TW202302602A - Fused-ring heterocycle derivative and medical application thereof - Google Patents

Abstract

Provided are a compound represented by general formula (I), or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, an intermediate thereof, and a preparation method therefor, as well as an application in the preparation of a drug for treating diseases related to PAR P7 activity or expression level.

Description

Paracyclic heterocyclic derivatives and their applications in medicine

The present invention relates to a compound described in general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and its intermediate and preparation method, As well as the application in the preparation of medicines for treating diseases related to PARP7 activity or expression.

The full name of PARP is poly-ADP-ribose polymerase, that is, poly-ADP-ribose polymerase, which is involved in a series of cellular processes including DNA repair and genome stability. The protein family consists of 17 members, divided into polyPARPs and monoPARPs. The MonoPARP family of proteins plays a role in multiple stress responses associated with the development of cancer, inflammatory diseases and neurodegenerative diseases, and its member PARP7 has been shown to be overactive in tumors and plays a key role in cancer cell survival.

The study found that many cancer cells depend on PARP7 for intrinsic cell survival, and that PARP7 enables cancer cells to "hide" from the immune system. Inhibiting PARP7 effectively inhibits cancer cell growth and restores interferon signaling, effectively releasing the "brakes" that cancer uses to hide from the immune system, inhibiting both innate and adaptive immune mechanisms. In several cancer models, PARP7 inhibitors exhibited durable tumor growth inhibition, potent antiproliferative activity, and restoration of interferon signaling. PARP7 inhibitors are expected to become targets for the development of new anticancer drugs.

The object of the present invention is to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof, which are used as PARP7 inhibitors. The compound in the invention can effectively inhibit PARP7 and can be used for treating diseases such as tumors.

(I) The present invention provides a compound described in general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein

(I)

In some embodiments, Y is selected from O, S, S(=O), S(=O) ₂ , S(=O) ₂ N(R ^y ), N(R ^y ), C _1-4 alkylene Group, -OC _1-3 alkylene-, -C _1-3 alkylene O-, -C _1-3 alkylene S-, -C _1-3 alkylene S(=O)-, - C _1-3 alkylene S(=O) ₂ -, -N(R ^y )C _1-3 alkylene-, -C _1-3 alkylene N(R ^y )-, said alkylene The group is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, =S, OH, cyano, C _1-6 alkyl, halogen substituted C ₁ Substituents of _-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl;

In some embodiments, Y is selected from O, N(R ^y ), C _1-3 alkylene, -OC _1-2 alkylene-, -C _1-2 alkylene O-, -C _{1- 2} alkylene S-, -C _1-2 alkylene S(=O) ₂ -, -N(R ^y )C _1-2 alkylene-, -C _1-2 alkylene N(R ^y )-, the alkylene group is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, =S, OH, cyano, C _1-4 Substituents of alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, Y is selected from O, N(R ^y ), -N(R ^y )C(=O)-, -C(=O)N(R ^y )-, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, -CH ₂ S-, -CH ₂ CH ₂ S-, -CH ₂ S(=O) ₂ -, -CH ₂ CH ₂ S(=O) ₂ -, -N(R ^y )CH ₂ -, -N(R ^y )CH ₂ CH ₂ -, -CH ₂ N(R ^y )-, -CH ₂ CH ₂ N(R ^y )-, -N(R ^y )C(=O)CH ₂ -, -CH ₂ C(=O)N(R ^y ) -, the CH ₂ is optionally further substituted by 0 to 2 (for example 0, 1 or 2) selected from H, =O, =S, OH, cyano, C _1-4 alkyl, halogen substituted C ₁ Substituents of _-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, Y is selected from O, -NHC(=O ₎ -, -C(=O)NH- _{, -CH2-} , _{-CH2CH2- , -CH2CH2CH2-} , - OCH ₂ -, -OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, -NHCH ₂ -, -NHCH ₂ CH ₂ -, -CH ₂ NH-, -CH ₂ CH ₂ NH- , -NHC(=O)CH ₂ -, -CH ₂ C(=O)NH-;

_In some embodiments, Y is selected from -NHC ₍ =O)-, -C(=O)NH-, _{-CH2CH2CH2- , -OCH2-} , _-CH2CH2- , _-CH2 O- _{, -CH2CH2O-} , _{-OCH2CH2- ;}

In some embodiments, Y is selected from O, -N( _CH3 )C(=O)-, -C(=O)N( _CH3 )-, _-CH2C (=O)NH-, -CH ₂ C(=O)N(CH ₃ )-;

In some embodiments, Y is selected from -CH ₂ S(=O) ₂ -;

In some embodiments, Y is selected _from -N( _CH2CH3 )C(=O)-, -N(CH( _CH3 ) ₂ )C(=O)-, -N( _CH2CH ( _CH3 ) ₂ )C(=O)-, -N(cyclopropyl)C(=O)-, -N(CH ₂ -cyclopropyl)C(=O)-, -C(=O)N(CH ₂ CH ₃ )-, -C(=O)N(CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N( Cyclopropyl)-, -C(=O)N(CH ₂ -cyclopropyl)-;

、

； In some embodiments, each Y is independently selected from -C(=O)N(CD ₃ )-, -C(=O)N(CH ₂ -oxetanyl)-, -C(=O) N(CH ₂ -oxolane)-, -C(=O)N(CH ₂ -azetidinyl)-, -C(=O)N(CH ₂ -pyrrolidinyl)-,- C(=O)N(CH ₂ -cyclopentyl)-, -C(=O)N(CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH(CH ₂ CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH ₂ CH(CH ₃ ) ₂ )-, -C(=O) N(CH ₂ CH(CH ₃ )CH ₂ CH ₃ )-, -C(=O)N(n-octyl)-, -C(=S)N(CH ₃ )-, -C(=S)N (CH ₂ CH ₃ )-, -C(=S)N(CH ₂ -cyclopropyl)-,

,

;

