the temperature of the reaction mixture was lowered to 0 ° C, and a solution of TBSCl (1.756 g) in DCM was added dropwise, and the reaction was stirred overnight at room temperature. The reaction mixture was diluted with DCM (20 mL), washed with water (30 mL * 2), and the organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EtOAc = 100: 0-1: 1). This gave 2.603 g of an oil, which is compound M3.

LC-MS [M + H] ⁺ = 286.1.

Preparation of intermediate M4:

The compound 5-bromo-1H-pyrazole-3-carboxylic acid ethyl ester (0.100 g) was dissolved in acetonitrile (2 mL), (Boc) ₂ O (0.110 g) and DMAP (0.020 g) were added, and the reaction was stirred at room temperature. 12hrs. The reaction solution was directly concentrated under reduced pressure, and the residue was added with 10 mL of water and 10 mL of ethyl acetate. The organic phase was dried by adding anhydrous sodium sulfate, filtered, and separated and purified by column chromatography to obtain 80 mg of a light yellow oily liquid, namely M4.

LC-MS [M + H] ⁺ = 319.0.

Preparation of intermediate M5:

M5-1 (0.500 g) was dissolved in DCM (10 mL), DMAP (30 mg) and triethylamine (0.490 g) were added, and the reaction mixture was cooled to 0 ° C. TBSCl (0.550 g) in DCM was added dropwise. The reaction was stirred overnight. The reaction mixture was diluted with DCM (10 mL), washed with water (20 mL * 2), and the organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EtOAc = 100: 0-1: 1). This gave 0.420 g of an oil, which is compound M5.

LC-MS [M + H] ⁺ = 320.2.

Preparation of intermediate M6:

Step 1: Preparation of compound M6-2

Dissolve methyl 2-cyano-4-fluorobenzoate (M6-1, 1.000 g) in THF (30 mL), cool to 0 ° C, slowly add lithium aluminum hydride (640 mg), and react at room temperature for 2 hrs. The reaction solution was cooled to 0 ° C, and water (0.64 mL), 15% aqueous sodium hydroxide solution (0.64 mL), and water (1.9 mL) were slowly added in this order, and then anhydrous sodium sulfate was added. After stirring for 10 minutes, the filtrate was concentrated to obtain 850mg of M6-2 was used directly in the next reaction.

LC-MS [M + H] ⁺ = 156.1.

Step 2: Preparation of compound M6

To a solution of compounds M6-3 (1.000g) and M6-2 (980.06mg) in DMF (10mL) were added HOBt (1.070g), EDCI (1.230g) and DIEA (2.040g, 2.83mL), and the mixture was stirred at 25 ° C. 12hrs. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (10 mL * 3), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was separated and purified by a column machine ( PE: EA = 5: 1 to 1: 1) to give compound M6 (2.000 g) as a brown oil.

LC-MS [M + H] ⁺ = 327.0.

Preparation of intermediate M7:

Dibromo neopentyl glycol (M7-1, 5.000 g) was dissolved in acetone (50 mL), p-toluenesulfonic acid (1.300 g) was added, and the reaction mixture was heated under reflux for 10 hrs. After cooling, the reaction mixture was concentrated under reduced pressure, water (50 mL) and EtOAc (50 mL) were added, the pH was adjusted to 7-8 with NaHCO ₃ , and the organic phase was separated. The EtOAc (50 mL) was continued to be extracted. The organic phases were combined, anhydrous Na ₂ SO ₄ Dry, concentrate under reduced pressure, and purify the residue by column chromatography (PE: EtOAc = 100: 1-10: 1) to obtain 702 mg of a solid, which is compound M7.

LC-MS [M + H] ⁺ = 301.0.

¹ H NMR (600 MHz, CDCl ₃ ) δ 3.81 (s, 4H), 3.59 (s, 4H), 1.43 (s, 6H).

Preparation of intermediate M8:

To a solution of compound M8-1 (15.000 g) in THF (400 mL) at 0 ° C and under the protection of N ₂ was added NaH (8.030 g) in portions, followed by stirring at 0 ° C for 0.5 hours. M8-2 (41.750g) was added at -20 ° C, and stirred at 25 ° C for 2 hours. The reaction solution was quenched with ice water (500 mL) at 0 ° C, extracted with ethyl acetate (200 mL * 3), and the organic phases were combined. The organic phases were washed with saturated brine (500 mL), dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was diluted with DCM (30 mL), PE (200 mL) was slowly added to the reaction solution, and a solid precipitated out. After filtration, the filter cake was compound M8 (18.700 g) as a yellow-brown solid.

LC-MS [M + H] ⁺ = 335.0.

Example 1: Compound 1 (8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -4,4-difluoro-2,3 , 4,5-Tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazalide-1-one)

Step 1: Preparation of Compound 1a

M-chlorobenzaldehyde (1.000 g) was dissolved in absolute ethanol (25 mL), 3-amino-2,2-difluoropropanol (790 mg) was added, and the mixture was heated to react at 60 ° C overnight. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in anhydrous methanol (25 mL), and sodium borohydride (810 mg) was added in portions under an ice bath condition. After the addition was completed, the reaction mixture was warmed to room temperature and reacted for 2 hrs. After the reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and extracted with EtOAc / THF (1: 1, 20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 1.020 g. Compound 1a.

LC-MS [M + H] ⁺ = 236.1.

Step 2: Preparation of Compound 1b

1a (700 mg) was dissolved in DCM (30 mL), triethylamine (600 mg) and DMAP (72 mg) were added, and a solution of TBSCl (448 mg) in DCM (5 mL) was added dropwise under an ice bath. After the dropwise addition, the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water and extracted with DCM (10 mL * 2). The organic phases were combined, washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 630 mg of compound 1b.

LC-MS [M + H] ⁺ = 350.1.

Step 3: Preparation of Compound 1c

Compound M1 (200 mg) was dissolved in DMA, HATU (326 mg) was added, DIEA (277 mg) was stirred for 10 min, 1b (375 mg) was added, and the mixture was heated to 35 ° C for 3 days to react. The reaction solution was added with water (10 mL) and EtOAc (10 mL), the organic phase was separated, washed with saturated brine (5 mL * 4), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 35 mg of compound 1c.

LC-MS [M + H] ⁺ = 611.2.

Step 4: Preparation of Compound 1d

Compound 1c (35 mg) was dissolved in DCM (5 mL), and TFA (0.5 mL) was added thereto, followed by stirring at room temperature for 4 hrs. DCM (5 mL) was added to the reaction solution, and the pH was adjusted to 7-8 with NHCO _{3. The} organic phase was separated, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 14 mg of compound 1d.

LC-MS [M + H] ⁺ = 497.1.

Step 5: Preparation of Compound 1

Compound 1d (14 mg) was dissolved in DCM (1.5 mL). Under the protection of nitrogen, PPh ₃ (21 mg) was added under ice bath conditions, and DIAD (14 mg) was slowly added. The reaction was carried out at room temperature for 1 h, and concentrated under reduced pressure. The residue was subjected to column chromatography. Purified to 7.9 mg.

LC-MS [M + H] ⁺ = 479.1.

Example 2: Compound 2 (7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -3- (hydroxymethyl) -3, Preparation of 4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one)

Step 1: Preparation of compound 2a

M-chlorobenzaldehyde (1.000 g) was dissolved in absolute ethanol (25 mL), serine (648 mg) was added, and the mixture was heated at 60 ° C. to react overnight. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in anhydrous methanol (25 mL), and sodium borohydride (410 mg) was added in portions under an ice bath condition. After the addition was completed, the reaction mixture was warmed to room temperature and reacted for 2 hrs. After the reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and extracted with EtOAc / THF (1: 1, 20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 1.100 g. Compound 2a.

LC-MS [M + H] ⁺ = 216.1.

Step 2: Preparation of Compound 2b

2a (1.100g) was dissolved in DCM (30mL), triethylamine (2.060g) and DMAP (0.130g) were added, and a solution of TBSCl (1.540g) in DCM (8mL) was added dropwise under an ice bath. At room temperature after the dropwise addition, Stir overnight. The reaction mixture was poured into ice water, extracted with DCM (30 mL * 2), the organic phases were combined, washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 1.554 g of compound 2b.

LC-MS [M + H] ⁺ = 444.2.

Step 3: Preparation of Compound 2c

Compound M1 (250 mg) was dissolved in DMA, HATU (408 mg) was added, DIEA (347 mg) was stirred for 10 min, 2b (476 mg) was added, and the reaction was carried out at room temperature for 1 h. Trace products were detected by LC-MS, and the reaction was heated at 50 ° C. overnight. Water (20 mL) and EtOAc (25 mL) were added to the reaction solution, and the organic phase was separated, washed with saturated brine (5 mL * 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 181 mg of compound 2c.

LC-MS [M + H] ⁺ = 705.3.

Step 4: Preparation of compound 2d

Compound 2c (181 mg) was dissolved in DCM (10 mL), and TFA (1 mL) was added thereto, followed by stirring at room temperature overnight. The reaction solution was added with DCM (10 mL), adjusted to pH = 7-8 with NHCO ₃ , the organic phase was separated, and extracted with EtOAc (5 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography. Purification yielded 25 mg of compound 2d.

LC-MS [M + H] ⁺ = 477.1.

Step 5: Preparation of Compound 2

Compound 2d (25 mg) was dissolved in DCM (1.5 mL), PPh ₃ (21 mg) was added under ice-bath condition, and DIAD (14 mg) was slowly added. The reaction was carried out at room temperature for 1 h, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 4 mg of compound 2.

LC-MS [M + H] ⁺ = 459.1.

1H NMR (600MHz, DMSO-d ₆ ) δ7.98 (s, 1H), 7.55 (d, J = 1.2Hz, 1H), 7.41-7.32 (m, 4H), 7.03 (d, J = 1.2Hz, 1H ), 6.62 (s, 1H), 6.39 (d, J = 7.2Hz, 1H), 5.15 (t, 1H), 5.12 (d, J = 15Hz, 1H), 4.42 (d, 1H), 4.32 (d, J = 15Hz, 1H), 4.21 (m, 1H), 3.96 (m, 1H), 3.70 (m, 1H), 3.46 (m, 1H), 3.22 (m, 1H), 1.14 (d, J = 5.4Hz , 6H).

Example 3: Compound 3 (8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(2- (hydroxymethyl) benzyl) -2 ′, 3 ′ -Dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one) Preparation

Step 1: Preparation of compound 3a

M1 (1.500 g) was dissolved in DMF, HOBt (869 mg), EDCI.HCl (2.049 g), DIEA (2.078 g), 2- (aminomethyl) benzyl alcohol (883 mg) were added, and the above mixture was stirred and reacted overnight. Water was added to the reaction mixture and extracted with EtOAc (100 mL * 3). The organic phase was washed with brine (30 mL * 4), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give 1.456 g of compound 3a. .

LC-MS [M + H] ⁺ = 399.2.

¹ H NMR (600 MHz, DMSO-d6) = 12.04-11.59 (m, 1H), 8.61 (t, J = 5.9 Hz, 1H), 7.97 (s, 1H), 7.44-7.39 (m, 1H), 7.36 ( br.s., 1H), 7.31-7.26 (m, 2H), 7.26-7.21 (m, 2H), 6.57 (s, 1 H), 6.41 (d, J = 7.7Hz, 1H), 5.20 (t, J = 5.3Hz, 1H), 4.62 (d, J = 5.1Hz, 2H), 4.50 (d, J = 5.9Hz, 2H), 3.94 (qd, J = 6.6, 13.5Hz, 1H), 1.14 (d, J = 6.2Hz, 6H).

Step 2: Preparation of Compound 3

Under nitrogen protection, compound 3a (1.456 g) was dissolved in DMA (40 mL), 3,3-bisbromomethyl-1-oxetane (890 mg), cesium carbonate (3.568 g) was added, and heated to 100 Reaction at ℃ for 1h. The reaction was detected by LC-MS. The mixture was cooled and poured into ice water. The mixture was extracted with EtOAc (100 mL * 3). The organic phases were combined, washed with saturated brine (30 mL * 4), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue Purification by column chromatography (PE: EtOAc = 1: 1) gave 706 mg of compound 3.

LC-MS [M + H] ⁺ = 481.2.

Example 4: Compound 4 (8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(3-chlorobenzyl) -2 ′, 3′-dihydro- Preparation of 1′H, 5′H-spiro [azetidin-3,4′-pyrrolo [1,2-a] [1,4] diazalide] -1′-one)

Step 1: Preparation of compound 4a

Compound M1 (1.000 g) was dissolved in DMA (30 mL), HATU (1.631 g), DIEA (1.384 g) were added, and the reaction was stirred at room temperature for 15 min. M-chlorobenzylamine (0.607 g) was added. The reaction was continued at room temperature for 6 hrs. The reaction was detected by TLC. The reaction mixture was extracted with water (50 mL) and EtOAc (50 mL * 3). The organic phases were combined, washed with saturated brine (15 mL * 4), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was subjected to column chromatography. (PE: EtOAc = 10: 1-1: 1) purified to 818 mg, compound 4a.

LC-MS [M + H] ⁺ = 403.1.

Step 2: Preparation of Compound 4b

Compound 4a (60 mg) and compound M2 (51 mg) were dissolved in DMA (2 mL), cesium carbonate (146 mg) was added, and the reaction was heated at 100 ° C for 1 h. The reaction was detected by TLC. The reaction mixture was cooled to room temperature, and extracted with ice water (5 mL) and EtOAc (5 mL * 2). The organic phases were combined, washed with saturated brine (3 mL * 4), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (PE: EtOAc = 3: 1-1: 1) to give 62 mg, which is compound 4b.

