Myt1 kinase inhibitor, pharmaceutical composition thereof, and use thereof

Abstract

The present invention belongs to the pharmaceutical field. Specifically, provided are an Myt1 kinase inhibitor compound, a pharmaceutical composition thereof, and the use thereof. Specifically, provided is a compound of formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein each variable has the meaning described in the description. The compound and the pharmaceutical composition thereof, as an Myt1 kinase inhibitor, can be used in the preparation of a drug for preventing or treating Myt1-associated diseases, and can particularly be used in the preparation of a drug for preventing or treating cancers.

Description

Myt1 kinase inhibitors, pharmaceutical compositions thereof, and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, in particular, the present application relates to a tyrosine and threonine specific cdc2 inhibitory kinase (Myt1 kinase) inhibitor, a pharmaceutical composition thereof, and the use of the compound and the pharmaceutical composition thereof in the preparation of a medicament for preventing or treating Myt1 related diseases. BACKGROUND

[0002] Myt1 is a cell cycle regulatory kinase, mainly located in the endoplasmic reticulum and Golgi complex. It is part of the Wee kinase family, including Wee1a and Wee1b. It is involved in the negative regulation of CDK1-cyclin B complex, which promotes the progression of cells from G2 phase to mitotic phase (M phase) of the cell cycle. Entry into mitosis is initiated by the M phase-promoting factor (MPF), which is a complex containing cdc2-protein kinase and cyclin B. Proper regulation of MPF can ensure that mitosis only occurs after the initial stage of the cell cycle ends. Early activation of Cd2 will lead to complete failure of mitosis and cell death. Inhibition of Myt1 is expected to cause early activation of cdc2, and thus can kill rapidly proliferating cells. Myt1 is considered a potential important cancer target because it is essential in many cancer cells. Overexpression of Myt1 has been observed in various cancers, including hepatocellular carcinoma and clear cell renal cell carcinoma. Therefore, it is necessary to develop effective Myt1 inhibitors for the treatment of related diseases, such as cancer. Compound 182 (i.e. RP-6306) disclosed in WO2021195781 is a Myt1 inhibitor with good anti-cancer activity. However, it is still necessary to develop Myt1 inhibitors with better therapeutic effect to cope with the treatment of cancer. SUMMARY

[0003] The present application provides a compound, or a pharmaceutical composition thereof, which can act as a Myt1 kinase inhibitor. The present application further relates to the use of the compound or the pharmaceutical composition thereof for the preparation of a medicament for treating Myt1 related diseases and / or conditions by inhibiting the activity. The diseases or conditions include the diseases, conditions or states described in the present application.

[0004] In one aspect, the present application provides a compound represented by Formula (I), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by Formula (I),

[0005] wherein,

[0006] as

[0007] B is

[0008] Ring C is a phenyl ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocyclic ring, wherein said ring C is optionally substituted with 1, 2, or 3 R a ;

[0009] Each R a is independently D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;

[0010] R 1 is H, D, or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, OH, F, Cl, Br, and CN;

[0011] R 2 is H, D, F, Cl, Br, CN, OH, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;

[0012] R 3 H, D, F, CI, Br, CN, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R q1 ;

[0013] R 4 H, D, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 R q2 ; or,

[0014] R 3 , R 4Together with the ring atoms attached to them, they form 5-6 membered heterocycles, 7-membered heterocycles, 8-membered heterocycles, or 5-10 membered heteroaromatic rings, wherein the 5-6 membered, 7-membered, 8-membered, and 5-10 membered heteroaromatic rings are each independently and optionally bounded by 1, 2, 3, or 4 R atoms. q3 Replaced;

[0015] R 5 R 5a R 6 R 6a R 7 R 7a and R 8 Each of the following is independently H, D, F, Cl, Br, CN, OH, NH2, NH(C) 1-6 alkyl), N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the NH2, NH(C 1-6 alkyl), N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally bounded by 1, 2, 3 or 4 R groups. q4 Replaced;

[0016] R q1 R q2 R q3 and R q4 Each of these can be independently represented as D, F, Cl, Br, I, CN, OH, oxo, or NR. 15a R 15b -OR 16 -C(=O)NR 15a R 15b -S(=O)2NR 15a R 15b -S(=O)2R16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl, 3-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0017] Or, R on two adjacent ring atoms q3 Together with the two ring atoms attached to them, they form 5-6 membered heterocycles, 7 membered heterocycles, or 5-6 membered heteroaromatic rings, wherein each of the 5-6 membered heterocycles, 7 membered heterocycles, and 5-6 membered heteroaromatic rings is independently and optionally composed of 1, 2, 3, or 4 R atoms. q3a Replaced;

[0018] Each R q3a Independently, it is D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b -OR 16 -C(=O)NR 15a R 15b -S(=O)2NR 15a R 15b -S(=O)2R 16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl, 3-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0019] R 15a R 15b and R 16 Each is independently H, D, CN, OH, C 1-6 Alkyl, C1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl.

[0020] In some embodiments, the compounds described herein are compounds of Formula (II) or Formula (III), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of Formula (II) or Formula (III),

[0021] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 5a , R 6a , R 7a , R 8 and ring C each have the definitions as described herein. In some embodiments, having one of the following sub-structural formulae,

[0022] wherein R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 9a , R 13a , R 13b and R 13c are each independently H, D, F, Cl, Br, I, CN, OH, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-6 alkyl, C 1-6 haloalkyl, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

[0023] R 5a , R 6a and R 7a each have the definition as described in the application.

[0024] In some embodiments, R 1 is H, D or C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of D, OH, F, Cl, Br and CN;

[0025] R 2 is H, D, F, Cl, Br, CN, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

[0026] In some embodiments, R 3 is H, D, F, Cl, Br, CN, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each independently optionally substituted with 1, 2, 3, or 4 R q1 , wherein R q1 have the definitions as described herein.

[0027] R 4 is H, D, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each independently optionally substituted with 1, 2, 3, or 4 R q2 , wherein R q2 have the definitions as described herein.

[0028] In some embodiments, R 3H, D, F, CI, Br, CN, NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, NH(CH2)3CH3, NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, -OCF3, -OCH2F, -OCHF2, -OCCl3, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl, wherein,NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, NH(CH2)3CH3, NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, -CH2F, -CHF2, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, -OCH2F, -OCHF2, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, and thiuranyl, each independently optionally substituted with 1, 2, 3, or 4 R q1 R q1 having the definitions as described in the present application;

[0029] R 4H, D, CN, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CºCCH2CH3, -CH2CºCCH3, -CH2CH2CºCCH, -CºCCºCH, -CF3, -CH2F, -CHF2, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiophuranyl, wherein said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CºCCH2CH3, -CH2CºCCH3, -CH2CH2CºCCH, -CºCCºCH, -CH2F, -CHF2, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiophuranyl are optionally substituted with 1, 2, 3, or 4 R q2 substituents, wherein R q2 have the definitions as described in the present application.

[0030] In some embodiments, R 3 , R 4and the ring atom to which they are attached form a pyrrolidine, pyrazolidine, imidazolidine, morpholine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazole, diazepine, oxazepine, dihydroimidazole, dihydropyrrole, pyridine, or pyrimidine, wherein each of said pyrrolidine, pyrazolidine, imidazolidine, morpholine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazole, dihydroimidazole, dihydropyrrole, diazepine, oxazepine, pyridine, and pyrimidine is independently optionally substituted with 1, 2, 3, or 4 R q3 , wherein R q3 has the meaning as described herein.

[0031] In some embodiments, R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , and R 8 are each independently H, D, F, Cl, Br, CN, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein said NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R q4 , wherein R q4 has the meaning as described herein.

[0032] In some embodiments, R 5 , R 5a , R 6 , R 6a , R7 , R 7a and R 8each independently H, D, F, CI, Br, CN, OH, NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, NH(CH2)3CH3, NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, -OCF3, -OCH2F, -OCHF2, -OCCl3, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl, wherein,NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, NH(CH2)3CH3, NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, -CH2F, -CHF2, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, -OCH2F, -OCHF2, -OCCl3, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, and thiuranyl, each independently optionally substituted with 1, 2, 3, or 4 R q4 , wherein R q4 has the meaning as described herein.

[0033] In some embodiments, ring C is benzene, imidazole, pyrrole, pyrazole, dihydroimidazole, dihydropyrrole, dihydrooxazole, dihydrothiazole, pyridine, pyrimidine, or pyrazine, wherein said ring C is optionally substituted with 1, 2, or 3 R a ;

[0034] each R a is independently D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-4 alkyl, C 1-4 haloalkyl, C1-4 hydroxyalkyl, C 1-4 cyanoalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein R 15a , R 15b and R 16 each have the definition as described in the application; or, each R a is independently D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CCl3, -CH2CF3, -(CH2)2CF3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CHCN, -(CH2)2CN, -(CH2)3CN, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl, wherein R 15a , R 15b and R 16 each have the definition as described in the application.

[0035] In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13R 14 R 9a R 13a R 13b R 13c each independently H, D, F, Cl, Br, I, CN, OH, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-4 1-6 alkyl, C 1-4 2-6 haloalkyl, C 1-4 2-6 hydroxyalkyl, C 1-4 2-6 cyanoalkyl, C 2-4 2-6 alkenyl, C 2-4 2-6 alkynyl, C 1-4 1-6 alkoxy, C 3-6 3-6 cycloalkyl, 3-6 heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein R 15a , R 15b , and R 16 each have the definition as described herein; or, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 9a , R 13a , R 13b , and R 13c each independently H, D, F, Cl, Br, I, CN, OH, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CCl3, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, -CHCN, -(CH2)2CN, -(CH2)3CN, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl, wherein R 15a 15b and R 16 each have the definition as described in the present application.

[0036] In some embodiments, R q1 , R q2 , R q3 , and R q4 each independently is D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein R 15a , R​15b and R 16 each have the definition as described in the present application; or, R q1 , R q2 , R q3 and R q4 are each independently D, F, CI, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CCl3, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl, wherein R 15a , R 15b and R 16 each have the definition as described in the present application.

[0037] In some embodiments, R q3Together with the two ring atoms attached to them, they form pyrrolidine, pyrazolidine, imidazoline, morpholine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazole, dihydroimidazol, dihydropyrrole, diazaphene, oxazaphene, pyrazole, imidazol, pyrrole, pyridine, or pyrimidine, wherein the pyrrolidine, pyrazolidine, imidazoline, morpholine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazole, dihydroimidazol, dihydropyrrole, diazaphene, oxazaphene, pyrazole, imidazol, pyrrole, pyridine, and pyrimidine are each independently and optionally separated by 1, 2, 3, or 4 R atoms. q3a Replaced;

[0038] Each R q3a Independently, it is D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b -OR 16 -C(=O)NR 15a R 15b -S(=O)2NR 15a R 15b -S(=O)2R 16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl, 3-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; or each R q3a Independently, it is D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b -OR 16 -C(=O)NR 15a R 15b -S(=O)2NR 15a R 15b -S(=O)2R 16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CC13, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CH2CºCCH3, -CH2CH2CºCCH3, -CºCCºCH, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl;

[0039] wherein R 15a , R 15b , and R 16 each have the definitions as described herein.

[0040] In some embodiments, R 15a , R 15b , and R 16 each independently is H, D, CN, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or, R 15a , R 15b , and R 16each independently H, D, CN, OH, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CCl3, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CºCCH2CH3, -CH2CºCCH3, -CH2CH2CºCCH2, -CºCCºCH, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl.

[0041] In some embodiments, the compound of the present application is a compound of Formula (II-1) or Formula (III-1), or a stereoisomer, a tautomer, a N-oxide, a solvate, a metabolite, or a pharmaceutically acceptable salt or prodrug of a compound of Formula (II-1) or Formula (III-1),

[0042] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 5a , R 6a , R 7a , R 8 and ring C each have the definitions as described in the present application.

[0043] In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application.

[0044] In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable adjuvant.

[0045] In some embodiments, the adjuvant of the present application includes, but is not limited to, a carrier, an excipient, a diluent, a vehicle, or a combination thereof. In some embodiments, the pharmaceutical composition can be in a liquid, solid, semi-solid, gel, or spray form.

[0046] In another aspect, the present application provides the use of the pharmaceutical composition of the present application for the preparation of a medicament for preventing, treating or alleviating a Myt1 -related disease.

[0047] In some embodiments, the Myt1 -related disease of the present application is a proliferative disease.

[0048] In some embodiments, the proliferative disease of the present application is cancer, psoriasis or rheumatoid arthritis.

[0049] In some embodiments, the Myt1 -related disease of the present application is uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, leukemia, liver cancer, bladder cancer, prostate cancer, cervical cancer or kidney cancer.

[0050] In another aspect, the present application also provides a method for preventing or treating a Myt1 -related disease, the method comprising administering to a patient a therapeutically effective amount of a compound of the present application or a pharmaceutical composition thereof.

[0051] In another aspect, the present application relates to a method for preparing, isolating and purifying a compound of formula (I), (II), (III), (II-1) or (III-1).

[0052] Unless otherwise indicated, all stereoisomers, tautomers, nitroso isomers, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of the present application are within the scope of the application.

[0053] In particular, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemical and toxicological, in relation to other components of the formulation and the mammal for treatment.

[0054] The salts of the compounds of the present application also include salts of intermediates used in making or purifying a compound of formula (I), (II), (III), (II-1) or (III-1), or a compound of formula (I), (II), (III), (II-1) or (III-1), or an isolated enantiomer of a compound of formula (I), (II), (III), (II-1) or (III-1), but not necessarily a pharmaceutically acceptable salt.

[0055] The foregoing outlines some aspects of the present application, but is not limited to such aspects. Additional aspects will be set forth in more detail in the description that follows.

[0056] Detailed description of the application

[0057] Definitions and general terms

[0058] Certain embodiments of the application are now described in detail by referring principally to and illustrating the described examples in the following written description and accompanying drawings. The application is intended to cover all alternatives, modifications and equivalents which can be included within the scope of the application as defined by the claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many methods and materials similar or equivalent to those described herein. The application is not intended to be limited to the methods and materials described herein. In the event that one or more of the incorporated references contradicts the prior description, including definitions of terms, then this application controls.

[0059] It should further be appreciated that certain of the application's features, while described in the context of separate embodiments, might also be provided in combination in a single embodiment. Conversely, various features of the application, while described in the context of a single embodiment, might also be provided separately or in any suitable subcombination. It is therefore contemplated to this extent that every single feature disclosed for a single embodiment is also expressly contemplated in any other embodiment, to the extent that such features are not mutually inconsistent.

[0060] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

[0061] The term "subject" as used herein refers to an animal. Typically the animal is a mammal. A subject, for example, also refers to a primate (e.g., human, male or female), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0062] The term "patient" as used herein refers to a human (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

[0063] The term "comprising" is used in the inclusive sense of "including" and not the exclusive sense (i.e., "consisting only of").

[0064] "Stereoisomers" refer to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like. Unless otherwise specified, all stereochemical isomers and mixtures of stereochemical isomers are intended to be within the scope of the application. In addition, unless otherwise specified, a formula depicted herein includes one or more isotopically enriched atoms.

[0065] The stereochemical definitions and rules generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0066] Any mixture of stereoisomers resulting can be separated into the individual isomers by conventional separation techniques, or any mixture of stereoisomers can be converted into an individual isomer, by conventional separation techniques.

[0067] The term "tautomer" or "tautomerism" refers to structural isomers that exist in equilibrium with one another through a low energy barrier. If tautomerism is possible (as in solution), a chemical equilibrium of the tautomers can be reached. For example, protontautomer (also known as prototropic tautomer) includes interconversion by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomer includes interconversion by reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the application are within the scope of the application.

[0068] As described herein, the compounds of the application can be independently optionally substituted with one or more substituents, such as the substituents of the general formulae above, or as in the specific examples, subgeneric classes, and generic classes of compounds embraced by the application. It will be appreciated that the terms "independently optionally substituted" or "optionally substituted" are used interchangeably with the term "substituted or unsubstituted." In general, the term "substituted" means that one or more hydrogens of the designated moiety are replaced by a non-hydrogen moiety. Unless otherwise indicated, an optionally substituted moiety can be substituted at each substitutable position of the moiety. When a structure is presented wherein more than one position of the structure can be substituted with one or more substituents selected from a particular group, the substituents can be the same or different at each occurrence.

[0069] Also, it is to be understood that the description and examples in this application use the description "each occurrence" and "independently" interchangeably, and that these terms are to be interpreted in their broadest context unless otherwise specified.

[0070] Throughout various portions of the specification, the substituents of the compounds disclosed herein are disclosed by group or range. In particular, it is intended that the application encompasses each and every independent subcombination of the members of those groups and ranges. For example, the term "C 1-6 alkyl" specifically refers to the individually disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0071] Throughout various portions of the specification, linking substituents are described. When the structure clearly requires a linking group, the Markush group recited for that group is to be construed as a linking group. For example, if the structure requires a linking group and the Markush group recited for that group recites "alkyl" or "aryl," then it is to be understood that the "alkyl" or "aryl" represents, respectively, an alkylene or arylene linking group.

[0072] The term "alkyl" denotes a straight or branched chain monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group can be optionally substituted with one or more substituents as described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, denoted as C 1-6 alkyl; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms, denoted as C 1-4 alkyl; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms, denoted as C 1-3Alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), i-propyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), i-butyl (i-Bu, -CH2CH(CH3)2), s-butyl (s-Bu, -CH(CH3)CH2CH3), t-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0073] The term "alkylene" denotes a saturated divalent hydrocarbyl radical resulting from the removal of two hydrogen atoms from a saturated straight chain or branched chain hydrocarbon. In some embodiments, the alkylene group contains 1-6 carbon atoms, denoted as C 1-6 alkylene; in other embodiments, the alkylene group contains 1-4 carbon atoms, denoted as C 1-4 alkylene; in other embodiments, the alkylene group contains 1-3 carbon atoms, denoted as C 1-3 alkylene; in other embodiments, the alkylene group contains 1-2 carbon atoms, denoted as C 1-2 Alkylene. Examples of alkylene groups include, but are not limited to: -CH2-, -CH2CH2-, -CH(CH3)CH2-, and the like.

[0074] The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon group containing from 2 to 12 carbon atoms, wherein there is at least one site of 2 unsaturation, i.e., one carbon-carbon sp2bond, wherein the alkenyl group can be optionally substituted with one or more substituents described herein, including "cis" and "trans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains from 2 to 6 carbon atoms, denoted as C 2-6 alkenyl; in yet another embodiment, the alkenyl group contains from 2 to 4 carbon atoms, denoted as C 2-4 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), 1-propenyl (i.e., propargyl, -CH=CH-CH3), and the like.

[0075] The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon group containing from 2 to 12 carbon atoms, wherein there is at least one site of 2-6 unsaturation, i.e., one carbon-carbon sp3bond, wherein the alkynyl group can be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains from 2 to 6 carbon atoms, denoted as C 2-4 alkynyl; in yet another embodiment, the alkynyl group contains from 2 to 4 carbon atoms, denoted as C 1-6 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), and the like.

[0076] The term "haloalkyl" denotes an alkyl group as described herein substituted by one or more halogen atoms. In some embodiments, the haloalkyl is C 1-6 haloalkyl, denoting C 1-4 alkyl group substituted by one or more halogen atoms; in other embodiments, the haloalkyl is C 1-4 haloalkyl, denoting C 1-3 alkyl group substituted by one or more halogen atoms; in other embodiments, the haloalkyl is C 1-3 haloalkyl, denoting C Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.

[0077] The term "hydroxyalkyl" denotes an alkyl group substituted by one or more hydroxy groups, wherein alkyl and hydroxy have the meaning as described herein. In some embodiments, the hydroxyalkyl group is C 1-6 hydroxyalkyl, denotes a C 1-6 alkyl group substituted by one or more hydroxy groups; in other embodiments, the hydroxyalkyl group is C 1-4 hydroxyalkyl, denotes a C 1-4 alkyl group substituted by one or more hydroxy groups; in other embodiments, the hydroxyalkyl group is C 1-3 hydroxyalkyl, denotes a C 1-3 alkyl group substituted by one or more hydroxy groups. Examples include, but are not limited to, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, and the like.

[0078] The term "cyanoalkyl" denotes an alkyl group substituted by one or more cyano groups, wherein alkyl and hydroxy have the meaning as described herein. In some embodiments, the cyanoalkyl group is C 1-6 cyanoalkyl, denotes a C 1-6 alkyl group substituted by one or more cyano groups; in other embodiments, the cyanoalkyl group is C 1-4 cyanoalkyl, denotes a C 1-4 alkyl group substituted by one or more cyano groups; in other embodiments, the cyanoalkyl group is C 1-3 cyanoalkyl, denotes a C 1-3 alkyl group substituted by one or more cyano groups. Examples include, but are not limited to, -CH2CN, -C(CH3)2CN, -(CH2)2CN, or -(CH2)3CN, and the like.

[0079] The term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein alkyl has the meaning as described herein. Unless otherwise specifically indicated, said alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, denotes a C 1-6 alkoxy; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms, denotes a C 1-4 alkoxy; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms, denotes a C 1-3Alkoxy. The alkoxy group can optionally be substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (-OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), and the like.

[0080] The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic carbon ring system of 3 to 12 carbon atoms, wherein a -CH2- group in the carbocyclic ring can optionally be replaced by -C(=O)- (or -(CO)-). In one embodiment, the cycloalkyl group comprises 3 to 10 ring carbon atoms, i.e. C 3-10 cycloalkyl; in another embodiment, the cycloalkyl group comprises 3 to 8 ring carbon atoms, i.e. C 3-8 cycloalkyl; in another embodiment, the cycloalkyl group comprises 3 to 6 ring carbon atoms, i.e. C 3-6 cycloalkyl; in another embodiment, the cycloalkyl group comprises 7 to 10 ring carbon atoms, i.e. C 3-7 cycloalkyl; in another embodiment, the cycloalkyl group comprises 3 to 5 ring carbon atoms, i.e. C 3-5 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-lH-indenyl, octahydrocyclopenta- dienyl, and the like. Examples of -CH2- groups in the carbocyclic ring that can be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, and the like.

[0081] The term "cycloalkenyl" denotes a monovalent monocyclic or bicyclic carbon ring system of 3 to 12 carbon atoms, wherein at least one unsaturation, i.e. one carbon-carbon sp 2A double-bonded carbocyclic -CH2- group can optionally be replaced by -C(=0)- (or -(CO)-). In one embodiment, the cycloalkenyl group contains 3 to 10 ring carbon atoms, i.e., C 3-10 cycloalkenyl; in another embodiment, the cycloalkenyl group contains 3 to 8 ring carbon atoms, i.e., C 3-8 cycloalkenyl; in another embodiment, the cycloalkenyl group contains 3 to 6 ring carbon atoms, i.e., C 3-6 cycloalkenyl; in another embodiment, the cycloalkenyl group contains 3 to 5 ring carbon atoms, i.e., C 3-5 cycloalkenyl. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, octahydro-lH-indenyl, octahydrocyclopenta- dienyl, and the like. Examples of -CH2- groups in carbocyclic rings that can be replaced by -C(=0)- include, but are not limited to, 2-cyclopentenone, 1-cyclobuten- 1-one, and the like.

[0082] The term "heterocycle," "heterocyclyl" means a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring system comprising 3-12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen; wherein the heterocycle or heterocyclyl is non-aromatic and does not contain any aromatic rings. When a heterocycle is attached to the remainder of the molecule through a single bond, the heterocycle is represented as a monovalent heterocyclyl radical. Unless otherwise specified, a heterocyclyl group can be carbocyclic or heterocyclic and -CH2- groups can optionally be replaced by -C(=O)- groups. Sulfur atoms of the ring can optionally be oxidized to the S-oxide form. Nitrogen atoms of the ring can optionally be oxidized to the N-oxide form. In some embodiments, the heterocycle or heterocyclyl group consists of 3-10 atoms, denoted 3-10 membered heterocycle or 3-10 membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl group consists of 3-9 atoms, denoted 3-9 membered heterocycle or 3-9 membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl group consists of 5-9 atoms, denoted 5-9 membered heterocycle or 5-9 membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl group consists of 7-10 atoms, denoted 7-10 membered heterocycle or 7-10 membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl group consists of 3-7 atoms, denoted 3-7 membered heterocycle or 3-7 membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl group consists of 3-6 atoms, denoted 3-6 membered heterocycle or 3-6 membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl group consists of 5-6 atoms, denoted 5-6 membered heterocycle or 5-6 membered heterocyclyl. Examples of heterocycles include, but are not limited to, oxirane, aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazolidine, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]hexane, 2,5-diazabicyclo[2.2.2]octane. Heterocyclyl groups include, but are not limited to, dihydropyridyl, tetrahydropyridyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazolyl, dihydroimidazolyl, dihydropyrrolyl, dihydrooxazolyl, dihydrothiazolyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.

[0083] The term "aryl" or "aromatic ring" means a monocyclic, bicyclic, or tricyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 atoms per ring. In some embodiments, aryl contains 6-12 ring atoms, denoted C 6-12aryl or 6-12 membered aryl. In some embodiments, aryl contains 6-10 ring atoms, denoted as C 6-10 aryl or 6-10 membered aryl. Examples of aryl groups can include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthracene. When aryl is used as a linking group, the term "aryl" is denoted as arylene, e.g., A in general formula (I) 2 as a linking group, can be C 6-10 arylene.