In some embodiments, ^{each Ry} is independently selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further replaced by 0 to 4 (for example, 0 , 1, 2, 3 or 4) selected from H, deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, 3 to 8 membered heterocyclyl Or substituted by a substituent of C _3-6 cycloalkyl, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;

In some embodiments, ^{each Ry} is independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further replaced by 0 to 4 (for example, 0 , 1, 2, 3 or 4) selected from H, deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 3 to 8 membered heterocyclic group Or substituted by a substituent of C _3-6 cycloalkyl, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;

In some embodiments, ^{each Ry} is independently selected from H, C _1-4 alkyl, and said alkyl or cycloalkyl is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4 ) selected from H, deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 3 to 8 membered heterocyclyl or C _3-6 cycloalkyl The substituent is substituted, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;

In some embodiments, each R ^y is independently selected from H, C _1-4 alkyl;

In some embodiments, each R ^y is independently selected from deuterated C _1-4 alkyl;

In some embodiments, each ^{Ry is} independently selected from _CD3 ;

In some embodiments, each ^Ry is independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, second-butyl, isobutyl, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, second butyl, isobutyl, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 Substituents of alkyl, C _1-4 alkoxy, 3 to 8 membered heterocyclic group or C _3-6 cycloalkyl, the heterocyclic group contains 1 to 3 selected from O, S, N heteroatoms;

In some embodiments, each ^Ry is independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, second-butyl, isobutyl, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, second butyl, isobutyl, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, deuterium, F, Cl, Br, CF ₃ , OH, cyano, NH ₂ , Methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, oxetane Substituents of pentyl, azetidinyl, pyrrolidinyl;

In some embodiments, each ^Ry is independently selected from H, methyl, ethyl;

In some embodiments, ring A is selected from C _6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclic group, and the heteroaryl or heterocyclic group contains 1 to 5 (for example 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N;

In some embodiments, Ring A is selected from 3(2H)-pyridazinone or 2(1H)-pyridinone;

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selected from

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selected from

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selected from

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In some embodiments, X ₁ , X ₂ , X ₃ , and X ₄ are each independently selected from N, CR ^x , and X ₁ , X ₂ , X ₃ , and X ₄ contain at most 2 Ns;

In some embodiments, _X1 is selected from N, _X2 is selected from CH, _X3 is selected from CH, CF, CCl, CCN or _CCF3 , _X4 is selected from CH or N;

In some embodiments, ring X is selected from C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 carbocycle or 5-10 membered heterocyclic group, and the heteroaryl or heterocyclic group Contains 1 to 5 (eg 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N;

In some embodiments, the ring X is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, and the heteroaryl or heterocyclic group contains 1 to 5 (such as 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N;

In some embodiments, Ring X is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, or imidazolyl;

In some embodiments, W ₁ is selected from N or C(R ^a4 );

In some embodiments, W _is selected from N or CH;

In some embodiments, W _is selected from N;

In some embodiments, R ^x and R ^a are each independently selected from H, halogen, cyano, OH, =0, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -SO ₂ -C _1-6 alkyl, -C(=O)C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 Carbocycle or -(CH ₂ ) _q -3 to 12-membered heterocycle, said -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, =O, NH ₂ , NH(C _1-6 alkyl), N(C _1-6 Alkyl) ₂ , C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl or 3 to 10 membered heterocyclic substituents substituted, The heterocycle contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;

In some embodiments, R ^a1 , R ^a2 , and R ^a4 are each independently selected from R ^a ;

In some embodiments, R ^a1 , R ^a2 , and R ^a4 are each independently selected from H, halogen, cyano, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -SO ₂ -C _1-6 alkyl, -C(=O)C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 Carbocycle or -(CH ₂ ) _q -3 to 12-membered heterocycle, said -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further C _1-6 alkyl, _{C 1 -6} alkoxy, C _3-6 cycloalkyl or 3 to 10 membered heterocyclic substituents, the heterocyclic ring contains 1 to 3 (such as 1, 2 or 3) selected from O, S , heteroatoms of N;

In some embodiments, R ^a3 is selected from H, C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 carbocycle or -(CH ₂ ) _q -3 to 12 membered heterocycle, said -CH ₂ -, alkyl, carbocycle or heterocycle is optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C _1-6 alkyl , halogen substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl or 3 to 10 membered heterocyclic substituents, the heterocyclic containing 1 to 3 ( For example 1, 2 or 3) heteroatoms selected from O, S, N;

In some embodiments, R ^a3 is selected from H, C _1-4 alkyl, and said alkyl is optionally further selected from 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, halogen, Substituted by OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, R ^a3 is selected from H, methyl, ethyl, propyl, isopropyl, and said methyl, ethyl, propyl or isopropyl is optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 Cycloalkyl substituents are substituted;

In some embodiments, R ^a2 is selected from H, F, Cl, Br, I, cyano, CF ₃ , CHF ₂ , CH ₂ F, methyl, methoxy, cyclopropyl;

In some embodiments, ^Ra3 is selected from H or methyl;

In some embodiments, R ^x , R ^a1 , R ^a2 , and R ^a4 are each independently selected from H, halogen, cyano, OH, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl base, C _1-4 alkoxy, C _1-4 alkylthio, -SO ₂ -C _1-4 alkyl, -C(=O)C _1-4 alkyl, -(CH ₂ ) _q -C _3-6 carbon ring or -(CH ₂ ) _q -3 to 6-membered heterocycle, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle C 1-4 alkyl optionally further substituted by 0 to 4 (for example 0 _, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, =O, C _1-4 alkyl, halogen , C _1-4 alkoxy, C _3-6 cycloalkyl or a substituent of a 3 to 6 membered heterocyclic ring containing 1 to 3 (eg 1, 2 or 3) members selected from Heteroatoms of O, S, N;