LC-MS [M + H] ⁺ = 584.2.

Step 3: Preparation of Compound 4

Compound 4b (434 mg) was added to 1,4-dioxane (10 mL), 6N HCl (1 mL) was added, and the reaction was stirred at room temperature overnight. The reaction was detected by TLC. The reaction mixture was concentrated under reduced pressure, half of the solvent was added, EtOAc (20 mL) was added, the pH was adjusted to 7-8 with NHCO ₃ , and the organic phase was separated. The aqueous phase was continuously extracted with EtOAc (15 mL, 10 mL). Anhydrous Na ₂ SO _{4 was} dried, concentrated under reduced pressure, and the residue was subjected to column chromatography (DCM: CH ₃ OH = 20: 1-10: 1) to obtain 149 mg, which is Compound 4.

LC-MS [M + H] ⁺ = 484.2.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.97 (s, 1 H), 7.64 (d, J = 1.8 Hz, 1 H), 7.45-7.38 (m, 3 H), 7.34 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 1.8Hz, 1H), 6.63 (s, 1H), 6.38 (d, J = 7.2Hz, 1H), 4.67 (s, 1H), 4.43 (s, 1H), 3.98- 3.92 (m, 1H), 3.49 (s, 4H), 3.40-3.39 (m, 2H), 3.17 (d, J = 4.2 Hz, 1H), 1.14 (d, J = 6.6 Hz, 6H).

Example 5: Compound 5 (8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -4,4-bis (hydroxymethyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazalide-1-one)

Step 1: Preparation of Compound 5a

Dibromo neopentyl glycol (5.000 g) was dissolved in acetone (50 mL), p-toluenesulfonic acid (1.300 g) was added, and the reaction mixture was heated under reflux for 10 hrs. After cooling, the reaction mixture was concentrated under reduced pressure, water (50 mL) and EtOAc (50 mL) were added, the pH was adjusted to 7-8 with NaHCO ₃ , and the organic phase was separated. The EtOAc (50 mL) was continued to be extracted. The organic phases were combined, anhydrous Na ₂ SO ₄ It was dried, concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EtOAc = 100: 1-10: 1) to obtain 702 mg of a solid, namely compound 5a.

LC-MS [M + H] ⁺ = 301.0.

¹ H NMR (600 MHz, CDCl ₃ ) δ 3.81 (s, 4H), 3.59 (s, 4H), 1.43 (s, 6H).

Step 2: Preparation of Compound 5b

Compound 4a (200 mg) was dissolved in DMA (3 mL), 5a (150 mg) and cesium carbonate (485 mg) were added, and the mixture was heated at 120 ° C for 1 h to react. The reaction was detected by TLC. The reaction mixture was cooled to room temperature, and extracted with ice water (10 mL) and EtOAc (15 mL * 2). The organic phases were combined, washed with saturated brine (3 mL * 4), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 270 mg of crude product was obtained, that is, 5b.

LC-MS [M + H] ⁺ = 543.2.

Step 3: Preparation of Compound 5

The crude compound 5b (270 mg) was dissolved in dichloromethane (10 mL) and methanol (10 mL), p-toluenesulfonic acid (128 mg) was added, and the reaction was heated at 30 ° C for 1 h. The reaction mixture was added with water (20 mL) and extracted with EtOAc (20 mL * 2). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc) to obtain 76 mg of solid, which is compound 5.

LC-MS [M + H] ⁺ = 503.2.

Example 6: Compound 6 (2 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -5 ′-(2- (hydroxymethyl) benzyl) -5 ′, 6, -Dihydro-4′H, 8′H-spiro [oxetane-3,7′-pyrazolo [1,5-a] [1,4] diazepine] -4′-one ) Preparation

Step 1: Preparation of compound 6b

6a (200 mg) and M4 (356 mg) were dissolved in dioxane (5 mL), cesium carbonate (606 mg) was dissolved in 1 mL of water and added to the reaction solution, and Pd (PPh ₃ ) ₄ (107 mg) was added under nitrogen protection, and the reaction was carried out. The liquid was heated to 100 ° C and stirred for 12 hrs. The reaction solution was filtered through celite, and the filter cake was washed once with EtOAc (50 mL). After the mother liquor was directly concentrated under reduced pressure, the residue was purified by column chromatography to obtain 210 mg of a colorless oily liquid, namely compound 6b.

LC-MS [M + H] ⁺ = 409.2.

Step 2: Preparation of Compound 6c

6b (210 mg) was dissolved in methanol (10 mL), concentrated hydrochloric acid (1 mL) was added, and the reaction was stirred at room temperature for 2 hrs. The reaction solution was directly concentrated under reduced pressure to obtain 320 mg of a residue, that is, 6c.

LC-MS [M + H ⁺ ] = 309.1.

Step 3: Preparation of compound 6d

Compound 6c (320mg) was dissolved in methanol (5mL), NaOH (208mg) was added, and the reaction was refluxed for 12hrs. The reaction solution was directly concentrated under reduced pressure. The residue was added with 1mL of water, and the pH was adjusted to 6-7 with concentrated hydrochloric acid. There was a white solid. Precipitate, filter, wash the filter cake twice with 1 mL of water, transfer the filter cake to a 100 mL conical flask, dissolve in methanol, add sodium sulfate to dry, filter, and concentrate under reduced pressure to obtain 200 mg of a white solid, 6d.

LC-MS [M + H] ⁺ = 281.1.

Step 4: Preparation of compound 6e

Compound 6d (200 mg), 2- (aminomethyl) benzyl alcohol (117 mg), HOBt (116 mg), EDCl.HCl (165 mg), DIEA (0.38 mL) were dissolved in DMF (10 mL), and the reaction was stirred at room temperature for 12 hrs. . The reaction solution was added with EtOAc (10 mL), 10 mL of water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 180 mg of an anhydrous oily compound, that is, 6e.

LC-MS [M + H] ⁺ = 400.2.

Step 5: Preparation of compound 6

Compound 6e (180 mg) was dissolved in DMA (5 mL), and 3,3-bisbromomethyl-1-oxetane (107 mg) and cesium carbonate (440 mg) were added. The reaction was stirred at 100 ° C for 2 hrs. 10 mL of ethyl acetate was added, the layers were separated, and the organic phase was washed again with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 85 mg of compound 6 as a white solid.

LC-MS [M + H] ⁺ = 482.2.

Example 7: Compound 7 (2- (5-chloro-2- (isopropylamino) pyridin-4-yl) -7- (chloromethyl) -7- (hydroxymethyl) -5- (2- Preparation of (hydroxymethyl) benzyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1,4] diazalide-4-one)

Compound 6 (50mg) was dissolved in methanol (3mL), concentrated hydrochloric acid (1mL) was added, and the reaction was stirred at room temperature for 2hrs. After the reaction solution was directly concentrated under reduced pressure, the residue was added with saturated sodium carbonate solution to adjust the pH = 7-8, and then 10 mL of ethyl acetate was added, the layers were separated, and the organic phase was washed again with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 15 mg of compound 7 as a white solid.

LC-MS [M + H] ⁺ = 518.2.

Example 8: Compound 8 (2- (5-chloro-2- (isopropylamino) pyridin-4-yl) -8- (3-chlorobenzyl) -7,8-dihydro-5H, 9H- Preparation of spiro [imidazo [1,2-a] [1,4] diazepine-6,3′-oxetane] -9-one)

Step 1: Preparation of Compound 8a

The raw material 4-bromo-1H-imidazole-2-carboxylic acid ethyl ester (218mg) was dissolved in THF (10mL), water (5mL) was added, and then lithium hydroxide monohydrate (210mg) was added. The oil bath was heated to reflux. After 2hrs, the reaction was monitored by LCMS. The reaction solution was spin-dried to obtain compound 8a for the next step.

LC-MS [M + H] ⁺ = 191.0.

Step 2: Preparation of Compound 8b

Compound 8a was dissolved in DMF (10 mL), DIPEA was added, and HATU was stirred at room temperature for 5 min, then (3-chlorophenyl) methylamine (169 mg) was added, and stirring was continued for 50 min. The reaction was monitored by LC-MS. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated aqueous ammonium chloride solution (3 * 40 mL), and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 50 mg of the product. , Which is 8b.

LC-MS [M + H] ⁺ = 314.0.

Step 3: Preparation of Compound 8c

Compound 8b (50 mg) was dissolved in DMF, cesium carbonate and 3,3-bisbromomethyloxetane (39 mg) were added at room temperature, and the reaction liquid was cooled at 120 ° C for 45 min. Diluted (10 mL), washed with saturated aqueous ammonium chloride solution (3 * 10 mL), separated the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by chromatography to obtain 30 mg of product, namely compound 8c.

LC-MS [M + H] ⁺ = 396.0.

Step 4: Preparation of Compound 8

Compound 8c (30 mg) was dissolved in dioxane (2 mL) and water (0.4 mL), (5-chloro-2- (isopropylamino) pyridin-4-yl) boronic acid (16 mg), and cesium carbonate were added. (74 mg), Pd (PPh ₃ ) ₄ (4 mg), three times after nitrogen substitution, and reacted at 110 ° C. for 2.5 hrs. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate (20 mL), washed with water (3 * 10 mL), the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and a chromatography plate (PE: EtOAc = 1: 2) was used to obtain 10 mg. The product is compound 8.

LC-MS [M + H] ⁺ = 486.1.

Example 9: Compound 9 (8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(3-chlorobenzyl) -1- (2,4-dimethyl (Oxybenzyl) -2 ', 3'-dihydro-1'H, 5'H-spiro [azetidin-3,4'-pyrrolo [1,2-a] [1,4] Preparation of diazepine] -1′-one)

Step 1: Preparation of compound 9a

The compound 3,3-bisbromomethyl-1-oxetane (2.000 g) was dissolved in DMF (20 mL), 3,4-dimethoxybenzylamine was added, and DBU (2.750 g) was added at room temperature. , And heated at 60 ° C for 18 hrs. The reaction mixture was cooled to room temperature, followed by extraction with water (30 mL) and EtOAc (30 mL * 4). The organic phases were combined, washed with saturated brine (15 mL * 4), dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was subjected to column chromatography (DCM). ) Purified to give 2.055 g of oil, which is compound 9a.

LC-MS [M + H] ⁺ = 250.1.

Step 2: Preparation of Compound 9b

Compound 9a was dissolved in ethyl acetate (40 mL), a 40% HBr (2 mL) aqueous solution was slowly added, and the reaction was stirred at room temperature for 15 min. LC-MS showed that the reaction was completed. The reaction mixture was added with water (20 mL), adjusted to pH = 7-8 with sodium bicarbonate, and extracted with EtOAc (40 mL * 4). The organic phases were combined, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give an oil. Compound 1.263g, which is compound 9b.

LC-MS [M + H] ⁺ = 330.1.

Step 3: Preparation of Compound 9c

Under nitrogen protection, compound 9b (0.500g) was dissolved in DCM (10mL), triphenylphosphine (0.477g) was added, the temperature was lowered to 0 ° C, carbon tetrabromide (0.603g) was added, and the reaction was continued at 0 ° C for 2hrs. , And then raised to room temperature for 1h. The reaction mixture was concentrated under reduced pressure, the residue was column chromatographed (DCM:CH ₃ OH = 100:0-20:1) was purified as a white solid 150mg, i.e., compounds 9c.

LC-MS [M + H] ⁺ = 392.0.

Step 4: Preparation of Compound 9

Compound 4a (108 mg) and compound 9c (105 mg) were dissolved in DMA (10 mL), cesium carbonate (261 mg) was added, and the reaction was heated at 120 ° C for 1 h. The reaction was detected by TLC. The reaction mixture was cooled to room temperature, and extracted with ice water (15 mL) and EtOAc (15 mL * 4). The organic phases were combined, washed with saturated brine (8 mL * 4), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was column chromatographed (DCM:CH ₃ OH = 10:1) to give 71 mg of purified, i.e. compound 9.

LC-MS [M + H] ⁺ = 634.2.

Example 10: Compound 10 ((S) -8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(1- (3-chlorophenyl) -2- (Hydroxyethyl) -2 ′, 3′-dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] di Preparation of azepine] -1′-one)

Step 1: Preparation of Compound 10a

Compound M1 (2.504 g) was dissolved in DMA (50 mL), HATU (4.083 g), DIEA (3.470 g) were added, and the reaction was stirred at room temperature for 15 minutes. Compound M3 (3.070 g) was added, and the reaction was continued at room temperature for 12 hrs. The reaction was detected by TLC. The reaction mixture was extracted with water (50 mL) and EtOAc (50 mL * 3). The organic phases were combined, washed with saturated brine (20 mL * 4), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was subjected to column chromatography. (PE: EtOAc = 3: 1) was purified to give 1.441 g, compound 10a.

LC-MS [M + H] ⁺ = 547.2.

Step 2: Preparation of Compound 10b

Compound 10a (1.394g1) was dissolved in DMA (40mL), 3,3-bisbromomethyl-1-oxetane (0.621g), cesium carbonate (2.493g) were added, and the reaction was heated at 100 ° C for 1.5hrs. . The reaction was detected by TLC. The reaction mixture was cooled to room temperature, and extracted with ice water (50 mL) and EtOAc (50 mL * 2). The organic phases were combined, washed with saturated brine (15 mL * 4), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (PE: EtOAc = 4: 1-1: 1) to give 1.189 g of white solid, ie 10b.