[0084] The term "heteroaryl" or "heteroaromatic" denotes a monovalent monocyclic, bicyclic, or tricyclic ring system containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic, and at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, sulfur. The heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. When a -CH2- group is present in the heteroaryl group, said -CH2- group can optionally be replaced with -C(=O)-. Unless otherwise indicated, said heteroaryl group can be attached to the remainder of the molecule (e.g., the main structure in general formula) through any reasonable site (which can be C or N). The term "heteroaryl" can be used interchangeably with the term "heteroaromatic" or "heteroaromatic compound". In some embodiments, the heteroaryl is a heteroaryl containing 5-12 ring atoms, denoted as 5-12 membered heteroaryl; in other embodiments, the heteroaryl is a heteroaryl containing 5-10 ring atoms, denoted as 5-10 membered heteroaryl; in other embodiments, the heteroaryl is a heteroaryl containing 5-6 ring atoms, denoted as 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, benzopyridyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolidinyl, and the like.

[0085] The term "alkylene", "alkenylene", "alkynylene", "cycloalkenylene", "arylene", "heteroarylene", "cycloalkylene", or "heterocyclylene" in the present invention denotes a divalent radical formed when "alkylene", "alkenylene", "alkynylene", "cycloalkenylene", "arylene", "heteroarylene", "cycloalkylene", or "heterocyclylene" serves as a linking group to link the two groups to its left and right.

[0086] The term "halogen" denotes F (fluorine), Cl (chlorine), Br (bromine), or I (iodine).

[0087] The term "oxo" denotes =O.

[0088] The term "hydroxy" denotes OH or -OH.

[0089] The term "cyano" means CN or -CN.

[0090] The term "composed of jk atoms" or "of jk elements" means that the cyclic group is composed of jk ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k > j; "jk" includes j, k and any natural number between them. For example, "composed of 3-8 atoms" or "3-8 elements", "composed of 3-6 atoms" or "3-6 elements", "composed of 5-10 atoms" or "5-10 elements", or "composed of 5-6 atoms" or "5-6 elements" indicates that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10), or 5-6 (i.e., 5 or 6) ring atoms, wherein the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, P, etc.

[0091] As used in this invention, the term "prodrug" refers to the in vivo conversion of a compound into a compound represented by formula (I), (II), (III), (II-1), or (III-1). Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group.

[0092] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0093] As used herein, "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the application. Pharmaceutically acceptable salts are well known in the art, as described in detail in S. M. Berge et al., J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid addition salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, perchloric, and organic acids, such as acetic, oxalic, maleic, tartaric, citric, succinic, malonic, and other similar acids. Salts can also be obtained by the use of other methods known to those of ordinary skill in the art, such as ion exchange techniques. The present application also contemplates quaternary ammonium salts of any of the compounds containing N. Water or oil-soluble or dispersible products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed by the addition of inorganic or organic acids to a free amine group of the present application. Such salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric, Cι-C8sulfonic, and aromatic sulfonic acids, and organic acids such as acetic, benzoic, maleic, fumaric, succinic, malonic, citric, and other similar acids.

[0094] As used herein, "solvate" refers to an association or complex of one or more solvent molecules and a compound of the present application. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to the complex that results when solvent molecules are water.

[0095] The term "hydrate" can be used when the solvent is water. In one embodiment, one molecule of a compound of the present application can be associated with one molecule of water, such as a monohydrate; in another embodiment, one molecule of a compound of the present application can be associated with more than one molecule of water, such as a dihydrate; in yet another embodiment, one molecule of a compound of the present application can be associated with less than one molecule of water, such as a hemihydrate. It is noted that the hydrates of the present application retain the biological effectiveness of the non-hydrated form of the compound.

[0096] The term "treat" or "treatment" of any disease or disorder, in some embodiments, means ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In other embodiments "treatment" means alleviating or improving at least one physical parameter, including parameters that can not be perceptible to the subject. In other embodiments, "treatment" means modulating the disease or disorder physically (e.g., stabilization of a perceptible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In other embodiments, "treatment" means preventing or delaying the onset, development, or worsening of a disease or disorder.

[0097] The term "prevent" or "prevention" means a reduction in risk of acquiring a disease or disorder (i.e., causing the at least one clinical symptom of the disease not to develop in a subject that can be, or predisposed to be, exposed to such disease, but who does not yet experience or exhibit symptoms of the disease).

[0098] The term "therapeutically effective amount" means an amount of a compound that, when administered to a subject for treatment of a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the condition, age, body weight, sex, of the subject to be treated.

[0099] The term "Myt1" means the membrane-associated tyrosine and threonine-specific cdc2 inhibitory kinase (Myt1) (gene name PKMYT1).

[0100] Unless otherwise stated, all isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of the present application are intended to be covered herein by the scope of the present application.

[0101] In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of the structure are intended to be covered herein and are included within the scope of the present application. When stereochemistry is indicated by a solid wedge or dashed wedge, then the stereochemistry of the structure is taken to be specifically as shown.

[0102] Nitrogen oxides of the compounds of the present application are also intended to be covered herein by the scope of the present application. Nitrogen oxides of the compounds of the present application can be prepared by oxidation of the corresponding nitrogenous base using a common oxidizing agent (e.g., hydrogen peroxide) at elevated temperature in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent such as peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperbenzoic acid in chloroform or dichloromethane.

[0103] The compounds of Formula (I), (II), (III), (II-1), or (III-1) can exist in a salt form.

[0104] Any structural formula presented herein encompasses both the non-isotopically enriched form of the compounds as well as isotopically enriched forms. Isotopically enriched compounds have the structure depicted by the general formula presented herein, except that one or more atoms are replaced by an atom having the selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I.

[0105] Description of the compounds of the present application

[0106] The present application provides a compound, or a pharmaceutical composition thereof, which can act as a Myt1 kinase inhibitor. The compounds of the present application have a high inhibitory selectivity for Myt1 kinase over other kinases, block the activity of PKMYT1 and effectively kill cancer cells with CCNE1 amplification. The present application further relates to the use of the compounds, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a relevant disease and / or disorder by inhibiting the activity of Myt1 kinase. The disease or disorder includes a disease, disorder, or condition described herein.

[0107] The superior properties of certain parameters of the compounds of the present application, such as half-life, clearance, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can result in a reduction of side effects, an enlargement of the therapeutic index, or an improvement in tolerability, etc.

[0108] In one aspect, the present application provides a compound of Formula (I), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound of Formula (I),

[0109] wherein, B, R 1 and R 2 each have the definitions as described herein.

[0110] In some embodiments, For wherein R 3 and R 4 each have the definitions as described herein.

[0111] In some embodiments, B is wherein, R 5 , R 6 , R 7 and R 8 each have the definitions as described herein.

[0112] In some embodiments, B is wherein, ring C, R 5a , R 6a and R 7a each have the definitions as described herein.

[0113] In some embodiments, ring C is a phenyl ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocyclic ring, wherein said ring C is optionally substituted with 1, 2, or 3 R a , wherein each R a has the definitions as described herein.

[0114] In some embodiments, ring C is a phenyl, imidazole, pyrrole, pyrazole, dihydroimidazole, dihydropyrrole, dihydrooxazole, dihydrothiazole, pyridine, pyrimidine, or pyrazine, wherein said ring C is optionally substituted with 1, 2, or 3 R a , wherein each R a has the definitions as described herein.

[0115] In some embodiments, each R a is independently D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein R 15a , R 15b and R 16 each have the definition as described in the application.

[0116] In some embodiments, each R a is independently D, F, CI, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein R 15a , R 15b and R 16 each have the definition as described in the application.

[0117] In some embodiments, each R a is independently D, F, CI, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CC13, -CH2CF3, -(CH2)2CF3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CHCN, -(CH2)2CN, -(CH2)3CN, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazyl, pyrimidyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl, wherein R 15a , R 15b , and R 16 each have the definition as described in the application.

[0118] In some embodiments, R 1 is H, D, or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, OH, F, Cl, Br, and CN.

[0119] In some embodiments, R 1 is H, D, or C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, OH, F, Cl, Br, and CN.

[0120] In some embodiments, R 2 is H, D, F, Cl, Br, CN, OH, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10aryl or 5-10 membered heteroaryl.

[0121] In some embodiments, R 2 is H, D, F, CI, Br, CN, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0122] In some embodiments, R 3 is H, D, F, CI, Br, CN, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R q1 groups, wherein each R q1 group has a definition as described herein.

[0123] In some embodiments, R 3 is H, D, F, CI, Br, CN, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 1-4alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein each of said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R q1 , wherein R q1 have the definitions as described herein.

[0124] In some embodiments, R 3H, D, F, CI, Br, CN, NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, NH(CH2)3CH3, NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, -OCF3, -OCH2F, -OCHF2, -OCCl3, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl, wherein,NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, -OCH2F, -OCHF2, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, and thiuranyl, each of which is independently optionally substituted with 1, 2, 3, or 4 R q1 substituted, wherein R q1 has the definition as described herein.

[0125] In some embodiments, R 4 is H, D, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, each of which is independently optionally substituted with 1, 2, 3, or 4 R q2 substituted, wherein each R q2 has the definition as described herein.

[0126] In some embodiments, R 4 is H, D, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R q2 , wherein R q2 have the definitions as described herein.

[0127] In some embodiments, R 4H, D, CN, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, -CF3, -CH2F, -CHF2, -CCl3, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl, wherein said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, -CH2F, -CHF2, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, and thiuranyl are optionally substituted with 1, 2, 3, or 4 R q2 , wherein each R q2 has the meaning as described in the present invention.

[0128] In some embodiments, R 3 , R 4 and the ring atom to which they are attached together form a 5-6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, or a 5-10 membered heteroaromatic ring, wherein said 5-6 membered heterocyclic ring, 7 membered heterocyclic ring, 8 membered heterocyclic ring, and 5-10 membered heteroaromatic ring are each independently optionally substituted with 1, 2, 3, or 4 R q3 , wherein each R q3 has the meaning as described in the present invention.

[0129] In some embodiments, R 3 , R 4 and the ring atom to which they are attached together form a 5-6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, or a 5-6 membered heteroaryl ring, wherein said 5-6 membered heterocyclic ring and 5-6 membered heteroaryl ring are each independently optionally substituted with 1, 2, 3, or 4 R q3 , wherein each R q3 has the definition as described herein.

[0130] In some embodiments, R 3 , R 4 and the ring atom to which they are attached together form a pyrrolidine, pyrazolidine, imidazolidine, morpholine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazole, dihydroimidazole, dihydropyrrole, diazepine, oxazepine, pyridine, or pyrimidine, wherein said pyrrolidine, pyrazolidine, imidazolidine, morpholine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazole, dihydroimidazole, dihydropyrrole, diazepine, oxazepine, pyridine, and pyrimidine are each independently optionally substituted with 1, 2, 3, or 4 R q3 , wherein R q3 has the definition as described herein.

[0131] In some embodiments, R 5 , R 5a , R 6 , R 6a , R 7 , R 7a and R 8 are each independently H, D, F, Cl, Br, CN, OH, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl. 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R q4 , wherein each R q4 has the definition as described herein.

[0132] In some embodiments, R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , and R 8 are each independently H, D, F, Cl, Br, CN, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein said NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R q4 , wherein R q4 has the definition as described herein.

[0133] In some embodiments, R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , and R 8each independently H, D, F, CI, Br, CN, OH, NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, NH(CH2)3CH3, NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, -OCF3, -OCH2F, -OCHF2, -OCCl3, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl, wherein,The following are listed: NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, NH(CH2)3CH3, NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH. -CH2F, -CHF2, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -OCH2F, -OCHF2, -OCCl3, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, tetrahydrofuranyl, tetrahydrothiaranyl, pyrrolylalkyl, pyrazolylalkyl, imidazoylalkyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazoyl, pyrrolyl, furanyl, and thiaranyl are each independently and optionally divided by 1, 2, 3, or 4 Rs. q4 Replaced, of which R q4 It has the definition as described in this invention.

[0134] In some implementation schemes, R q1 R q2 R q3 and R q4 Each of these can be independently represented as D, F, Cl, Br, I, CN, OH, oxo, or NR. 15a R 15b -OR 16 -C(=O)NR 15a R 15b -S(=O)2NR 15a R 15b -S(=O)2R 16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 2-6 alkenyl, C2-6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein R 15a , R 15b and R 16 each have the definition as described in the present application.

[0135] In some embodiments, R q1 , R q2 , R q3 and R q4 are each independently D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein R 15a , R 15b and R 16 each have the definition as described in the present application.

[0136] In some embodiments, R q1 , R q2 , R q3 and R q4 are each independently D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16-S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF3, -CH2F, -CHF2, -CCl3, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH= CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, tetrahydrofuranyl, tetrahydrothiaranyl, pyrrolylalkyl, pyrazolylalkyl, imidazolyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl or thiaranyl, wherein R 15a R 15b and R 16 Each has the definition as described in this invention.

[0137] In some implementations, R on two adjacent ring atoms q3 Together with the two ring atoms attached to them, they form 5-6 membered heterocycles, 7 membered heterocycles, or 5-6 membered heteroaromatic rings, wherein each of the 5-6 membered heterocycles, 7 membered heterocycles, and 5-6 membered heteroaromatic rings is independently and optionally composed of 1, 2, 3, or 4 R atoms. q3a Replaced, of which each R q3a It has the definition as described in this invention.

[0138] In some implementations, R on two adjacent ring atoms q3and the two ring atoms to which they are attached together form a pyrrolidine, pyrazolidine, imidazolidine, morpholine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazole, dihydroimidazole, dihydropyrrole, diazepine, oxazepine, pyrazole, imidazole, pyrrole, pyridine, or pyrimidine, wherein each of said pyrrolidine, pyrazolidine, imidazolidine, morpholine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazole, dihydroimidazole, dihydropyrrole, diazepine, oxazepine, pyrazole, imidazole, pyrrole, pyridine, and pyrimidine is independently optionally substituted with 1, 2, 3, or 4 R q3a each R q3a has the definition as described herein.

[0139] each R q3a is independently D, F, CI, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein each R 15a , R 15b , and R 16 has the definition as described herein.

[0140] each R q3a is independently D, F, CI, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b-S(=O)2R 16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein R 15a , R 15b and R 16 each have the definition as described in the application.

[0141] In some embodiments, each R q3a is independently D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CC13, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CºCCºCH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazyl, pyrimidyl, pyrrolyl, furanyl, or thiuranyl, wherein R 15a 15b 16 each have the definition as described in the application.

[0142] In some embodiments,

[0143] In some embodiments, R 15a 15b 16 each independently is H, D, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl.

[0144] In some embodiments, R 15a 15b 16 each independently is H, D, CN, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 ​​​​​​​alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0145] In some embodiments, R 15a , R 15b , and R 16 each independently is H, D, CN, OH, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CCl3, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazyl, pyrimidyl, pyrrolyl, furanyl, or thiuranyl.

[0146] In some embodiments, has one of the following sub-structural formulae, wherein R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 9a , R 13a , R 13b , R 13c , R 5a , R 6a , and R 7a each has the definition as described in the present application.

[0147] In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 9a , R 13a , R 13b , and R13c each independently H, D, F, CI, Br, I, CN, OH, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein R 15a , R 15b and R 16 each have the definition as described in the application.

[0148] In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 9a , R 13a , R 13b and R 13c each independently H, D, F, CI, Br, I, CN, OH, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, C 2-4 alkenyl, C2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein R 15a R 15b and R 16 Each has the definition as described in this invention.

[0149] In some implementation schemes, R 9 R 10 R 11 R 12 R 13 R 14 R 9a R 13a R 13b and R 13c Each of the following is independently H, D, F, Cl, Br, I, CN, OH, NR 15a R 15b -OR 16 -C(=O)NR 15a R 15b -S(=O)2NR 15a R 15b -S(=O)2R 16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF3, -CH2F, -CHF2, -CCl3, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, -CHCN, -(CH2)2CN, -(CH2)3CN, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=C HCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, tetrahydrofuranyl, tetrahydrothiaranyl, pyrrolylalkyl, pyrazolylalkyl, imidazolyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl or thiaranyl, wherein R 15a R 15b and R16 each has the definition as described in the present application.

[0150] In some embodiments, the compound described in the present application is a compound described in Formula (II), or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound described in Formula (II),

[0151] wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 each has the definition as described in the present application.

[0152] In some embodiments, the compound described in the present application is a compound described in Formula (III), or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound described in Formula (III),

[0153] wherein, R 1 , R 2 , R 3 , R 4 , R 5a , R 6a , R 7a and ring C each has the definition as described in the present application.

[0154] In some embodiments, the compound described in the present application is a compound described in Formula (II-1), or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound described in Formula (II-1),

[0155] wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 each has the definition as described in the present application.

[0156] In some embodiments, the compound described in the present application is a compound described in Formula (III-1), or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound described in Formula (III-1),

[0157] wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 6a , R 7a and ring C each has the definition as described in the present application.

[0158] In some embodiments, the compound of the present application is a compound of the following structure, or a stereoisomer, a tautomer, a N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

[0159] In some embodiments, the compound of the present application is a compound of the following structure, or a stereoisomer, a tautomer, a N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

[0160] In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application.

[0161] In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable adjuvant.

[0162] In some embodiments, the adjuvant of the present application includes, but is not limited to, a carrier, an excipient, a diluent, a vehicle, or a combination thereof. In some embodiments, the pharmaceutical composition can be in a liquid, solid, semi-solid, gel or spray form.

[0163] In another aspect, the present application provides use of the pharmaceutical composition of the present application in the manufacture of a medicament for preventing, treating or alleviating a Myt1 -related disease.

[0164] In some embodiments, the Myt1 -related disease of the present application is a Myt1 -related proliferative disease.

[0165] In some embodiments, the Myt1 -related proliferative disease of the present application is a Myt1 -related cancer, psoriasis or rheumatoid arthritis.

[0166] In some embodiments, the Myt1 -related disease of the present application is a Myt1 -related uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, leukemia, liver cancer, bladder cancer, prostate cancer, cervical cancer or kidney cancer.

[0167] In another aspect, the present application also provides a method for preventing or treating a Myt1 -related disease, the method comprising administering to a patient a therapeutically effective amount of a compound of the present application or a pharmaceutical composition thereof.

[0168] In another aspect, the present application relates to a method for preparing, isolating and purifying a compound of Formula (I), (II), (III), (II-1) or (III-1).

[0169] Unless otherwise indicated, all stereoisomers, tautomers, nitroso isomers, hydrates, solvates, metabolites, salts, and prodrugs of the compounds of the present application are within the scope of the application.

[0170] In particular, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemical or toxicological, with other components of the formulation and for the mammal being treated.

[0171] The salts of the compounds of the present application also include salts of intermediates used in making or purifying a compound of Formula (I), (II), (III), (II-1) or (III-1), or isolated enantiomers of a compound of Formula (I), (II), (III), (II-1) or (III-1), but are not necessarily pharmaceutically acceptable salts.

[0172] Formulation, administration and use of pharmaceutical compositions of the compounds of the present application

[0173] The pharmaceutical compositions of the present application feature a compound of Formula (I), (II), (III), (II-1) or (III-1), a compound listed in the present application, or a compound of the Examples, and a pharmaceutically acceptable carrier. The amount of compound in the pharmaceutical compositions of the present application is effective to treat or alleviate a Myt1 -mediated disease in a patient.

[0174] The compounds of the present application exist in free form or in a suitable, pharmaceutically acceptable derivative. According to the present application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative which upon administration to a patient is capable of providing (directly or indirectly) a compound described in other aspects of the present application, a metabolite or residue thereof.

[0175] As described herein, the pharmaceutically acceptable compositions of the present application further comprise a pharmaceutically acceptable carrier, which as used herein includes any and all solvents, diluents, or other liquid vehicles, suspending agents, or dispersing agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, and the like, as suited to the particular dosage form desired. General considerations relating to various pharmaceutically acceptable carriers can also be found in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the compounds of the application, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this application.

[0176] Suitable excipients for tablets and capsules are well known in the art. Such excipients include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, surfactants, and mixtures thereof. Binders suitable for use herein include, but are not limited to, starch, gelatin, sugars, molasses, polyvinylpyrrolidone, cellulose, and derivatives thereof, and polymethacrylates. Fillers suitable for use herein include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, sugar, dextrates, kaolin, calcium sulfate, sodium chloride, dry powdered ispaghula, and mixtures thereof. Disintegrants suitable for use herein include, but are not limited to, starch, methyl cellulose, powdered cellulose, starch, alginates, sodium starch glycolate, sodium starch acetate, sodium bicarbonate, calcium carbonate, and mixtures thereof. Lubricants suitable for use herein include, but are not limited to, magnesium stearate, stearic acid, glyceryl monostearate, talc, waxes, and mixtures thereof. Glidants suitable for use herein include, but are not limited to, colloidal silicon dioxide, starch, talc, and mixtures thereof. Surfactants suitable for use herein include, but are not limited to, sodium lauryl sulfate, polysorbates, and mixtures thereof. Suitable excipients for tablets and capsules are well known in the art. Such excipients include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, surfactants, and mixtures thereof. Binders suitable for use herein include, but are not limited to, starch, gelatin, sugars, molasses, polyvinylpyrrolidone, cellulose, and derivatives thereof, and polymethacrylates. Fillers suitable for use herein include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, sugar, dextrates, kaolin, calcium sulfate, sodium chloride, dry powdered ispaghula, and mixtures thereof. Disintegrants suitable for use herein include, but are not limited to, starch, methyl cellulose, powdered cellulose, starch, alginates, sodium starch glycolate, sodium starch acetate, sodium bicarbonate, calcium carbonate, and mixtures thereof. Lubricants suitable for use herein include, but are not limited to, magnesium stearate, stearic acid, glyceryl monostearate, talc, waxes, and mixtures thereof. Glidants suitable for use herein include, but are not limited to, colloidal silicon dioxide, starch, talc, and mixtures thereof. Surfactants suitable for use herein include, but are not limited to, sodium lauryl sulfate, polysorbates, and mixtures thereof.

[0177] In making the pharmaceutical compositions of the application, the active ingredients will be mixed with a pharmaceutically acceptable carrier, diluted by a carrier or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. If the carrier serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The compositions can therefore be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid forms or in liquid media), ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as a tablet or capsule.

[0178] The compounds or pharmaceutical compositions of this application can be administered in a form of an oral dosage, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered in intravenous (bolus injection or infusion), intraperitoneal, subcutaneous or intramuscular form, all using dosage forms well known in the pharmaceutical art. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0179] The compounds or pharmaceutical compositions of this application can be administered in a form of an oral dosage, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered in intravenous (bolus injection or infusion), intraperitoneal, subcutaneous or intramuscular form, all using dosage forms well known in the pharmaceutical art. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0180] The compounds or pharmaceutical compositions of this application can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0181] The compounds or pharmaceutical compositions of the present application can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyethylene glycol, pyran co-polymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present application can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymer of poly-lactic and poly-glycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyortho esters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block co-polymers of hydrogels.

[0182] The dosage regimen for compounds or pharmaceutical compositions of the present application will vary according to various factors, such as the pharmacokinetic characteristics of the particular agent and its mode of administration; the species, age, sex, health, medical condition, and body weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment(s); the frequency with which treatment is to be effected; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian will determine and prescribe the effective amount of the drug that is appropriate for a particular set of circumstances. It is expected that the dosage regimen will include 1 to 4 doses per day.

[0183] According to general principles, to achieve the desired effects, the dosage of each active ingredient used will range from about 0.001 to 1000 mg / kg body weight per day, orally, preferably from about 0.01 to 100 mg / kg body weight per day. The compounds of the present application can be administered once a day, or can be administered in two, three or four doses per day.

[0184] Each unit dose of the dosage form (pharmaceutical composition) suitable for administration can contain from about 1 mg to about 100 mg of the active ingredient. In these pharmaceutical compositions, the weight of active ingredient generally will comprise from about 0.5 to 95 percent of the total weight of the composition.

[0185] The compounds and compositions described herein can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of the present application can be administered simultaneously or sequentially with other therapeutic agents, by the same or different routes of administration. The compounds of the present application can be included in a single formulation with other therapeutic agents or in separate formulations.

[0186] When the compounds of the present application are administered with other therapeutic agents, generally the amount of each component in the typical daily dose and in the typical dosage form can be reduced relative to the amount of each component that would be used when administered alone, taking into account the additive or synergistic effects of the combination.

[0187] The compound, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a pharmaceutical composition thereof, can be effectively used for preventing, treating or alleviating a patient from a disease mediated by Myt1.

[0188] In some embodiments, the Myt1 -related disease is a proliferative disease.

[0189] In some embodiments, the proliferative disease is cancer, psoriasis or rheumatoid arthritis.

[0190] In some embodiments, the Myt1 -related disease is uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, leukemia, liver cancer, bladder cancer, prostate cancer, cervical cancer or kidney cancer.

[0191] General synthetic procedures

[0192] For the purpose of describing the present application, the present application will be further illustrated by the following examples, which are intended to be illustrative only and not limiting to the scope of the present application. In the following examples, the technical means or methods not specifically mentioned are the conventional technical means or methods in the art.

[0193] Unless otherwise indicated, the definitions of substituents recited herein are intended to apply independently to each occurrence of such substituents. The following reaction schemes and examples are presented to further illustrate the content of the present application.

[0194] Those skilled in the art will appreciate that the chemical reactions described herein can be used to prepare other compounds of the application according to synthetic routes known in the art and described in the references provided herein. For example, the synthesis of those non-exemplified compounds according to the application can be successfully performed by modifications apparent to those skilled in the art, by virtue of the benefit of the teachings of the present application. For example, the synthesis of non-exemplified compounds according to the application can be successfully performed by employing other methods in place of those methods described herein. Such other methods include other reaction conditions, other reagents, other protecting groups, and other synthetic routes.