In some embodiments, R ^x , R ^a1 , and R ^a2 are each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH _3. -C(=O)CH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl radical, vinyl, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , - C(=O)CH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, Substituted by OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, each R ^x is independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, acetylene base, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl , ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4) Substituents selected from H, F, OH, cyano, methyl, ethyl, methoxy or ethoxy;

In some embodiments, each ^Rx is independently selected from H, F, Cl, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, _ethoxy , _-SO2CH3 , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , cyclopropyl;

In some embodiments, R ^a1 is selected from H, F, Cl, Br, I, cyano, CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl, propyl, isopropyl, ethynyl, methyl Oxy, Ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , Cyclopropyl, Cyclobutyl, Cyclopentyl or Cyclohexyl;

In some embodiments, R ^a1 is selected from H, F, Cl, Br, I, cyano, CF ₃ , methyl;

In some embodiments, ^Ra2 is selected from H;

In some embodiments, Ring B is selected from 4 to 11 membered nitrogen-containing heterocycles, _C4-10 carbocycles;

In some embodiments, ring B is selected from 4-7 membered monocyclic nitrogen-containing heterocycles, 5-11 membered spirocyclic nitrogen-containing heterocycles, 5-11 membered double ring nitrogen-containing heterocycles, 5-11 membered bridged rings containing Nitrogen heterocycle or C _4-7 monocyclic carbocycle;

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； In some embodiments, Ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,

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，左側與L連接； In some embodiments,

selected from

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, the left side is connected with L;

In some embodiments, each R ^b is independently selected from H, halogen, cyano, OH, =0, C _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _q -C _{3- 6} Cycloalkyl, the -CH ₂ -, alkyl, alkoxy or cycloalkyl is optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH , cyano, NH ₂ , C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy or C _3-6 cycloalkyl;

In some embodiments, each R ^b is independently selected from H, halogen, cyano, OH, =0, C _1-4 alkyl, C _1-4 alkoxy, -(CH ₂ ) _q -C _{3- 6} Cycloalkyl, the -CH ₂ -, alkyl, alkoxy or cycloalkyl is optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH , cyano, NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl;

In some embodiments, each R ^b is independently selected from H, F, Cl, Br, I, cyano, OH, =0, methyl, ethyl, propyl or isopropyl, said methyl, Ethyl, propyl or isopropyl is optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, Halogen substituted C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl substituents;

In some embodiments, ^{each R} is independently selected from H, F, Cl, Br, I, cyano, OH, =0, methyl, ethyl, propyl, or isopropyl;

In some embodiments, W is selected from a bond, C _1-3 alkylene or Q2, and the alkylene shown is optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, Halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy substituents;

In some embodiments, W is selected from a bond;

In some embodiments, L is selected from L1, L2 or L3;

In some embodiments, L1 is selected from -Q1-Ak1-Q2-Ak2-Q3-, the right side is connected to ring B;

In some embodiments, L1 is selected from -N(R ^q )-Ak1-O-Ak2-C(=O)-, -O-Ak1-O-Ak2-C(=O)-, -O-Ak1- N(R ^q )-Ak2-C(=O)-, -N(R ^q )-Ak1-N(R ^q )-Ak2-C(=O)-, -N(R ^q )-Ak1-O- Ak2-N(R ^q )C(=O)-, -O-Ak1-O-Ak2-N(R ^q )C(=O)-, -N(R ^q )-Ak1-Ak2-C(=O )-, -N(R ^q )-Ak1-Ak2-N(R ^q )C(=O)-, -O-Ak1-N(R ^q )-Ak2-N(R ^q )C(=O)- , -S-Ak1-O-Ak2-C(=O)-, -O-Ak1-S-Ak2-C(=O)-, -N(R ^q )-Ak1-O-Ak2-S(=O ) ₂ -, -O-Ak1-O-Ak2-S(=O) ₂ -, -N(R ^q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, the right side is connected to ring B ;

In some embodiments, L1 is selected from -N(R ^q )-Ak1-O-Ak2-C(=O)N(R ^q )-, -O-Ak1-N(R ^q )-Ak2-C(= O)N(R ^q )-, -O-Ak1-OC(=O)N(R ^q )-, the right side is connected to ring B;

，右側與環B連接； In some embodiments, L1 is selected from

, the right side is connected with ring B;

、

，右側與環B連接； In some embodiments, L1 is selected from

,

, the right side is connected with ring B;

In some embodiments, L1 is selected from -NH-Ak1-O-Ak2-C(=O)-, -O-Ak1-O-Ak2-C(=O)-, -N(CH ₃ )-Ak1- O-Ak2-C(=O)-, -O-Ak1-NH-Ak2-C(=O)-, -O-Ak1-N(CH ₃ )-Ak2-C(=O)-, -N( CH ₃ )-Ak1-NH-Ak2-C(=O)-, -NH-Ak1-NH-Ak2-C(=O)-, -S-Ak1-O-Ak2-C(=O)-, - O-Ak1-S-Ak2-C(=O)-, -NH-Ak1-O-Ak2-S(=O) ₂ -, -O-Ak1-O-Ak2-S(=O) ₂ -,- NH-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, the right side is connected to ring B;

，右側與環B連接； In some embodiments, L2 is selected from

, the right side is connected with ring B;

，右側與環B連接； In some embodiments, L2 is selected from

, the right side is connected with ring B;

或

，右側與環B連接； In some embodiments, L2 is selected from

or

, the right side is connected with ring B;

或

，右側與環B連接； In some embodiments, L3 is selected from

or

, the right side is connected with ring B;

、

、

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或

，右側與環B連接； In some embodiments, L3 is selected from

,

,

,

,

,

,

or

, the right side is connected with ring B;

In some embodiments, L4 is selected from -Ak3-Q4-Ak4-K1-Q5-K2-Ak5-Q6- or -Ak3-Q4-Ak4-K1-Q5-, the right side is connected to loop B;

In some embodiments, L4 is selected from -Ak3-O-K1-C(=O)-, -Ak3-N(R ^q )-K1-C(=O)-, -Ak3-N(R ^q )- K1-C(=O)-, the right side is connected with ring B;