LC-MS [M + H] ⁺ = 629.2.

Step 3: Preparation of Compound 10

Compound 10b (1.189 g) was dissolved in dioxane (60 mL), 5% HCl (20 mL) was added, and the reaction was stirred at room temperature for 1 h. The reaction was checked by TLC, diluted with EtOAc (50 mL), adjusted to pH 7-8 with sodium bicarbonate, EtOAc (50 mL * 3), dried over anhydrous Na ₂ SO _{4 in the} organic phase, concentrated under reduced pressure, and column chromatography the residue ( PE: EtOAc = 3: 1-1: 2) was purified to give 563 mg of solid, compound 10.

LC-MS [M + H] ⁺ = 515.3.

The synthetic compounds of Table 1 were synthesized according to the synthetic procedures of the similar compounds in the commercially available reference compound.

Table 1

NMR data of compound 12: ¹ H NMR (600 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.47 (s, 1H), 7.43-7.34 (m, 3H), 7.01 (d, J = 2.4Hz, 1H), 6.61 (s, 1H), 6.40 (d, J = 7.8Hz, 1H), 4.66 (s, 2H), 4.51 (s, 2H), 4.26 ( d, J = 6.6Hz, 2H), 4.14 (d, J = 6.6Hz, 2H), 3.95 (m, 1H), 3.54 (s, 2H), 1.14 (d, J = 6.6Hz, 6H).

Example 35: Compound 35 (8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(2- (hydroxymethyl) benzyl) -1-methyl- 2 ′, 3′-dihydro-1′H, 5′H-spiro [azetidine-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1 ′ -Keto) Preparation

Compound 28 (200 mg) was dissolved in 6 mL of dichloromethane, 35% aqueous formaldehyde (288 mg) and acetic acid (60 mg) were added, and the mixture was stirred at room temperature for 2 hrs. After the reaction was completed, the temperature was lowered to 0 ° C and sodium borohydride (100 mg) was added in portions. After completion, warm to room temperature and stir for 2hrs. The reaction solution was directly subjected to column chromatography (DCM: MeOH = 10: 1), and 10 mg of the product was isolated.

LC-MS [M + H] ⁺ = 494.2.

Example 36: Compound 36 ((R) -7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) Preparation of 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one)

Step 1: Preparation of Compound 36b

Compound 36a (25.000 g) was dissolved in anhydrous THF (150 mL), N-methylmorpholine (12.5 mL) was added, the liquid nitrogen was cooled to -15 ° C, and isobutyl chloroformate was slowly added dropwise under the protection of N ₂ ( 15.0 mL). After the dropwise addition, an aqueous solution (30 mL) in which sodium borohydride (13.000 g) was dissolved was added dropwise. The dropwise addition was completed within 40 minutes, and the mixture was stirred at -15 ° C for 2 hrs. At the end of the reaction, the reaction mixture was diluted with EtOAc (300 mL), water (100 mL) was added, the pH was adjusted to 6-7 with dilute hydrochloric acid, and the mixture was extracted with EtOAc (100 mL * 2). The organic phases were combined and washed with saturated brine (100 mL * 3). Anhydrous Na ₂ SO _{4 was} dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE: EtOAc = 1: 1) to obtain 21.000 g, which is compound 36b.

LC-MS [M + H] ⁺ = 206.1.

Step 2: Preparation of Compound 36c

Add imidazole (27.300g), triethylamine (23.100g) and dichloromethane (500mL) to a 1000mL three-necked flask, evacuate, protect with N ₂ , lower liquid nitrogen to -50 ° C, and start adding dichlorosulfoxide dropwise. (15.900g). After the dropping, the compound 36b (21.000g) was dissolved in dichloromethane (150mL) and added dropwise to the above reaction system at -50 ° C. The dropping was completed within 40 minutes and the reaction was held for 2hrs. After the reaction, the reaction solution was added to ice water (300 mL), and the layers were separated. The aqueous phase was extracted with dichloromethane (150 mL). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous Na ₂ SO ₄ and filtered. , Concentrated under reduced pressure, and the residue was purified by column chromatography (DCM) to obtain 21.300 g, which is compound 36c.

LC-MS [M + H] ⁺ = 252.1.

Step 3: Preparation of Compound 36d

Compound 36c (21.300g), acetonitrile (185mL), water (100mL) and ruthenium trichloride were added to a 500mL three-necked flask, cooled to 0 ° C, sodium periodate (22.400g) was added in portions, and stirred at 0 ° C for 3hrs After the reaction was completed, EtOAc (500 mL) and water (300 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with EtOAc (300 mL). The organic phases were combined, washed with saturated brine (300 mL * 2), and anhydrous Na ₂ SO _4. Dry, filter, and concentrate under reduced pressure to obtain a brown liquid 21.900 g, which is compound 36d.

LC-MS [M + H] ⁺ = 268.1.

Step 4: Preparation of Compound 36f

Compound 36d (10.000 g) and 4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (36e, 5.100 g) were dissolved in dioxane (150 mL), and 18-crown ether-6 was added under nitrogen protection. Potassium carbonate (31.000g) was added, and the reaction was held at 60 ° C for 5hrs. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated. The concentrated residue was added to water (150mL) and stirred, and extracted with EtOAc (100mL * 2). The organic phases were combined, washed with saturated brine (100 mL * 2), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give 10.100 g of a light brown solid, which is compound 36f.

LC-MS [M + H] ⁺ = 391.1.

Step 5: Preparation of Compound 36h

Compound 36f (5.100 g) was dissolved in dichloromethane (100 mL). Under nitrogen protection, a 15% trifluoroacetic acid solution in dichloromethane (100 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the solution was concentrated and dissolved, 7N ammonia in methanol (40 mL) was added and stirred at room temperature for 6 hrs. After the reaction solution was concentrated, dichloromethane (200 mL) was added, washed with water (100 mL * 2), washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain 3.000 g of a solid, which is a compound 36 h.

LC-MS [M + H] ⁺ = 259.0.

Step 6: Preparation of Compound 36j

The compound 36h (3.000g) was dissolved in dichloromethane (50mL), and NaH (510mg) was added under the protection of nitrogen. After stirring at room temperature for 0.5h, methyl 2-bromomethyl-4-fluorobenzoate (36i, 2.900g), stirred at room temperature for 0.5h, after the reaction was complete, added saturated ammonium chloride solution (100mL), extracted with EtOAc (100mL * 2), combined organic phases, water (100mL), washed with saturated brine (100mL), anhydrous dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure to give a solid 4.5g, i.e., compound 36j.

LC-MS [M + H] ⁺ = 425.0.

Step 7: Preparation of compound 36k

Compound 36j (3.500 g), pinacol diborate (5.200 g), potassium acetate (1.300 g) and XPhos (0.800 g) were dissolved in 1,4-dioxane (50 mL) and added under nitrogen. Pd ₂ (dba) ₃ (380mg), incubated at 90 ° C for 2hrs. After the reaction, the reaction mixture was filtered, the filtrate was concentrated, the concentrated residue was added to water (100mL) and stirred, and extracted with EtOAc (50mL * 3). The organic phases were combined, It was washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE: EtOAc = 2: 1) to obtain 3.600 g, which is compound 36k.

LC-MS [M + H] ⁺ = 473.2.

Step 8: Preparation of the compound 36l

Compound 36k (3.600 g), 5-chloro-4-iodo-N-isopropylpyridine-2-amine (M1-2, 2.700 g), sodium carbonate (2, 00 g) were dissolved in DMF (36 mL) and In a mixed solution of water (30 mL), (PPh ₃ ) ₂ PdCl ₂ (380 mg) was added under the protection of nitrogen, and the reaction was held at 80 ° C. for ₂ hrs. After the reaction was completed, EtOAc (50 mL) and water (50 mL) were added and stirred. The layers were separated and the aqueous phase was stirred. (50mL * 2) and extracted with EtOAc, the combined organic phases were washed with water (50mL * 2), washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO _4, filtered, and concentrated under reduced pressure, the residue was column chromatographed (PE:EtOAc = 1: 1) was purified to give 2.200 g, which is compound 36l.

LC-MS [M + H] ⁺ = 515.2.

Step 9: Preparation of Compound 36

Compound 36l (2.200g) was dissolved in tetrahydrofuran (30mL). After nitrogen substitution three times, the temperature was lowered to 0 ° C, and lithium tetrahydroaluminum (327mg) was added in portions. The reaction was held at 0 ° C for 1h. After the reaction was completed, water (0.3 after mL) to quench the reaction, then add 15% aqueous sodium hydroxide solution (0.3 mL), was added and finally water (0.9 mL of), stirred for 5min added over anhydrous Na ₂ SO ₄ dried 30min, filtered, the filter cake was washed with tetrahydrofuran and the filtrate reduced The solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM: MeOH = 50: 1) to obtain 768 mg, which is Compound 36.

LC-MS [M + H] ⁺ = 487.3.

Example 37: Compound 37 (8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4- ( (Hydroxymethyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazalide-1-one)

Step 1: Preparation of Compound 37b

Dissolve methyl 3-bromo-2- (bromomethyl) propionate (37a, 1.000 g) in anhydrous THF (20 mL), and cool to -70 ° C under nitrogen, dropwise add DIBAl-H (8.08 mL) After dripping, the temperature was naturally raised to 0 ° C for 45 minutes. 1N HCl (20 mL) was added dropwise to quench the reaction, and then extracted with MTBE (20 mL), the organic phase was washed with water (20 mL * 2), dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was subjected to column chromatography to obtain 753 mg of an oily substance. That is, compound 37a.

LC-MS [M + H] ⁺ = 231.0.

Step 2: Preparation of Compound 37

Compound 37b (620 mg) and compound 3a (350 mg) were dissolved in DMF (18 mL), cesium carbonate (820 mg) was added, and the mixture was reacted at 100 ° C for 1 h. After the reaction was completed, water (20 mL) was added dropwise, and the mixture was extracted with EA (30 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 32 mg of a pale yellow solid, that is, Compound 37.

LC-MS [M + H] ⁺ = 487.2.

Example 38: Compound 38 (8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -2,3 -Dihydro-1H, 5H-spiro [pyrrolo [1,2-a] [1,4] diazepine-4,5 '-[1,3] dioxane] -1-one)

Step 1: Preparation of Compound 38b

Dibromoneopentyl glycol (38a, 2.500g) was added to a formaldehyde solution (3.5mL), con.HCl (2mL) was added, and the reaction was heated under reflux for 12hrs. The temperature was lowered, water (25mL) was added, and extraction was performed with DCM (25mL * 2). The combined organic phases with saturated NaHCO ₃ (20mL * 2) washed, dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure to give an oil 2.544g, i.e., compound 38b.

LC-MS [M + H] ⁺ = 272.9.

Step 2: Preparation of Compound 38

Compound 38b (66 mg) and compound 3a (100 mg) were dissolved in DMF (5 mL), cesium carbonate (235 mg) was added, and the mixture was reacted at 100 ° C for 1 h. After the reaction was completed, water (20 mL) was added dropwise, extracted with EA (30 mL), washed with saturated brine (10 mL * 4), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 83 mg of a white solid, namely compound 38 .

LC-MS [M + H] ⁺ = 529.2.

Example 39: Compound 39 (8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4,4 -Preparation of bis (methoxymethyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazalide-1-one)

Step 1: Preparation of Compound 39a

Compound M6 (2.322 g), triethylamine (2.151 g) and DMAP (173 mg) were dissolved in DCM (35 mL), TBDPSCl (2.789 g) was added dropwise at 0 ° C, and the reaction was stirred at room temperature for 12 hrs. The reaction solution was diluted with 35 mL of DCM, 40 mL of water was added, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 2.950 g of a colorless oil, namely compound 39a.

LC-MS [M + H] ⁺ = 565.1.

Step 2: Preparation of Compound 39b

Under nitrogen protection, compound 39a (2.950 g) was dissolved in DMF (60 mL), compound M7 (1.575 g) and cesium carbonate (5.083 g) were added, and the mixture was heated at 90 ° C. for 1 h to react. The reaction was detected by LC-MS. The mixture was cooled and poured into ice water. The mixture was extracted with EtOAc (100 mL * 2). The organic phases were combined, washed with saturated brine (30 mL * 4), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue Purification by column chromatography (PE: EtOAc = 1: 1) gave 1.767 g of compound 39b.

LC-MS [M + H] ⁺ = 705.2.

Step 3: Preparation of Compound 39c

Compound 39b (1.567 g) was dissolved in dioxane (75 mL), 1N HCl (30 mL) was added, and the reaction was performed at RT for 2.5 hrs. TLC showed that the reaction was complete. Add water (50 mL) and EA (50 mL), adjust the pH to 7-8 with NaHCO ₃ , separate the organic phase, wash with water (50 mL * 2), dry over anhydrous Na ₂ SO ₄ , concentrate under reduced pressure, and purify the residue by column chromatography. This gave 1.100 g of compound 39c.

LC-MS [M + H] ⁺ = 665.2.