[0195] Unless otherwise indicated, all temperatures are set forth in degrees Celsius (C). Room temperature, unless otherwise indicated, means 15 °C to 30 °C; in some embodiments, room temperature is 20 °C to 30 °C. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and used without further purification. Unless otherwise indicated, general reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemicals Co., Ltd., Tianjin Fumian Chemical Reagent Factory, Wuhan Xinhua Yuan Science and Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haoyang Chemical Factory.

[0196] Anhydrous tetrahydrofuran, dioxane, toluene, diethyl ether were dried over sodium metal. Anhydrous dichloromethane and chloroform were dried over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were used as received.

[0197] The following reactions were generally performed under an atmosphere of nitrogen or argon at positive pressure or under anhydrous conditions in a dry box (unless otherwise indicated), reaction vessels were fitted with a septum cap and substrates were introduced via syringe. Glassware was oven- or flame-dried.

[0198] Chromatography columns were packed with silica gel. Silica gel (300-400 mesh) was purchased from Qingdao Haoyang Chemical Factory.

[0199] 1 H NMR spectra were recorded on a Bruker 400 MHz or 600 MHz NMR spectrometer. 1 H NMR spectra were recorded in CDC13, DMSO-d6, CD3OD or acetone-d6 as solvent (in ppm) with TMS (0 ppm) or chloroform (7.26 ppm) as reference standard. When multiplets occur, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), br s (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, J, are reported in Hertz (Hz).

[0200] Low resolution mass spectrometry (MS) data were measured on an Agilent 6120 quadrupole HPLC-MS (column type: Zorbax SB-C18, 2.1 x 15 mm, 3.5 micron, 6 min, 0.6 mL / min flow rate. Mobile phase: 5-95% (CH3CN with 0.1% formic acid) in (H2O with 0.1% formic acid), with UV detection at 210 nm / 254 nm. using electrospray ionization (ESI).

[0201] Pure compounds were measured on an Agilent 1260-HPLC (column type: Agilent Eclipse Plus C18 4.6*100 mm, 3.5 um), with UV detection at 220 nm.

[0202] The following abbreviations are used throughout this application: Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene NBS N-bromosuccinimide NaBH4 sodium borohydride TFA trifluoroacetic acid TsOH-H2O p-toluenesulfonic acid monohydrate LiAlH4-THF lithium aluminum hydride in tetrahydrofuran PE petroleum ether EA ethyl acetate CDCl3 deuterated chloroform DCM dichloromethane MeOH methanol DMF N,N-dimethylformamide DMSO dimethylsulfoxide THF tetrahydrofuran EtOH ethanol SFC supercritical fluid chromatography RT, rt room temperature °C degrees Celsius

[0203] Synthesis Scheme 1: Synthesis of compound (IV)

[0204] Synthesis of compound (IV) can be prepared by the route method of synthesis scheme 1. Wherein, R 3 , R 4 , R 5 , R 6 , R 7 and R 8each has the definition as described in the present application, Pg is a hydroxyl protecting group, including but not limited to Bn. Compound (IV-1) is reacted with NBS in a suitable solvent to obtain compound (IV-2); compound (IV-2) is coupled with compound (IV-3) under suitable conditions (such as in the presence of cesium carbonate, palladium acetate and Xantphos in 1,4-dioxane solvent) to obtain compound (IV-4); compound (IV-4) is reacted with malononitrile under suitable conditions (such as in the presence of cuprous iodide, L-piperidine-2-carboxylic acid and potassium carbonate in dimethyl sulfoxide solvent) to obtain compound (IV-5); compound (IV-5) is reacted with formamide under heating conditions to obtain compound (IV-6); compound (IV-6) is reacted in the presence of concentrated sulfuric acid to obtain compound (IV).

[0205] Synthetic Scheme 2: Synthesis of intermediate compound (IV-6)

[0206] Synthesis of intermediate compound (IV-6) can be prepared by the route method of synthetic scheme 2. Wherein, R 3 , R 4 , R 5 , R 6 , R 7 and R 8 each has the definition as described in the present application, Pg is a hydroxyl protecting group, including but not limited to Bn. Compound (IV-5) is reacted in the presence of concentrated sulfuric acid to obtain compound (IV-5-1); compound (IV-5-1) is reacted with trimethyl orthoformate in the presence of p-toluenesulfonic acid monohydrate to obtain compound (IV-5-2); compound (IV-5-2) is reacted with phosphorus oxychloride to obtain compound (IV-5-3); compound (IV-5-3) is reacted with ammonia water to obtain intermediate compound (IV-6).

[0207] Synthetic Scheme 2: Synthesis of compound (V)

[0208] Synthesis of compound (V) can be prepared by the route method of synthetic scheme 3. Wherein, R 3 , R 4 , R 5a , R 6a and R 7aeach has the definition as described in the present application. Compound (IV-2) is coupled with compound (V-1) under suitable conditions (such as in the presence of cesium carbonate, palladium acetate and Xantphos in 1,4-dioxane solvent) to give compound (V-2); compound (V-2) is reacted with malononitrile under suitable conditions (such as in the presence of cuprous iodide, L-piperidine-2-carboxylic acid and potassium carbonate in dimethylsulfoxide solvent) to give compound (V-3); compound (V-3) is reacted with formamide under heating conditions to give compound (V).

[0209] The compounds, pharmaceutical compositions and uses thereof provided by the present application are further illustrated by the following examples. When the name of a compound is inconsistent with its corresponding structure, the compound is represented by the structure. Examples

[0210] Example 1: (S)-3-(4-amino-2-methyl-3-(trifluoromethyl)pyrazolo[4',3':4,5]pyrrolo[2,3- d]pyrimidin-8(2H)-yl)-2,4-dimethylphenol

[0211] Step 1: Synthesis of 4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine

[0212] A reaction flask was charged with 5-trifluoromethyl-1H-pyrazol-3-amine (3.00 g, 18.17 mmol) and dichloromethane (50.0 mL), N-bromosuccinimide (3.56 g, 19.99 mmol) was added portionwise with stirring at 0 °C. The reaction progress was monitored by TLC, after the starting material was consumed, the stirring was stopped, water (100.0 mL) was added to the reaction system, extracted with dichloromethane (100 mL x 3), the combined organic phase was concentrated under vacuum at 45 °C, the concentrate was purified by column chromatography (PE:EA (v:v) = 4:1) to give a light yellow solid (4.30 g, yield: 96.99 %). LC-MS (ESI, pos.ion) m / z: 244.00, 246.00 [M+H] + .

[0213] Step 2: Synthesis of N-(3-(benzyloxy)-2,6-dimethylphenyl)-4-bromo-1-methyl-5- (trifluoromethyl)-1H-pyrazol-3-amine

[0214] A reaction flask was charged with 4-bromo-l-methyl-5-(trifluoromethyl)-lH- pyrazol-3-amine (1.50 g, 6.15 mmol), l-benzyloxy-3-iodo-2,4-dimethylbenzene (2.18 g, 6.46 mmol), palladium acetate (0.28 g, 1.23 mmol), cesium carbonate (5.01 g, 15.38 mmol), Xantphos (1.42 g, 2.46 mmol) and 1,4-dioxane (20.0 mL). After purging with nitrogen for three times, the reaction flask was placed in a 100 °C oil bath. The reaction was monitored by TLC until the starting material was consumed. The heating was turned off and water (100.0 mL) was added to the reaction mixture. The mixture was extracted with EA (100 mL x 3). The organic phase was combined and concentrated under vacuum at 45 °C. The residue was purified by silica gel column chromatography (PE:EA (v:v) = 18:1) to give a white solid (2.50 g, yield: 89.52%). LC-MS (ESI, pos.ion) m / z: 454.10, 456.10 [M+H] + .

[0215] Step 3: Synthesis of 5-amino-6-(3-benzyloxy-2,6-dimethylphenyl)-2-methyl-3- trifluoromethyl-2,6-dihydropyrrolo[2,3-c]pyrazole-4-carbonitrile

[0216] A reaction flask was charged with N-(3-(benzyloxy)-2,6-dimethylphenyl)-4-bromo- 1-methyl-5-(trifluoromethyl)-lH-pyrazol-3-amine (2.50 g, 5.50 mmol), cuprous iodide (0.21 g, 1.10 mmol), L-piperidine-2-carboxylic acid (0.28 g, 2.20 mmol), malononitrile (0.91 g, 13.75 mmol), potassium carbonate (2.28 g, 16.50 mmol) and dimethyl sulfoxide (15.0 mL). After purging with nitrogen for three times, the reaction flask was placed in a 120 °C oil bath. The reaction was monitored by TLC until the starting material was consumed. The heating was turned off and water (100.0 mL) was added to the reaction mixture. The mixture was extracted with EA (100 mL x 3). The organic phase was combined and concentrated under vacuum at 45 °C. The residue was purified by column chromatography (PE:EA (v:v) = 3:1) to give a light yellow solid (0.39 g, yield: 16.13%). LC-MS (ESI, pos.ion) m / z: 440.20, 441.30 [M+H] + .

[0217] Step 4: Synthesis of 8-(3-(benzyloxy)-2,6-dimethylphenyl)-2-methyl-3- trifluoromethyl-2,8-dihydropyrrolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine

[0218] Into a reaction flask was placed 5-amino-6-(3-benzyloxy-2,6-dimethylphenyl)-2- methyl-3-trifluoromethyl-2,6-dihydropyrrolo[2,3-c]pyrazol-4-carbonitrile (0.37 g, 0.84 mmol) and formamide (15.0 mL) and the reaction was moved to a 160 °C oil bath kettle; the reaction was monitored by TLC until the starting material was consumed, the heating was turned off, water (100.0 mL) was added to the reaction, the mixture was extracted with EA (100 mL x 3), the organic phases were combined and concentrated under vacuum at 45 °C, the concentrate was purified by silica gel column chromatography (PE:EA (v:v) = 2:1) to give a white solid (0.37 g, yield: 94.21%). LC-MS (ESI, pos.ion) m / z: 467.30, 468.20 [M+H] + .

[0219] Step 5: Synthesis of (S)-3-(4-amino-2-methyl-3-(trifluoromethyl)pyrazolo[4',3':4,5]pyrrolo[2,3- d]pyrimidin-8(2H)-yl)-2,4-dimethylphenol

[0220] Into a reaction flask was placed 8-(3-(benzyloxy)-2,6-dimethylphenyl)-2-methyl-3- trifluoromethyl-2,8-dihydropyrrolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (0.39 g, 0.84 mmol) and dichloromethane (6.0 mL), concentrated sulfuric acid (0.22 mL, 4.20 mmol) was added with stirring at room temperature, stirring was continued at room temperature for about 6.0 h, the stirring was stopped, a little water was slowly added to the reaction, the pH of the solution was adjusted to 7 with saturated NaHC03 aqueous solution, then the mixture was extracted with EA (200 mL x 2), the organic phases were combined and washed with water twice, then concentrated, the concentrate was purified by silica gel column chromatography (DCM:MeOH (v:v) = 30:1) to give a white racemate 0.19 g; the racemate was separated by chiral resolution to give (S)-3-(4-amino-2-methyl-3- (trifluoromethyl)pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-8(2H)-yl)-2,4-dimethylphenol (0.06 g, yield: 19.07%) as a white solid, the retention time of the product in chiral analytical HPLC was 25.55 min. Resolution method: (Waters SFC TI-00631 column: Chiralpak IA Chiral column 10*250mm, 5um, separation condition: 27% isopropanol + 73% CO2, flow rate 8 mL / min). Chiral HPLC detection condition: column: Chiralpak IC 4.6X250mm, 5um; mobile phase: n-hexane: ethanol = 95:5; flow rate: 1 ml / min; run time: 50 min; detection wavelength: 220 nm. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.19 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.55 (s, 2H), 4.09 (s, 3H), 1.77 (s, 3H), 1.67 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 159.50 (s), 157.67 (s), 155.46 (s), 154.57 (s), 150.88 (s), 133.81 (s), 128.13 (s), 126.84 (s), 123.76 (s), 121.04 (d, J C-F = 268.66 Hz), 121.01 (s), 120.61 (s), 115.87 (s), 104.37 (s), 90.84 (s), 17.39 (s), 11.39 (s); HR-MS m / z: 377.1377 [M+H] + .

[0221] Example 2: (S)-3-(4-amino-5,6,7,8-tetrahydro-11H-pyrido[1”,2”:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol

[0222] Step 1: Synthesis of ethyl 1-(4-ethoxy-4-oxobutyl)-3-nitro-1H-pyrazole-5-carboxylate

[0223] Ethyl 5-nitro-pyrazole-3-carboxylate (0.5 g, 2.70 mmol), ethyl 4-bromobutyrate (0.63 g, 3.24 mmol), potassium carbonate (0.37 g, 2.7 mmol) and acetonitrile (5.00 mL) were placed in a reaction flask, which was transferred to 80 °C and stirred overnight. After the reaction was completed, the filtrate was directly rotary evaporated to give a yellow oil crude product, which was directly used in the next reaction. LC-MS (ESI, pos.ion) m / z: 300.10 [M+H] + .

[0224] Step 2: Synthesis of ethyl 2-nitro-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate

[0225] A reaction flask was charged with ethyl 1-(4-ethoxy-4-oxobutyl)-3-nitro-1H- pyrazole-5-carboxylate (2.3 g, 7.69 mmol), toluene / tetrahydrofuran (20 mL / 20 mL), and potassium tert-butoxide (1.73 g, 15.38 mmol), and the reaction was stirred at 90 °C overnight. After the reaction was completed, the reaction was directly filtered, and the filter residue was obtained as a light yellow solid, which was directly used in the next reaction. LC-MS (ESI, pos.ion) m / z: 254.10 [M+H] + .

[0226] Step 3: Synthesis of 2-nitro-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one

[0227] A reaction flask was charged with ethyl 2-nitro-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridine-5-carboxylate (15 g, 59.24 mmol), hydrochloric acid (100.00 mL), and water (100.00 mL), and the reaction was stirred at 100 °C overnight. After the reaction was completed, the solution was adjusted to pH 7 with saturated NaHCO3 aqueous solution, and then extracted with EA (200 mL x 2). The combined organic phase was washed with water twice and concentrated. The concentrate was purified by silica gel column chromatography (EA:PE (v:v) = 1:2) to obtain a light yellow solid (3.3 g, total yield of steps 1, 2, and 3: 30.75%). LC-MS (ESI, pos.ion) m / z: 182.10 [M+H] + .

[0228] Step 4: Synthesis of 2-amino-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one

[0229] A reaction flask was charged with 2-nitro-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (3.3 g, 18.22 mmol), iron powder (5.09 g, 91.1 mmol), and ammonium chloride (4.87 g, 91.1 mmol) in a mixture of ethanol (20 mL) and water (10 mL), and the reaction was stirred at 80 °C for about 2 h. After the starting material was consumed, the reaction was stopped, cooled to room temperature, and filtered. The filter residue was rotary evaporated to obtain a light yellow solid of the target compound (2.1 g, yield: 76.26%). LC-MS (ESI, pos.ion) m / z: 152.20 [M+H] + .

[0230] Step 5: Synthesis of 2-amino-3-bromo-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one

[0231] To a solution of 2-amino-6,7-dihydropyrazolo[l,5-a]pyridin-4(5H)-one (2.1 g, 13.89 mmol) in DCM (20 mL) was added at 0 °C, NBS (2.72 g, 15.28 mmol) was added portionwise and the reaction was stirred. The progress of the reaction was monitored by TLC and the reaction was completed on completion of starting material. The aqueous phase was washed with DCM (3 x 50 mL), the organic layers were combined and washed with saturated NaCl solution (3 x 20 mL), the organic layers were combined and dried over Na2S04, the combined organic phase was concentrated under vacuum at 45 °C, the concentrate was purified by column chromatography on silica gel (EA) to give a light yellow solid (0.5 g, yield: 15.64 %). LC-MS (ESI, pos.ion) m / z: 230.10, 232.10 [M+H] + .

[0232] Step 6: Synthesis of 3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-6,7- dihydropyrazolo[l,5-a]pyridin-4(5H)-one

[0233] To a solution of 2-amino-3-bromo-6,7-dihydropyrazolo[l,5-a]pyridin-4(5H)-one (3.0 g, 13.04 mmol), l-methoxy-3-iodo-2,4-dimethylbenzene (3.76 g, 14.34 mmol), palladium acetate (1.17 g, 5.22 mmol), cesium carbonate (10.62 g, 32.60 mmol), Xantphos (3.02 g, 5.22 mmol) and 1,4-dioxane (50.00 mL) in a reaction flask, the reaction was stirred after three times of nitrogen replacement and was transferred into a 110 °C oil bath. The reaction was monitored by TLC and the reaction was completed on completion of starting material. The heating was turned off and water (100.0 mL) was added to the reaction system, which was extracted with EA (100 mL x 3), the organic layers were combined and concentrated under vacuum at 45 °C, the concentrate was purified by column chromatography on silica gel (EA: PE (v:v) = 1:5) to give a light yellow solid (2.0 g, yield: 42.11 %). LC-MS (ESI, pos.ion) m / z: 364.00, 366.10 [M+H] + .

[0234] Step 7: Synthesis of 2-amino-l-(3-methoxy-2,6-dimethylphenyl)-4-oxo-4,5,6,7- tetrahydro-lH-pyrrolo[2',3':3,4]pyrazolo[l,5-a]pyridine-3-carbonitrile

[0235] A mixture of 3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-6,7- dihydropyrazolo[l,5-a]pyridin-4(5H)-one (4.5 g, 12.35 mmol), cuprous iodide (2.35 g, 12.35 mmol), L-hydroxyproline (1.62 g, 12.35 mmol), malononitrile (2.45 g, 37.05 mmol), potassium carbonate (4.27 g, 30.88 mmol) and dimethyl sulfoxide (50.00 mL) was placed in a reaction flask, and after being replaced with nitrogen three times, it was moved to a 120 °C oil bath for reaction. TLC monitoring was performed until the starting material was completely reacted, and the reaction was stopped. Water (100.0 mL) was added to the reaction system, and extraction was performed with EA (100 mL x 3). The combined organic phases were concentrated under vacuum at 45 °C, and the concentrate was purified by column chromatography (EA:PE (v:v) = 3:2) to obtain a light yellow solid (0.43 g, yield: 9.96%). LC-MS (ESI, pos.ion) m / z: 350.20 [M+H] + .

[0236] Step 8: Synthesis of 2-amino-l-(3-methoxy-2,6-dimethylphenyl)-4,5,6,7- tetrahydro-lH-pyrrolo[2',3':3,4]pyrazolo[l,5-a]pyridine-3-carbonitrile

[0237] To a mixture of 2-amino-l-(3-methoxy-2,6-dimethylphenyl)-4-oxo-4,5,6,7- tetrahydro-lH-pyrrolo[2',3':3,4]pyrazolo[l,5-a]pyridine-3-carbonitrile (0.43 g, 1.23 mmol), NaBH4(0.28 g, 7.38 mmol) and dichloromethane (10.00 mL) was slowly added TFA (1.83 mL, 24.6 mmol) under an ice water bath. The reaction was stirred at room temperature, and TLC monitoring was performed until the starting material was completely reacted. The stirring was stopped, a small amount of water was slowly added to the reaction system, and extraction was performed with DCM (200 mL x 2). The combined organic phases were washed with water twice and concentrated. The concentrate was purified by column chromatography (EA:PE (v:v) = 1:1) to obtain a light yellow solid (0.35 g, yield: 84.79%). LC-MS (ESI, pos.ion) m / z: 336.20, 337.30 [M+H] + Step 9: Synthesis of 2-amino-l-(3-methoxy-2,6-dimethylphenyl)-4,5,6,7- tetrahydro-lH-pyrrolo[2',3':3,4]pyrazolo[l,5-a]pyridine-3-carboxamide

[0238] A reaction flask was charged with 2-amino-1-(3-methoxy-2,6-dimethylphenyl)- 4,5,6,7-tetrahydro-1H-pyrrolo[2',3':3,4]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.13 g, 0.39 mmol) and dichloromethane (10.00 mL), and concentrated sulfuric acid (0.72 mL, 13.55 mmol) was added with stirring at room temperature. The reaction was stirred at room temperature for about 2.0 h, and then the stirring was stopped. A small amount of water was slowly added to the reaction system, and the solution was adjusted to pH 7 with saturated NaHC03 aqueous solution. The solution was extracted with EA (200 mL x 2), and the organic phase was combined. The organic phase was washed with water twice, and then concentrated to give a light yellow solid (0.10 g, yield: 73.00%). LC-MS (ESI, pos.ion) m / z: 354.10, 355.15 [M+H] + .

[0239] Step 10: Synthesis of 11-(3-methoxy-2,6-dimethylphenyl)-5,7,8,11-tetrahydro- 6H-pyrido[1",2":1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-ol

[0240] A reaction flask was charged with 2-amino-1-(3-methoxy-2,6-dimethylphenyl)- 4,5,6,7-tetrahydro-1H-pyrrolo[2',3':3,4]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.13 g, 0.39 mmol) and dichloromethane (10.00 mL), and concentrated sulfuric acid (0.72 mL, 13.55 mmol) was added with stirring at room temperature. The reaction was stirred at room temperature for about 2.0 h, and then the stirring was stopped. A small amount of water was slowly added to the reaction system, and the solution was adjusted to pH 7 with saturated NaHC03 aqueous solution. The solution was extracted with EA (200 mL x 2), and the organic phase was combined. The organic phase was washed with water twice, and then concentrated to give a light yellow solid (0.10 g, yield: 73.00%). LC-MS (ESI, pos.ion) m / z: 354.10, 355.15 [M+H]

[0241] Step 11: Synthesis of 4-chloro-11-(3-methoxy-2,6-dimethylphenyl)-5,7,8,11- tetrahydro-6H-pyrido[1",2":1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine

[0242] Into a reaction vial, 4-chloro-11-(3-methoxy-2,6-dimethylphenyl)-5,7,8,11- tetrahydro-6H-pyrido[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine (0.12 g, 0.31 mmol) and ammonia (6.00 mL) and 1,4-dioxane (3.00 mL) were placed in a sealed tube and moved to a 120 °C oil bath for reaction overnight; the reaction was stopped and cooled to room temperature, the reaction solution was concentrated under vacuum at 45 °C, the concentrate was purified by silica gel column chromatography (EA as eluent) to give a light yellow solid (0.08 g, yield: 70.24%). LC-MS (ESI, pos.ion) m / z: 362.80, 364.15 [M+H]

[0243] Step 12: Synthesis of 11-(3-methoxy-2,6-dimethylphenyl)-5,7,8,11-tetrahydro-6H- pyrido[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine

[0244] Into a reaction vial, 4-chloro-11-(3-methoxy-2,6-dimethylphenyl)-5,7,8,11- tetrahydro-6H-pyrido[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine (0.12 g, 0.31 mmol) and ammonia (6.00 mL) and 1,4-dioxane (3.00 mL) were placed in a sealed tube and moved to a 120 °C oil bath for reaction overnight; the reaction was stopped and cooled to room temperature, the reaction solution was concentrated under vacuum at 45 °C, the concentrate was purified by silica gel column chromatography (EA as eluent) to give a light yellow solid (0.08 g, yield: 70.24%). LC-MS (ESI, pos.ion) m / z: 362.80, 364.15 [M+H] + .

[0245] Step 13: (S)-3-(4-amino-5,6,7,8-tetrahydro-11H-pyrido[l",2":l',5']pyrazolo[4',3':4,5] pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol

[0246] To a solution of 11-(3-methoxy-2,6-dimethylphenyl)-5,7,8,11-tetrahydro-6H- pyrido[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (0.19 g, 0.52 mmol) in DCM (6.00 mL) was added BBr3(2.6 mL, 2.6 mmol, 1.0 M) slowly under ice water bath, the reaction was stirred for about 4.0 h, the stirring was stopped, a little methanol was added to the reaction mixture to quench the reaction, the organic liquid was removed directly by rotary evaporation under reduced pressure, water (100.0 mL) was added to the reaction mixture, extracted with DCM (100 mL x 3), the organic phase was combined and concentrated under vacuum at 45 °C, the concentrate was purified by column chromatography (DCM:MeOH (v:v) = 10:1), then chiral resolution to give white solid (S)-3-(4-amino-5,6,7,8-tetrahydro-11H-pyrido[l",2":l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethyl (0.022 g, yield: 12.05%). Resolution method: (Waters SFC TI-00631 column: Chiralcel IA Chiral column 10 x 250 mm, 5 μm, separation condition: 40% ethanol + 60% CO2, flow rate 8 mL / min); LC-MS (ESI, pos.ion) m / z: 349.15, 350.25 [M+H] + ; 1 H NMR (599 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.05 (s, 1H), 7.00 (d, J = 7.9 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.34 (s, 2H), 4.13 (br, 2H), 2.04 (br, 2H), 1.91 (br, 2H), 1.77 (s, 3H), 1.67 (s, 3H), 1.24 (br, 2H); 13 C NMR (151 MHz, DMSO-d6) δ 158.34 (s), 156.46 (s), 154.44 (s), 153.25 (s), 152.30 (s), 134.93 (s), 131.36 (s), 127.85 (s), 126.95 (s), 123.81 (s), 115.33 (s), 101.21 (s), 93.69 (s), 48.87 (s), 23.42 (s), 23.27 (s), 20.40 (s), 17.56 (s), 11.50 (s); HR-MS m / z: 349.1784 [M+H] + .