In some embodiments, L4 is selected from -Ak3-O-K1-C(=O)-, -Ak3-NH-K1-C(=O)-, -Ak3-N(CH ₃ )-K1-C( =O)-, the right side is connected with ring B;

In some embodiments, Ak1 and Ak2 are each independently selected from C _1-4 alkylene, C _2-4 alkenylene, and C _2-4 alkynylene, and the Ak1 is optionally further replaced by 0 to 4 ( For example 0, 1, 2, 3 or 4) R ^k1 is substituted, and said Ak2 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k2 ;

In some embodiments, Ak1 and Ak2 are each independently selected from C _1-3 alkylene, C _2-3 alkenylene, and C _2-3 alkynylene, and the Ak1 is optionally further replaced by 0 to 4 ( For example 0, 1, 2, 3 or 4) R ^k1 is substituted, and said Ak2 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k2 ;

In some embodiments, Ak1 and Ak2 are each independently selected from methylene, ethylene, propylene, vinylidene, propenylene, ethynylene, propynylene, and the Ak1 is optionally further 0 to 4 (for example 0, 1, 2, 3 or 4) R ^k1 are substituted, and said Ak2 is optionally further substituted by 0 to 4 (for example 0, 1, 2, 3 or 4) R ^k2 ;

In some embodiments, Ak3, Ak4, Ak5 are each independently selected from a bond, C _1-4 alkylene, C _2-4 alkenylene, C _2-4 alkynylene, and the Ak3 is optionally further replaced by O to 4 (e.g. 0, 1, 2, 3 or 4) R ^k3 substitutions, said Ak4 is optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4) R ^k4s , said Ak5 being any selected to be further replaced by 0 to 4 R ^k5 ;

In some embodiments, Ak3, Ak4, Ak5 are each independently selected from a bond, C _1-3 alkylene, C _2-3 alkenylene, C _2-3 alkynylene, and the Ak3 is optionally further replaced by O to 4 (e.g. 0, 1, 2, 3 or 4) R ^k3 substitutions, said Ak4 is optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4) R ^k4s , said Ak5 being any Optionally be further replaced by 0 to 4 R ^k5 (eg 0, 1, 2, 3 or 4);

In some embodiments, Ak3, Ak4, and Ak5 are each independently selected from a bond, methylene, ethylene, propylene, vinylene, propenylene, ethynylene, propynylene, and the Ak3 optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R ^k3 , said Ak4 optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R ^k4 , the Ak5 is optionally further substituted by 0 to 4 ^Rk5 ;

In some embodiments, K1 or K2 is selected from a C _1-2 alkylene group, a C _3-10 carbocycle or a 3-12 membered heterocycle, and the alkylene group is optionally further surrounded by 0 to 4 (such as 0 , 1, 2, 3 or 4) R ^k6 is substituted, and the carbocycle or heterocycle is optionally further 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyanide radical, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, -C _1-6 alkane Substituents of -OC _1-6 alkyl, -OC _1-6 alkyl -OC _1-6 alkyl, -OC _3-8 carbocycle, C _3-8 carbocycle, 4 to 10 membered heterocycle , the heterocycle contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;

In some embodiments, K1 or K2 is selected from C _1-2 alkylene, C _3-6 carbocycle or 3 to 7 membered heterocycle, and said alkylene is optionally further replaced by 0 to 4 (such as 0 , 1, 2, 3 or 4) R ^k6 is substituted, and the carbocycle or heterocycle is optionally further 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyanide radical, NH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkane Substituents of -OC _1-4 alkyl, -OC _1-4 alkyl -OC _1-4 alkyl, -OC _3-6 carbocycle, C _3-6 carbocycle, 4 to 7-membered heterocycle , the heterocycle contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;

In some embodiments, K1 or K2 is selected from methylene, ethylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl , piperazine, morpholine, oxetanyl, oxolyl, oxanyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine, the methylene, ethylene optionally further Substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k6 , said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl , azacyclohexyl, piperazine, morpholine, oxetanyl, oxolyl, oxanyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine are optionally further replaced by 0 to 4 ( For example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OC _1-4 alkyl, -OC _1-4 alkyl-OC _1-4 alkyl, -OC _3-6 carbon ring, C _3-6 carbocycle, 4 to 7-membered heterocyclic ring containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N ;

In some embodiments, R ^k1 , R ^k2 , R ^k3 , R ^k4 , R ^k5 , R ^k6 , R ^L1 , R ^L2 are each independently selected from H, halogen, cyano, OH, =0, NH ₂ , NHC _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, -OC _{3- 6} carbon rings, C _3-6 carbon rings or 4 to 7 membered heterocyclic rings, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic or heterocyclic rings are optionally further replaced by 0 to 4 (such as 0 , 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halogen substituted C _1- Substituents of ₆ alkyl, C _1-6 alkoxy, -OC _3-8 carbocycle, C _3-8 carbocycle, 4 to 10 membered heterocycle, the heterocycle contains 1 to 3 ( For example 1, 2 or 3) heteroatoms selected from O, S, N;

In some embodiments, R ^k1 , R ^k2 , R ^k3 , R ^k4 , R ^k5 , R ^k6 , R ^L1 , R ^L2 are each independently selected from H, halogen, cyano, OH, =0, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocycle or 4 to 7 membered heterocycle, said alkane Base, alkoxy, carbocycle or heterocycle are optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkane C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocycle (such as C ₃ , C ₄ , C ₅ or C ₆ ), 4 to 6 members (such as 4, 5 or 6-membered) heterocyclic substituents, said heterocyclic containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