Step 4: Preparation of the compound 39d

Under nitrogen protection, compound 39c (300 mg) was dissolved in anhydrous THF (10 mL), the temperature was lowered to 0 ° C, and NaH (54 mg) was added in portions. The reaction was stirred for 30 minutes, and CH ₃ I (192 mg) was added dropwise. Reaction for 2hrs.

Treatment: Water (20 mL) was added dropwise under ice bath conditions, followed by extraction with EA (20 mL * 2), washing with water (10 mL), drying with anhydrous Na ₂ SO ₄ , concentration under reduced pressure, and purification of the residue by column chromatography to obtain 130 mg of compound 39d.

LC-MS [M + H] ⁺ = 693.2.

Step 5: Preparation of Compound 39e

Compound 6a (80 mg) and compound 39d (130 mg) were dissolved in dioxane (5 mL), sodium carbonate (60 mg) was dissolved in 0.5 mL of water and added to the reaction solution, and Pd (dppf) Cl ₂ (8 mg) was added under nitrogen protection. ), The reaction solution was heated to 80 ° C. and stirred for 12 hrs. The reaction solution was filtered through celite, and the filter cake was washed once with EtOAc (10 mL). After the mother liquor was directly concentrated under reduced pressure, the residue was purified by column chromatography to obtain 60 mg of a solid, which is compound 39e.

LC-MS [M + H] ⁺ = 783.3.

Step 6: Preparation of Compound 39

Compound 39e (60 mg) was dissolved in dioxane (2 mL), 6N HCl (1 mL) was added, and the reaction was performed for 12 hrs at RT. TLC showed that the reaction was complete. Add water (10 mL) and EA (10 mL), adjust the pH to 7-8 with NaHCO ₃ , separate the organic phase, wash with water (5 mL), dry over anhydrous Na ₂ SO ₄ , concentrate under reduced pressure, and purify the residue by column chromatography to obtain white 14.6 mg of solid, compound 39.

LC-MS [M + H] ⁺ = 545.2.

Example 40: Compound 40 ((R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5- Preparation of fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one)

Step 1: Preparation of Compound 36j

Add (R) -7-bromo-3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one (36h, 12.0g) Dissolved in DMF (23mL), added cesium carbonate (37.7g) and methyl 2- (bromomethyl) -4-fluorobenzoate (36i, 37.7g). After 16 hours of reaction at room temperature, the reaction was monitored by LC-MS. It was quenched by adding water (200 mL), diluted with ethyl acetate (2 * 200 mL), the organic phases were separated and combined, and washed with a 5% lithium chloride aqueous solution (3 * 200 mL). The organic phases were separated, dried over anhydrous sodium sulfate, filtered, and concentrated. 20.0g of crude. The crude product was pulped with petroleum ether to methyl tert-butyl ether (4: 1) in volume ratio to obtain 14.7 g of pure solid. The mother liquor was concentrated and passed through a column (petroleum ether: ethyl acetate = 3: 1) to obtain 4.2 g of pure product. The product was 18.9 g, which was compound 36j.

LC-MS [M + H] ⁺ = 425.0.

Step 2: Preparation of Compound 40d

Compound (R) -2-((7-bromo-3- (methoxymethyl) -1-oxo-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H ) -Methyl) methyl) -4-fluorobenzoic acid methyl ester (40c, 14.7g) was dissolved in THF (220mL), cooled to -50 ° C under nitrogen protection, and lithium tetrahydroaluminum (1.3g) was added slowly in portions. , Control the temperature between -30 ℃ and -40 ℃. After one and a half hours, the reaction was detected to be complete by TLC. Water (1.3 mL), 15% aqueous sodium hydroxide solution (1.3 mL), water (3.9 mL), anhydrous sodium sulfate (70 g) were sequentially added to the reaction solution. It was allowed to react at room temperature for 10 minutes, filtered, and the filtrate was concentrated to obtain 13.7 g of product, which is compound 40d.

LC-MS [M + H] ⁺ = 397.1.

Step 3: Preparation of Compound 40e

(R) -7-Bromo-2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -one (40d, 13.7g) is dissolved in 1,4-dioxane, and pinacol biboronate (22.0g) and potassium acetate (5.4g) are added in sequence at room temperature. , Tris (dibenzylideneacetone) dipalladium (1.5g), XPhos (3.3g), degassed three times with nitrogen, and placed in an oil bath at 70 ° C for 18hrs. After the reaction was completed, it was cooled to room temperature. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (100mL * 3), and the filtrate was washed with water (100mL * 3). The organic phase was separated, dried, concentrated, and passed through a column (first with pure The dichloromethane was washed away, and then petroleum ether to ethyl acetate (2: 1 to 1: 2) was used to obtain 16.5 g of the product, which is compound 40e.

LC-MS [M + H] ⁺ = 445.2.

Step 4: Preparation of compound 40g

((R) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -7- (4,4,5,5-tetramethyl-1 , 3,2-dioxoborolan-2-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one (40e, 15.5g) To dimethyl ether and water (300mL: 60mL), 2-bromo-5-chloro-4-iodopyridine (40f, 11.1g), sodium bicarbonate (8.8g), and Pd (dppf) Cl ₂ were sequentially added at room temperature. DCM (1.5g). After degassing with nitrogen for three times, it was placed in an oil bath at 60 ° C for 18hrs. LC-MS showed that about 20% of the raw materials were unreacted. Pd (dppf) Cl ₂ DCM (0.75g) was added to continue the reaction for 3hrs. After the reaction was completed, it was cooled to room temperature. The reaction solution was filtered through celite, the filter cake was washed with ethyl acetate (100 mL * 2), and the filtrate was washed with water (100 mL * 3). The organic phase was separated, dried, concentrated, and passed through a column (dichloromethane (Methanol: 25: 1). After obtaining the crude product, it was slurried with methyl tert-butyl ether (50 mL), filtered to obtain 6.0 g of a solid product, and the mother liquor was spin-dried to obtain 5.0 g of a crude product, that is, 40 g of a compound.

LC-MS [M + H] ⁺ = 508.0.

Step 5: Preparation of Compound 40

(R) -7- (2-Bromo-5-chloropyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl)- 3,4-Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one (40 g, 4.3 g) was dissolved in toluene (70 mL), and 1-methyl-5-amino was added sequentially at room temperature. Pyrazole (40h, 1.0g), cesium carbonate (8.3g), BINAP (1.6g), and tris (dibenzylideneacetone) dipalladium (0.8g). After degassing for three times with nitrogen, it was placed in an oil bath at 70 ° C for reaction 18hrs. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered through celite, the filter cake was washed with ethyl acetate (50 mL * 2), the filtrate was concentrated, and passed through a column (dichloromethane: methanol = 25: 1) to obtain 4.0 g of a crude product. Purified by Pre-TLC (dichloromethane: isopropanol = 10: 1) to obtain 2.28 g, which is compound 40.

LC-MS [M + H] ⁺ = 525.2.

Example 41: Compound 41 ((R) -2- (5-chloro-2- (isopropylamino) pyridin-4-yl) -7- (5-fluoro-2- (hydroxymethyl) benzyl) -6- (methoxymethyl) -6,7-dihydroimidazo [1,2-a] pyrazine-8- (5H) -one)

The compound 41 was synthesized following the procedure for synthesizing similar compounds in the compound of the example.

Example 42: Compound 42 ((R) -7- (5-chloro-3-fluoro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2 -(5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H)- Ketone)

Step 1: Preparation of Compound 42c

The raw material 1-methyl-5-aminopyrazole (42b, 566 mg) was dissolved in DMF, cooled to 0 ° C, sodium hydrogen (348 mg) was added, and after stirring for 30 minutes, 5-chloro-2,3-difluoro 4-Iodopyridine (42a, 1.600 g) was reacted at room temperature for 30 minutes. The reaction solution was quenched with water (1 mL), diluted with ethyl acetate (50 mL), washed with 5% lithium chloride aqueous solution (20 mL * 3), the organic phase was separated, dried, concentrated, and passed through a column (petroleum ether: ethyl acetate = 1: 1) 940 mg of product is obtained, which is compound 42c.

LC-MS [M + H] ⁺ = 352.9.

Step 2: Preparation of Compound 42

5-Chloro-3-fluoro-4-iodo-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine (42c, 352mg), (R) -2- (5- Fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -7- (4,4,5,5-tetramethyl-1,3,2-dioxolane- 2-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one (40e, 444 mg), sodium carbonate (318 mg), and (PPh ₃ ) ₂ PdCl ₂ (35 mg ) Were mixed in 1,4-dioxane and water (V: V = 8mL: 2mL), replaced with nitrogen three times, and left to react at 70 ° C for 3 hours. After the reaction was completed, ethyl acetate was diluted (20 mL), washed with water (10 mL * 3), and the organic phase was separated, dried, concentrated, and passed through a column (petroleum ether: ethyl acetate = 1: 2) to obtain 113.5 mg of the product, which is compound 42.

LC-MS [M + H] ⁺ = 543.2.

Example 43: Compound 43 ((3R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5- Fluoro-2- (1-hydroxyethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one) Preparation

Step 1: Preparation of Compound 43a

In a 50 mL three-necked flask, compound 40 (200 mg), DCM, 5 mL, and PCC (164 mg) were added. The nitrogen was replaced and protected. The RT reaction was performed for 2 hrs. The LC-MS detection reaction was completely post-treated, filtered through silica gel, and the filtrate was desolvated. , Which is compound 43a.

LC-MS [M + H] ⁺ = 523.2.

Step 2: Preparation of Compound 43

Into a 50mL three-necked flask, 43a (65mg) and 4mL of THF were added. The nitrogen was replaced and protected. The temperature was lowered to 0 ° C, and 3N methylmagnesium bromide (0.2mL) was added dropwise. The reaction was continued at a low temperature for 1h, and slowly heated to 25 The reaction was carried out at ℃ for 2hrs. The reaction was completely post-processed by LC-MS detection, 10 mL of saturated NH ₄ Cl solution was added dropwise, and EA 50 mL was added. The layers were stirred, washed with 10 mL of saturated NaCl solution, dried with sodium sulfate, and the solvent was removed. 7.9 mg product, which is compound 43.

LC-MS [M + H] ⁺ = 540.0.

Example 44: Compound 44 ((R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5- Fluoro-2- (2-hydroxypropyl-2-yl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H ) -Keto) Preparation

Compound 44a was synthesized by referring to the synthetic steps of similar compounds in the examples.

In a 50 mL three-necked flask, add compound 44a (100 mg) and 4 mL of THF, replace with nitrogen and protect, cool down to 0 ° C, add 3N methylmagnesium bromide (0.2 mL) dropwise, drop in for about 1 hour, continue the low temperature reaction for 1 hour, and slowly heat to The reaction was carried out at 45 ° C for 2hrs. The reaction was completely post-processed by LC-MS detection, 10 mL of saturated NH ₄ Cl solution was added dropwise, and EA 50 mL was added. The product is 36.1 mg, which is compound 44.

LC-MS [M + H] ⁺ = 554.0.

Example 45: Compound 45 ((R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5- Preparation of fluoro-2- (fluoromethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one)

Compound 40 (60 mg) was dissolved in dichloromethane, and the system was lowered to -78 ° C with dry ice. 45a (109 mg) was added to the reaction system at -78 ° C, and after stirring for 30 minutes, the temperature was raised to room temperature and stirred overnight. The reaction was stopped, and the reaction was quenched by adding water (50 mL), and extracted with dichloromethane (50 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and separated by column chromatography to obtain 12.6 mg of a pale yellow solid, which was compound 45.

LC-MS [M + H] ⁺ = 528.0.

Example 46: Compound 46 ((R) -7- (5-chloro-2-((4-fluoro-1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl)- 2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -Keto) Preparation

Preparation of compound 46c

Compound 40h (1000 mg) was dissolved in dichloromethane, and the system was lowered to 0 ° C with ice water. Compound 46b (3649 mg) was added to the reaction system at 0 ° C, and after stirring for 30 minutes, the mixture was warmed to room temperature and stirred for 2 hours. Stop the reaction, remove the solvent under reduced pressure, wash with saturated brine (200 mL), extract with ethyl acetate (150 mL * 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and separate by column chromatography to obtain 302 mg of a pale yellow liquid. That is compound 46c.

LC-MS [M + H] ⁺ = 116.1.

Compound 46 was synthesized by following the procedures for synthesizing similar compounds in the examples.

Example 47: Compound 47 ((R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (3- Preparation of hydroxyphenyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one)

Compounds 47b, 47c, 47d, and 47e were synthesized according to the above synthetic route with reference to the synthetic steps of similar compounds in the compound of the example.

Preparation of compound 47

Compound 47e (300 mg) was dissolved in anhydrous dichloromethane (10 mL), and after pre-cooling at -20 ° C, titanium tetrachloride (976 mg, 0.56 mL) was added dropwise, and the reaction was carried out for 30 min. Saturated sodium bicarbonate (10 mL) was added, water (10 mL) and dichloromethane (10 mL) were extracted three times. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by crude column chromatography to obtain 49.1 mg of a white solid, that is Compound 47.

LC-MS [M + H] ⁺ = 493.2.

Example 48: Compound 48 ((R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (2- Preparation of hydroxyphenyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one)

Compound 48 was synthesized according to the above synthetic route with reference to the synthetic steps of similar compounds in the compounds of the examples.

Example 49: Compound 49 ((R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((2 -Hydroxypyridin-3-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one)

Compound 49e was synthesized according to the above synthetic route with reference to the synthetic steps of similar compounds in the compound of the example.