[0247] Example 3: (S)-3-(4-amino-7,8-dihydro-11H-pyrido[1”,2’:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol

[0248] Step 1: Synthesis of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-4-oxo-4,5,6,7- tetrahydro-1H-pyrrolo[2',3':3,4]pyrazolo[1,5-a]pyridine-3-carboxamide

[0249] A reaction flask was charged with 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-4- oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2',3':3,4]pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.35 g, 1.00 mmol) and dichloromethane (20.00 mL), and concentrated sulfuric acid (2.00 mL, 20.00 mmol) was added slowly to the reaction system. After stirring at room temperature for about 2.5 h, the stirring was stopped, and the reaction solution was slowly added to water. The aqueous phase was extracted with DCM (200 mL x 2), and the combined organic phase was washed twice with water and concentrated. The concentrate was purified by column chromatography (EA:PE (v:v) = 2:3) to obtain a light yellow solid (0.21 g, yield: 57.06%). LC-MS (ESI, pos.ion) m / z: 368.2 [M+H] + .

[0250] Step 2: Synthesis of 2-amino-4-hydroxy-1-(3-methoxy-2,6-dimethylphenyl)-4,5,6,7- tetrahydro-1H-pyrrolo[2',3':3,4]pyrazolo[1,5-a]pyridine-3-carboxamide

[0251] Under an ice water bath, to a solution of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)- 4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2',3':3,4]pyrazolo[1,5-a]pyridine-3-carboxamide (0.03 g, 0.082 mmol) in MeOH (5.00 mL) was added NaBH4(0.0062 g, 0.16 mmol) in portions. The reaction was stirred at the same temperature, and the reaction was monitored by TLC until the starting material was completely consumed. The stirring was stopped, and the reaction was directly rotary evaporated. The concentrate was purified by column chromatography (EA as eluent) to obtain a light yellow solid (0.025 g, yield: 82.88%). LC-MS (ESI, pos.ion) m / z: 370.2 [M+H] + .

[0252] Step 3: Synthesis of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6,7-dihydro-1H- pyrrolo[2',3':3,4]pyrazolo[1,5-a]pyridine-3-carboxamide

[0253] 2-amino-4-hydroxy-1-(3-methoxy-2,6-dimethylphenyl)-4,5,6,7-tetrahydro-1H- pyrrolo[2',3':3,4]pyrazolo[1,5-a]pyridine-3-carboxamide (0.45 g, 1.22 mmol), p-toluenesulfonic acid monohydrate (0.035 g, 0.18 mmol) and toluene (10 mL) were transferred into a 125 °C stirring reaction for about 2.0 h, stop stirring, cool to room temperature, direct rotary evaporation, the concentrate was purified by column chromatography (DCM:MeOH (v:v) = 20:1) to get a light yellow solid (0.24 g, yield: 57.07%). LC-MS (ESI, pos.ion) m / z: 352.2 [M+H] + .

[0254] Step 4: Synthesis of 11-(3-methoxy-2,6-dimethylphenyl)-7,11-dihydro-8H- pyrido[1",2":1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimin-4-ol

[0255] 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6,7-dihydro-1H-pyrrolo[2',3':3,4]pyrazolo[1,5- a]pyridine-3-carboxamide (0.23 g, 0.56 mmol), TsOH H2O (0.019 g, 0.098 mmol) and trimethyl orthoformate (8.00 mL) were placed in a reaction bottle, which was transferred into a 40 °C oil bath for reaction; TLC was used to monitor the reaction until the starting material was completely consumed, the heating was turned off, and the reaction was cooled to room temperature. The reaction solution was concentrated under vacuum at 45 °C to obtain a light yellow solid crude compound (0.18 g, yield: 76.10%). LC-MS (ESI, pos.ion) m / z: 362.2 [M+H] + .

[0256] Step 5: Synthesis of 4-chloro-11-(3-methoxy-2,6-dimethylphenyl)-7,11-dihydro-8H- pyrido[1",2":1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine

[0257] Into a reaction flask, 11-(3-methoxy-2,6-dimethylphenyl)-7,11-dihydro-8H- pyrido[1”,2”:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-4-ol (0.18 g, 0.50 mmol) and phosphorus oxychloride (6.00 mL) were placed and moved to a 100 °C oil bath kettle for reaction; TLC was used to monitor the reaction until the starting material was consumed, the heating was turned off, and the reaction was concentrated under vacuum at 45 °C. The concentrate was purified by column chromatography (EA:PE (v:v) = 1:2) to give a white solid (0.12 g, yield: 63.43%). LC-MS (ESI, pos.ion) m / z: 380.2 [M+H] + .

[0258] Step 6: Synthesis of 11-(3-methoxy-2,6-dimethylphenyl)-7,11-dihydro-8H- pyrido[1”,2”:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-4-amine

[0259] Into a reaction flask, 4-chloro-11-(3-methoxy-2,6-dimethylphenyl)-7,11-dihydro-8H- pyrido[1”,2”:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidine (0.12 g, 0.32 mmol) and ammonia water (6.00 mL) and 1,4-dioxane (3.00 mL) were placed and sealed, and moved to a 140 °C oil bath kettle for reaction overnight; the reaction was stopped, cooled to room temperature, and concentrated under vacuum. The concentrate was purified by silica gel column chromatography (EA as eluent) to give a white solid (0.09 g, yield: 79.04%).

[0260] Step 7: Synthesis of (S)-3-(4-amino-7,8-dihydro-11H-pyrido[1”,2”:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol

[0261] To a solution of 11-(3-methoxy-2,6-dimethylphenyl)-7,11-dihydro-8H- pyrido[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (0.125 g, 0.35 mmol) in DCM (10.00 mL) was added BBr3(1.75 mL, 1.75 mmol, 1.0 M) slowly under ice water bath, the reaction was stirred at the same temperature for about 15 min, then transferred to room temperature to stir for about 2.0 h, a little of methanol was added slowly to quench the reaction, the organic liquid was removed directly by rotary evaporation under reduced pressure, the concentrate was concentrated under vacuum at 45 °C, the concentrate was purified by column chromatography (DCM:MeOH (v:v) = 14:1), and chiral resolution to obtain

[0262] White solid (S)-3-(4-amino-7,8-dihydro-11H-pyrido[l",2':l',5']pyrazolo[4',3':4,5] pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol (0.028 g, yield: 21.89%). Resolution method: (Waters SFC TI-00631 column: Chiralcel IA Chiral column 10 x 250 mm, 5 μm, separation condition: 35% isopropyl alcohol + 65% CO2, flow rate 8 mL / min); LC-MS (ESI, pos.ion) m / z: 347.10, 348.10 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.08 (s, 1H), 7.30 (d, J = 9.9 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.65 (s, 2H), 6.24 - 6.12 (m, 1H), 4.19 (t, J = 7.7 Hz, 2H), 2.68 (d, J = 3.3 Hz, 2H), 1.77 (s, 3H), 1.68 (s, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 158.94 (s), 156.68 (s), 154.48 (s), 153.90 (s), 152.29 (s), 134.70 (s), 129.50 (s), 127.92 (s), 126.94 (s), 126.48 (s), 123.81 (s), 118.57 (s), 115.45 (s), 100.82 (s), 92.87 (s), 46.73 (s), 24.70 (s), 17.52 (s), 11.47 (s); HR-MS m / z: 347.1672 [M+H] + .

[0263] Example 4: (S)-4-amino-11-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7,8- dihydro-6H-pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(l lH)- one

[0264] Step 1: Synthesis of 5-methyl-2-nitro-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)- one

[0265] To a solution of 3-nitro-lH-pyrazole-5-carboxylic acid (2.0 g, 12.73 mmol) and 2-(methylamino)ethan-l-ol (1.43 g, 19.09 mmol) in dichloromethane (20 mL) was added slowly dropwise sulfurous acid chloride (7.75 g, 63.65 mmol) and one drop of DMF at -5 °C, after 10 min of stirring at this temperature, the reaction was transferred to 50 °C for 16 h. After the end of the reaction, it was cooled to room temperature, DCM was removed under reduced pressure, the residue was dissolved in DMF (20 mL), triethylamine (3.86 g, 38.19 mmol) was added, and it was left to react at room temperature for about 16 h. The reaction was stopped; it was poured into ice water, the aqueous phase was washed with dichloromethane (3 x 50 mL), the organic phases were combined and washed with a saturated NaCl solution (3 x 20 mL), the organic phases were combined and dried with Na2S04, filtered and evaporated; it was passed through a column (eluent: EA:PE (v:v) = 1:10 to 1:4), the effluents were collected and evaporated; it was concentrated under reduced pressure. White solid (1.8 g, 72.07 %); LC-MS (ESI, pos.ion) m / z: 196.1, 197.1 [M+1] + ; 1 H NMR (400 MHz, CDC13) δ 7.42 (s, 1H), 4.57 - 4.49 (m, 2H), 3.95 - 3.74 (m, 2H), 3.20 (s, 3H).

[0266] Step 2: Synthesis of 2-amino-5-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)- one

[0267] To 5-methyl-2-nitro-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (1.8 g, 9.18 mmol), iron powder (2.56 g, 45.9 mmol), ammonium chloride (2.46 g, 45.9 mmol) were added to a mixture of ethanol (25 mL) and water (10 mL) and transferred to 80 °C and stirred for 3 h. The reaction was monitored by TLC and upon completion of the reaction, the reaction was stopped, cooled to room temperature and filtered. The filtrate was evaporated to get the desired compound as a light yellow solid (1.27 g, 83.28 %). LC-MS (ESI, pos.ion) m / z: 166.2, 167.2 [M+1] + .

[0268] Step 3: Synthesis of 2-amino-3-bromo-5-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one

[0269] To 2-amino-5-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (1.27 g, 7.64 mmol) was added to DCM (20 mL) and transferred to 0 °C and NBS (1.50 g, 8.40 mmol) was added in three portions and stirred. The reaction was monitored by TLC and upon completion of the reaction, the aqueous layer was washed with dichloromethane (3 x 50 mL), the organic layers were combined and washed with saturated NaCl solution (3 x 20 mL), the organic layers were combined and dried over Na2S04, filtered and evaporated. The product was recrystallized from EA / PE to get the desired compound as a light yellow solid (1.6 g, 85.43 %); LC-MS (ESI, pos.ion) m / z: 245.1, 246.1 [M+H] + Step 4: Synthesis of 2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3-bromo-5-methyl-6,7- dihydropyrazolo[l,5-a]pyrazin-4(5H)-one

[0270] A reaction flask was charged with 2-amino-3-bromo-5-methyl-6,7-dihydropyrazolo[l,5- a]pyrazin-4(5H)-one (2.10 g, 8.57 mmol), l-benzyloxy-3-iodo-2,4-dimethylbenzene (3.04 g, 9.00 mmol), palladium acetate (0.38 g, 1.71 mmol), cesium carbonate (6.98 g, 21.43 mmol), Xantphos (1.98 g, 3.43 mmol) and 1,4-dioxane (50.00 mL). After purging with nitrogen for three times, the reaction flask was moved to a 105 °C oil bath. The reaction was monitored by TLC until the starting material was consumed. The heating was turned off and water (100.0 mL) was added to the reaction mixture. The mixture was extracted with EA (100 mL x 3). The organic phase was combined and concentrated under vacuum at 45 °C. The residue was purified by column chromatography on silica gel (EA:PE (v:v) = 3: 1) to give a white solid (3.20 g, yield: 82.01%). LC-MS (ESI, pos.ion) m / z: 455.20, 457.10 [M+H] + .

[0271] Step 5: Synthesis of 2-amino-l-(3-(benzyloxy)-2,6-dimethylphenyl)-5-methyl-4-oxo- 4,5,6,7-tetrahydro-lH-pyrrolo[2',3':3,4]pyrazolo[l,5-a]pyrazine-3-carbonitrile

[0272] A reaction flask was charged with 2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3- bromo-5-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (1.60 g, 3.51 mmol), cuprous iodide (0.67 g, 3.51 mmol), L-hydroxyproline (0.92 g, 7.02 mmol), malononitrile (0.7 g, 10.53 mmol), potassium carbonate (1.46 g, 10.53 mmol) and dimethyl sulfoxide (10.00 mL). After purging with nitrogen for three times, the reaction flask was moved to a 130 °C oil bath. The reaction was monitored by TLC until the starting material was consumed. The heating was turned off and water (100.0 mL) was added to the reaction mixture. The mixture was extracted with EA (100 mL x 3). The organic phase was combined and concentrated under vacuum at 45 °C. The residue was purified by column chromatography (EA:PE (v:v) = 10: 1) to give a light yellow solid (0.32 g, yield: 20.67%). LC-MS (ESI, pos.ion) m / z: 441.20 [M+H] + .

[0273] Step 6: Synthesis of 4-amino-11-(3-(benzyloxy)-2,6-dimethylphenyl)-6-methyl-7,8- dihydro-6H-pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(l lH)- one

[0274] A reaction flask was charged with 2-amino-l-(3-(benzyloxy)-2,6-dimethylphenyl)-5- methyl-4-oxo-4,5,6,7-tetrahydro-lH-pyrrolo[2',3':3,4]pyrazolo[l,5-a]pyrazine-3-carbonitrile (0.06 g, 0.14 mmol) and formamide (8.00 mL), and was placed in a 160 °C oil bath kettle; the reaction was monitored by TLC until the starting material was consumed, the heating was turned off, water (100.0 mL) was added to the reaction, and the mixture was extracted with EA (100 mL x 3), the organic phases were combined and concentrated under vacuum at 45 °C, the concentrate was purified by silica gel column chromatography (MeOH:DCM (v:v) = 1:30) to give a white solid (0.045 g, yield: 70.67%). LC-MS (ESI, pos.ion) m / z: 468.20 [M+H] + .

[0275] Step 7: Synthesis of (S)-4-amino-11-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7,8- dihydro-6H-pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(l lH)-one

[0276] A reaction flask was charged with 4-amino-11-(3-(benzyloxy)-2,6-dimethylphenyl)- 6-methyl-7,8-dihydro-6H-pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin- 5(l lH)-one (0.40 g, 0.86 mmol) and dichloromethane (20.00 mL), concentrated sulfuric acid (0.23 mL, 4.30 mmol) was added with stirring at room temperature, stirred at room temperature for about 6.0 h, stop stirring, add a little water to the reaction system slowly, adjust the pH of the solution to 7 with saturated NaHC03 aqueous solution, then extract with EA (200 mL x 2), combine the organic phase, wash the organic phase with water twice, then concentrate, the concentrate was purified by silica gel column chromatography (DCM:MeOH (v:v) = 20:1) to obtain white racemic compound 4-amino-11-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7,8-dihydro-6H- pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(l lH)-one 0.17 g; the racemic compound was separated by chiral resolution to obtain white solid (S)-4-amino-11-(3- hydroxy-2,6-dimethylphenyl)-6-methyl-7,8-dihydro-6H-pyrazino[l",2':l',5']pyrazolo[4',3':4,5] pyrrolo[2,3-d]pyrimidin-5(l lH)-one (0.03 g, yield: 9.29%). Resolution method: (Waters SFC TI-00631 column: chiral column 10 x 250 mm, 5 μm, separation conditions: 35% isopropanol + 65% CO2, flow rate 8 mL / min); LC-MS (ESI, pos.ion) m / z: 378.10 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 4.46 (t, J = 6.2 Hz, 2H), 3.91 (t, J = 6.3 Hz, 2H), 3.11 (s, 3H), 1.78 (s, 3H), 1.68 (s, 3H); HR-MS: m / z: 378.1688 [M+H] + .

[0277] Example 5: (S)-3-(4-amino-6-methyl-5,6,7,8-tetrahydro-11H-pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol

[0278] To a solution of 4-amino-11-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7,8- dihydro-6H-pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(l lH)- one (0.34 g, 0.90 mmol) in THF (10.00 mL) at 0 °C, LiAlH4-THF (3.6 mL, 9.0 mmol, 2.5 M) was added slowly, then stirred at 70 °C for about 7.0 h, stop stirring, add a little water to the reaction system slowly, remove the organic liquid directly by rotary evaporation under reduced pressure, the concentrate was purified by silica gel column chromatography (DCM:MeOH (v:v) = 15:1) to give white racemate 0.19 g; the racemate was resolved by chiral separation to give white solid isomer (S)-3-(4-amino-6-methyl-5,6,7,8-tetrahydro-11H-pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol (0.06 g, yield: 18.33%). Resolution method: (Waters SFC TI-00631 column: Chiralcel IA column 10 x 250 mm, 5 μm, separation condition: 25% isopropanol + 75% CO2, flow rate 8 mL / min); LC-MS (ESI, pos.ion) m / z: 364.15 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.06 (s, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.43 (s, 2H), 4.15 (s, 4H), 2.91 (t, J = 5.2 Hz, 2H), 2.47 (s, 3H), 1.76 (s, 3H), 1.67 (s, 3H); HR-MS m / z: 364.1880 [M+H] + .

[0279] Example 6: (R)-3-(4-amino-6,7-dimethyl-5,6,7,8-tetrahydro-11H-pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol

[0280] Step 1: Synthesis of (6R)-2-amino-5,6-dimethyl-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazin-4-one

[0281] To (6R)-2-nitro-5,6-dimethyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-4-one (1.50 g, 7.14 mmol), iron powder (1.99 g, 35.70 mmol) was added to ethanol (30 mL), and a prepared solution of ammonium chloride (1.91 g, 35.70 mmol) in water (5 mL) was added. After the addition was complete, the reaction was stirred at 80 °C for about 10 h. TLC tracking, the raw material was reacted. The reaction liquid was added to EA (50 mL), and the silica was extracted and filtered. The filter cake was washed with EA (50 mL). The reaction liquid was directly concentrated to dryness. Dichloromethane (100 mL) was added (stirring at room temperature for 30 min), and anhydrous sodium sulfate was dried. The filtrate was filtered and concentrated under reduced pressure at 60 °C. A light yellow solid (1.1 g, yield: 85.53%) was obtained.

[0282] Step 2: Synthesis of (6R)-2-amino-3-bromo-5,6-dimethyl-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazin-4-one

[0283] To (6R)-2-amino-5,6-dimethyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-4-one (1.10 g, 6.10 mmol) was added to dichloromethane (50 mL), and the solution was stirred at 0 °C. NBS (1.19 g, 6.71 mmol) was added, and the reaction was incubated for about 2 h. TLC tracking, the raw material was reacted. The reaction liquid was added to a saturated brine solution (100 mL) and washed. The organic phase was taken. The aqueous phase was washed with DCM (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give a brown oil (1.50 g, yield: 94.84%).

[0284] Step 3: Synthesis of (R)-2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3-bromo-5,6- dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one

[0285] (6R)-2-amino-3-bromo-5,6-dimethyl-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazin-4-one (1.3 g, 5.02 mmol), l-(benzyloxy)-3-iodo-2,4-dimethylbenzene (1.87 g, 5.52 mmol), palladium acetate (0.56 g, 2.51 mmol), cesium carbonate (3.27 g, 10.04 mmol) and xantphos (0.73 g, 1.25 mmol) were added into 1,4-dioxane (10 mL), protected by nitrogen, and transferred to 110 °C for stirring for about 6 h. TLC tracking, the raw material was reacted completely. The reaction solution was directly concentrated, and the concentrate was purified by column chromatography (PE:EA (v:v) = 5:1-1:1) to obtain a brown solid (0.417 g, yield: 17.71%). LC-MS (ESI, pos.ion) m / z: 469.3, 471.3 [M+H] + .

[0286] Step 4: Synthesis of (R)-2-amino-l-(3-(benzyloxy)-2,6-dimethylphenyl)-5,6- dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-pyrrolo[2',3':3,4]pyrazolo[l,5-a]pyrazine-3- carboxamide

[0287] (R)-2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3-bromo-5,6-dimethyl-6,7- dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (0.32 g, 0.68 mmol), cuprous iodide (0.065 g, 0.34 mmol), potassium carbonate (0.28 g, 2.04 mmol), malononitrile (0.13 g, 2.04 mmol) and 4-hydroxyproline (0.045 g, 0.34 mmol) were added into DMSO (6 mL), protected by nitrogen, and transferred to 100 °C for stirring for about 15 h. The reaction was stopped. TLC tracking, the raw material was reacted completely. The reaction solution was directly added to mercaptosilica gel. Stirring for 10 min. Filtration, concentration, and the concentrate was purified by column chromatography (PE:EA (v:v) = 2:1-1:2) to obtain a light brown solid (0.16 g, yield: 51.63%).

[0288] Step 5: Synthesis of (7R)-4-amino-l l-[3-(benzyloxy)-2,6-dimethylphenyl]-6,7- dimethyl-5,6,7,8-tetrahydropyrazino[2',l':5',l']pyrazolo[3',4':2,3]pyrrolo[5,4-d]pyrimidin- 5-one

[0289] To (6R)-2-amino-l-[3-(benzyloxy)-2,6-dimethylphenyl]-5,6-dimethyl-4- oximino-4,5,6,7-tetrahydropyrrolo[2',3':3,4]pyrazolo[l,5-a]pyrazine-3-carbonitrile (0.16 g, 0.35 mmol) was added to formamide (5 mL) and transferred to 160 °C for stirring for about 6 h. To the reaction solution was added tap water (30 mL) and stirred at room temperature for 20 min, suction filtered, and the filter cake was washed with tap water. The filter cake was dissolved in dichloromethane (50 mL). Concentration was performed, and the concentrate was purified by column chromatography (DCM:MeOH (v:v) = 100:1-50:1) to give a light yellow solid (0.062 g, yield: 36.57%). LC-MS (ESI, pos.ion) m / z: 482.30 [M+H] + .

[0290] Step 6: Synthesis of (7R)-4-amino-l l-(3-hydroxy-2,6-dimethylphenyl)-6,7- dimethyl-5,6,7,8-tetrahydropyrazino[2',l':5',l']pyrazolo[3',4':2,3]pyrrolo[5,4-d]pyrimidin- 5-one

[0291] To (7R)-4-amino-l l-[3-(benzyloxy)-2,6-dimethylphenyl]-6,7-dimethyl-5,6,7,8- tetrahydropyrazino[2',l':5',l']pyrazolo[3',4':2,3]pyrrolo[5,4-d]pyrimidin-5-one (0.062 g, 0.13 mmol) was added to dichloromethane (5 mL) and dissolved. Sulfuric acid (0.093 g, 0.95 mmol) was added and stirred at room temperature for about 6 h. The reaction solution was added to ice water (10 mL) with a dropper, saturated sodium bicarbonate was added to adjust the pH to basic, EA (50 mL x 5) was added, and the combined organic phase was dried over anhydrous sodium sulfate. Filtration and concentration were performed to give a brownish yellow solid (0.05 g, yield: 99.27%).

[0292] Step 7: Synthesis of (R)-3-(4-amino-6,7-dimethyl-5,6,7,8-tetrahydro-l lH- pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-l l-yl)-2,4-dimethylphenol

[0293] To (7R)-4-amino-11-(3-hydroxy-2,6-dimethylphenyl)-6,7-dimethyl-5,6,7,8- tetrahydropyrazino[2',1':5',1']pyrazolo[3',4':2,3]pyrrolo[5,4-d]pyrimidin-5-one (0.05 g, 0.13 mmol) was added to THF (10 mL) and transferred to stirring at 0 °C. Lithium aluminum hydride in tetrahydrofuran (4 mL, 2.5 M) was added dropwise and the reaction was stirred at 70 °C for about 4 h. The reaction was cooled to room temperature. The reaction was quenched by the dropwise addition of tap water (0.5 mL). The reaction was directly concentrated. The residue was purified by column chromatography (DCM:MeOH (v:v) = 50:1-30:1) to give a white solid (0.0035 g, yield: 7.26 %). HRMS-ESI m / z: 378.2054, 379.2072 [M+H] + .

[0294] Example 7: (S)-3-(4-amino-6,7-dimethyl-5,6,7,8-tetrahydro-11H-pyrazino[1',2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol

[0295] Step 1: Synthesis of (S)-N-(1-hydroxypropan-2-yl)-N-methyl-3-nitro-1H-pyrazole-5- carboxamide

[0296] To a reaction flask was added 3-nitro-1H-pyrazole-5-carboxylic acid (13 g, 82.76 mmol), 3-(ethylenemethylideneamino)-N,N-dimethylpropan-1-amine hydrochloride (20.62 g, 107.59 mmol) and 1-hydroxybenzotriazole (14.54 g, 107.59 mmol), then (2S)-2-(methylamino)propan-1-ol (8.11 g, 91.04 mmol), triethylamine (12.56 g, 124.14 mmol) and dichloromethane (300 mL) were added and the reaction was stirred at room temperature for 16 h. The reaction was stopped by the addition of saturated ammonium chloride (60 mL) and the reaction was extracted with dichloromethane (80 mL) several times, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (DCM:MeOH (v:v) = 100:1) to give the target compound (S)-N-(1-hydroxypropan-2-yl)-N-methyl-3-nitro-1H-pyrazole-5-carboxamide (12.3 g, yield: 65.13 %). LC-MS (ESI, pos.ion) m / z: 229.09 [M+H] + .

[0297] Step 2: Synthesis of (S)-5,6-dimethyl-2-nitro-6,7-dihydropyrazolo[l,5- a]pyrazin-4(5H)-one

[0298] (S)-N-(l-hydroxypropan-2-yl)-N-methyl-3-nitro-lH-pyrazole-5-carboxamide (9.4 g, 41.19 mmol), triphenylphosphine (19.45 g, 74.14 mmol) were weighed into a reaction flask, appropriate amount of tetrahydrofuran (200 mL) was added, nitrogen protection, stirred for 30 min at 0 °C; di-tert-butyl azodicarboxylate (20.87 g, 90.62 mmol) was added, and the temperature was raised to 50 °C for 12 h; TLC detection of raw materials reaction was complete. Stop the reaction, cool to room temperature, the reaction liquid was directly spin dry, then column chromatography PE:EA((v:v) = 100:40-100:70) purification to obtain (S)-5,6-dimethyl-2-nitro-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (4.4 g, yield: 50.82%). LC-MS (ESI, pos.ion) m / z: 211.11 [M+H] + .