In some embodiments, R ^k1 , R ^k2 , R ^k3 , R ^k4 , R ^k5 , R ^k6 , R ^L1 , R ^L2 are each independently selected from H, F, Cl, Br, I, cyano, OH, = O, NH ₂ , NH(CH ₃ ), N(CH ₃ ) ₂ , methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, azacyclopentyl, azetidinyl, oxetanyl, oxolyl, oxanyl, pyridine, phenyl, the methyl, ethyl, propyl, Methoxy, Ethoxy, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Azetidinyl, Azacyclopentyl, Azacyclohexyl, Oxetanyl, Oxolane Base, oxanyl, pyridine, phenyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkane C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocycle (such as C ₃ , C ₄ , C ₅ or C ₆ ), 4 to 6 members (such as 4, 5 or 6-membered) heterocyclic substituents, said heterocyclic containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

In some embodiments, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 , R ^k3 and R ^k3 , R ^k4 and R ^k4 , R ^k5 and R ^k5 , R ^k6 and R ^k6 are directly linked to form C _3-6 carbocycle (such as C ₃ , C ₄ , C ₅ or C ₆ ) or heterocycle with 4 to 7 members (such as 4, 5, 6 or 7 members), the carbocycle or heterocycle is optionally C 1-6 alkyl, C further substituted by 0 to 4 _{(such as 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, C 1-6 alkyl} , halogen Substituted by _1-6 alkoxy, C _3-6 cycloalkyl substituents, the heterocycle contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;

In some embodiments, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 , R ^k3 and R ^k3 , R ^k4 and R ^k4 , R ^k5 and R ^k5 , R ^k6 and R ^k6 are directly linked to form C _3-6 carbocycle (such as C ₃ , C ₄ , C ₅ or C ₆ ) or heterocycle with 4 to 7 members (such as 4, 5, 6 or 7 members), the carbocycle or heterocycle is optionally C _{1-4 alkyl, C further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, C 1-4 alkyl} , halogen _1-4 alkoxy, C _3-6 cycloalkyl substituents, the heterocycle contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;

In some embodiments, Q1, Q5 are each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O ), C(=O)O, OC(=O), S(=O), S(=O) ₂ , S(=O) ₂ N(R ^q ), N(R ^q )S(=O) _2. N(R ^q )C(=O)N(R ^q ), N(R ^q )C(=O)N(R ^q );

In some embodiments, Q1, Q5 are each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O ), S(=O) ₂ ;

In some embodiments, Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1;

In some embodiments, Ring E is selected from a _C3-6 carbocycle or a 4 to 7 membered heterocycle containing 1 to 3 (eg 1, 2 or 3) members selected from O, S, N heteroatoms;

In some embodiments, ring E is selected from a _C3-6 carbocycle or a 4 to 6 membered heterocycle containing 1 to 3 (eg 1, 2 or 3) members selected from O, S, N heteroatoms;

In some embodiments, ring E is selected from phenyl or 5-6 membered heteroaryl containing 1 to 3 (eg 1, 2 or 3) heteroaryls selected from O, S, N atom;

In some embodiments, Ring E is selected from a benzene ring or a pyridine;

In some embodiments, each R ^q is independently selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further replaced by 0 to 4 (such as 0 , 1, 2, 3 or 4) Substituents selected from H, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy;

In some embodiments, each ^Rq is independently selected from H, C _1-4 alkyl, and said alkyl is optionally further selected from H by 0 to 4 (eg 0, 1, 2, 3 or 4) , halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents;

In some embodiments, each ^Rq is independently selected from H, methyl, ethyl;

In some embodiments, R ^q is directly linked to R ^k1 or R ^k2 to form a 4 to 7-membered heterocycle, which is optionally further surrounded by 0 to 4 (eg, 0, 1, 2, 3 or 4 ) Substituents selected from H, halogen, =O, OH, cyano, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl Substituted, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

In some embodiments, R ^q and R ^k1 , R ^q and R ^k2 are directly connected to form a heterocyclic ring with 4 to 7 members, and the heterocyclic ring is optionally further surrounded by 0 to 4 (such as 0, 1, 2, 3 Or 4) selected from H, halogen, =O, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl Substituents are substituted, and the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

In some embodiments, R ^q and R ^k1 , R ^q and R ^k2 are directly connected to form a heterocyclic ring with 4 to 7 members, and the heterocyclic ring is optionally further surrounded by 0 to 4 (such as 0, 1, 2, 3 Or 4) Substituents selected from H, halogen, =O, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, said The heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

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，右側與環B連接； In some embodiments, L1 is selected from

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, the right side is connected with ring B;

，右側與環B連接； In some embodiments, L1 is selected from

, the right side is connected with ring B;

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，右側與環B連接； In some embodiments, L1 is selected from or L1 is selected from

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, the right side is connected with ring B;

或者

，或者Y選自-CH ₂S(=O) ₂-； In some embodiments, L is selected from

or

, or Y is selected from -CH ₂ S(=O) ₂ -;

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，右側與環B連接； In some embodiments, L is selected from

,

,

,

, the right side is connected with ring B;

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，右側與環B連接； In some embodiments, L is selected from

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, the right side is connected with ring B;

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，右側與環B連接； In some embodiments, L2 is selected from

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, the right side is connected with ring B;

，右側與環B連接； In some embodiments, L3 is selected from

, the right side is connected with ring B;

In some embodiments, each q is independently selected from 0, 1, 2, 3 or 4;

In some embodiments, a is selected from 0, 1, 2, 3 or 4;

In some embodiments, b is selected from 0, 1, 2, 3 or 4;

In some embodiments, x is selected from 0, 1, 2, 3 or 4;

In some embodiments, s1 is selected from 0, 1, 2, 3 or 4;

In some embodiments, s2 is selected from 0, 1, 2, 3 or 4;

In some embodiments, s3 is selected from 0, 1, 2, 3 or 4.