Preparation of compound 49

Compound 49e (238 mg) was dissolved in 1,4-dioxane (2.4 mL), concentrated hydrochloric acid (1.3 mL), and water (1.3 mL), and the mixture was reacted at reflux for 4 hours. After the reaction was completed, water (15 mL) and dichloromethane (15 mL) were added for extraction three times. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 99.7 mg of a white solid, namely compound 49.

LC-MS [M + H] ⁺ = 494.2.

Example 50: Compound 50 ((R) -7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -3- (methoxymethyl) -2- (2-(( Preparation of methylsulfonyl) methyl) benzyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one)

Step 1: Preparation of Compound 50b

The raw material 1,2-bis (bromomethyl) benzene (2.000 g) was dissolved in DMF, sodium methanesulfonate (0.800 g) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with 5% lithium chloride aqueous solution (3 * 20 mL), and the organic phase was separated, dried, concentrated, and passed through a column (petroleum ether: ethyl acetate = 4: 1) to obtain the product. 0.600 g, which is compound 50b.

LC-MS [M + H] ⁺ = 263.0.

Compounds 50c and 50 were synthesized according to the above synthetic route with reference to the synthetic steps of similar compounds in the compounds of the examples.

Example 51: Compound 51 (8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (2- (1-hydroxycyclobutyl) benzyl) -4,4- Preparation of bis (hydroxymethyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazalide-1-one)

Step 1: Preparation of compound 51b

In a 100 mL three-necked flask, compound 51a (2.500 g) and 40 mL of THF were added. The nitrogen was replaced and protected. The temperature was lowered to -70 ° C. 2N isopropyl magnesium chloride (5.5 mL) was added dropwise. The reaction was continued at a low temperature for 1 h. Add a solution of cyclobutanone (1.100g) in 20mL THF, drip in about 30min, and continue the low temperature reaction for 1h. The reaction was completely post-processed by LC-MS detection, 20mL of saturated NH ₄ Cl solution was added dropwise, and 100mL of EA was added. The layers were stirred and separated, washed with 20 mL of a saturated NaCl solution, dried over sodium sulfate, and desolvated.

LC-MS [M + H] ⁺ = 174.1.

Step 2: Preparation of Compound 51c

In a 250mL flask, add LAH (491mg) and THF 100mL, replace with nitrogen and protect, cool to -20 ° C, dropwise add a solution of compound 51b (1120mg) dissolved in 30mL of THF, dropwise in about 30min, and keep the reaction at about -20 ° C for 2hrs. The reaction is complete and post-treatment: 20 mL of saturated NaCl solution is added dropwise to extract, 100 mL of EA is added, dried over sodium sulfate, filtered, and the filtrate is desolvated under reduced pressure to obtain 1.200 g of the product, which is compound 51c, which is directly used as the next step.

LC-MS [M + H] ⁺ = 178.1.

Step 3: Preparation of Compound 51e

In a 250mL three-necked flask, add compound 51d (1.890g), compound 51c (1.200g), HATU (3.090g), DIPEA (2.620g), and 100mL DMF, replace with nitrogen and protect, and react overnight at RT. The reaction is complete. EA was added in 100 mL, water was added in 20 mL, and the layers were stirred and separated. The organic phase was washed with 20 mL of a saturated NaCl solution, dried over sodium sulfate, desolvated, and passed through a column (EA: PE = 1: 1) to obtain 127 mg of a solid product, namely compound 51e.

LC-MS [M + H] ⁺ = 439.2.

Step 4: Preparation of Compound 51

A 25 mL three-necked flask was charged with compound 51e (127 mg), compound 51f (113 mg), Cs ₂ CO ₃ (282 mg), and 5 mL of DMF. Nitrogen replacement and protection, heating to 90 ° C for 2 hours, reaction completed, post-treatment: cooling, desolvating, adding EA 30mL, water 10mL, stirring and layering, washing the organic phase with 10mL brine, adding 2N hydrochloric acid 5mL, stirring for 30min After desolvation, 30 mL of EA was added, and 10 mL of saturated NaHCO ₃ solution was added. The layers were stirred, washed with brine, dried with sodium sulfate, desolvated, and passed through a column (EA: PE = 1: 1) to obtain 47.2 mg of product 51, that is, compound 51.

LC-MS [M + H] ⁺ = 539.2.

Example 52: Compound 52 (8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2-methoxybenzyl) -4,4-bis ( (Hydroxymethyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one)

Step 1: Preparation of Compound 52b

Dissolve 5-fluoro-2-methoxybenzonitrile (52a, 1.000 g) in tetrahydrofuran, slowly add aluminum tetrahydride (1.000 g) at room temperature, and stir at room temperature for 3 hours. Slowly add water (1 mL), 15% aqueous sodium hydroxide solution (1 mL), water (3 mL) to the reaction solution in order, and add anhydrous sodium sulfate and stir for 15 minutes. Filter and concentrate the mother liquor to obtain 0.900 g of crude product, which is compound 52b. , Directly used in the next reaction.

LC-MS [M + H] ⁺ = 156.1.

Compounds 52c, 52d, and 52 were synthesized according to the above synthetic route with reference to the synthetic steps of similar compounds in the compound of the example.

Example 53: Compound 53 (8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (2-((difluoromethoxy) methyl) -5-fluorobenzyl ) -4,4-bis (hydroxymethyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazalide-1-one) Preparation

Step 1: Preparation of Compound 53a

Compound 33 (278.5 mg) and KHF ₂ (156.2 mg) were dissolved in DCM (1 mL) and water (1 mL). TMSCF ₂ Br (203.1 mg) was added to the reaction solution, and the reaction was stirred at room temperature for 16 hours. The reaction solution was diluted with DCM (5 mL), washed with water (2 mL) twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 330 mg of a white solid, namely compound 53a, which was directly used in the next reaction without further purification.

LC-MS [M + H] ⁺ = 607.2.

Compound 53 was synthesized according to the above synthetic route with reference to the synthetic steps of similar compounds in the compounds of the examples.

Example 54: Compound 54 ((R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5- Fluoro-2- (hydroxymethyl) benzyl) -3-((methoxymethoxy) methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -Keto) Preparation

Step 1: Preparation of Compound 54a

Compound 36j (220 mg) and DIPEA (274 mg) were dissolved in anhydrous DCM (4 mL), and MOMCl (128 mg) was added to the reaction solution under ice-water bath cooling, and then the reaction was stirred at room temperature for 16 hours. The reaction solution was added with DCM (10 mL), 10 mL of water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 80 mg of a colorless oily compound, namely compound 54a.

LC-MS [M + H] ⁺ = 455.1.

Compound 54 was synthesized by following the synthetic procedures of similar compounds in the example compounds.

Example 55: Compound 55 ((R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (2- Preparation of (1-hydroxycyclopropyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one)

Step 1: Preparation of Compound 55b

To a solution of titanium tetraisopropoxide (2.120 g) in THF (20 mL) at room temperature, methyl magnesium bromide (3.73 mL, 3.0 mol / L) was added. After stirring for 10 min, it was cooled to 0 ° C, and compound 55a ( 1.000 g), and ethyl magnesium bromide (12.7 mL, 1.0 mol / L) was added dropwise thereto. Transfer to room temperature for 1h. To the reaction solution was added a 10% sulfuric acid (7 mL) solution, EtOAc (30 mL), 30 mL of water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by crude column chromatography to obtain 630 mg of Color oily liquid, namely compound 55b.

LC-MS [M + H] ⁺ = 165.1.

Step 2: Preparation of Compound 55c

Compound 55b (500 mg) was dissolved in anhydrous DCM (10 mL), carbon tetrabromide (1.520 g) was added, and precooled at 0 ° C. Triphenylphosphine (1.200 g) was dissolved in anhydrous DCM (10 mL) and It was added dropwise to the pre-cooled reaction solution, and the addition was completed in 30 minutes. Reaction for 1h. Water (20 mL) was added to the reaction solution, and the layers were separated. The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and separated and purified by crude column chromatography (hexane / ethyl acetate = 10/1) to obtain 510 mg of a colorless oily liquid. , Which is compound 55c.

LC-MS [M + H] ⁺ = 227.0.

Compounds 55d, 55e, and 55 were synthesized according to the above synthetic route with reference to the synthetic steps of similar compounds in the compound of the example.

Example 56: Compound 56 ((R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5- Fluoro-2-((methoxymethoxy) methyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 ( 2H) -Ketone) Preparation

Precooled at 0 ° C. Compound 40 (50 mg), diisopropylethylamine (49.1 mg) were dissolved in anhydrous dichloromethane (2 mL), and chloromethyl methyl ether (22.9 mg) was added thereto. Then transfer to room temperature and overnight. After the reaction was completed, water (10 mL) was added, and dichloromethane (10 mL) was added for extraction three times. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 5.5 mg of a white solid, namely compound 56.

LC-MS [M + H] ⁺ = 569.2.

Example 57: Compound 57 ((R) -7- (5-chloro-2-((1- (difluoromethyl) -1H-pyrazol-5-yl) amino) pyridin-4-yl) -2 -(5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H)- Ketone)

Compound 57a (3000 mg), compound 57b (8300 mg) and sodium bicarbonate (6000 mg) were dissolved in DMF (120 mL) under a nitrogen atmosphere, and the mixture was heated to 90 ° C and stirred overnight. Stop heating. After the system was cooled to room temperature, saturated brine (200 mL) was added to the system, followed by extraction with ethyl acetate (150 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and separated by column chromatography to obtain 445 mg of a yellow liquid. Is compound 57c.

LC-MS [M + H] ⁺ = 134.1.

Compound 57 was synthesized by following the synthetic procedures of similar compounds in the example compounds.

Example 58: Compound 58 ((R) -7- (5-chloro-2-((1-ethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5- Preparation of fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one)

(R) -7- (2-Bromo-5-chloropyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl)- 3,4-Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one (40 g, 50 mg) was dissolved in toluene (70 mL), and 1-ethyl-5-aminopyridine was added sequentially at room temperature. The azole (33 mg), cesium carbonate (98 mg), BINAP (18 mg) and tris (dibenzylideneacetone) dipalladium (9 mg) were degassed three times with nitrogen and placed in an oil bath at 70 ° C for 6 hrs. After the reaction was completed, it was cooled to room temperature. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (5 mL * 2), the filtrate was concentrated, and the product was purified by climbing the plate to obtain 29 mg, which is compound 58.

LC-MS [M + H] ⁺ = 539.2.

The commercially available raw materials were used to synthesize the similar compounds in the example compounds to synthesize the example compounds 59-147 in Table 2.

Table 2

Example 149: Compound 148 ((R) -2-((7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3 -(Methoxymethyl) -1-oxo 3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) methyl) -4-fluorobenzaldehyde)

Step 1: Preparation of Compound 149a

Compound 36j (2000 mg), PBD (1422 mg), Xphos (429 mg), Pd ₂ dba ₃ (183 mg), and KOAc (736 mg) were added to 1,4 dioxane (20 mL); under a nitrogen atmosphere, the temperature was maintained at 80 ° C. Reaction for 6 hours. The reaction solution was added with EtOAc (350 mL), water (250 mL), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 1770 mg of a pale yellow foamy solid, namely 149a .

LC-MS [M + H] ⁺ = 473.23.

Step 2: Preparation of Compound 149b

Compound 149a (47.2 g) was dissolved in DMF (400 mL), and compound M8 (33.5 g), PdCl ₂ (PPh ₃ ) ₂ (3510 mg), K ₃ PO ₄ (46.7 g), and water (50 mL) were added; nitrogen Protect and keep at 80 ° C for 3 hours. The reaction mixture was cooled to room temperature and filtered; the filtrate was collected and added to water (2000 mL), and off-white solid particles precipitated; then filtered, the solid particles were collected and dissolved with dichloromethane (400 mL); dried over anhydrous sodium sulfate, filtered, It was concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain 27.5 g of a pale yellow foamy solid, that is, 149b.

LC-MS [M + H] ⁺ = 553.17.

Step 3: Preparation of Compound 149c

Compound 149b (13.82 g) was dissolved in THF (100 mL) and MeOH (100 mL), LiOH.H ₂ O (4.20 g) was added, and water (100 mL) was added; the reaction was held at 40 ° C. for 3 hours. The reaction mixture was concentrated to remove THF and MeOH, and water (200 mL) was added. The pH was adjusted to 5 with 1 mol / L dilute hydrochloric acid, and a white solid precipitated out; dissolved with dichloromethane (400 mL), and separated; dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave 12.13 g of a residue as a slightly yellow foamy solid, which was 149c.

Step 4: Preparation of the compound 149d

Compound 149c (4280 mg), methoxymethylamine hydrochloride (927 mg), HOBt (1284 mg), EDCI.HCl (3020 mg) were dissolved in DMF (50 mL), and then DIEA (4084 mg) was added. Under nitrogen, Incubate at 40 to 45 ° C for 5 hours. The reaction solution was added with 300 mL of EtOAc and 200 mL of water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 2820 mg of a white solid powder, which was 149 d.

LC-MS [M + H] ⁺ = 582.27.

Step 5: Preparation of the compound 149

Compound 149d (2690 mg) was dissolved in anhydrous THF (35 mL), and LiAlH ₄ (263 mg) was added to the reaction solution in portions under cooling in an ice water bath, and then the reaction was stirred at room temperature for 1 hour. The reaction solution was added with water (3 drops), 15% NaOH aqueous solution (3 drops), water (9 drops), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 1685 mg of light pink foam. The solid is 149.