[0299] Step 3: Synthesis of (S)-2-amino-5,6-dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)- one

[0300] (S)-5,6-dimethyl-2-nitro-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (4 g, 19.03 mmol) was dissolved in ethanol (100 mL), iron powder (5 g, 89.53 mmol) and ammonium chloride (7 g, 130.87 mmol) in water (20 mL) were added; the temperature was raised to 80 °C and refluxed for 1 h. TLC detection of raw materials reaction was complete, diatomite filtration, water, ethyl acetate extraction several times, anhydrous sodium sulfate drying, filtration, concentration, column chromatography (DCM:MeOH (v:v) = 100:1.8-100:2.8) purification to obtain (S)-2-amino-5,6-dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (2.2 g, Yield 64.15%) LC-MS (ESI, pos.ion) m / z: 181.21 [M+H] +

[0301] Step 4: Synthesis of (S)-2-amino-3-bromo-5,6-dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin- 4(5H)-one

[0302] (S)-2-amino-5,6-dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (2.5 g, 13.87 mmol) was dissolved in DCM (60 mL), NBS (2.59 g, 14.56 mmol) was added at 0 °C; the solution color was darkened, TLC detection after 1 h reaction, the starting material was completely reacted. Quenching with water (30 mL), dichloromethane (30 mL x 3) extraction, saturated sodium chloride (25 mL) washing once, anhydrous sodium sulfate drying, sample column chromatography (DCM:MeOH (v:v) = 100:1.8) purification, the target compound (S)-2-amino-3-bromo-5,6-dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (2.9 g, yield: 80.68%) was obtained as a red solid.

[0303] Step 5: Synthesis of (S)-2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3-bromo-5,6- dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one

[0304] (S)-2-amino-3-bromo-5,6-dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (2.8 g, 10.81 mmol), l-(benzyloxy)-3-iodo-2 and 4-xylene (5.48 g, 16.21 mmol) were dissolved in 1,4-dioxane (50 mL), palladium acetate (1.0 g, 4.43 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.00 g, 8.65 mmol), cesium carbonate (5.28 g, 16.21 mmol) were weighed into the reaction bottle, nitrogen protection, heating to 110 °C reflux reaction; reaction for 2 days, TLC detection, a small amount of starting material remained; filter out the insoluble impurities, concentrated, column chromatography (PE:EA (v:v) = 100:60) purification, the target compound (S)-2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3-bromo-5,6-dimethyl-6,7- dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (8 g) was obtained, mixed with part of the ligand. LC-MS (ESI, pos.ion) m / z: 469.12, 471.20 [M+H] +

[0305] Step 6: Synthesis of (S)-2-amino-l-(3-(benzyloxy)-2,6-dimethylphenyl)-5,6-dimethyl-4-oxo- 4,5,6,7-tetrahydro-lH-pyrrolo[2',3':3,4]pyrazolo[l,5-a]pyrazine-3-carbonitrile

[0306] (S)-2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3-bromo-5,6-dimethyl-6,7- dihydro pyrazolo[1,5-a]pyrazin-4(5H)-one (1 g, 2.13 mmol), malononitrile (0.42 g, 6.39 mmol), L-hydroxyproline (0.14 g, 1.06 mmol), cuprous iodide (0.4 g, 2.13 mmol) and potassium carbonate (0.88 g, 6.39 mmol) were charged into a reaction flask, DMSO (10 mL) was added; nitrogen protection, temperature was raised to 100 °C for 20 h; TLC detection of the raw material was substantially complete, stop heating, cool to room temperature, filter out the insoluble impurities, add water (30 mL), extract with ethyl acetate (40 mL x 3), wash with saturated sodium chloride (40 mL) once, dry over anhydrous sodium sulfate, spin dry and mix, column chromatography (DCM:MeOH (v:v) = 100:1.5) to purify the target compound (S)-2-amino-1 -(3-(benzyloxy)-2,6-dimethylphenyl)-5,6-dimethyl-4-oxo-4,5,6,7- tetrahydro-1 H-pyrrolo[2',3':3,4]pyrazolo[1,5-a]pyrazine-3-carbonitrile (0.54 g, yield: 55.76%) LC-MS (ESI, pos.ion) m / z: 455.42 [M+H] +

[0307] Step 7: Synthesis of (S)-4-amino-1 1 -(3-(benzyloxy)-2,6-dimethylphenyl)-6,7- dimethyl-7,8-dihydro-6H-pyrazino[1 ",2":1 ',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin- 5(1 1 H)-one

[0308] (S)-2-amino-l-(3-(benzyloxy)-2,6-dimethylphenyl)-5,6-dimethyl-4-oxo-4,5,6,7- tetrahydro-lH-pyrrolo[2',3':3,4]pyrazolo[l,5-a]pyrimidine-3-carbonitrile (1.4 g, 3.08 mmol) was dissolved in formamide (50 mL) and warmed to 160 °C for 16 h. TLC indicated the reaction was complete. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL) three times. The combined organic layers were washed with saturated sodium chloride (20 mL) once, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA (v / v) = 100:50-100:70) to give the target compound (S)-4-amino-l l-(3-(benzyloxy)-2,6-dimethylphenyl)-6,7-dimethyl-7,8-dihydro- 6H-pyrazino[l",2":l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(l lH)-one (1.2 g, 80.9% yield). LC-MS (ESI, pos.ion) m / z: 482.53 [M+H] + ; 1 H NMR (599 MHz, CDC13) δ 8.37 (s, 1H), 7.46 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 5.76 (s, 2H), 5.11 (s, 2H), 4.61 (dd, J = 13.0, 4.8 Hz, 1H), 4.28 (dd, J = 13.0, 2.5 Hz, 1H), 3.95 (ddt, J = 8.8, 6.5, 4.7 Hz, 1H), 3.22 (s, 3H), 1.99 - 1.94 (m, 6H), 1.45 (d, J = 6.8 Hz, 3H).

[0309] Step 8: Synthesis of (S)-4-amino-l l-(3-hydroxy-2,6-dimethylphenyl)-6,7-dimethyl-7,8- dihydro-6H-pyrazino[l",2":l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(l lH)-one

[0310] (S)-4-amino-11-(3-(benzyloxy)-2,6-dimethylphenyl)-6,7-dimethyl-7,8-dihydro- 6H-pyrazino[1”,2”:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-5(11H)-one (1.2 g, 2.49 mmol) was dissolved in DCM (20 mL), concentrated sulfuric acid (2.44 g, 24.9 mmol) was added, stirred at room temperature for 2 h; water (20 mL) was added, potassium carbonate was added to adjust the pH to basic, TLC detection of the complete reaction of the raw material. Dichloromethane (20 mL x 3) was extracted, washed once with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH (v:v) = 100:3) to obtain the target compound (S)-4-amino-11-(3-hydroxy-2,6-dimethylphenyl)-6,7-dimethyl-7,8-dihydro- 6H-pyrazino[1”,2”:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-5(11H)-one (400 mg, yield: 41.01%) as a white solid. LC-MS (ESI, pos.ion) m / z: 392.68 [M+H] + ;

[0311] Step 9: Synthesis of (S)-3-(4-amino-6,7-dimethyl-5,6,7,8-tetrahydro-11H- pyrazino[1”,2”:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol

[0312] (S)-4-amino-11-(3-hydroxy-2,6-dimethylphenyl)-6,7-dimethyl-7,8-dihydro-6H- pyrazino[1”,2”:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-5(11H)-one (380 mg, 0.97 mmol) was dissolved in THF (35 mL), LiAlH4(3.1 mL, 7.76 mmol) was added at 0 °C, and the reaction was heated to 70 °C and refluxed for 3 h; TLC detection, complete reaction of the raw material, stop heating, cool to room temperature, quench with water at 0 °C, add silica gel, and purify by column chromatography (DCM:MeOH (v:v) = 100:7) to obtain a white solid, which was separated by chiral separation to obtain (S)-3-(4-amino-6,7-dimethyl-5,6,7,8-tetrahydro-11H-pyrazino[1”,2”:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol (100 mg, yield 27.29%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.07 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.46 (s, 2H), 4.59 (d, J = 15.8 Hz, 1H), 4.16 (dd, J = 12.3, 4.0 Hz, 1H), 3.89 (d, J = 15.9 Hz, 1H), 3.80 (dd, J = 12.3, 9.1 Hz, 1H), 3.00 - 2.82 (m, 1H), 2.40 (s, 3H), 1.76 (d, J = 2.6 Hz, 3H), 1.67 (d, J = 2.8 Hz, 3H), 1.15 (d, J = 6.3 Hz, 3H).

[0313] Example 8: (8S,S)-3-(4-amino-6,8-dimethyl-5,6,7,8-tetrahydro-11H-pyrazino[1",2":1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol / (8R,S)-3-(4-amino-6,8-dimethyl-5,6,7,8-tetrahydro-11H-pyrazino[1",2":1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol and Example 9: (8R,S)-3-(4-amino-6,8-dimethyl-5,6,7,8-tetrahydro-11H-pyrazino[1",2":1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol / (8R,S)-3-(4-amino-6,8-dimethyl-5,6,7,8-tetrahydro-11H-pyrazino[1",2":1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol

[0314] Example 8 compound:

[0315] Example 9 compound:

[0316] Step 1: Synthesis of ethyl 1-(1-(tert-butoxycarbonyl)amino)propan-2-yl)-3-nitro-1H-pyrazole-5-carboxylate

[0317] 5-nitro-pyrazole-3-carboxylic acid ethyl ester (1 g, 5.40 mmol) and triphenylphosphine (2.55 g, 9.72 mmol) were dissolved in tetrahydrofuran (40 mL), and an appropriate amount of N-(2-hydroxypropyl)tert-butylcarbamate (1.14 g, 6.48 mmol) was added, and the mixture was stirred under nitrogen protection at 0 °C for 30 min; di-tert-butyl azodicarboxylate (2.49 g, 10.8 mmol) was added in two portions; the reaction was allowed to proceed overnight at room temperature; TLC detection showed that the reaction was complete, and the reaction was stopped; water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, concentrated and triturated, and purified by column chromatography (PE:EA (v / v) = 100:5) to obtain 1-(1-(tert-butoxycarbonyl)amino)propan-2-yl)-3-nitro-1H-pyrazole-5-carboxylic acid ethyl ester (1.3 g, yield: 70.30%) as a white solid. LC-MS (ESI, pos.ion) m / z: 343.21 [M+H] + .

[0318] Step 2: Synthesis of 1-(1-amino-propan-2-yl)-3-nitro-1H-pyrazole-5-carboxylic acid ethyl ester

[0319] 1-(1-(tert-butoxycarbonyl)amino)propan-2-yl)-3-nitro-1H-pyrazole-5-carboxylic acid ethyl ester (4 g, 11.684 mmol) was dissolved in a solution of hydrogen chloride (7.277 g, 58.42 mmol) in 1,4-dioxane (15 mL), and the mixture was allowed to react at room temperature for 1 h; the reaction solution gradually changed from colorless and clear to white turbidity, and a large amount of white solid was precipitated; TLC detection showed that the reaction was complete, and the reaction was stopped, and the white solid crude product 1-(1-amino-propan-2-yl)-3-nitro-1H-pyrazole-5-carboxylic acid ethyl ester (2.5 g, yield: 88.33%) was obtained by concentration; the solid was directly used in the next step. LC-MS (ESI, pos.ion) m / z: 243.20 [M+H] + .

[0320] Step 3: Synthesis of 7-methyl-2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[0321] Dissolve 1-(1-aminopropan-2-yl)-3-nitro-1H-pyrazole-5-carboxylic acid ethyl ester (8 g, 33.03 mmol) in a mixture of tetrahydrofuran (50 mL) and water (50 mL), completely dissolved; after stirring at room temperature for 5 min, add sodium carbonate (14 g, 132.12 mmol), stir at room temperature overnight, stop the reaction. Pour the reaction solution into water (5 mL), extract with ethyl acetate (10 mL x 3), wash with saturated sodium chloride (15 mL) once, dry over anhydrous sodium sulfate, concentrate, purify by column chromatography (DCM:MeOH (v:v) = 100:1) to obtain white solid 7-methyl-2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (6 g, yield: 92.61%). LC-MS (ESI, pos.ion) m / z: 197.17 [M+H] + .

[0322] Step 4: Synthesis of 5,7-dimethyl-2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[0323] Dissolve 7-methyl-2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (7 g, 35.69 mmol) in DMF (40 mL), stir at 0 °C for 5 min, then add NaH (1.43 g, 35.69 mmol), stir for another 30 min after adding, then add iodomethane (5.07 g, 35.69 mmol) dropwise, react at 0 °C for 1 h; TLC detects that the raw material is completely reacted, stop the reaction by adding crushed ice, extract with ethyl acetate (60 mL x 3) three times, wash with saturated sodium chloride (50 mL) once, dry over anhydrous sodium sulfate, filter and concentrate to obtain white solid crude product 5,7-dimethyl-2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (10 g), which is directly used in the next step. LC-MS (ESI, pos.ion) m / z: 211.13 [M+H] + .

[0324] Step 5: Synthesis of 2-amino-5,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[0325] 5,7-Dimethyl-2-nitro-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (7g, 33.3 mmol) was dissolved in EtOH (120 mL), iron powder (7.44 g, 133.2 mmol) was added, then a solution of ammonium chloride (7.12 g, 133.2 mmol) in water (30 mL) was added; the reaction was heated to 80 °C and refluxed for 45 min; TLC indicated that the starting material was completely consumed, the reaction was stopped, filtered, the filtrate was added water (60 mL), extracted with dichloromethane (100 mL) several times, concentrated and purified by column chromatography (DCM:MeOH (v:v) = 100:2) to give 2-amino-5,7-dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (6g, yield: 99.97%) as a white solid. LC-MS (ESI, pos.ion) m / z: 188.13 [M+H] + ;

[0326] Step 6: Synthesis of 2-amino-3-bromo-5,7-dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one

[0327] 2-Amino-5,7-dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (6.5 g, 36.07 mmol) was dissolved in DCM (100 mL), after stirring for 5 min at -10 °C, NBS (6.42 g, 36.07 mmol) was added in portions, the reaction was continued at low temperature for 15 min. TLC indicated that the starting material was completely consumed, the reaction was stopped, quenched with water (20 mL); extracted with dichloromethane (50 mL) several times, washed with saturated sodium chloride once, dried over anhydrous sodium sulfate, purified by column chromatography (DCM) to give 2-amino-3-bromo-5,7-dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (7g, yield: 74.9%) as a white solid. LC-MS (ESI, pos.ion) m / z: 259.06 [M+H] + .

[0328] Step 7: Synthesis of 3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-5,7-dimethyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one

[0329] 2-amino-3-bromo-5,7-dimethyl-6,7-dihydropyrano[1,5-a]pyrazol-4(5H)-one (3g, 11.58 mmol), 1-(methoxy)-3-iodo-2,4-dimethylbenzene (3.64 g, 13.90 mmol) were dissolved in 1,4-dioxane (50 mL), palladium acetate (1.04 g, 4.63 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.36 g, 9.26 mmol), potassium tert-butoxide (1.95 g, 17.37 mmol) were added, and the reaction was refluxed at 110 °C under nitrogen protection. The reaction was carried out overnight, and TLC detection showed that the starting material was completely reacted. The insoluble impurities were filtered off, the filtrate was concentrated, and column chromatography (PE:EA (v:v) = 100:40) was used for purification to obtain the target compound 3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-5,7-dimethyl-6,7-dihydropyrano[1,5-a]pyrazol-4(5H)-one (1.4 g, Yield 30.74%). LC-MS (ESI, pos.ion) m / z: 393.09, 393.16 [M+H] +

[0330] Step 8: Synthesis of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,7-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2',3':3,4]pyrazolo[1,5-a]pyrazine-3-carbonitrile

[0331] ​3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-5,7-dimethyl-6,7- dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (1.2 g, 3.05 mmol), malononitrile (604.45 mg, 9.15 mmol), L-hydroxyproline (0.20 g, 1.52 mmol), cuprous iodide (580.87 mg, 3.05 mmol) and potassium carbonate (1264.62 mg, 9.15 mmol) were charged into a reaction flask, DMSO (50 mL) was added. Nitrogen protection, heated to 100 °C for 20 h. TLC detection of the raw material is basically complete, stop heating, cool to room temperature, filter out the insoluble impurities, add water (20 mL), extract with ethyl acetate (20 mL x 3), wash with saturated sodium chloride (40 mL) once, dry over anhydrous sodium sulfate, spin dry, mix, column chromatography (PE:EA (v:v) = 100:80) to purify the target compound 2-amino-l-(3-methoxy-2,6-dimethylphenyl)-5,7-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-pyrrolo[2',3':3,4]pyrazolo[l,5-a]pyrazine-3-carbonitrile (0.6 g, yield: 51.96%) LC-MS (ESI, pos.ion) m / z: 379.23 [M+H] +

[0332] Step 9: Synthesis of 4-amino-l l-(3-methoxy-2,6-dimethylphenyl)-6,8-dimethyl-7,8- dihydro-6H-pyrazino[l",2":l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(l lH)-one

[0333] 2-amino-l-(3-methoxy-2,6-dimethylphenyl)-5,7-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH- pyrrolo[2',3':3,4]pyrazolo[l,5-a]pyrazine-3-carbonitrile (1.2 g, 3.17 mmol) was dissolved in formamide (50 mL), heated to 160 °C for 12 h. TLC detection of the raw material is complete, add water (30 mL), extract with ethyl acetate (30 mL x 3), wash with saturated sodium chloride (20 mL) once, dry over anhydrous sodium sulfate, concentrate, column chromatography (PE:EA (v:v) = 100:70) to purify the target compound 4-amino-l l-(3-methoxy-2,6-dimethylphenyl)-6,8-dimethyl-7,8-dihydro-6H-pyrazino[l",2":l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(l lH)-one (1 g, yield: 77.78%). LC-MS (ESI, pos.ion) m / z: 406.23 [M+H] + ​.

[0334] Step 10: Synthesis of 4-amino-11-(3-hydroxy-2,6-dimethylphenyl)-6,8-dimethyl-7,8- dihydro-6H-pyrazino[l",2":l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(l lH)- one

[0335] 4-amino-11-(3-hydroxy-2,6-dimethylphenyl)-6,8-dimethyl-7,8-dihydro-6H-pyrazino[l",2":l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(l lH)-one (50 mg, 0.12 mmol) was dissolved in DCM (5 mL), added boron tribromide (90 mg, 0.36 mmol, 1 M), TLC monitored for completion of reaction. Quenched with methanol, concentrated. Purified by column chromatography (DCM:MeOH (v:v) = 100:2.5) to get the target compound 4-amino-11-(3-hydroxy-2,6-dimethylphenyl)-6,8-dimethyl-7,8-dihydro-6H-pyrazino[l",2":l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(l lH)-one (42 mg, yield: 87.01%). LC-MS (ESI, pos.ion) m / z: 392.24 [M+H] + .

[0336] Step 11: Synthesis of (8S,S)-3-(4-amino-6,8-dimethyl-5,6,7,8-tetrahydro-11H-pyrazino[l",2":l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol and (8R,S)-3-(4-amino-6,8-dimethyl-5,6,7,8-tetrahydro-11H-pyrazino[l",2":l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol

[0337] 4-amino-11-(3-hydroxy-2,6-dimethylphenyl)-6,8-dimethyl-7,8-dihydro-6H- pyrazino[1',2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(11H)-one (800 mg, 2.04 mmol) was dissolved in THF (60 mL), LiAlH4(4.9 mL, 12.24 mmol) was added at -10 °C, after the addition was completed, the reaction was warmed to 70 °C and refluxed for 4 h. TLC detection, the raw material was completely reacted, the heating was stopped, cooled to room temperature, water (3 mL) was added dropwise at 0 °C to quench, silica gel was added, column chromatography (DCM:MeOH (v:v) = 100:7) was used to obtain the product, which was subjected to chiral separation (instrument: Waters Prep SFC 150Mgm, column: Daice1 ChiralPak IC, 40mm 1D.x250 mm, 10 μm, separation conditions: 50% methanol + 50% CO2, flow rate 120 mL / min), to obtain the compound of Example 8 (peak time t R was a white solid, which was (8S,S)-3-(4-amino-6,8-dimethyl-5,6,7,8-tetrahydro- 11H-pyrazino[1',2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4- dimethylphenol or (8R,S)-3-(4-amino-6,8-dimethyl-5,6,7,8-tetrahydro-11H- pyrazino[1',2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol (50 mg, yield 6.48%), and the compound of Example 9 (peak time t R was a white solid, which was (8S,S)-3-(4-amino-6,8-dimethyl-5,6,7,8-tetrahydro- 11H-pyrazino[1',2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4- dimethylphenol or (8R,S)-3-(4-amino-6,8-dimethyl-5,6,7,8-tetrahydro-11H- pyrazino[1',2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-11-yl)-2,4-dimethylphenol (50 mg, yield 6.48%). HRMS-ESI m / z: 378.2060 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 9.42 (d, J = 3.0 Hz, 1H), 8.06 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.43 (s, 2H), 4.35 (dt, J = 11.4, 5.5 Hz, 1H), 4.24 (dd, J = 15.2, 3.2 Hz, 1H), 4.01 (dd, J = 15.2, 2.9 Hz, 1H), 3.04 (dd, J = 12.0, 4.4 Hz, 1H), 2.57 (dd, J = 12.0, 7.1 Hz, 1H), 2.45 (s, 3H), 1.77 (d, J = 4.4 Hz, 3H), 1.67 (d, J = 4.7 Hz, 3H), 1.43 (d, J = 6.4 Hz, 3H).

[0338] Example 10: 2-methyl-8-(5-methyl-1H-indazol-4-yl)-3-(trifluoromethyl)- 2,8-dihydropyrrolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine

[0339] Step 1: Synthesis of N-(4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5- methyl-1-(tetrahydro-2H-pyrazol-2-yl)-1H-indazol-4-amine

[0340] A reaction flask was charged with 4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol- 3-amine (0.50 g, 2.05 mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (0.67 g, 2.25 mmol), palladium acetate (0.092 g, 0.41 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.47 g, 0.82 mmol), cesium carbonate (1.67 g, 5.13 mmol) and 1,4-dioxane (20.0 mL), and purged with nitrogen for three times, then moved to a 100 °C oil bath for reaction; the reaction was carried out for about 16.0 h, the reaction was stopped and the reaction liquid was concentrated under vacuum at 45 °C, then purified by column chromatography (PE:EA (v:v) = 10:1) to give N-(4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-1- (tetrahydro-2H-pyrazol-2-yl)-1H-indazol-4-amine (0.57 g, yield: 60.70%) as a yellow sticky liquid. LC-MS (ESI, pos.ion) m / z: [M+H] + : 458.10, 460.05)

[0341] Step 2: Synthesis of 5-amino-2-methyl-6-(5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-4-yl)-3-(trifluoromethyl)-2,6-dihydropyrrolo[2,3-c]pyrazole-4-carbonitrile

[0342] N-(4-bromo-l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-5-methyl-l-(tetrahydro-2H- pyran-2-yl)-lH-indazol-4-amine (3.39 g, 7.40 mmol), malononitrile (1.22 g, 18.5 mmol), cuprous iodide (0.28 g, 1.48 mmol,), L-piperidine-2-carboxylic acid (0.38 g, 2.96 mmol), potassium carbonate (3.07 g, 22.20 mmol), and dimethyl sulfoxide (20.0 mL) were placed in a reaction flask, purged with nitrogen three times, and then moved to an oil bath at 100 °C for reaction; the reaction was stopped after about 16.0 h. Water (100.0 mL) and EA (200.0 mL) were added to the reaction solution, and the layers were allowed to separate. The organic phase was collected and concentrated under vacuum at 45 °C. The above concentrate was purified by column chromatography (PE:EA (v:v) = 3:1) to obtain 5-amino-2-methyl-6-(5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)-3- (trifluoromethyl)-2H,6H-pyrrolo[2,3-c]pyrazole-4-carbonitrile (1.19 g, yield 36.28%) as a light red solid. (LC-MS (ESI, pos.ion) m / z: 444.10 [M+H] + ).

[0343] Step 3: Synthesis of 2-methyl-8-(5-methyl-lH-indazol-4-yl)-3-(trifluoromethyl)-2,8- dihydropyrrolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine

[0344] 5-amino-2-methyl-6-(5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)-3- (trifluoromethyl)-2,6-dihydropyrrolo[2,3-c]pyrazole-4-carbonitrile (0.50 g, 1.13 mmol) and formamide (11.34 g, 251.78 mmol) were placed in a reaction flask, and then moved to an oil bath at 160 °C for reaction; the reaction was stopped after about 22.0 h, and water (50.0 mL) and EA (100.0 mL) were added to the reaction solution. The layers were allowed to separate, and the organic phase was collected and concentrated under vacuum at 45 °C. The above concentrate was purified by column chromatography (PE:EA (v:v) = 1:1) to obtain a light yellow solid (0.11 g, yield: 25.25%). 1H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.21 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 15.5 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.60 (s, 2H), 4.05 (d, J = 23.4 Hz, 3H), 2.11 (s, 2H); HR-MS m / z: 387.1288 [M+H] + .