As the first embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

Y is selected from O, S, S(=O), S(=O) ₂ , S(=O) ₂ N(R ^y ), N(R ^y ), C _1-4 alkylene, -OC _{1- 3} alkylene-, -C _1-3 alkylene O-, -C _1-3 alkylene S-, -C _1-3 alkylene S(=O)-, -C _1-3 alkylene Group S(=O) ₂ -, -N(R ^y )C _1-3 alkylene-, -C _1-3 alkylene N(R ^y )-, said alkylene is optionally further replaced by 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, =O, =S, OH, cyano, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C Substituents of _1-6 alkoxyl groups and C _3-6 cycloalkyl groups;

R ^y is each independently selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, 3 to 8 membered heterocyclyl or C _3-6 ring The substituent of the alkyl group is substituted, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;

Ring A is selected from C _6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclic group, the heteroaryl or heterocyclic group contains 1 to 5 selected from O, S, N heteroatom;

Ring X is selected from C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 carbocycle or 5-10 membered heterocyclic group, and the heteroaryl or heterocyclic group contains 1 to 5 optional Heteroatoms from O, S, N;

R ^x and R ^a are each independently selected from H, halogen, cyano, OH, =0, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy , C _1-6 alkylthio, -SO ₂ -C _1-6 alkyl, -C(=O)C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 carbocycle or -(CH ₂ ) _q -3 to 12-membered heterocycle, said -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle is optionally further replaced by 0 to 4 ( For example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, =O, NH ₂ , NH(C _1-6 alkyl), N(C _1-6 alkyl) ₂ , C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl or substituents of 3 to 10 membered heterocycles, the heterocycles contain 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

Ring B is selected from 4 to 11 membered nitrogen-containing heterocycles, C _4-10 carbocycles;

R ^b are each independently selected from H, halogen, cyano, OH, =0, C _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _q -C _3-6 cycloalkyl, so The -CH ₂ -, alkyl, alkoxy or cycloalkyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy or C _3-6 cycloalkyl substituents;

W is selected from a bond, C _1-3 alkylene or Q2, and the alkylene shown is optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, CF ₃ , OH , cyano, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy substituents;

L is selected from L1, L2 or L3;

L1 is selected from -Q1-Ak1-Q2-Ak2-Q3-, the right side is connected with ring B;

，右側與環B連接； L2 is selected from

, the right side is connected with ring B;

或

，右側與環B連接； L3 selected from

or

, the right side is connected with ring B;

L4 is selected from -Ak3-Q4-Ak4-K1-Q5-K2-Ak5-Q6- or -Ak3-Q4-Ak4-K1-Q5-, and the right side is connected to ring B;

Ak1 and Ak2 are each independently selected from C _1-4 alkylene, C _2-4 alkenylene, and C _2-4 alkynylene, and the Ak1 is optionally further substituted by 0 to 4 R ^k1 , and the Ak2 optionally further substituted by 0 to 4 R ^K2 ;

Ak3, Ak4, and Ak5 are each independently selected from a bond, a C _1-4 alkylene group, a C _2-4 alkenylene group, and a C _2-4 alkynylene group, and the Ak3 is optionally further replaced by 0 to 4 (such as 0 , 1, 2, 3 or 4) R ^k3 substitution, said Ak4 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k4 , said Ak5 is optionally further substituted by 0 to 4 one (for example 0, 1, 2, 3 or 4) R ^k5 substitutions;

K1 or K2 is selected from C _1-2 alkylene, C _3-10 carbocyclic or 3 to 12 membered heterocyclic rings, and the alkylene is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4) R ^k6 is substituted, and the carbocycle or heterocycle is optionally further 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, -C _1-6 alkyl-OC _1-6 Alkyl, -OC _1-6 alkyl -OC _1-6 alkyl, -OC _3-8 carbocycle, C _3-8 carbocycle, 4 to 10 membered heterocyclic substituents, the heterocyclic Contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

R ^k1 , R ^k2 , R ^k3 , R ^k4 , R ^k5 , R ^k6 , R ^L1 , and R ^L2 are each independently selected from H, halogen, cyano, OH, =O, NH ₂ , NHC _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, -OC _3-6 carbocycle, C _{3 -6} carbon ring or 4 to 7 membered heterocycle, said alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halogen substituted C _1-6 alkyl, C ₁ Substituents of _-6 alkoxy, -OC _3-8 carbocycle, C _3-8 carbocycle, 4 to 10-membered heterocycle, the heterocycle contains 1 to 3 (such as 1, 2 or 3 a) a heteroatom selected from O, S, N;

Alternatively, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 , R ^k3 and R ^k3 , R ^k4 and R ^k4 , R ^k5 and R ^k5 , R ^k6 and R ^k6 are directly connected to form C _{3- 6} carbon rings or 4 to 7-membered heterocycles, said carbocycles or heterocycles are optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) members selected from H, halogen, =O, OH , cyano, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl substituents, the heterocycle contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;

Q1 and Q5 are each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O), C(=O )O, OC(=O), S(=O), S(=O) ₂ , S(=O) ₂ N(R ^q ), N(R ^q )S(=O) ₂ , N(R ^q )C(=O)N(R ^q ), N(R ^q )C(=O)N(R ^q );

Q2, Q3, Q4, and Q6 are each independently selected from the key or Q1;

Ring E is selected from a _C3-6 carbocyclic ring or a 4-7 membered heterocyclic ring containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

R ^q are each independently selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 Or 4) Substituents selected from H, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy;

Alternatively, R ^q is directly connected to R ^k1 or R ^k2 to form a 4 to 7-membered heterocycle, which is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) members selected from Substituted by H, halogen, =O, OH, cyano, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, The heterocycle contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;

q are each independently selected from 0, 1, 2, 3 or 4;

a is selected from 0, 1, 2, 3 or 4;

b is selected from 0, 1, 2, 3 or 4;

x is selected from 0, 1, 2, 3 or 4;

s1 is selected from 0, 1, 2, 3 or 4;

s2 is selected from 0, 1, 2, 3 or 4;

s3 is selected from 0, 1, 2, 3 or 4.