LC-MS [M + H] ⁺ = 523.21.

¹ H NMR (600 MHz, DMSO-d6) of compound 61 = 8.05-7.92 (m, 1H), 7.66-7.57 (m, 1H), 7.43 (dd, J = 6.4, 7.9 Hz, 1H), 7.21-7.13 ( m, 1H), 7.11-6.96 (m, 2H), 6.62 (s, 1H), 6.40 (d, J = 7.3Hz, 1H), 5.35-5.23 (m, 1H), 5.19 (t, J = 5.1Hz , 1H), 4.76-4.64 (m, 2H), 4.61-4.43 (m, 3H), 4.23-4.12 (m, 1H), 3.99-3.90 (m, 1H), 3.37-3.25 (m, 3H), 1.14 (d, J = 6.2Hz, 6H).

¹ H NMR (600 MHz, CHLOROFORM-d) of compound 86 = 8.55 (d, J = 4.4 Hz, 1 H), 8.17 (s, 1 H), 7.71 (d, J = 7.7 Hz, 1 H), 7.52 (d, J = 1.8Hz, 1H), 7.44 (s, 1H), 7.33 (d, J = 1.7Hz, 1H), 7.30 (dd, J = 5.0, 7.7Hz, 1H), 7.24 (d, J = 1.7Hz, 1H ), 7.09 (s, 1H), 6.62 (s, 1H), 6.40 (br.s., 1H), 6.19-6.14 (m, 1H), 5.56 (d, J = 1.8Hz, 1H), 5.42 (d , J = 15.6 Hz, 1H), 4.90-4.77 (m, 1H), 4.30-4.13 (m, 1H), 3.79 (s, 1H), 3.73-3.66 (m, 1H), 3.49-3.42 (m, 1H), 3.41-3.35 (m, 1H), 3.34-3.29 (m, 1H), 1.62-1.55 (m, 1H), 1.51-1.46 (m, 1H), 1.31-1.23 (m, 1H), 0.92- 0.82 (m, 1H), 0.09-0.06 (m, 7H).

1H NMR (500 MHz, DMSO-d6) of compound 124 = 8.84 (s, 1H), 8.15 (s, 1H), 7.68 (s, 1H), 7.45-7.27 (m, 2H), 7.15-7.03 (m, 1H) ), 6.94 (s, 1H), 6.28-6.18 (m, 2H), 4.91 (d, J = 16.5Hz, 1H), 4.53-4.33 (m, 2H), 4.17 (d, J = 16.5Hz, 1H) , 4.06-3.90 (m, 1H), 3.67 (s, 3H), 3.44-3.37 (m, 1H), 3.33-3.29 (m, 3H), 3.27-3.17 (m, 3H).

¹ H NMR (600 MHz, DMSO-d6) of compound 135 = 8.92 (s, 1H), 8.18 (s, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.51-7.41 (m, 2H), 7.13 -7.07 (m, 3H), 7.00 (s, 1H), 6.44 (t, J = 4.0Hz, 1H), 6.37 (d, J = 1.8Hz, 1H), 6.34 (t, J = 4.0Hz, 1H) , 6.25 (t, J = 4.1Hz, 1H), 5.76 (s, 1H), 5.23-5.16 (m, 2H), 4.58-4.48 (m, 3H), 4.40-4.30 (m, 3H), 3.92-3.86 (m, 1H), 3.48-3.39 (m, 1H), 3.29 (dd, J = 8.2, 9.8Hz, 1H), 3.22 (s, 3H), 1.99 (s, 1H), 1.20-1.14 (m, 1H ).

¹ H NMR (600 MHz, DMSO-d6) of compound 138 = 8.83 (s, 1H), 8.15 (s, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H ), 7.06 (d, J = 1.8Hz, 1H), 6.97-6.92 (m, 1H), 6.89-6.85 (m, 1H), 6.84-6.81 (m, 2H), 6.24 (d, J = 1.8Hz, 1H), 6.04 (d, J = 1.7 Hz, 2H), 5.76 (s, 1H), 5.13 (d, J = 15.4 Hz, 1H), 4.36 (d, J = 12.5 Hz, 1H), 4.27-4.21 ( m, 2H), 3.97-3.88 (m, 1H), 3.67 (s, 2H), 3.42 (dd, J = 5.6, 10.0 Hz, 1H), 3.24 (s, 2H).

Comparative Example

Comparative Example 1: Comparative compound 1 (7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (2-hydroxy-1- (3- (trifluoromethyl) benzene (Ethyl) ethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one)

Step 1: Preparation of Compound D1a

Compounds M1 (200 mg), M5 (271 mg), HOBt (115 mg), EDCI (170 mg) and DIEA (0.35 mL) were dissolved in DMF (5 mL), and the reaction was stirred at room temperature for 12 hrs. The reaction solution was added with EtOAc (10 mL), 10 mL of water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 180 mg of a colorless oil, D1a.

LC-MS [M + H] ⁺ = 581.2.

Step 2: Preparation of Compound D1b

Compound D1a (180 mg) and 1,2-dibromoethane (651 mg) were dissolved in DCE (5 mL), and an aqueous solution of NaOH (3.5 mL, 1 M) and TBAI (13 mg) were added. The reaction was stirred at 80 ° C. for 12 hrs. The reaction solution was added with DCM (10 mL), 10 mL of water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 120 mg of a colorless oil, namely D1b.

LC-MS [M + H] ⁺ = 607.2.

Step 3: Preparation of Comparative Compound D1

Compound D1b (120 mg) was dissolved in DCM (5 mL), TFA (0.5 mL) was added, and the reaction was stirred at room temperature for 2 hrs. The reaction solution was added with DCM (10 mL), 10 mL of water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 5.3 mg of pale yellow oil, D1.

LC-MS [M + H] ⁺ = 493.2.

Reference Example Compound and Synthesis Method of Similar Compound of Comparative Compound 1 Comparative Compound 2 (7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-fluorobenzyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one, D2).

Pharmacological experiment

Example A: Kinase test

The compound was diluted to the desired concentration with DMSO, 100 μL was transferred to a 96-well plate, and gradient dilution was performed. Take 10 μL of compound from each well and mix it with 90 μL of kinase buffer, and then transfer 5 μL from each well to a 384-well plate. Add kinase and FAM-labeled peptide and ATP to 1x kinase alkaline buffer to obtain 2.5x enzyme solution and 2.5x peptide solution. Add 10 μL of 2.5x enzyme solution to the 384-well assay plate. After incubating for 10 minutes at room temperature, add 10 μL of 2.5x peptide solution to the 384-well plate. After reacting at 28 ° C for a specific time, add 25 μL of stop buffer to stop the reaction. . After reading the collected data on Caliper, convert the data to percent inhibition:

Percent inhibition = (maximum value-conversion value) / (maximum value-minimum value) * 100.

"Maximum" is the DMSO control; "Minimum" is the low control group.

Graphpad Prism software was used for curve fitting and IC ₅₀ values were obtained.

All Example compounds have excellent inhibition on ERK1 and ERK2, most of the compound to inhibit ERK1 and ERK2 IC ₅₀ <20nM, embodiments of the compound in Example IC ₅₀ data for inhibition of ERK1 and ERK2 in Table 3.

table 3

Note: "/" means not tested

Example B: Cell Proliferation Test (COLO205)

COLO205 cells were plated in a 96-well plate at 2000 cells at 135 μL / well. After overnight incubation, a compound solution with a gradient concentration was prepared, and 15 μL of each concentration of the test compound DMSO solution was added to each well cell. 0 nM (all final DMSO concentrations were 0.5%). Incubate at 37 ° C, 5% CO ₂ for 120 h. Add 50 μL of Cell-titer Glo working solution to each well, mix by shaking and incubate at room temperature for 10 minutes, read the luminescence luminescence value with a multi-functional microplate reader, and convert the luminescence value reading to the percent inhibition:

Percent inhibition = (maximum-reading) / (maximum-minimum) * 100.

The "maximum" is the DMSO control; the "minimum" is the acellular control group.

Graphpad Prism software was used for curve fitting and IC ₅₀ values were obtained.

All the compounds of the examples have good inhibition on COLO205 cells. Most of the compounds inhibit the IC ₅₀ of COLO205 cells <200 nM. The IC ₅₀ data of the compounds of Examples and Comparative Examples D1 and D2 and AZD0364 on COLO205 cells are shown in Table 4. .

Table 4

Example C: Cell proliferation test (HCT 116)

HCT 116 cells were plated in a 96-well plate at 1200 cells, 160 μL / well. After overnight incubation, a compound solution with a gradient concentration was prepared, and 40 μL of each concentration of the test compound DMSO solution was added to each well cell. The final compound concentration was 30000, 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6, 0 nM (all final DMSO concentrations were 0.5%). Incubate at 37 ° C, 5% CO ₂ for 120 hrs. Add 50 μL of Cell-titer Glo working solution to each well, mix by shaking and incubate at room temperature for 10 minutes, read the luminescence luminescence value with a multi-functional microplate reader, and convert the luminescence value reading to the percent inhibition:

Percent inhibition = (maximum-reading) / (maximum-minimum) * 100.

The "maximum" is the DMSO control; the "minimum" is the acellular control group.

Graphpad Prism software was used for curve fitting and IC ₅₀ values were obtained.

All the compounds of the examples have good inhibition on HCT 116 cells. Most of the compounds inhibit the IC _{50 of} HCT 116 cells by less _than 100 nM. See Table 5 for the IC ₅₀ data of the compounds of the examples and the inhibition of HCT 116 cells by AZD0364.

table 5

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

Claims (41)

A compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof,

among them, X or Y is arbitrarily selected from N or CH; Z or U is arbitrarily selected from N or CR ₁₀ , and R _{10 is} arbitrarily selected from H or unsubstituted or optionally substituted C _1-8 alkyl; V is arbitrarily selected from O or S; R _{1 is} arbitrarily selected from H, halogen, hydroxyl, CN, C _1-8 alkyl,-(C = O) OC _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, C _5-10 heteroaryl or C _3-10 heterocyclyl, said C _1-8 alkyl,-(C = O) OC _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, C _5-10 Heteroaryl or C _3-10 heterocyclyl is unsubstituted or optionally substituted with halogen, hydroxyl, C _1-8 alkyl, C _1-8 alkoxy or -C _1-8 alkoxy-C _1-8 alkane Oxo substitution R _{2 is} arbitrarily selected from halogen, hydroxy, CN, C _1-8 alkyl,-(C = O) OC _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _{2- 8} alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, C _5-10 heteroaryl or C _3-10 heterocyclyl, said C _1-8 alkyl,-(C = O) OC _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, C _5-10 heteroaryl Or C _3-10 heterocyclyl is unsubstituted or optionally substituted by halogen, hydroxy, C _1-8 alkyl, C _1-8 alkoxy or -C _1-8 alkoxy-C _1-8 alkoxy Replace; or R ₁ and R ₂ together with the C atom to which they are attached form a C _3-10 cycloalkyl or C _3-10 heterocyclyl, said C _3-10 cycloalkyl or C _3-10 heterocyclyl being unsubstituted or Optionally substituted with halogen, hydroxy, oxo, C _1-8 alkyl or C _1-8 alkyl-C _5-10 aryl; R _{3 is} arbitrarily selected from H, halogen, hydroxyl, CN, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, or C _2-8 alkynyl, said C _1-8 alkynyl Group, C _1-8 alkoxy, C _2-8 alkenyl or C _2-8 alkynyl is unsubstituted or optionally substituted with halogen, hydroxyl or C _1-8 alkyl; R _{4 is} optionally selected from C _3-10 heterocyclyl, C _6-10 aryl, or C _5-10 heteroaryl, said C _3-10 heterocyclyl, C _6-10 aryl, or C _5-10 Heteroaryl is unsubstituted or optionally substituted by halogen, hydroxy, cyano, C _1-8 alkyl, C _1-8 alkoxy, C _3-10 cycloalkyl, -C _3-10 heteroaryl, C _{1 -8} alkylcarbonyl or-(C = O) NHR ₁₁ substitution, said C _1-8 alkyl, C _1-8 alkoxy, C _3-10 cycloalkyl, -C _3-10 heteroaryl or -(C = O) NHR ₁₁ is unsubstituted or arbitrarily substituted by hydroxyl, halogen, C _1-8 alkyl, C _3-10 heterocyclyl, C _1-8 alkoxy, -O (C = O) (CH ₂ ) _p R ₁₁ , -sulfonyl-C _1-8 alkyl, halogen-substituted C _1-8 alkoxy, or -C _1-8 alkoxy-C _1-8 alkoxy; R _{11 is} optionally Selected from amino or C _1-8 alkyl; R _{5 is} arbitrarily selected from H, halogen, hydroxyl, CN, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl , C _6-10 aryl, C _5-10 heteroaryl or C _3-10 heterocyclyl, said C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _{2 -8} alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, C _5-10 heteroaryl or C _3-10 heterocyclyl is unsubstituted or optionally substituted with halogen, hydroxyl or C _1-8 alkane Radical substitution R _{6 is} optionally selected from halogen, hydroxy, amino, CN, C _1-8 alkyl or NR ₇ R ₈ ; R ₇ or R _{8 is} arbitrarily selected from H, halogen, hydroxyl, CN, C _1-8 alkyl,-(C = O) C _1-8 alkyl, C _3-10 cycloalkyl, C _6-10 aromatic Group,-(C = O) _p -C _5-10 heteroaryl or C _3-10 heterocyclyl, the C _1-8 alkyl group,-(C = O) C _1-8 alkyl group, C _{3 -10} cycloalkyl, C _6-10 aryl,-(C = O) _p -C _5-10 heteroaryl or C _3-10 heterocyclyl is unsubstituted or optionally substituted by halogen, hydroxyl, amino, CN, C _1-8 alkyl, C _1-8 alkoxy, halogen-substituted C _1-8 alkyl, C _3-10 heterocyclyl, -C _3-10 heteroaryl-C _1-8 alkyl, C _3-10 heteroaryl or-(C = O) C _1-8 alkyl substituted; R _{9 is} arbitrarily selected from H, halogen, hydroxy, C _1-8 alkyl or C _1-8 alkoxy, said C _1-8 alkyl or C _1-8 alkoxy being unsubstituted or optionally halogen , Hydroxy or C _1-8 alkyl substitution; The above heterocyclic or heteroaryl ring group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O or S; m, n or p is arbitrarily selected from 0, 1 or 2. The compound according to claim 1, wherein X and Y are both N. The compound according to claim 1 or 2, wherein Z is N and U is CH or Z is CH and U is N. The compound according to claim 1 or 2, wherein Z and U are both CH. The compound according to any one of claims 1-4, wherein V is O. The compound according to any one of claims 1-5, wherein R ₁ is H, and R ₂ is hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, -C _1-6 alkyl Hydroxy, -C _1-6 alkyl-C _1-6 alkoxy, -C _1-6 alkyl-C _1-6 alkoxy-C _1-6 alkoxy, or-(C = O) OC _{1 -6} alkyl. The compound according to any one of claims 1-6, wherein R ₁ is H, and R ₂ is hydroxy, methyl, methoxy, hydroxy-substituted methoxy, hydroxy-substituted methyl, methoxy Methyl substituted,-(C = O) OCH ₃ or -CH ₂ OCH ₂ OCH ₃ . The compound according to any one of claims 1-7, wherein R ₁ is H and R ₂ is