[0345] Example 11: (R)-3-(4-amino-8,9,9a,10-tetrahydro-7H-pyrrolo[1",2":4",5"]pyrazolo[1",2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-13(5H)-yl)-2,4-dimethylphenol

[0346] Step 1: Synthesis of (R)-2-nitro-7,8,8a,9-tetrahydro-4H,6H-pyrrolo[1,5-a]pyrazolo[1,2-d]pyrimidin-4-one

[0347] To a solution of 3-nitro-1H-pyrazole-5-carboxylic acid (2.0 g, 25.46 mmol) and (R)-pyrrolidin-2-ylmethanol (2.58 g, 25.46 mmol) in dichloromethane (40 mL) was added sulfurous acid chloride (15.14 g, 127.30 mmol) and one drop of DMF slowly at -5 °C, after stirring at this temperature for 10 minutes, the reaction was transferred to 50 °C and reacted overnight. After the reaction was completed, it was cooled to room temperature, DCM was removed under reduced pressure, the residue was dissolved in DMF (100 mL), triethylamine (7.73 g, 76.38 mmol) was added, after reacting at room temperature for about 16 h, it was poured into ice water, the aqueous phase was washed with dichloromethane (3 x 50 mL), the combined organic layers were washed with saturated NaCl solution (3 x 20 mL), the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated, slurried with EA as solvent, and suction filtered to give a light yellow solid (2.5 g, 44.18%). LC-MS (ESI, pos.ion) m / z: 223.20 [M+H] + .

[0348] Step 2: Synthesis of (R)-2-amino-7,8,8a,9-tetrahydro-4H,6H-pyrrolo[1,5-a]pyrazolo[1,2-d]pyrimidin-4-one

[0349] (R)-2-nitro-7,8,8a,9-tetrahydro-4H,6H-pyrazolo[l,5-a]pyrazolo[l,2- d]pyrazin-4-one (2.5 g, 11.25 mmol), iron powder (3.14 g, 56.25 mmol), ammonium chloride (3.01 g, 56.25 mmol) were added to a mixture of ethanol (50 mL) and water (10 mL) and stirred at 80 °C. The reaction was monitored by TLC. After completion of the reaction, the reaction was stopped, cooled to room temperature, filtered, and the filtrate was evaporated to get the crude product as off-white solid (1.80 g, 83.23 %). LC-MS (ESI, pos.ion) m / z: 193.20 [M+H] + .

[0350] Step 3: Synthesis of (R)-2-amino-3-bromo-7,8,8a,9-tetrahydro-4H,6H- pyrazolo[l,5-a]pyrazolo[l,2-d]pyrazin-4-one

[0351] To a solution of (R)-2-amino-7,8,8a,9-tetrahydro-4H,6H-pyrazolo[l,5- a]pyrazolo[l,2-d]pyrazin-4-one (1.80 g, 9.36 mmol) in DCM (100 mL) was added NBS (1.67 g, 9.36 mmol) portion wise at 0 °C. The reaction was monitored by TLC. After completion of the reaction, a small amount of water was added. The aqueous phase was washed with dichloromethane (3 x 50 mL), the organic layers were combined and washed with saturated NaCl solution (3 x 20 mL), the organic layers were combined and dried over Na2S04, filtered and evaporated to get the crude product as light yellow solid (2.0 g, 78.78 %). LC-MS (ESI, pos.ion) m / z: 271.10, 273.05 [M+H] + .

[0352] Step 4: Synthesis of (R)-2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3- bromo-7,8,8a,9-tetrahydro-4H,6H-pyrazolo[l,5-a]pyrazolo[l,2-d]pyrazin-4-one

[0353] (R)-2-amino-7,8,8a,9-tetrahydro-4H,6H-pyrazolo[l,5-a]pyrrolo[l,2-d]pyrazin-4- one (2.0 g, 7.38 mmol), palladium acetate (0.33 g, 1.48 mmol), Xant-phos (1.71 g, 2.95 mmol), cesium carbonate (6.01 g, 18.45 mmol) and l-(benzyloxy)-3-iodo-2,4- dimethylbenzene (2.75 g, 8.12 mmol) were added into 1,4-dioxane (30 mL), after addition, nitrogen protection, transferred to 110 °C under stirring, reaction overnight. Cooled to room temperature, add a little water, the aqueous phase with EA (3 x 50 mL), combined organic layer and washed with saturated NaCl solution (3 x 20 mL), combined organic phase and concentrated under vacuum at 45 °C, the concentrate was purified by silica gel column chromatography (EA:PE (v:v) = 1:3 to 1:2), white solid (2.1 g, 59.14%) was obtained. LC-MS (ESI, pos.ion) m / z: 481.25, 483.20 [M+H] + .

[0354] Step 5: Synthesis of (R)-2-amino-l-(3-(benzyloxy)-2,6-dimethylphenyl)-4-oxo- 1,4,7,8,8a,9-hexahydro-6H-pyrrolo[l,2-a]pyrrolo[2',3':3,4]pyrazolo[l,5-d]pyrazine-3- carbonitrile

[0355] (R)-2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3-bromo-7,8,8a,9-tetrahydro-4H,6H- pyrazolo[l,5-a]pyrrolo[l,2-d]pyrazin-4-one (2.1 g, 4.36 mmol), malononitrile (0.86 g, 13.08 mmol), potassium carbonate (1.51 g, 10.9 mmol), copper iodide (0.17 g, 0.87 mmol) and L-piperidine acid (0.23 g, 1.74 mmol) were added into DMSO (20 mL), after nitrogen protection, transferred to 100 °C under stirring, reaction overnight, the raw material was reacted, water was added to the reaction system, the aqueous phase was extracted with EA (3 x 50 mL), the organic layers were combined and washed with saturated NaCl solution (3 x 20 mL), the organic phases were combined and concentrated under vacuum at 45 °C, the concentrate was purified by silica gel column chromatography (EA:PE (v:v) = 1:1-2:1), a light yellow solid (0.90 g, 44.22%) was obtained. LC-MS (ESI, pos.ion) m / z: 467.30 [M+H] + .

[0356] Step 6: Synthesis of (R)-4-amino-13-(3-(benzyloxy)-2,6-dimethylphenyl)- 8,9,9a,10-tetrahydro-7H-pyrrolo[1''',2''':4'',5'']pyrazino[1'',2'':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(13H)-one

[0357] (R)-2-amino-l-(3-(benzyloxy)-2,6-dimethylphenyl)-4-oxo-l,4,7,8,8a,9- hexahydro-6H-pyrrolo[l,2-a]pyrazolo[2',3':3,4]pyrazolo[l,5-d]pyrazine-3-carbonitrile (0.90 g, 0.93 mmol) and formamide (10.00 mL) were placed in a reaction flask, which was then moved into a 160 °C oil bath for reaction; the reaction was monitored by TLC, and the starting material was consumed completely. The heating was turned off, and the reaction was allowed to cool to room temperature. Water (100.0 mL) was added to the reaction system, which was then extracted with EA (100 mL x 3). The organic phases were combined and concentrated under vacuum at 45 °C to give the crude target compound as a light yellow solid (0.75 g, yield: 78.77%). LC-MS (ESI, pos.ion) m / z: 494.25 [M+H] + .

[0358] Step 7: Synthesis of (R)-4-amino-13-(3-hydroxy-2,6-dimethylphenyl)-8,9,9a,10- tetrahydro-7H-pyrrolo[1''',2''':4'',5'']pyrazino[1'',2'':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3- d]pyrimidin-5(13H)-one

[0359] (R)-2-amino-l-(3-(benzyloxy)-2,6-dimethylphenyl)-4-oxo-l,4,7,8,8a,9- hexahydro-6H-pyrrolo[l,2-a]pyrazolo[2',3':3,4]pyrazolo[l,5-d]pyrazine-3-carbonitrile (0.80 g, 1.62 mmol) and dichloromethane (30.00 mL) were placed in a reaction flask, and concentrated sulfuric acid (7.00 mL, 75.04 mmol) was slowly added with stirring at room temperature. The stirring was continued at room temperature for about 2.0 h. The stirring was stopped, and a small amount of water was slowly added to the reaction system. The pH of the solution was adjusted to 7 with saturated NaHC03 aqueous solution, and then the solution was extracted with EA (200 mL x 2). The organic phases were combined and washed with water twice. The organic phase was concentrated, and the concentrate was purified by silica gel column chromatography (DCM:MeOH (v:v) = 10: 1) to give the target product as a white solid (0.33 g, yield: 50.45%). LC-MS (ESI, pos.ion) m / z: 404.30 [M+H] + .

[0360] Step 8: Synthesis of (R)-3-(4-amino-8,9,9a,10-tetrahydro-7H-pyrrolo[1",2":4",5"]pyrazino[1",2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-13(5H)-yl)-2,4-dimethylphenol

[0361] To a solution of (R)-4-amino-13-(3-hydroxy-2,6-dimethylphenyl)-8,9,9a,10- tetrahydro-7H-pyrrolo[1",2":4",5"]pyrazino[1",2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3- d]pyrimidin-5(13H)-one (0.33 g, 0.82 mmol) in THF (15.00 mL) was added LiAlH4-THF (3.28 mL, 8.20 mmol, 2.5 M) slowly at 0 °C, stirred at 70 °C for about 7.0 h, the stirring was stopped, a little water was added to the reaction system slowly, the organic liquid was removed directly by rotary evaporation under reduced pressure, the concentrate was purified by silica gel column chromatography (DCM:MeOH (v:v) = 10:1) to give white solid racemate (0.17 g, yield: 53.37%). LC-MS (ESI, pos.ion) m / z: 390.20 [M+H] + ; 1 HNMR (599 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.07 (s, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.43 (s, 2H), 4.93 (d, J = 15.1 Hz, 1H), 4.39 - 4.34 (m, 1H), 3.85 (t, J = 11.1 Hz, 1H), 3.71 (d, J = 15.0 Hz, 1H), 3.23 (s, 1H), 2.80 - 2.68 (m, 1H), 2.36 (q, J = 8.8 Hz, 1H), 2.04 (d, J = 7.6 Hz, 1H), 1.88 (d, J = 8.3 Hz, 2H), 1.77 (d, J = 3.0 Hz, 3H), 1.67 (d, J = 3.0 Hz, 3H), 1.57 (dd, J = 11.9, 5.5 Hz, 1H); HR-MS m / z: 388.1896 [M+H] + .

[0362] Example 12: 3-(4-amino-6-methyl-6,7,8,9-tetrahydropyrimido[5",4":4',5']pyrrolo[2',3':3,4]pyrazolo[1,5-a][1,4]diazepin-12(5H)-yl)-2,4-dimethylphenol

[0363] Step 1: Synthesis of 5-methyl-2-nitro-5, 6, 7, 8-tetrahydro-4H-pyrazolo[l, 5- a] [l, 4]diazepin-4-one

[0364] To a solution of 3-nitro-lH-pyrazole-5-carboxylic acid (0.2 g, 1.27 mmol) and 3- (methylamino)-propanol (0.17 g, 1.91 mmol) in dichloromethane (8 mL) was added dropwise dichlorosulfoxide (0.76 g, 6.35 mmol) and one drop of DMF (0.1 mL) at -5 °C. After stirring for 10 min at -5 °C, the temperature was raised to 50 °C and the reaction was allowed to proceed for 16 h. The reaction was stopped and cooled to room temperature. DCM was removed under reduced pressure. The residue was dissolved in DMF (8 mL) and TEA (0.39 g, 3.81 mmol) was added. A large amount of flocculent precipitate appeared. The reaction was stirred at room temperature for 16 h. TLC indicated that the starting material was consumed completely. The reaction was quenched by the addition of crushed ice. The mixture was extracted with dichloromethane (20 mL x 3), washed with saturated sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (PE:EA (v:v) = 5:1-1:1) to give the target compound as a light yellow solid (0.16 g, yield: 59.79%)

[0365] Step 2: Synthesis of 2-amino-5-methyl-5, 6, 7, 8-tetrahydro-4H-pyrazolo[l, 5- a] [l, 4]diazepin-4-one

[0366] To a reaction flask were added 5-methyl-2-nitro-5, 6, 7, 8-tetrahydro-4H-pyrazolo[l, 5- a] [l, 4]diazepin-4-one (80 mg, 0.38 mmol), iron powder (0.11 g, 1.9 mmol) and ammonium chloride (0.10 g, 1.9 mmol). A mixture of EtOH (5 mL) and water (2.5 mL) was added. The reaction was heated to 80 °C and refluxed for 2 h. TLC indicated that the starting material was consumed completely. The reaction was filtered to remove insoluble impurities. The filtrate was concentrated and purified by column chromatography (DCM:MeOH (v:v) = 40:1) to give a light yellow liquid (38 mg, yield: 55.40%).

[0367] Step 3: Synthesis of 2-amino-3-bromo-5-methyl-5, 6, 7, 8-tetrahydro-4H-pyrazolo[l, 5- a] [l, 4]diazepin-4-one

[0368] 2-amino-5-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin-4-one (0.1 g, 0.55 mmol) was dissolved in DCM (5 mL), NBS (0.12 g, 0.66 mmol) was added at 0 °C, TLC test showed the starting material was consumed after 0.5 h, quenched with water (10 mL), extracted with dichloromethane (15 mL x 3), washed with saturated sodium chloride (25 mL x 3), dried over sodium sulfate, column chromatography (DCM:MeOH (v:v) = 50:1) to give 2-amino-3-bromo-5-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin-4-one (0.06 g, yield: 41.73%) as red solid.

[0369] Step 4: Synthesis of 2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3-bromo-5- methyl-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin-4-one

[0370] 2-amino-3-bromo-5-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin-4-one (100 mg, 0.39 mmol), l-(benzyloxy)-3-iodo-2,4-dimethylbenzene (0.17 g, 0.51 mmol), palladium acetate (0.018 g, 0.078 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.090 g, 0.16 mmol) and potassium tert-butoxide (0.057 g, 0.51 mmol) were charged into a reaction flask, protected by nitrogen, heated to 110 °C and refluxed for 10 h, TLC test showed the starting material was consumed, filtered to remove insoluble impurities, the filtrate was concentrated. Column chromatography on silica gel (PE:EA (v:v = 10:1) to give a yellow solid (680 mg, Yield 62.56%)

[0371] Step 5: Synthesis of 2-amino-l-(3-(benzyloxy)-2,6-dimethylphenyl)-5-methyl-4-oxo- 1,4,5,6,7,8-hexahydropyrrolo[2',3':3,4]pyrazolo[l,5-a][l,4]diazepine-3-carbonitrile

[0372] 2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3-bromo-5-methyl-5,6,7,8- tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin-4-one (5.6 g, 11.93 mmol), malononitrile (2.36 g, 35.79 mmol), L-hydroxyproline (0.62 g, 4.77 mmol), cuprous iodide (0.45 g, 2.39 mmol) and potassium carbonate (4.12 g, 29.82 mmol) were charged into a reaction flask, appropriate amount of DMSO (60 mL) was added; nitrogen protection, temperature was raised to 100 °C for 20 h; TLC detection of the raw material was substantially complete, stop heating, cool to room temperature, filter out the insoluble impurities, add water (30 mL), extract with ethyl acetate (100 mL x 3), wash with saturated sodium chloride (100 mL), dry over anhydrous sodium sulfate, concentrate, purify by column chromatography (DCM:MeOH (v:v) = 100:1.5) to obtain a light yellow solid (1 g, yield: 18.44%)

[0373] Step 6: Synthesis of 4-amino-12-(3-(benzyloxy)-2,6-dimethylphenyl)-6-methyl- 6,7,8,9-tetrahydropyrimido[5",4":4',5']pyrrolo[2',3':3,4]pyrazolo[l,5-a][l,4]diazepin- 5(12H)-one

[0374] 2-amino-l-(3-(benzyloxy)-2,6-dimethylphenyl)-5-methyl-4-oxo-l,4,5,6,7,8- hexahydropyrrolo[2',3':3,4]pyrazolo[l,5-a][l,4]diazepine-3-carbonitrile (50 mg, 0.11 mmol) was dissolved in formamide (5 mL), and the temperature was raised to 160 °C for overnight. TLC detection of the raw material was complete, add water (20 mL), extract with ethyl acetate (15 mL x 3), wash with saturated sodium chloride (20 mL), dry over anhydrous sodium sulfate, concentrate, purify by column chromatography (DCM:MeOH (v:v) = 30:1) to obtain a light yellow solid (41 mg, yield: 77.40%)

[0375] Step 7: Synthesis of 4-amino-12-(3-hydroxy-2,6-dimethylphenyl)-6-methyl- 6,7,8,9-tetrahydropyrimido[5",4":4',5']pyrrolo[2',3':3,4]pyrazolo[l,5-a][l,4]diazepin- 5(12H)-one

[0376] 4-amino-12-(3-(benzyloxy)-2,6-dimethylphenyl)-6-methyl-6,7,8,9-tetrahydropyrimido[5",4":4',5']pyrrolo[2',3':3,4]pyrazolo[l,5-a][l,4]diazepin-5(12H)-one (50 mg, 0.10 mmol) was dissolved in DCM (4 mL), concentrated sulfuric acid (0.098 g, 1 mmol) was added, stirred at room temperature for 10 h; water (15 mL) was added, potassium carbonate was added to adjust the pH to basic, TLC detection showed that the raw material was completely reacted, and the target point was generated; dichloromethane (20 mL x 3) was extracted, washed once with saturated sodium chloride (10.0 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM:MeOH (v:v) = 100:3) to obtain a light yellow solid (30 mg, yield 73.81%)

[0377] Step 8: Synthesis of 3-(4-amino-6-methyl-6,7,8,9-tetrahydropyrimido[5",4":4',5']pyrrolo[2',3':3,4]pyrazolo[l,5-a][l,4]diazepin-12(5H)-yl)-2,4-dimethylphenol

[0378] 4-amino-12-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-6,7,8,9-tetrahydropyrimido[5",4":4',5']pyrrolo[2',3':3,4]pyrazolo[l,5-a][l,4]diazepin-5(12H)-one (180 mg, 0.46 mmol) was dissolved in THF (8 mL), LiAlH4(1.2 mL, 3.26 mmol) was added at 0 °C, and the reaction was heated to 70 °C and refluxed for 18 h; TLC detection showed that a small amount of raw material remained, heating was stopped, and the temperature was cooled to room temperature; water was added dropwise at 0 °C for quenching, silica gel was added for mixing, and column chromatography (DCM:MeOH (v:v) = 100:3-100:5) was used for purification to obtain the target compound (()) (82 mg, yield: 47.24%). 1 H NMR (599 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.07 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.44 (s, 2H), 4.38 - 4.34 (m, 2H), 4.21 (s, 2H), 2.98 (t, J = 4.8 Hz, 2H), 2.26 (s, 3H), 1.76 (s, 5H), 1.67 (s, 3H); HRMS-ESI m / z: 378.2045 [M+H] + .

[0379] Example 13: (S)-3-((7S,9aS)-4-amino-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4',5']pyrazolo[1',2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-13(5H)-yl)-2,4-dimethylphenol

[0380] Step 1: Synthesis of tert-butyl (2S,5S)-2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate

[0381] (2S,5S)-1-[(tert-butoxy)carbonyl]-5-methylpyrrolidine-2-carboxylic acid (12.3 g, 53.65 mmol) was added to tetrahydrofuran (120 mL) and cooled to 0 °C. Borane tetrahydrofuran complex (6.92 g, 80.47 mmol, 1 M in THF) was added dropwise slowly. After the addition was completed, the reaction was allowed to warm to room temperature and stirred for 7 h. The reaction was quenched by the slow addition of methanol (50 mL) at 0 °C. The reaction mixture was evaporated to dryness. The residue was dissolved in dichloromethane (80 mL) and washed with water three times. The organic phase was dried over sodium sulfate and concentrated to give a yellow oil (10.00 g, 86.58% yield). LC-MS (ESI, pos.ion) m / z: 116.2 [M-Boc+H] + .

[0382] Step 2: Synthesis of ((2S,5S)-5-methylpyrrolidin-2-yl)methanol

[0383] A single-neck flask was charged with tert-butyl (2S,5S)-2-(hydroxymethyl)-5- methylpyrrolidine-1-carboxylate (0.50 g, 2.32 mmol), hydrochloric acid dioxane solution (1.27 g, 34.8 mmol, 4 M in 1,4-dioxane), and the reaction was allowed to warm to 40 °C and stirred for 5 h. The reaction was quenched by the addition of saturated sodium bicarbonate solution. The aqueous phase was extracted with EA (50.0 mL x 3). The organic phase was dried over sodium sulfate and concentrated to give a yellow oil (0.16 g, 59.82% yield). LC-MS (ESI, pos.ion) m / z: 116.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 3.62 (dd, J = 10.8, 3.6 Hz, 1H), 3.42 (dd, J = 10.7, 6.0 Hz, 1H), 3.36 (m, 1H), 3.31 - 3.24 (m, 1H), 1.93 - 1.86 (m, 1H), 1.83 (dt, J = 12.8, 5.9 Hz, 1H), 1.61 (ddd, J = 17.2, 10.9, 5.7 Hz, 1H), 1.38 - 1.31 (m, 1H), 1.18 (d, J = 6.2 Hz, 3H).

[0384] Step 3: Synthesis of ((2S,5S)-2-(chloromethyl)-5-methylpyrrolidin-l-yl)(3-nitro-lH- pyrazol-5-yl)methanone

[0385] To 5-nitro-3-pyrazolecarboxylic acid (3.00 g, 19.10 mmol), dichloromethane (35 mL), ((2S,5S)-5-methylpyrrolidin-2-yl)methanol (2.64 g, 22.92 mmol) and N,N- dimethylformamide (0.028 g, 0.38 mmol) was stirred at 0 °C, dropwise added dichloro sulfoxide (11.36 g, 95.5 mmol,) and reacted at room temperature for 2 hours. ((2S,5S)-5- methylpyrrolidin-2-yl)methanol (2.64 g, 22.92 mmol) was added and reacted at 50 °C overnight. It was cooled and concentrated to dryness. It was used directly for the next step. LC-MS (ESI, pos.ion) m / z: 273.1, 275.1 [M+H] + .

[0386] Step 4: Synthesis of (6S,8aS)-6-methyl-2-nitro-7,8,8a,9-tetrahydro-4H,6H-pyrazolo[l,5- a]pyrrolo[l,2-d]pyrazin-4-one

[0387] ((2S,5S)-2-(chloromethyl)-5-methylpyrrolidin-l-yl)(3-nitro-lH-pyrazol-5-yl)methanone (5.21 g, 19.11 mmol), N,N-dimethylformamide (50 mL) and triethylamine (5.80 g, 57.33 mmol) were added into a single-neck flask and reacted at room temperature for 9 hours. It was concentrated and purified by column chromatography (DCM) to give a brown solid (3.46 g, yield 76.66%). LC-MS (ESI, pos.ion) m / z: 237.10 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 4.67 (dd, J = 12.6, 3.8 Hz, 1H), 4.43 - 4.37 (m, 1H), 4.21 - 4.15 (m, 1H), 4.09 (t, J = 12.6 Hz, 1H), 2.31 - 2.25 (m, 1H), 2.16 (ddd, J = 12.9, 9.6, 5.4 Hz, 1H), 2.01 - 1.94 (m, 1H), 1.87 (dd, J = 12.6, 6.6 Hz, 1H), 1.35 (d, J = 6.5 Hz, 3H).

[0388] Step 5: Synthesis of (6S,8aS)-2-amino-6-methyl-7,8,8a,9-tetrahydro-4H,6H- pyrazolo[l,5-a]pyrrolo[l,2-d]pyrazin-4-one

[0389] A single-necked flask was charged with (6S,8aS)-6-methyl-2-nitro-7,8,8a,9- tetrahydro-4H,6H-pyrazolo[l,5-a]pyrrolo[l,2-d]pyrazin-4-one (3.56 g, 15.07 mmol), reduced iron powder (5.05 g, 90.42 mmol), ammonium chloride (4.84 g, 90.42 mmol), ethanol (30 mL) and water (10 mL), and warmed to 85 °C until the starting material was consumed. Filtered, washed with copious amounts of methanol solvent, collected the filtrate, and dried in vacuo. Purified by column chromatography (DCM:CH3OH (v:v) = 99:1) to give a yellow solid (2.70 g, yield: 86.87%). LC-MS (ESI, pos.ion) m / z: 207.2 [M+H] + .

[0390] Step 6: Synthesis of (6S,8aS)-2-amino-3-bromo-6-methyl-7,8,8a,9-tetrahydro-4H,6H- pyrazolo[l,5-a]pyrrolo[l,2-d]pyrazin-4-one

[0391] A single-necked flask was charged with (6S,8aS)-2-amino-6-methyl-7,8,8a,9- tetrahydro-4H,6H-pyrazolo[l,5-a]pyrrolo[l,2-d]pyrazin-4-one (0.152 g, 0.74 mmol) and dichloromethane (4 mL), and NBS (0.14 g, 0.81 mmol) was added at 0 °C for 20 min. Washed with water, extracted with DCM (50.0 mL x 3), concentrated, and purified by column chromatography (DCM:CH3OH (v:v) = 99:1) to give a yellow solid 0.20 g, yield 95.17%). LC-MS (ESI, pos.ion) m / z: 285.1, 287.1 [M+H] + .