As the second embodiment of the present invention, the compound represented by the following general formula (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

(II)

(II)

W ₁ is selected from N or C(R ^a4 );

Ring X is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, and said heteroaryl or heterocyclic group contains 1 to 5 heteroatoms selected from O, S, N;

R ^a1 , R ^a2 , and R ^a4 are each independently selected from H, halogen, cyano, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy , C _1-6 alkylthio, -SO ₂ -C _1-6 alkyl, -C(=O)C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 carbocycle or -(CH ₂ ) _q -3 to 12-membered heterocycle, said -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle is optionally further replaced by 0 to 4 ( For example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, =O, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, Substituents of C _3-6 cycloalkyl or 3 to 10 membered heterocyclic rings, the heterocyclic rings contain 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;

R ^a3 is selected from H, C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 carbocycle or -(CH ₂ ) _q -3 to 12-membered heterocycle, the -CH ₂ -, alkane The radical, carbocyclic or heterocyclic ring is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C _1-6 alkyl, halogen substituted C _{1 -6} alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl or 3 to 10 membered heterocyclic substituents containing 1 to 3 (such as 1, 2 or 3 a) a heteroatom selected from O, S, N;

The definitions of the remaining groups are the same as those of the first embodiment of the present invention.

As the third embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

Y is selected from O, N(R ^y ), C _1-3 alkylene, -OC _1-2 alkylene-, -C _1-2 alkylene O-, -C _1-2 alkylene S- , -C _1-2 alkylene S(=O) ₂ -, -N(R ^y )C _1-2 alkylene-, -C _1-2 alkylene N(R ^y )-, said Alkylene is optionally further substituted by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, =O, =S, OH, cyano, C _1-4 alkyl, halogen Substituents of C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

R ^y are each independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 3 to 8 membered heterocyclyl or C _3-6 ring The substituent of the alkyl group is substituted, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;

R ^x , R ^a1 , R ^a2 , and R ^a4 are each independently selected from H, halogen, cyano, OH, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 Alkoxy, C _1-4 alkylthio, -SO ₂ -C _1-4 alkyl, -C(=O)C _1-4 alkyl, -(CH ₂ ) _q -C _3-6 carbocycle or -(CH ₂ ) _q -3 to 6-membered heterocycle, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, =O, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkane Oxygen, C _3-6 cycloalkyl or substituents of 3 to 6 membered heterocyclic rings, the heterocyclic rings contain 1 to 3 (eg 1, 2 or 3) selected from O, S, N heteroatom;

R ^a3 is selected from H, C _1-4 alkyl, and said alkyl is optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C Substituents of _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

Ring B is selected from 4-7 membered monocyclic nitrogen-containing heterocycle, 5-11 membered spiro nitrogen-containing heterocycle, 5-11 membered double-ring nitrogen-containing heterocycle, 5-11 membered bridged ring nitrogen-containing heterocycle or C _{4 -7} monocyclic carbocycles;

R ^b are each independently selected from H, halogen, cyano, OH, =0, C _1-4 alkyl, C _1-4 alkoxy, -(CH ₂ ) _q -C _3-6 cycloalkyl, so The -CH ₂ -, alkyl, alkoxy or cycloalkyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl substituents;

Ak1 and Ak2 are each independently selected from C _1-3 alkylene, C _2-3 alkenylene, and C _2-3 alkynylene, and the Ak1 is optionally further replaced by 0 to 4 (such as 0, 1, 2 , 3 or 4) R ^k1 substitution, said Ak2 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k2 ;

Ak3, Ak4, and Ak5 are each independently selected from a bond, a C _1-3 alkylene group, a C _2-3 alkenylene group, and a C _2-3 alkynylene group, and the Ak3 is optionally further replaced by 0 to 4 (such as 0 , 1, 2, 3 or 4) R ^k3 substitution, said Ak4 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k4 , said Ak5 is optionally further substituted by 0 to 4 one (for example 0, 1, 2, 3 or 4) R ^k5 substitutions;

K1 or K2 is selected from C _1-2 alkylene, C _3-6 carbocycle or 3 to 7 membered heterocycle, and described alkylene is optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4) R ^k6 is substituted, and the carbocycle or heterocycle is optionally further 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OC _1-4 Substituents of alkyl, -OC _1-4 alkyl -OC _1-4 alkyl, -OC _3-6 carbocycle, C _3-6 carbocycle, 4 to 7-membered heterocycle, said heterocycle Contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

R ^k1 , R ^k2 , R ^k3 , R ^k4 , R ^k5 , R ^k6 , R ^L1 , and R ^L2 are each independently selected from H, halogen, cyano, OH, =O, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocycle or 4 to 7-membered heterocycle, the alkyl, alkoxy, Carbocycle or heterocycle is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) C selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocycle (eg C ₃ , C ₄ , C ₅ or C ₆ ), 4 to 6 membered (eg 4, 5 or 6 membered) heterocycle The substituent is substituted, and the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

Alternatively, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 , R ^k3 and R ^k3 , R ^k4 and R ^k4 , R ^k5 and R ^k5 , R ^k6 and R ^k6 are directly connected to form C _{3- 6} carbon rings (such as C ₃ , C ₄ , C ₅ or C ₆ ) or heterocyclic rings with 4 to 7 members (such as 4, 5, 6 or 7 members), said carbocyclic or heterocyclic rings are optionally further surrounded by 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 Substituents of alkoxy, C _3-6 cycloalkyl, the heterocycle contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;

Q1 and Q5 are each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O), S(=O ) ₂ ;

Q2, Q3, Q4, and Q6 are each independently selected from the key or Q1;

Ring E is selected from a _C3-6 carbocyclic ring or a 4-6 membered heterocyclic ring containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

R ^q are each independently selected from H, C _1-4 alkyl, and said alkyl is optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, CF ₃ , Substituents of OH, cyano, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy;

Alternatively, R ^q and R ^k1 , R ^q and R ^k2 are directly connected to form a 4 to 7-membered heterocycle, which is optionally further surrounded by 0 to 4 (eg 0, 1, 2, 3 or 4) Substituents selected from H, halogen, =O, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl Substituted, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

The definitions of the remaining groups are the same as those in the second embodiment of the present invention.