The compound according to claim 1, wherein R ₁ or R _{2 is} arbitrarily selected from the group consisting of halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, and -C _{1- 6} alkylhydroxy, -C _1-6 alkyl-C _1-6 alkoxy or halogen-substituted C _1-6 alkyl. The compound according to any one of claims 1 to 5 or 9, wherein R ₁ or R _{2 is} arbitrarily selected from F, Cl, hydroxyl, methyl, methoxy, hydroxyl-substituted methyl, and methoxy Methyl substituted or halogen substituted methyl. The compound according to claim 1, wherein R ₁ and R ₂ together with the C atom to which they are attached form a C _3-8 cycloalkyl or C _3-8 heterocyclyl, wherein C _3-8 heterocyclyl optionally contains 1 or 2 heteroatoms independently selected from N, O or S, the C _3-8 cycloalkyl or C _3-8 heterocyclyl is unsubstituted or arbitrarily Substituted by halogen, hydroxy, oxo, C _1-6 alkyl or C _1-6 alkyl-phenyl. The compound according to claim 1, wherein R ₁ and R ₂ together with the C atom to which they are attached form the following substituents:

The compound according to any one of claims 1 to 12, wherein R _{3 is} arbitrarily selected from H, hydroxyl, halogen, or -C _1-6 alkyl-hydroxy. The compound according to claim 1, wherein R _{3 is} selected from H. The compound according to claim 1, wherein R _{4 is} selected from C _3-10 heterocyclyl, C _6-10 aryl or C _5-10 heteroaryl, and C _{3- 10} heterocyclyl, C _6-10 aryl or C _5-10 heteroaryl is unsubstituted or arbitrarily substituted by halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkane , -C _3-10 heteroaryl-C _1-6 alkyl, C _1-8 alkyl carbonyl or-(C = O) NHR ₁₁ substitution, said C _1-6 alkyl, C _1-6 alkane Oxy, C _3-10 cycloalkyl, -C _3-10 heteroaryl-C _1-6 alkyl, or-(C = O) NHR ₁₁ is unsubstituted or optionally hydroxy, halogen, C _3-6 hetero Cyclic group, C _1-8 alkoxy, -O (C = O) (CH ₂ ) _p R ₁₁ , -sulfonyl-C _1-6 alkyl, halogen-substituted C _1-6 alkoxy, or -C _1-6 alkoxy-C _1-6 alkoxy substitution; R _{11 is} optionally selected from amino or C _1-3 alkyl, p is selected from 0 or 1; said C _5-10 heteroaryl or C _{3 The -10} heterocyclyl optionally contains 1 or 2 heteroatoms selected from N, O or S. The compound according to any one of claims 1-15, wherein R _{4 is} selected from phenyl, pyridyl,

The phenyl, pyridyl or

Unsubstituted or arbitrarily substituted with F, Cl, methyl, hydroxy, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted isopropyl, monofluoromethyl, trifluoromethyl, -CH ₂ O (C = O) CH ₂ NH ₂ , -CH ₂ O (C = O) CH ₃ , -methylene-sulfonyl-methyl,-(C = O) NHCH ₃ , hydroxy-substituted cyclopropyl, hydroxy-substituted Cyclobutyl, methoxy, methoxy-substituted methyl, difluoromethoxy-substituted methyl, formyl, -CH ₂ OCH ₂ OCH ₃ , acetyl, CN or

To replace. The compound according to any one of claims 1 to 16, wherein R _{5 is} arbitrarily selected from H, halogen, hydroxyl, amino, CN, or C _1-6 alkyl, and the C _1-6 alkyl is not Substituted or optionally substituted with halogen. The compound according to any one of claims 1 to 17, wherein R _{5 is} arbitrarily selected from H, F, Cl, hydroxyl, amino, CN or C _1-3 alkyl, and the C _1-3 alkyl The group is unsubstituted or optionally substituted with halogen. The compound according to any one of claims 1 to 18, wherein R ₅ is H, F, Cl, -CF ₃ , CN, or methyl. The compound according to any one of claims 1 to 19, wherein R _{6 is} arbitrarily selected from halogen, hydroxy, C _1-6 alkyl, or NR ₇ R ₈ . The compound according to any one of claims 1-20, wherein R ₆ is NR ₇ R ₈ , and R ₇ or R _{8 is} arbitrarily selected from H, halogen, hydroxyl, C _1-6 alkyl,-( C = O) -C _1-6 alkyl, C _3-7 cycloalkyl, phenyl,-(C = O) C _5-6 heteroaryl or C _3-10 heterocyclyl, said C _{1- 6} alkyl, C _3-7 cycloalkyl, phenyl,-(C = O) C _5-6 heteroaryl or C _3-10 heterocyclyl is unsubstituted or optionally substituted with halogen, hydroxyl, amino, C _{1 -6} alkyl, C _1-6 alkoxy, halogen-substituted C _1-6 alkyl, C _3-10 heterocyclyl, -C _3-10 heteroaryl-C _1-6 alkyl, C _{3- 10} heteroaryl, or-(C = O) C _1-6 alkyl substituted. The compound according to any one of claims 1 to 21, wherein R ₆ is NR ₇ R ₈ , and R ₇ or R _{8 is} arbitrarily selected from H, methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, hydroxy-substituted isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxy-substituted cyclohexyl, acetyl,

The compound according to any one of claims 1 to 22, wherein R ₆ is NR ₇ R ₈ , R ₇ is H, and R ₈ is isopropyl or