[0392] Step 7: Synthesis of (6S,8aS)-2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3- bromo-6-methyl-7,8,8a,9-tetrahydro-4H,6H-pyrazolo[l,5-a]pyrrolo[l,2-d]pyrazin-4- one

[0393] A mixture of (6S,8aS)-2-amino-3-bromo-6-methyl-7,8,8a,9-tetrahydro-4H,6H- pyrazolo[l,5-a]pyrrolo[l,2-d]pyrazin-4-one (0.24 g, 0.84 mmol), l-(benzyloxy)-3- iodo-2,4-dimethylbenzene (0.31 g, 0.92 mmol), cesium carbonate (0.68 g, 2.1 mmol), cesium carbonate (0.038 g, 0.17 mmol), Xantphos (0.19 g, 0.34 mmol) and dioxane (30 mL) was heated at 110 °C under nitrogen overnight. Concentration and purification by column chromatography (PE:EA (v:v) = 75:25) gave the product (0.201 g, yield 48.20%). LC-MS (ESI, pos.ion) m / z: 495.2, 497.2 [M+H] + .

[0394] Step 8: Synthesis of (6S,8aS)-2-amino-l-(3-(benzyloxy)-2,6-dimethylphenyl)-6- methyl-4-oxo-l,4,7,8,8a,9-hexahydro-6H-pyrrolo[l,2-a]pyrrolo[2,3':3,4]pyrazolo[l,5- d]pyrazine-3-carbonitrile

[0395] A single-neck flask was charged with (6S,8aS)-2-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-3-bromo-6-methyl-7,8,8a,9-tetrahydro-4H,6H-pyrazolo[l,5-a]pyrrolo[l,2- d]pyrazin-4-one (2.00 g, 4.04 mmol), malononitrile (0.80 g, 12.12 mmol), copper iodide (0.15 g, 0.81 mmol), L-piperidine acid (0.21 g, 1.62 mmol), potassium carbonate (1.68 g, 12.12 mmol) and dimethyl sulfoxide (20 mL), and heated at 100 °C overnight after nitrogen replacement. Water (80 mL) was added, and EA (100.0 mL x 3) was used for extraction. Concentration and purification by column chromatography (PE:EA (v:v) = 20:80) gave a gray solid (0.75 g, yield: 38.66%). LC-MS (ESI, pos.ion) m / z: 481.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 7.5 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 6.76 (s, 2H), 5.19 (s, 2H), 4.45 (dd, J = 12.1, 3.9 Hz, 1H), 4.22 - 4.18 (m, 1H), 4.16 - 4.12 (m, 1H), 3.96 (t, J = 12.2 Hz, 1H), 2.14 - 2.06 (m, 2H), 1.93 (d, J = 5.6 Hz, 3H), 1.89 (d, J = 8.0 Hz, 3H), 1.88 - 1.85 (m, 1H), 1.71 (dd, J = 11.5, 6.7 Hz, 1H), 1.26 (d, J = 6.4 Hz, 3H).

[0396] Step 9: Synthesis of (7S,9aS)-4-amino-13-(3-(benzyloxy)-2,6-dimethylphenyl)-7- methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[l",2":4",5"]pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(13H)-one

[0397] A single-neck flask was charged with (6S,8aS)-2-amino-l-(3-(benzyloxy)-2,6- dimethylphenyl)-6-methyl-4-oxo-l,4,7,8,8a,9-hexahydro-6H-pyrrolo[l,2-a]pyrazolo[2',3':3,4]pyrazolo[l,5-d]pyrimidine-3-carbonitrile (0.70 g, 1.46 mmol) and formamide (6.58 g, 146 mmol) and warmed to 160 °C for 6 h. 80 mL of water was added and a solid precipitated. The solid was filtered to give a brown solid (665 mg, yield: 89.94%). LC-MS (ESI, pos.ion) m / z: 508.3 [M+H] + .

[0398] Step 10: Synthesis of (7S,9aS)-4-amino-13-(3-hydroxy-2,6-dimethylphenyl)-7-methyl- 8,9,9a,10-tetrahydro-7H-pyrrolo[l",2':4",5"]pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(13H)-one

[0399] A single-neck flask was charged with (7S,9aS)-4-amino-13-(3-(benzyloxy)-2,6- dimethylphenyl)-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1,,2,:4,,5 ]pyrazino[1,,2:1,,5 ]pyrazolo[4,,3:4,5]pyrrolo[2,3-d]pyrimidin-5(13H)-one (0.55 g, 1.08 mmol) and dichloromethane (10 mL), and concentrated sulfuric acid (3.71 g, 37.80 mmol) was added at room temperature. The reaction was stirred for 9 h. The reaction was quenched with a small amount of water and neutralized with saturated sodium bicarbonate solution. The solvent was removed by rotary evaporation and the residue was purified by column chromatography (DCM:CH3OH (v:v) = 95:5) to give a yellow solid (235 mg, 51.95% yield). LC-MS (ESI, pos.ion) m / z: 418.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.16 (s, 1H), 8.01 (d, J = 13.9 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 4.68 (dd, J = 12.3, 4.0 Hz, 1H), 4.40 - 4.33 (m, 1H), 4.33 - 4.29 (m, 1H), 4.26 (td, J = 12.6, 4.3 Hz, 1H), 2.22 - 2.12 (m, 2H), 1.99 (dd, J = 15.2, 8.1 Hz, 1H), 1.81 (d, J = 11.0 Hz, 3H), 1.79 - 1.76 (m, 1H), 1.72 (d, J = 12.5 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H).

[0400] Step 11: Synthesis of 3-((7S,9aS)-4-amino-7-methyl-8,9,9a,10-tetrahydro-7H- pyrrolo[1,,2,:4,,5 ]pyrazino[1,,2:1,,5 ]pyrazolo[4,,3:4,5]pyrrolo[2,3-d]pyrimidin-13(5H)-yl)- 2,4-dimethylphenol

[0401] To (7S,9aS)-4-amino-13-(3-hydroxy-2,6-dimethylphenyl)-7-methyl-8,9,9a,10- tetrahydro-7H-pyrrolo[1''',2':4'',5'']pyrazino[1'',2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3- d]pyrimidin-5(13H)-one (0.185 g, 0.44 mmol) in tetrahydrofuran (4 mL) at 0 °C was added lithium aluminum hydride solution (0.17 g, 4.4 mmol, 2.5 M in THF) and the reaction was transferred to 70 °C with stirring. Quench with 2 mL water, spin dry, column chromatography (DCM:CH3OH (v:v) = 0:1) to give a pair of diastereomers, which were separated by chiral resolution to give the target compound. LC-MS (ESI, pos.ion) m / z: 404.3 [M+H] + ; 1 H NMR (599 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.09 (s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.55 (s, 2H), 4.94 (d, J = 15.0 Hz, 1H), 4.38 (dd, J = 11.6, 3.6 Hz, 1H), 3.88 (t, J = 11.0 Hz, 1H), 3.58 (d, J = 15.0 Hz, 1H), 2.89 - 2.83 (m, 1H), 2.58 - 2.57 (m, 1H), 2.12 - 2.06 (m, 1H), 2.03 - 1.99 (m, 1H), 1.80 (s, 3H), 1.70 (s, 3H), 1.59 (dd, J = 9.3, 5.4 Hz, 1H), 1.53 - 1.48 (m, 1H), 1.27 (d, J = 6.2 Hz, 3H); HR-MS m / z: 404.2245 [M+H] + .

[0402] Example 14: (S)-3-(4-amino-7,8,9,10,10a,11-hexahydropyrido[1''',2''':4'',5'']pyrazino[1'',2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-14(5H)-yl)-2,4-dimethylphenol

[0403] Step 1: Synthesis of (S)-(2-(hydroxymethyl)piperidin-1-yl)(3-nitro-1H-pyrazol-5-yl)methanone

[0404] To a solution of 3-nitro-lH-pyrazole-5-carboxylic acid (10.00 g, 63.66 mmol) in dichloromethane (100 mL) was added slowly dropwise at -5 °C sulfuric chloride (37.87 g, 318.30 mmol), after the addition was completed, the reaction was transferred to room temperature and stirred for about 2 h, the organic liquid was removed by concentration, to the residue was added DCM (100 mL), followed by the addition of TEA (19.33 g, 190.98 mmol) and [(2S)-piperidin-2-yl]methanol (8.06 g) in turn, the reaction was carried out at room temperature overnight. After the reaction was completed, the organic liquid was removed by concentration to obtain the white solid crude product (15 g).

[0405] Step 2: Synthesis of (S)-(2-(chloromethyl)piperidin-l-yl)(3-nitro-lH-pyrazol-5-yl)methanone

[0406] To a solution of (S)-(2-(hydroxymethyl)piperidin-l-yl)(3-nitro-lH-pyrazol-5-yl)methanone (15.00 g, 59.00 mmol) in dichloromethane (100 mL) was added slowly dropwise at -5 °C sulfuric chloride (35.10 g, 295 mmol), after the addition was completed, the reaction was transferred to 50 °C and stirred for about 9 h, after the reaction was completed, the organic liquid was removed by concentration to obtain the yellowish oil liquid crude product (14 g).

[0407] Step 3: Synthesis of (S)-2-nitro-6,7,8,9,9a,10-hexahydro-4H-pyrazolo[l,5-a]pyrimido[l,2-d]pyrazin-4-one

[0408] A solution of (S)-(2-(chloromethyl)piperidin-l-yl)(3-nitro-lH-pyrazol-5-yl)methanone (14.00 g, 51.34 mmol) and potassium tert-butoxide (6.91 g, 61.61 mmol) in DMF (100 mL) was stirred at 80 °C for about 8 h, the reaction was stopped, the aqueous phase was extracted with EA (3 x 50 mL), the organic layers were combined and washed with saturated NaCl solution (3 x 20 mL), concentrated, and the concentrate was purified by silica gel column chromatography (DCM as eluent) to obtain a yellowish solid (2.45 g, total yield of three steps: 16%). LC-MS (ESI, pos.ion) m / z: 237.20 [M+H] + .

[0409] Step 4: Synthesis of (S)-2-amino-6,7,8,9,9a,10-hexahydro-4H-pyrazolo[l,5-a]pyrimido[l,2-d]pyrazin-4-one

[0410] To a mixture of (S)-2-nitro-6,7,8,9,9a,10-hexahydro-4H-pyrazolo[l,5- a]pyrido[l,2-d]pyrazin-4-one (2.50 g, 11.25 mmol), iron powder (2.95 g, 52.9 mmol) and ammonium chloride (2.83 g, 52.9 mmol) in ethanol (40 mL) and water (15 mL) was stirred at 80 °C, TLC was used to monitor the reaction progress, after the starting material was consumed, the reaction was stopped, cooled to room temperature, filtered, and the filtrate was concentrated, the residue was purified by silica gel column chromatography (DCM:MeOH (v:v) = 10:1) to give a white solid (1.80 g, yield: 82.47%). LC-MS (ESI, pos.ion) m / z: 207.30 [M+H] + .

[0411] Step 5: Synthesis of (S)-2-amino-3-bromo-6,7,8,9,9a,10-hexahydro-4H- pyrazolo[l,5-a]pyrido[l,2-d]pyrazin-4-one

[0412] To a solution of (S)-2-amino-6,7,8,9,9a,10-hexahydro-4H-pyrazolo[l,5- a]pyrido[l,2-d]pyrazin-4-one (1.80 g, 8.73 mmol) in DCM (40 mL) was added NBS (1.63 g, 9.17 mmol) portionwise at 0 °C, TLC was used to monitor the reaction progress, after the starting material was consumed, a small amount of water was added to the reaction system, the aqueous phase was extracted with dichloromethane (3 x 50 mL), the combined organic layers were washed with saturated NaCl solution (3 x 20 mL), the combined organic layers were dried over Na2S04, filtered and concentrated to give a yellowish crude solid target (2.1 g, yield: 84.38%). LC-MS (ESI, pos.ion) m / z: 285.10, 287.10 [M+H] + .

[0413] Step 6: Synthesis of (S)-3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)- 6,7,8,9,9a,10-hexahydro-4H-pyrazolo[l,5-a]pyrido[l,2-d]pyrazin-4-one

[0414] A mixture of (S)-2-amino-3-bromo-6,7,8,9,9a,10-hexahydro-4H-pyrazolo[l,5- a]pyrimidine[ 1,2-d]pyrazin-4-one (2.1 g, 7.36 mmol), palladium acetate (0.33 g, 1.47 mmol), Xant-phos (1.70 g, 2.94 mmol), cesium carbonate (6.00 g, 18.40 mmol) and l-(methoxy)-3-iodo-2,4-dimethylbenzene (2.12 g, 8.10 mmol) in 1,4-dioxane (50 mL) was protected by nitrogen, then transferred to 110 °C and stirred overnight. After the starting material was consumed, a small amount of water was added to the reaction system, the aqueous phase was extracted with EA (3 x 50 mL), the combined organic layers were washed with saturated NaCl solution (3 x 20 mL), the combined organic phases were concentrated under vacuum at 45 °C, and the concentrate was purified by silica gel column chromatography (EA:PE (v:v) = 1:4 to 1:1) to give the target product as a light yellow solid (1.5 g, yield: 48.57%). LC-MS (ESI, pos.ion) m / z: 419.15, 421.20 [M+H] + .

[0415] Step 7: Synthesis of (S)-2-amino-l-(3-methoxy-2,6-dimethylphenyl)-4-oxo- 1,4,6,7,8,9,9a,10-octahydropyrido[l,2-a]pyrrolo[2',3':3,4]pyrazolo[l,5-d]pyrazine-3- carbonitrile

[0416] To (S)-3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-6,7,8,9,9a,10- hexahydro-4H-pyrazolo[l,5-a]pyrimidine[ 1,2-d]pyrazin-4-one (1.9 g, 3.84 mmol), malononitrile (0.76 g, 11.52 mmol), potassium carbonate (1.33 g, 9.6 mmol), copper iodide (0.15 g, 0.77 mmol) and L-piperidine acid (0.20 g, 1.54 mmol) were added to DMSO (20 mL), protected by nitrogen, then transferred to 100 °C and stirred overnight. After the starting material was consumed, a small amount of water was added, the aqueous phase was extracted with EA (3 x 50 mL), the combined organic layers were washed with saturated NaCl solution (3 x 20 mL), the combined organic phases were concentrated under vacuum at 45 °C, and the concentrate was purified by silica gel column chromatography (EA:PE (v:v) = 1:1) to give a light yellow solid (0.58 g, 31.47%).

[0417] Step 8: Synthesis of (S)-4-amino-14-(3-methoxy-2,6-dimethylphenyl)- 7,8,9,10,10a,11-hexahydropyrido[l",2":4",5"]pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3- d]pyrimidin-5(14H)-one

[0418] (S)-2-amino-l-(3-methoxy-2,6-dimethylphenyl)-4-oxo-l,4,6,7,8,9,9a,10- octahydropyrido[l,2-a]pyrrolo[2',3':3,4]pyrazolo[l,5-d]pyrazine-3-carbonitrile (0.58 g, 1.43 mmol) and formamide (20.00 mL) were placed in a reaction flask and moved to a 160 °C oil bath kettle for reaction; TLC was used to monitor the reaction until the starting material was completely consumed, the heating was turned off, water (100.0 mL) was added to the reaction system, and EA (100 mL x 3) was used to extract, the organic phases were combined and concentrated under vacuum at 45 °C to give a light yellow solid (0.58 g, yield: 93.74%). LC-MS (ESI, pos.ion) m / z: 432.30 [M+H] + .

[0419] Step 9: Synthesis of (S)-4-amino-14-(3-hydroxy-2,6-dimethylphenyl)- 7,8,9,10,10a,11-hexahydropyrido[l",2":4",5"]pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3- d]pyrimidin-5(14H)-one

[0420] To a solution of (S)-4-amino-14-(3-methoxy-2,6-dimethylphenyl)- 7,8,9,10,10a,11-hexahydropyrido[l",2":4",5"]pyrazino[l",2':l',5']pyrazolo[4',3':4,5]pyrrolo[2,3- d]pyrimidin-5(14H)-one (0.60 g, 1.39 mmol) in dichloromethane (30.00 mL) was slowly added boron tribromide (6.95 mL, 6.95 mmol) at 0 °C, after stirring at room temperature for about 3.0 h, the stirring was stopped, and methanol was slowly added to the reaction system to quench the reaction, the organic phase was concentrated by rotary evaporation, and the concentrate was purified by silica gel column chromatography (DCM:MeOH (v:v) = 15: 1) to give a light yellow target solid (0.32 g, yield: 55.13%). LC-MS (ESI, pos.ion) m / z: 418.25 [M+H] + .

[0421] Step 10: Synthesis of (S)-3-(4-amino-7,8,9,10,10a,11- hexahydropyrimido[1,,2':4",5"]pyrazino[1",2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3- d]pyrimidin-14(5H)-yl)-2,4-dimethylphenol

[0422] To a solution of (S)-4-amino-14-(3-hydroxy-2,6-dimethylphenyl)-7,8,9,10,10a,11- hexahydropyrimido[1,,2':4",5"]pyrazino[1",2':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3- d]pyrimidin-5(14H)-one (0.32 g, 0.77 mmol) in THF (20.00 mL) was added LiAlH4-THF (3.08 mL, 7.70 mmol, 2.5 M) slowly at 0 °C, stirred at 70 °C for about 9.0 h, the stirring was stopped, a little water was added slowly to the reaction system, the organic liquid was removed directly by rotary evaporation under reduced pressure, the concentrate was purified by silica gel column chromatography (DCM:MeOH (v:v) = 12:1) to give a white solid racemate (0.20 g, yield: 64.67%). LC-MS (ESI, pos.ion) m / z: 404.30 [M+H] + ; 1 H NMR (599 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.06 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.45 (s, 2H), 4.72 (d, J = 15.5 Hz, 1H), 4.17 (dd, J = 12.3, 3.3 Hz, 1H), 4.11 (q, J = 5.3 Hz, 1H), 3.77 (t, J = 11.4 Hz, 1H), 3.61 (d, J = 15.5 Hz, 1H), 3.18 (d, J = 5.3 Hz, 2H), 3.09 (d, J = 11.3 Hz, 1H), 2.66 - 2.55 (m, 1H), 2.19 (t, J = 10.7 Hz, 1H), 1.82 (d, J = 7.8 Hz, 1H), 1.76 (s, 3H), 1.75 - 1.68 (m, 2H), 1.66 (s, 3H); HR-MS: m / z: 404.2234 [M+H] + .

[0423] Example 15: 4-amino-10-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-6,7- dihydroimidazo[1,,5':1',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(10H)-one

[0424] Step 1: Synthesis of (methylamino)methanol

[0425] Into a single-neck flask was added methylamine hydrochloride (5.00 g, 74.05 mmol), sodium bicarbonate (6.22 g, 74.05 mmol) and water (15 mL) at room temperature, and a 37% formaldehyde solution (6.01 g, 74.05 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 1 hour. After being heated at 50 °C for 4 hours, the reaction was stopped by cooling. A large amount of sodium chloride solid was added to absorb water, dichloromethane was added to separate the layers, and sodium chloride solid was added to dry the dichloromethane solution, which was used in the next step. LC-MS (ESI, pos.ion) m / z: 62.3 [M+H] + .

[0426] Step 2: Synthesis of 5-methyl-2-nitro-5,6-dihydro-4H-imidazo[1,5-b]pyrazol-4-one

[0427] Into a single-neck flask was added methylamine hydrochloride (5.00 g, 74.05 mmol), sodium bicarbonate (6.22 g, 74.05 mmol) and water (15 mL) at room temperature, and a 37% formaldehyde solution (6.01 g, 74.05 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 1 hour. After being heated at 50 °C for 4 hours, the reaction was stopped by cooling. A large amount of sodium chloride solid was added to absorb water, dichloromethane was added to separate the layers, and sodium chloride solid was added to dry the dichloromethane solution, which was used in the next step. LC-MS (ESI, pos.ion) m / z: 62.3 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 7.56 (s, 1H), 5.77 (s, 2H), 3.11 (s, 3H).

[0428] Step 3: Synthesis of 2-amino-5-methyl-5,6-dihydro-4H-imidazo[1,5-b]pyrazol-4-one

[0429] A single-necked flask was charged with 5-methyl-2-nitro-5,6-dihydro-4H- imidazo[l,5-b]pyrazol-4-one (0.85 g, 4.67 mmol), ammonium chloride (1.50 g, 28.02 mmol), iron powder (1.56 g, 28.02 mmol), ethanol (9 mL) and water (3 mL), and heated to 85 °C for 30 min. The starting material was consumed. Purification by column chromatography (DCM:CH3OH (v:v) = 97:3) gave a yellow solid (0.29 g, yield: 40.84%). LC-MS (ESI, pos.ion) m / z: 153.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 5.65 (s, 1H), 5.31 (s, 2H), 5.03 (s, 2H), 2.98 (s, 3H).

[0430] Step 4: Synthesis of 2-amino-3-bromo-5-methyl-5,6-dihydro-4H-imidazo[l,5-b]pyrazol- 4-one

[0431] A single-necked flask was charged with 2-amino-5-methyl-5,6-dihydro-4H- imidazo[l,5-b]pyrazol-4-one (0.10 g, 0.66 mmol) and dichloromethane (2 mL), and NBS (0.12 g, 0.69 mmol) was added at 0 °C for 15 min. The reaction was quenched with water, extracted with DCM (7 mL x 2), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:CH3OH (v:v) = 98:2) to give the target product as a light yellow solid (0.118 g, yield 77.70%). LC-MS (ESI, pos.ion) m / z: 231.0, 233.0 [M+H] + .

[0432] Step 5: Synthesis of 3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-5-methyl- 5,6-dihydro-4H-imidazo[l,5-b]pyrazol-4-one

[0433] A single-necked flask was charged with 2-amino-3-bromo-5-methyl-5,6-dihydro-4H- imidazo[l,5-b]pyrazol-4-one (0.115 g, 0.50 mmol), 2-iodo-4-methoxy-l,3-dimethylbenzene (0.14 g, 0.53 mmol), palladium acetate (0.022 g, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol), cesium carbonate (0.49 g, 1.5 mmol) and 1,4-dioxane (3 mL), and purged with nitrogen. The temperature was raised to 100 °C and stirred for 20 h. Concentrated, purified by column chromatography (DCM:CH3OH (v:v) = 200: 1) to get yellow solid (82 mg, yield: 45.11%). LC-MS (ESI, pos.ion) m / z: 365.1, 367.1 [M+H] + .

[0434] Step 6: Synthesis of 2-amino-l-(3-methoxy-2,6-dimethylphenyl)-5-methyl-4-oxo- 1,4,5,6-tetrahydroimidazo[l,5-b]pyrrolo[3,2-d]pyrazole-3-carbonitrile

[0435] A single-necked flask was charged with 3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)- 5-methyl-5,6-dihydro-4H-imidazo[l,5-b]pyrazol-4-one (0.012 g, 0.028 mmol), malononitrile (0.028 g, 0.42 mmol), copper iodide (0.013 g, 0.070 mmol), L-piperidine acid (0.009 g, 0.070 mmol) and potassium carbonate (0.058 g, 0.42 mmol), and purged with nitrogen. The temperature was raised to 100 °C and stirred for 8 h. Added 5 mL water, extracted with EA (100.0 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by thin layer preparative chromatography to give a yellow solid product (7 mg, yield 14.59%). LC-MS (ESI, pos.ion) m / z: 350.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 7.26 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 6.83 (s, 2H), 5.49 (s, 2H), 3.87 (s, 3H), 3.04 (s, 3H), 1.93 (s, 3H), 1.83 (s, 3H).

[0436] Step 7: Synthesis of 4-amino-10-(3-methoxy-2,6-dimethylphenyl)-6-methyl-6,7- dihydroimidazo[l",5":l',5']pyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-5(10H)-one

[0437] A single-neck flask was charged with 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5- methyl-4-oxo-1,4,5,6-tetrahydroimidazo[1,5-b]pyrrolo[3,2-d]pyrazole-3-carbonitrile (0.21 g, 0.60 mmol), formamide (2.70 g, 60 mmol), and heated to 160 °C for 8 h. Added water 12 mL, extracted with EA (100.0 mL x 3), dried over anhydrous sodium sulfate, and purified by column chromatography (DCM:CH3OH (v:v) = 100:0-99:1) to give a yellow solid (0.27 g, yield: 100%). LC-MS (ESI, pos.ion) m / z: 378.2 [M+H] + .

[0438] Step 8: Synthesis of 4-amino-10-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-6,7- dihydroimidazo[1”,5”:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-5(10H)-one

[0439] A single-neck flask was charged with 4-amino-10-(3-methoxy-2,6-dimethylphenyl)-6- methyl-6,7-dihydroimidazo[1”,5”:1’,5’]pyrazolo[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-5(10H)- one (0.097 g, 0.26 mmol) and dichloromethane (5 mL), added boron tribromide (0.26 g, 1.04 mmol), and reacted at room temperature overnight. The reaction was quenched with methanol, and purified by column chromatography (DCM:CH3OH (v:v) = 96:4) to give (25 mg, yield: 26.77%). LC-MS (ESI, pos.ion) m / z: 364.2 [M+H] + ; 1 H NMR (599 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.32 (s, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 5.77 (s, 2H), 3.16 (s, 3H), 1.83 (s, 3H), 1.73 (s, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 158.84, 158.10, 156.24, 154.58, 134.94, 133.92, 128.17, 127.99, 127.74, 126.78, 123.69, 115.89, 96.99, 91.67, 66.45, 28.51, 17.40, 11.41. HR-MS m / z: 364.1555 [M+H] +.