The compound according to any one of claims 1 to ₂₃ , wherein R ₉ is H or F. The compound according to any one of claims 1 to 24, wherein m or n is arbitrarily selected from the following group: (i) m and n are both 1; (ii) m is 0 and n is 1; (iii) m is 1, n is 0. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 1) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -4,4-difluoro-2,3,4,5- Tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 2) 7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -3- (hydroxymethyl) -3,4-dihydropyrrole And [1,2-a] pyrazine-1 (2H) -one; 3) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(2- (hydroxymethyl) benzyl) -2 ′, 3′-dihydro-1 'H, 5'H-spiro [oxetane-3,4'-pyrrolo [1,2-a] [1,4] diazepine] -1'-one; 4) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(3-chlorobenzyl) -2 ′, 3′-dihydro-1′H, 5 'H-spiro [azetidine-3,4'-pyrrolo [1,2-a] [1,4] diazalide] -1'-one; 5) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -4,4-bis (hydroxymethyl) -2,3, 4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 6) 2 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -5 ′-(2- (hydroxymethyl) benzyl) -5 ′, 6, -dihydro-4 'H, 8'H-spiro [oxetane-3,7'-pyrazolo [1,5-a] [1,4] diazepine] -4'-one; 7) 2- (5-chloro-2- (isopropylamino) pyridin-4-yl) -7- (chloromethyl) -7- (hydroxymethyl) -5- (2- (hydroxymethyl) Benzyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1,4] diazepine-4-one; 8) 2- (5-chloro-2- (isopropylamino) pyridin-4-yl) -8- (3-chlorobenzyl) -7,8-dihydro-5H, 9H-spiro [imidazo [ 1,2-a] [1,4] diazepine-6,3'-oxetane] -9-one; 9) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(3-chlorobenzyl) -1- (2,4-dimethoxybenzyl) -2 ′, 3′-dihydro-1′H, 5′H-spiro [azetidin-3,4′-pyrrolo [1,2-a] [1,4] diazalide] -1′-one; 10) (S) -8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(1- (3-chlorophenyl) -2-hydroxyethyl)- 2 ′, 3′-dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine]- 1′-one; 11) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -4,4-dimethyl-2,3,4,5 -Tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 12) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(3-chlorobenzyl) -2 ′, 3′-dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazalide] -1′-one; 13) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -1-oxo-2,3,4,5-tetrahydro- 1H-pyrrolo [1,2-a] [1,4] diazepine-4-carboxylic acid methyl ester; 14) (S) -7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -3-methyl-3,4-dihydro Pyrrolo [1,2-a] pyrazine-1 (2H) -one; 15) 2 ′-(4-chloro-2- (hydroxymethyl) benzyl) -8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′, 3′- Dihydro-1′H, 5′H-spiro [cyclopropane-1,4′-pyrrolo [1,2-a] [1,4] diazalide] -1′-one; 16) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-chlorobenzyl) -4-hydroxy-2,3,4,5-tetrahydro- 1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 17) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(pyridin-2-ylmethyl) -2 ′, 3′-dihydro-1′H , 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one; 18) 2 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -5 ′-(3-chlorobenzyl) -5 ′, 6′-dihydro-4′H, 8′H-spiro [oxetane-3,7′-pyrazolo [1,5-a] [1,4] diazepine] -4′-one; 19) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(5-fluoro-2- (hydroxymethyl) benzyl) -2 ′, 3′- Dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one; 20) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(2- (morpholinemethyl) benzyl) -2 ′, 3′-dihydro- 1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one; 21) 2- (5-chloro-2- (isopropylamino) pyridin-4-yl) -8- (2- (hydroxymethyl) benzyl) -7,8-dihydro-5H, 9H-spiro [Imidazo [1,2-a] [1,4] diaza-6,3′-oxetane] -9-one; 22) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(3-fluoro-2- (hydroxymethyl) benzyl) -2 ′, 3′- Dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one; 23) (S) -8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(1- (3-fluorophenyl) -2-hydroxyethyl)- 2 ′, 3′-dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine]- 1′-one; 24) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(4-fluoro-2- (hydroxymethyl) benzyl) -2 ′, 3′- Dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one; 25) (S) -2 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -5 ′-(1- (3-fluorophenyl) -2-hydroxyethyl)- 5 ′, 6′-dihydro-4′H, 8′H-spiro [oxetane-3,7′-pyrazolo [1,5-a] [1,4] diazalide] -4′-one; 26) (S) -8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(1- (3,4-difluorophenyl) -2-hydroxyethyl Group) -2 ′, 3′-dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diaza Zhuo] -1′-one; 27) (S) -2 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -5 ′-(1- (3,4-difluorophenyl) -2-hydroxyethyl Group) -5 ′, 6′-dihydro-4′H, 8′H-spiro [oxetane-3,7′-pyrazolo [1,5-a] [1,4] diaze Hetero] -4′-one; 28) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(2- (hydroxymethyl) benzyl) -2 ′, 3′-dihydro-1 ′ H, 5′H-spiro [azetidin-3,4′-pyrrolo [1,2-a] [1,4] diazepine] -1′-one; 29) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(4,5-difluoro-2- (hydroxymethyl) benzyl) -2 ′, 3′-dihydro-1′H, 5′H-spiro [oxetane-3,4′-pyrrolo [1,2-a] [1,4] diazepine-1′-one ; 30) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (2- (hydroxymethyl) benzyl) -2 ′, 2′-dimethyl-2, 3-dihydro-1H, 5H-spiro [pyrrolo [1,2-a] [1,4] diazepine-4,5 '-[1,3] dioxane] -1-one; 31) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -4,4-bis (hydroxymethyl) -2- (2- (hydroxymethyl) benzyl) -2 , 3,4,5-tetrahydro-1H pyrrolo [1,2-a] [1,4] diazalide-1-one; 32) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4-hydroxy-2,3, 4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 33) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -2 ′, 2′-dimethyl -2,3-dihydro-1H, 5H-spiro [pyrrolo [1,2-a] [1,4] diazepine-4,5 '-[1,3] dioxane] -1 -ketone; 34) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4,4-bis (hydroxymethyl ) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazazol-1-one; 35) 8 ′-(5-chloro-2- (isopropylamino) pyridin-4-yl) -2 ′-(2- (hydroxymethyl) benzyl) -1-methyl-2 ′, 3 ′ -Dihydro-1′H, 5′H-spiro [azetidin-3,4′-pyrrolo [1,2-a] [1,4] diazalide] -1′-one; 36) (R) -7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (formaldehyde (Oxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 37) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4- (hydroxymethyl)- 2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 38) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -2,3-dihydro-1H , 5H-spiro [pyrrolo [1,2-a] [1,4] diazepine-4,5 '-[1,3] dioxane] -1-one; 39) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4,4-bis (methoxy Methyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 40) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 41) (R) -2- (5-chloro-2- (isopropylamino) pyridin-4-yl) -7- (5-fluoro-2- (hydroxymethyl) benzyl) -6- (formaldehyde (Oxymethyl) -6,7-dihydroimidazo [1,2-a] pyrazine-8- (5H) -one; 42) (R) -7- (5-chloro-3-fluoro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 43) (3R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( 1-hydroxyethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 44) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( 2-hydroxypropyl-2-yl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 45) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( Fluoromethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 46) (R) -7- (5-chloro-2-((4-fluoro-1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5- Fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 47) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (3-hydroxyphenyl)- 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 48) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (2-hydroxyphenyl)- 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 49) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((2-hydroxypyridine-3 -Yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 50) (R) -7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -3- (methoxymethyl) -2- (2-((methylsulfonyl) (Methyl) benzyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 51) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (2- (1-hydroxycyclobutyl) benzyl) -4,4-bis (hydroxymethyl ) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazalide-1-one; 52) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2-methoxybenzyl) -4,4-bis (hydroxymethyl)- 2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 53) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (2-((difluoromethoxy) methyl) -5-fluorobenzyl) -4, 4-bis (hydroxymethyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 54) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( Hydroxymethyl) benzyl) -3-((methoxymethoxy) methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 55) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (2- (1-hydroxy ring Propyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 56) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( (Methoxymethoxy) methyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 57) (R) -7- (5-chloro-2-((1- (difluoromethyl) -1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 58) (R) -7- (5-chloro-2-((1-ethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 59) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4-methoxy-2, 3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 60) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -4- (hydroxymethyl)- 4- (methoxymethyl) -2,3,4,5-4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 61) 7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -1-oxo-1,2 , 3,4-tetrahydropyrrolo [1,2-a] pyrazine-3-carboxylic acid ethyl ester; 62) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (trifluoromethyl) benzyl) -4,4-bis (hydroxyl (Methyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 63) 8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (4-chloro-5-fluoro-2- (hydroxymethyl) benzyl) -4,4- Bis (hydroxymethyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1-one; 64) (R) -7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (hydroxyl (Methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 65) (R) -7- (5-chloro-2- (oxetan-3-ylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl ) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 66) (3R) -7- (5-chloro-2-((tetrahydrofuran-3-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl)- 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 67) (R) -7- (5-chloro-2-((tetrahydro-2H-pyran-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Group) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 68) (R) -7- (5-chloro-2-((3,3-difluorocyclobutyl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 69) (R) -7- (2- (tert-butylamino) -5-chloropyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (formaldehyde (Oxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 70) (R) -7- (5-chloro-2-((2-hydroxy-2-methylpropyl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl ) Benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 71) (R) -7- (5-chloro-2-((1-methylpiperidin-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl ) Benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 72) (R) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -7- (2-((tetrahydro-2H-pyran-4) -Yl) amino) pyridin-4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 73) (R) -7- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2- (3-fluorobenzyl) -3- (methoxymethyl) -3, 4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 74) (R) -7- (5-chloro-2-((4,4-difluorocyclohexyl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl ) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 75) (R) -7- (5-chloro-2-((4-methyltetrahydro-2H-pyran-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2 -(Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 76) (R) -7- (5-chloro-2- (cyclobutylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (formaldehyde (Oxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 77) (R) -7- (5-chloro-2-((((1R, 4R) -4-hydroxycyclohexyl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl Group) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 78) (R) -7- (5-chloro-2- (cyclohexylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxy Methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 79) 7- (5-chloro-2-((1-isopropylpiperidin-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl ) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 80) (R) -7- (5-chloro-2- (cyclopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (formaldehyde (Oxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 81) (R) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -7- (5-fluoro-2- (isopropylamino) pyridin-4-yl) -3- (formaldehyde (Oxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 82) (R) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -7- (2- (isopropylamino) -5- (trifluoromethyl) pyridin-4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 83) (R) -7- (5-chloro-2- (cyclopentylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (formaldehyde (Oxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 84) (3R) -7- (5-chloro-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl) amino) pyridin-4-yl) -2- (5- Fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 85) (3R) -7- (5-chloro-2-((5,5-dimethyltetrahydrofuran-3-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxyl (Methyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 86) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((2- (hydroxymethyl ) Pyridin-3-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 87) (R) -7- (5-chloro-2-((5-methylisoxazol-3-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Group) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 88) (R) -7- (5-chloro-3-methyl-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5- Fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 89) (R) -7- (5-chloro-2-((3,5-dimethylisoxazol-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 90) (R) -7- (5-chloro-2- (oxazol-2-ylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3 -(Methoxymethyl) -3,4 dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 91) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl)- 2-((1-methyl-1H-indazol-6-yl) methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 92) (R) -7- (5-chloro-2-((3-methylisoxazol-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Group) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 93) (R) -7- (5-chloro-2- (thiazol-2-ylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (Methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 94) (R) -7- (5-chloro-2-((5-methylthiazol-2-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 95) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-3-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 96) (R) -7- (5-chloro-2-((3-methylisoxazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Group) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 97) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 98) (R) -7- (5-chloro-2-((1,3-dimethyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -2- (5-fluoro- 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 99) (R) -7- (5-chloro-2-((4,5-dimethylthiazol-2-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxyl (Methyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 100) (R) -7- (5-chloro-2-((4-methylthiazol-2-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) Benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 101) (R) -7- (5-chloro-2- (isoxazol-3-ylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl)- 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 102) (R) -7- (5-chloro-2- (isoxazol-5-ylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl)- 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 103) (R) -7- (5-chloro-2-((6,7-dihydro-4H-pyrano [4,3-d] thiazol-2-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H )-ketone; 104) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl)- 2-((1-methyl-1H-indazol-7-yl) methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 105) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl)- 2-((1-methyl-1H-indazol-4-yl) methyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 106) (R) -2-((1H-indazol-4-yl) methyl) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) Pyridin-4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 107) (R) -2-((1H-benzo [d] imidazol-4-yl) methyl) -7- (5-chloro-2-((1-methyl-1H-pyrazole-5- Yl) amino) pyridin-4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 108) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (4,5-difluoro- 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 109) (R) -7- (5-chloro-2-((1,3-dimethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro- 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 110) (R) -7- (5-chloro-2-((1,4-dimethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro- 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 111) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( Trifluoromethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 112) (R) -2- (Benzo [d] oxazole-4-methylene) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino ) Pyridin-4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 113) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (3-fluoro-2- ( (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 114) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (4-fluoro-2- ( (Hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 115) (R) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -7- (2-((1-methyl-1H-pyrazole -5-yl) amino) -5- (trifluoromethyl) pyridin-4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 116) (R) -4- (2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -1-oxo-1,2,3,4- Tetrahydropyrrolo [1,2-a] pyrazine-7-yl) -6-((1-methyl-1H-pyrazol-5-yl) amino) nicotinonitrile; 117) (R) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -7- (5-methyl-2-((1-methyl -1H-pyrazol-5-yl) amino) pyridin-4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 118) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (2- (hydroxymethyl) -5- (trifluoromethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 119) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((3- (hydroxymethyl ) -6-methylpyridin-2-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one ; 120) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((4- (hydroxymethyl ) -6-methylpyridin-3-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one ; 121) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((2- (hydroxymethyl ) -6- (trifluoromethyl) pyridin-3-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 ( 2H) -one; 122) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((3- (hydroxymethyl ) Pyridin-2-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 123) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((4- (hydroxymethyl ) Pyridin-3-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 124) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((6-hydroxypyridine-2 -Yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 125) (R) -7- (5-chloro-3-fluoro-2- (isopropylamino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl)- 3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 126) 2-((8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -4,4-bis (hydroxymethyl) -1-oxo-4,5-dihydro- 1H-pyrrolo [1,2-a] [1,4] diazepine-2 (3H) -yl) methyl) -4-fluorobenzyl glycine ester; 127) 2-((8- (5-chloro-2- (isopropylamino) pyridin-4-yl) -4,4-bis (hydroxymethyl) -1-oxo-4,5-dihydro -1H-pyrrolo [1,2-a] [1,4] diazepine-2 (3H) -yl) methyl) -4-fluorobenzyl acetate; 128) 7- (2-((1-acetylpiperidin-4-yl) amino) -5-chloropyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 129) (R) -2-((7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxy (Methyl) -1-oxo-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) methyl) -4-fluoro-N-methylbenzamide; 130) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (2-((difluoromethyl (Oxy) methyl) -5-fluorobenzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 131) (R) -7- (5-chloro-2-((4-methoxycyclohexyl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl ) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 132) (R) -N- (5-chloro-4- (2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -1-oxo-1 , 2,3,4-tetrahydropyrrolo [1,2-a] pyrazin-7-yl) pyridin-2-yl) acetamide; 133) (R) -7- (5-chloro-2-((((1-methyl-1H-pyrazol-5-yl) methyl) amino) pyridin-4-yl) -2- (5-fluoro 2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 134) (R) -7- (5-chloro-2-((1- (2,2-difluoroethyl) -1H-pyrazol-3-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one ; 135) (R) -7- (5-chloro-2-((1- (2,2-difluoroethyl) -1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one ; 136) (R) -7- (5-chloro-2-((oxazole-4-methylene) amino) pyridin-4-yl) -2- (5-fluoro-2- (hydroxymethyl) benzyl Yl) -3- (methoxymethyl) -3,4-dihydropyrrole [1,2-a] pyrazine-1 (2H) -one; 137) (R) -N- (5-chloro-4- (2- (5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -1-oxo-1 , 2,3,4-tetrahydropyrrolo [1,2-a] pyrazin-7-yl) pyridin-2-yl) -2-methylthiazole-4-carboxamide; 138) (R) -2- (Benzo [d] [1,3] dioxolane-4-methylene) -7- (5-chloro-2-((1-methyl-1H -Pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H)- ketone; 139) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl)- 2- (2- (1-methyl-1H-1,2,4-triazol-3-yl) benzyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 ( 2H) -one; 140) (R) -2- (2-acetyl-5-fluorobenzyl) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridine- 4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 141) (R) -2- (Benzo [d] [1,3] dioxol-5-ylmethyl) -7- (5-chloro-2-((1-methyl-1H -Pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H)- ketone; 142) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (3-methoxybenzyl ) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 143) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2- ( Methoxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 144) (R) -7- (5-chloro-2-((1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) amino) pyridin-4-yl) -2 -(5-fluoro-2- (hydroxymethyl) benzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H)- ketone; 145) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2- (5-fluoro-2-methyl (Oxybenzyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; 146) (R) -3-((7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxy (Methyl) -1-oxo-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) methyl) -4- (hydroxymethyl) benzonitrile; 147) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2-((2,3-dihydro Benzo [b] [1,4] dioxane-5-yl) methyl) -3- (methoxymethyl) -3,4-dihydropyrrolo [1,2-a] Pyrazine-1 (2H) -one; 148) (R) -7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxymethyl)- 2- (3,4,5-trifluoro-2- (hydroxymethyl) benzyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; or 149) (R) -2-((7- (5-chloro-2-((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (methoxy (Methyl) -1-oxo 3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) methyl) -4-fluorobenzaldehyde. A pharmaceutical composition, comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 26 and at least one pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 27, wherein the mass percentage of the compound and the pharmaceutically acceptable excipient is 0.0001: 1-10. Use of a compound according to any one of claims 1 to 26 or a pharmaceutical composition according to claim 27 or 28 in the preparation of a medicament. The use according to claim 29, wherein the medicament is used to treat, prevent, delay or prevent the occurrence or progression of cancer or cancer metastasis. The use according to claim 29, wherein the compound is used in the preparation of a medicament for treating a disease mediated by ERK. The use according to claim 31, wherein the disease is cancer. The application according to claim 30 or 32, wherein 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, hepatocellular carcinoma, head and neck cancer, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, Thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma. The use according to claim 29, wherein the medicament is used as an ERK inhibitor. The application according to claim 31 or 34, wherein the ERK comprises ERK1 and / or ERK2. A method for treating and / or preventing diseases mediated by ERK, characterized in that a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a medicament according to claim 27 or 28 is administered to a subject to be treated combination. The method according to claim 36, wherein the ERK comprises ERK1 and / or ERK2. The method according to claim 36 or 37, wherein the ERK-mediated disease is cancer. The method according to claim 38, wherein the cancer is selected from the group consisting of breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, and small cells Lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma. A method for treating cancer, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutical composition according to claim 27 or 28 to a subject, wherein the cancer is a breast Cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, Hepatocellular carcinoma, head and neck cancer, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, slippery Mesosarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma. The method according to claim 36 or 40, wherein the treatment subject is a human.