[0440] Example 16: 3-(4-amino-7,8-dihydropyrimido[5',4':4',5']pyrrolo[2',3':3,4]pyrazolo[5,1- c][1,4]oxazin-11(5H)-yl)-2,4-dimethylphenol

[0441] Step 1: Synthesis of ethyl 1-(2-fluoroethyl)-3-nitro-1H-pyrazole-5-carboxylate

[0442] Ethyl 3-nitro-1H-pyrazole-5-carboxylate (5.0 g, 27.01 mmol) and acetonitrile (50 mL) were placed in a reaction flask, potassium carbonate (11.20 g, 81.03 mmol) was added under stirring at room temperature, after stirring for 30 min, 1-fluoro-2-iodoethane (7.05 g, 40.52 mmol) was added, the reaction was stirred at 80 °C; TLC monitoring reaction to complete the original reaction; water (100.0 mL) and EA (200.0 mL) were added to the reaction liquid, the organic phase was collected after the layers were separated, and the organic phase was concentrated under vacuum at 45 °C to obtain the target product ethyl 1-(2-fluoroethyl)-3-nitro-1H-pyrazole-5-carboxylate (6.24 g, yield: 99.95%); LC-MS (ESI, pos.ion) m / z: 232.20 [M+H] + .

[0443] Step 2: Synthesis of ethyl 3-amino-1-(2-fluoroethyl)-1H-pyrazole-5-carboxylate

[0444] Ethyl 1-(2-fluoroethyl)-3-nitro-1H-pyrazole-5-carboxylate (6.24 g, 26.99 mmol), palladium on carbon (5.74 g, 5.40 mmol), ammonium formate (8.51 g, 134.95 mmol), and methanol (100 mL) and water (10 mL) were placed in a reaction flask, stirred at room temperature, and the reaction was monitored by TLC until the original reaction was complete; the filter cake was washed with methanol (50.0 mL), and then the filtrate was concentrated under vacuum at 45 °C, and the concentrate was purified by column chromatography (PE:EA (v:v) = 1:1) to obtain yellowish liquid ethyl 3-amino-1-(2-fluoroethyl)-1H-pyrazole-5-carboxylate (3.3 g, yield: 60.76%). LC-MS (ESI, pos.ion) m / z: 202.10 [M+H] + .

[0445] Step 3: Synthesis of ethyl 3-amino-4-bromo-1-(2-fluoroethyl)-1H-pyrazole-5-carboxylate

[0446] A reaction flask was charged with 3-amino-1-(2-fluoroethyl)-1H-pyrazole-5- carboxylic acid ethyl ester (3.3 g, 16.40 mmol) and dichloromethane (100 mL), and stirred at 0 °C. NBS (2.92 g, 16.4 mmol) was added, and the reaction was stirred at 0 °C. The reaction was monitored by TLC until the starting material was consumed. The reaction was stopped, and water (50.0 mL) and EA (100.0 mL) were added to the reaction mixture. The organic phase was collected, and the organic phase was concentrated under vacuum at 45 °C to give a light yellow solid (4.59 g, yield: 99.91 %). LC-MS (ESI, pos.ion) m / z: 280.90, 281.90 [M+H] + .

[0447] Step 4: Synthesis of 3-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-4-bromo-1-(2- fluoroethyl)-1H-pyrazole-5-carboxylic acid ethyl ester

[0448] A reaction flask was charged with 3-amino-4-bromo-1-(2-fluoroethyl)-1H-pyrazole-5- carboxylic acid ethyl ester (4.30 g, 13.86 mmol), 2-iodo-4-methoxy-1,3-dimethylbenzene (1.96 g, 7.50 mmol), palladium acetate (0.32 g, 1.43 mmol), Xantphos (1.65 g, 2.86 mmol), cesium carbonate (5.82 g, 17.85 mmol), and 1,4-dioxane (20.0 mL), and the reaction was purged with nitrogen three times. The reaction was then placed in a 100 °C oil bath. The reaction was monitored by TLC until the starting material was consumed. The reaction was concentrated under vacuum at 45 °C. The concentrate was purified by column chromatography (PE:EA (v:v) = 10:1) to give 3-((3-(benzyloxy)-2,6-dimethylphenyl)amino)-4-bromo-1-(2-fluoroethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (2.50 g, yield: 71.40 %) as a light yellow solid.

[0449] Step 5: Synthesis of 5-amino-6-(3-benzyloxy-2,6-dimethylphenyl)-4-cyano-2-(2- fluoroethyl)-2,6-dihydropyrrolo[2,3-c]pyrazole-3-carboxylic acid ethyl ester

[0450] Ethyl 5-amino-4-cyano-2-(2-fluoroethyl)-6-(3-methoxy-2,6-dimethylphenyl)- 2,6-dihydropyrrolo[2,3-c]pyrazole-3-carboxylate (0.30 g, 0.63 mmol) and formamide (1.13 g, 25.18 mmol) were placed in a reaction flask, which was then moved to an oil bath at 130 °C for reaction. The reaction was stopped after about 24.0 h. Water (100.0 mL) and EA (200.0 mL) were added to the reaction mixture, and the layers were allowed to separate. The organic phase was collected and concentrated under vacuum at 45 °C. Purification by column chromatography (PE; EA = 1:1) gave ethyl 4-amino-8-(3-(benzyloxy)-2,6-dimethylphenyl)-2-(2-fluoroethyl)- 2,8-dihydropyrrolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine-3-carboxylate (0.16 g, yield: 50.46%) as a light yellow solid. LC-MS (ESI, pos.ion) m / z: 503.2 [M+H]

[0451] Step 6: Synthesis of ethyl 4-amino-8-(3-(benzyloxy)-2,6-dimethylphenyl)-2-(2- fluoroethyl)-2,8-dihydropyrrolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine-3-carboxylate

[0452] Ethyl 5-amino-4-cyano-2-(2-fluoroethyl)-6-(3-methoxy-2,6-dimethylphenyl)- 2,6-dihydropyrrolo[2,3-c]pyrazole-3-carboxylate (0.30 g, 0.63 mmol) and formamide (1.13 g, 25.18 mmol) were placed in a reaction flask, which was then moved to an oil bath at 130 °C for reaction. The reaction was stopped after about 24.0 h. Water (100.0 mL) and EA (200.0 mL) were added to the reaction mixture, and the layers were allowed to separate. The organic phase was collected and concentrated under vacuum at 45 °C. Purification by column chromatography (PE; EA = 1:1) gave ethyl 4-amino-8-(3-(benzyloxy)-2,6-dimethylphenyl)-2-(2-fluoroethyl)- 2,8-dihydropyrrolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine-3-carboxylate (0.16 g, yield: 50.46%) as a light yellow solid. LC-MS (ESI, pos.ion) m / z: 503.2 [M+H] + .

[0453] Step 7: Synthesis of (4-amino-8-(3-(benzyloxy)-2,6-dimethylphenyl)-2-(2- fluoroethyl)-2,8-dihydropyrrolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-3-yl)methanol

[0454] A reaction flask was charged with 4-amino-8-(3-(benzyloxy)-2,6-dimethylphenyl)- 2-(2-fluoroethyl)-2,8-dihydropyrrolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid ethyl ester (0.16 g, 0.32 mmol), ethanol (10.0 mL) and sodium borohydride (0.23 g, 6.4 mmol), then moved to an oil bath pot at 50 °C; TLC monitoring until the starting material was consumed, then the reaction was concentrated under vacuum at 45 °C, the concentrate was purified by column chromatography (PE:EA (v:v) = 1:1) to give a white solid (0.10 g, yield: 68.21%), LC-MS (ESI, pos.ion) m / z: 461.20 [M+H] + .

[0455] Step 8: Synthesis of 11-(3-(benzyloxy)-2,6-dimethylphenyl)-5,7,8,11- tetrahydropyrrolo[5',4':4',5']pyrrolo[2',3':3,4]pyrazolo[5,1-c][1,4]oxazin-4-amine

[0456] A reaction flask was charged with (4-amino-8-(3-(benzyloxy)-2,6-dimethylphenyl)- 2-(2-fluoroethyl)-2,8-dihydropyrrolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin-3-yl)methanol (0.15 g, 0.33 mmol), potassium tert-butoxide (0.09 g, 0.80 mmol) and THF (10.0 mL), stirred at room temperature; the reaction was stopped after about 24.0 h, the reaction was concentrated under vacuum at 45 °C, the concentrate was purified by column chromatography (PE:EA (v:v) = 1:1) to give a yellow solid (0.05 g, yield: 33.3%), LC-MS (ESI, pos.ion) m / z: 441.20 [M+H] + .

[0457] Step 9: Synthesis of 3-(4-amino-7,8-dihydropyrrolo[5',4':4',5']pyrrolo[2',3':3,4]pyrazolo[5,1-c][1,4]oxazin-11(5H)-yl)-2,4-dimethylphenol

[0458] Into a reaction vial was placed 11-(3-(benzyloxy)-2,6-dimethylphenyl)-5,7,8,11- tetrahydropyrimido[5',4':4',5']pyrrolo[2',3':3,4]pyrazolo[5,1-c][1,4]oxazin-4-amine (0.05 g, 0.11 mmol) and dichloromethane (3.0 mL), drop 3 drops of concentrated sulfuric acid, then stirred at room temperature for about 4.0 h; stop the reaction, slowly add water (3.0 mL) into the reaction solution, then adjust to neutral with saturated aqueous sodium bicarbonate solution, extract with DCM (20.0 mL x 3), combine the organic phase and concentrate, purify by column chromatography to give a white solid (0.02 g, yield: 57.38%), LC-MS (ESI, pos.ion) m / z: 351.20 [M+H] + .

[0459] Activity test examples

[0460] I. Assessing the effect of compounds on enzyme activity

[0461] Experimental procedure:

[0462] a) Pipette 60 μL of compound stock solution (10 mM) into a 384-well plate;

[0463] b) Dilute the compound 1:4 with DMSO;

[0464] c) Pipette 0.05 μL of diluted compound into a new 384-well plate, 2 replicates per compound using Echo instrument;

[0465] d) Followed by adding 2.5 μL of MYT1 or WEE1 enzyme working solution, centrifuge at 1000 rpm for 1 min;

[0466] e) Incubate the 384-well plate in a 25 °C incubator for 10 min;

[0467] f) Add 2.5 μL of substrate working solution (ATP & substrate);

[0468] g) Incubate the 384-well plate in a 25 °C incubator for 60 min;

[0469] h) Add 4 μL of ADP-Glo working solution;

[0470] i) Incubate the 384-well plate in a 25 °C incubator for 40 min;

[0471] g) Add 8 μL of detection working solution;

[0472] k) Incubate the 384-well plate in a 25 °C incubator for 40 min;

[0473] l) Detection: Relative luminescence unit was detected by BMG instrument

[0474] Data analysis:

[0475] a) Compound inhibition rate per well (%inh) = 100 * (high control mean - compound well value) / (high control mean - low control mean)

[0476] b) Experimental system stability test using low control and high control data:

[0477] S / B = high control mean / low control mean

[0478] CV% (low control) = 100 * (low control SD value / low control mean)

[0479] CV% (high control) = 100 * (high control SD value / high control mean)

[0480] Z' = 1 - 3 * (low control SD value + high control SD value) / (high control mean - low control mean)

[0481] c) IC of the compound was fitted by non-linear regression equation of XLfit 5.5.0 software. 50

[0482] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope))

[0483] X: log value of compound concentration

[0484] Y: inhibition rate (%inh)

[0485] Conclusion: The results of the experiment of the effect of the compound on enzyme activity showed that the compound of the present application could effectively inhibit the enzyme activity of MYT1, and the selectivity of the compound of the present application to the MYT1 enzyme was high in terms of selectivity (WEE1 / MYT1). The experimental results of some of the compounds of the present application are as follows in Table 1:

[0486] Table 1

[0487] II. Evaluation of the pharmacokinetic properties of the compound in vivo in mice

[0488] ​Instrument: SCIEX Triple Quad 5500+ triple quadrupole liquid chromatography-mass spectrometry, operating software is Analyst 1.6.3 (Applied Biosystems); LC-40B XR liquid chromatography system (Shimadzu), and Microsoft Excel is used for calculating and processing data. The WinNolin 8.3.4 software is used for calculating pharmacokinetic parameters by statistical moment method, mainly including kinetic parameters Tmax, T1 / 2, Cmax and AUClast, etc. ChromCore AQ C18, 3 μm, 2.1 x 50 mm is used as the chromatographic column; mobile phase A is 0.2% formic acid water, mobile phase B is methanol, the flow rate is 0.4 mL / min, gradient elution is adopted, and the elution gradient is: 1.30 min: 90% B; 2.10 min: 90% B; 2.11 min: 38% B; 3.70 min: stop.

[0489] Animals: 6 Balb / c male mice with a body weight range of 20-25 g are purchased and used after being raised in the experimental animal center laboratory for 3 days, fasted for 12 hours before administration and 4 hours after administration, and allowed to drink water freely during the test period. Blood samples are taken at the specified time after intragastrically and intravenously administering the drug to the mice.

[0490] Solvent: 5% DMSO + 5% HS15 + 89% Saline + 1% (2% HC1) (adjusting pH = 5-6).

[0491] Administration and determination: administration is carried out at a dose of 5 mg / kg by gavage and 2 mg / kg by intravenous injection, respectively, and three mice are included in each group. Blood is taken from the orbit at 0.083, 0.25, 0.5, 1, 2, 5, 7 and 24 hours after gavage administration; blood is taken from the orbit at 0.083, 0.25, 0.5, 1, 2, 5, 7 and 24 hours after intravenous injection administration. 5 μL of the plasma sample (blank sample and internal standard blank sample plus 5 μL of blank plasma) is transferred to the corresponding well of a deep well plate, and 250 μL of methanol solution containing an internal standard is added (250 μL of methanol is added to the double blank sample). After vortexing the sample for 2 minutes, centrifugation is carried out at 3800 rpm for 15 minutes, and 200 μL of supernatant is transferred for LC-MS / MS analysis. The compound is accurately weighed and prepared into different concentrations, quantitative analysis is carried out on the mass spectrometer, a standard curve is established, and then the concentration of the compound in the above-mentioned plasma is tested to obtain the concentration of the compound at different time points. All the measured data are collected and processed by the relevant software, and the statistical moment method is used for calculating the pharmacokinetic parameters (mainly including kinetic parameters Tmax, T1 / 2, Cmax and AUClast, etc.). The pharmacokinetic data of some representative compounds are shown in Table 2.

[0492] Table 2 Pharmacokinetic parameters of the compounds of the present application in mice

[0493] Conclusion: The compound of the present application has good pharmacokinetic properties.

[0494] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "some embodiments", "example", "specific example" or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative description of the above terms does not necessarily mean the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. Furthermore, the person skilled in the art can combine and combine the different embodiments, embodiments or examples described in the present specification and the features of the different embodiments, embodiments or examples without contradiction.

[0495] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and cannot be construed as limiting the present application, and the person skilled in the art can make changes, modifications, replacements and variations to the above-described embodiments without departing from the principles and spirit of the present application within the scope of the present application, and the scope of the present application is defined by the claims and their equivalents.

Claims

1. A compound that is a compound of Formula (I), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of Formula (I), ###0001### (I) wherein For B is Ring C is a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle, wherein ring C is optionally surrounded by 1, 2, or 3 R groups. a Replaced; Each R a Independently, it is D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b -OR 16 -C(=O)NR 15a R 15b -S(=O)2NR 15a R 15b -S(=O)2R 16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups; R 1 is H, D or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of D, OH, F, CI, Br and CN; R 2 is H, D, F, Cl, Br, CN, OH, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; R 3 is H, D, F, Cl, Br, CN, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R q1 ; R 4 is H, D, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl is independently optionally substituted with 1, 2, 3, or 4 R q2 ; or, R 3 R 4 and the ring atom to which they are attached to form a 5-6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, or a 5-10 membered heteroaromatic ring, wherein said 5-6 membered heterocyclic ring, 7 membered heterocyclic ring, 8 membered heterocyclic ring, and 5-10 membered heteroaromatic ring are each independently optionally substituted with 1, 2, 3, or 4 R q3 ; R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , and R 8 are each independently H, D, F, Cl, Br, CN, OH, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R q4 ; R q1 R q2 R q3 and R q4 Each of these can be independently represented as D, F, Cl, Br, I, CN, OH, oxo, or NR. 15a R 15b -OR 16 -C(=O)NR 15a R 15b -S(=O)2NR 15a R 15b -S(=O)2R 16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl, 3-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; or R and R together with the two ring atoms on which they are attached form a 5-6 membered heterocyclyl ring or a 5-6 membered heteroaryl ring, wherein said 5-6 membered heterocyclyl ring and 5-6 membered heteroaryl ring are each independently optionally substituted with 1, 2, 3, or 4 R q3 and the two ring atoms to which they are attached form a 5-6 membered heterocyclyl ring, a 7 membered heterocyclyl ring, or a 5-6 membered heteroaryl ring, wherein said 5-6 membered heterocyclyl ring, 7 membered heterocyclyl ring, and 5-6 membered heteroaryl ring are each independently optionally substituted with 1, 2, 3, or 4 R q3a ​ Each R q3a Independently, it is D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b -OR 16 -C(=O)NR 15a R 15b -S(=O)2NR 15a R 15b -S(=O)2R 16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl, 3-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; R 15a , R 15b , and R 16 are each independently H, D, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl.

2. The compound of claim 1, which is a compound of Formula (II) or Formula (III), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of Formula (II) or Formula (III), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 5a , R 6a , R 7a , R 8 and ring C each have the definition as recited in claim 1.

3. The compound of claim 1 or 2, wherein, having one of the following substructural formulae, Among them, R 9 R 10 R 11 R 12 R 13 R 14 R 9a R 13a R 13b and R 13c Each of the following is independently H, D, F, Cl, Br, I, CN, OH, NR 15a R 15b -OR 16 -C(=O)NR 15a R 15b -S(=O)2NR 15a R 15b -S(=O)2R 16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; R 5a , R 6a and R 7a each have the definition as indicated in claim 1.

4. The compound according to any one of claims 1 to 3, wherein R 1 is H, D or C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of D, OH, F, CI, Br and CN; R 2 H, D, F, Cl, Br, CN, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

5. The compound according to any one of claims 1 to 4, wherein R 3 H, D, F, Cl, Br, CN, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein each of the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl is independently optionally substituted with 1, 2, 3, or 4 R q1 groups; R 4 H, D, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein each of said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl is independently optionally substituted with 1, 2, 3, or 4 R q2 groups.

6. The compound according to any one of claims 1 to 5, wherein R 3 H, D, F, CI, Br, CN, NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, NH(CH2)3CH3, NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, -OCF3, -OCH2F, -OCHF2, -OCCl3, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl, wherein,NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, NH(CH2)3CH3, NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CH2CH2CºCCH3, -CºCCºCH, -CH2F, -CHF2, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, -OCH2F, -OCHF2, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, and thiuranyl are each independently optionally substituted with 1, 2, 3, or 4 R q1 substituents; R 4 H, D, CN, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiopyranyl, each of which is independently optionally substituted with 1, 2, 3, or 4 R q2 substituents.

7. The compound according to any one of claims 1 to 4, wherein R 3 , R 4 and the ring atom to which they are attached together form a pyrrolidine, pyrazolidine, imidazolidine, morpholine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazole, dihydroimidazole, dihydropyrrole, diazepine, oxazepine, pyridine or pyrimidine, wherein each of said pyrrolidine, pyrazolidine, imidazolidine, morpholine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazole, dihydroimidazole, dihydropyrrole, diazepine, oxazepine, pyridine and pyrimidine is independently optionally substituted with 1, 2, 3 or 4 R q3 .

8. The compound according to any one of claims 1 to 7, wherein R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , and R 8 are each independently H, D, F, Cl, Br, CN, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein said NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R q4 .

9. The compound according to any one of claims 1 to 8, wherein R 5 , R 5a , R 6 , R 6a , R 7 , R 7a and R 8 each independently H, D, F, CI, Br, CN, OH, NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, NH(CH2)3CH3, NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, -OCF3, -OCH2F, -OCHF2, -OCCl3, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl, wherein,each instance of NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, NH(CH2)3CH3, NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CH2CºCCH3, -CH2CH2CºCCH3, -CºCCºCH, -CH2F, -CHF2, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, -OCH2F, -OCHF2, -OCCl3, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, and thiuranyl are each independently optionally substituted with 1, 2, 3, or 4 R q4 each instance of NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, NH(CH2)3CH3, NHCH2CH(CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)(CH2CH3), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -CºCCH3, -CH2CºCCH3, -CH2CºCCH3, -CH2CH2CºCCH3, -CºCCºCH, -CH2F, -CHF2, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, -OCH2F, -OCHF2, -OCCl3, -OCH2CF3, -O(CH2)2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, and thiuranyl are each independently optionally substituted with 1, 2, 3, or 4 R 10. The compound of any one of claims 1-2, 4-9, wherein, Ring C is benzene, imidazole, pyrrole, pyrazole, dihydroimidazole, dihydropyrrole, dihydrooxazole, dihydrothiazole, pyridine, pyrimidine, or pyrazine, wherein said ring C is optionally substituted with 1, 2, or 3 R a substituted; Each R a Independently, it is D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b -OR 16 -C(=O)NR 15a R 15b -S(=O)2NR 15a R 15b -S(=O)2R 16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or, each R a Independently, it is D, F, Cl, Br, I, CN, OH, oxo, NR 15a R 15b -OR 16 -C(=O)NR 15a R 15b -S(=O)2NR 15a R 15b -S(=O)2R 16 -S(=O)2OR 16 -C(=O)OR 16 -C(=O)R 16 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CC13, -CH2CF3, -(CH2)2CF3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CHCN, -(CH2)2CN, -(CH2)3CN, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl.

11. The compound according to any one of claims 3 to 9, wherein R 9 R 10 R 11 R 12 R 13 R 14 R 9a R 13a R 13b R 13c each independently H, D, F, Cl, Br, I, CN, OH, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-4 1-6 alkyl, C 1-4 1-6 haloalkyl, C 1-4 1-6 hydroxyalkyl, C 1-4 1-6 cyanoalkyl, C 2-4 1-6 alkenyl, C 2-4 1-6 alkynyl, C 1-4 1-6 alkoxy, C 3-6 1-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or, R 9 R 10 R 11 R 12 R 13 R 14 R 9a R 13a R 13b R 13c each independently H, D, F, Cl, Br, I, CN, OH, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CC13, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, -CHCN, -(CH2)2CN, -(CH2)3CN, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl.

12. The compound of any one of claims 1-11, wherein, R q1 , R q2 , R q3 , and R q4 are each independently D, F, CI, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-4 1-6 alkyl, C 1-4 1-6 haloalkyl, C 1-4 1-6 hydroxyalkyl, C 1-4 1-6 cyanoalkyl, C 2-4 1-6 alkenyl, C 2-4 1-6 alkynyl, C 1-4 1-6 alkoxy, C 3-6 1-6 cycloalkyl, C 3-6 1-6 cycloalkenyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or, R q1 , R q2 , R q3 , and R q4 are each independently D, F, CI, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CC13, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl.

13. The compound according to any one of claims 1-4 or 7, R q3 and the two ring atoms to which they are attached together form a pyrrolidine, pyrazolidine, imidazolidine, morpholine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazole, dihydroimidazole, dihydropyrrole, dioxazane, oxazepine, pyrazole, imidazole, pyrrole, pyridine, or pyrimidine, wherein each of said pyrrolidine, pyrazolidine, imidazolidine, morpholine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazole, dihydroimidazole, dihydropyrrole, dioxazane, oxazepine, pyrazole, imidazole, pyrrole, pyridine, and pyrimidine is independently optionally substituted with 1, 2, 3, or 4 R q3a groups; each R is independently D, F, CI, Br, I, CN, OH, oxo, NR q3a R 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or each R q3a is independently D, F, CI, Br, I, CN, OH, oxo, NR 15a R 15b , -OR 16 , -C(=O)NR 15a R 15b , -S(=O)2NR 15a R 15b , -S(=O)2R 16 , -S(=O)2OR 16 , -C(=O)OR 16 , -C(=O)R 16 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CC13, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl.

14. The compound of any one of claims 1-13, wherein, R 15a , R 15b , and R 16 are each independently H, D, CN, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or, R 15a , R 15b , and R 16 are each independently H, D, CN, OH, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CF3, -CH2F, -CHF2, -CCl3, -CH2CF3, -(CH2)2CF3, -CH2OH, -C(CH3)2OH, -(CH2)2OH, -(CH2)3OH, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH=CH2, -C≡CCH3, -CH2C≡CH, -C≡CCH2CH3, -CH2C≡CCH3, -CH2CH2C≡CH, -C≡CC≡CH, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, or thiuranyl.

15. The compound of any one of claims 1-14, which is a compound of Formula (II-1) or Formula (III-1), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of Formula (II-1) or Formula (III-1), wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 5a , R 6a , R 7a , R 8 and ring C each have the definition as claimed in any one of claims 1 to 14.

16. The compound of any one of claims 1-14 which is one of the following compounds, or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt or prodrug of one of the following compounds, 17. The compound of any one of claims 1-15, which is one of the following compounds, or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of one of the following compounds, 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.

19. Use of a compound according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18 for the manufacture of a medicament for preventing, treating or alleviating a Myt1 -related disease.

20. The use according to claim 19, wherein, The Myt1 -related disease is a Myt1 -related proliferative disease, optionally, the Myt1 -related proliferative disease is a Myt1 -related cancer, psoriasis or rheumatoid arthritis.

21. The use according to claim 20, wherein, The Myt1 -related disease is a Myt1 -related uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, leukemia, liver cancer, bladder cancer, prostate cancer, cervical cancer or kidney cancer.

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