As the fourth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

W ₁ is selected from N or CH;

Ring X is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl or imidazolyl;

R ^x , R ^a1 , and R ^a2 are each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, ethylene radical, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(= O) CH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, acetylene radical, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C Substituents of _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

R ^a3 is selected from H, methyl, ethyl, propyl, isopropyl, and the methyl, ethyl, propyl or isopropyl is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4) A substituent selected from H, halogen, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl replaced by

Y is selected from O, N(R ^y ), -N(R ^y )C(=O)-, -C(=O)N(R ^y )-, -CH ₂ -, -CH ₂ CH ₂ -, - CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, -CH ₂ S-, -CH ₂ CH ₂ S-, -CH ₂ S(=O) ₂ -, -CH ₂ CH ₂ S(=O) ₂ -, -N(R ^y )CH ₂ -, -N(R ^y )CH ₂ CH ₂ -, -CH ₂ N(R ^y )-, -CH ₂ CH ₂ N(R ^y )-, -N(R ^y )C(=O)CH ₂ -, -CH ₂ C(=O)N(R ^y )-, the CH ₂ C _1-4 alkyl, _{C 1 -4} alkoxy, C _3-6 cycloalkyl substituents substituted;

Ry ^is each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, second butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, third butyl, second butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, ring Hexyl is optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _{1- 4} alkoxy, 3 to 8 membered heterocyclic group or substituent of C _3-6 cycloalkyl, said heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;

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； Ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,

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R ^b are each independently selected from H, F, Cl, Br, I, cyano, OH, =0, methyl, ethyl, propyl or isopropyl, the methyl, ethyl, propyl or Isopropyl is optionally further substituted with 0 to 4 ₍ eg 0, 1, 2, 3 or 4) _{C 1-} Substituents of ₄ alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl;

Ak1 and Ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene, propynylene, and the Ak1 is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4) R ^k1 substitution, said Ak2 is optionally further substituted by 0 to 4 R ^k2 ;

Ak3, Ak4, and Ak5 are each independently selected from a bond, methylene, ethylene, propylene, vinylidene, propenylene, ethynylene, propynylene, and the Ak3 is optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k3 substitutions, said Ak4 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k4s , said Ak5 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k5 ;

K1 or K2 is selected from methylene, ethylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, piperazine, morpholine , Oxetanyl, Oxolyl, Oxanyl, Benzene, Pyridine, Pyrazine, Pyrimidine, Pyridazine, the methylene and ethylene are optionally further replaced by 0 to 4 ( For example 0, 1, 2, 3 or 4) R ^k6 is substituted, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, Piperazine, morpholine, oxetanyl, oxolyl, oxanyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine are optionally further replaced by 0 to 4 (for example 0, 1, 2 , 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OC 1-4 alkyl _, -OC _1-4 alkyl-OC _1-4 alkyl, -OC _3-6 carbocycle, C _3-6 Substituents of carbocycles, 4 to 7-membered heterocycles, said heterocycles contain 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

R ^k1 , R ^k2 , R ^k3 , R ^k4 , R ^k5 , R ^k6 , R ^L1 , R ^L2 are each independently selected from H, F, Cl, Br, I, cyano, OH, =O, NH ₂ , NH (CH ₃ ), N(CH ₃ ) ₂ , methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, Azacyclopentyl, azacyclohexyl, oxetanyl, oxolyl, oxanyl, pyridine, phenyl, the methyl, ethyl, propyl, methoxy, ethoxy Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Azetidinyl, Azacyclopentyl, Azacyclohexyl, Oxetanyl, Oxolyl, Oxanyl , pyridine, phenyl are optionally further substituted by 0 to 4 (for example 0, 1, 2, 3 or 4) C selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen Substituents of _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocycle, 4 to 6-membered heterocycle, the heterocycle contains 1 to 3 (such as 1, 2 or 3 a) a heteroatom selected from O, S, N;

Alternatively, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 , R ^k3 and R ^k3 , R ^k4 and R ^k4 , R ^k5 and R ^k5 , R ^k6 and R ^k6 are directly connected to form C _{3- 6} carbon rings (such as C ₃ , C ₄ , C ₅ or C ₆ ) or heterocyclic rings with 4 to 7 members (such as 0, 1, 2, 3 or 4), said carbocyclic or heterocyclic rings are optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _{1- 4} alkoxy, C _3-6 cycloalkyl substituents, the heterocycle contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;

Q1 and Q5 are each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O), S(=O ) ₂ ;

Q2, Q3, Q4, and Q6 are each independently selected from the key or Q1;

Ring E is selected from phenyl or 5-6 membered heteroaryl, and said heteroaryl contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

R ^q are each independently selected from H, methyl, ethyl;

Alternatively, R ^q and R ^k1 , R ^q and R ^k2 are directly connected to form a 4 to 7-membered heterocycle, which is optionally further surrounded by 0 to 4 (eg 0, 1, 2, 3 or 4) Substituents selected from H, halogen, =O, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl Substituted, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;

The definitions of the remaining groups are the same as any one of the second or third embodiment of the present invention.

As the fifth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

選自

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，左側與L連接；

selected from

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, the left side is connected with L;

L1 is selected from -N(R ^q )-Ak1-O-Ak2-C(=O)-, -O-Ak1-O-Ak2-C(=O)-, -O-Ak1-N(R ^q )- Ak2-C(=O)-, -N(R ^q )-Ak1-N(R ^q )-Ak2-C(=O)-, -N(R ^q )-Ak1-O-Ak2-N(R ^q )C(=O)-, -O-Ak1-O-Ak2-N(R ^q )C(=O)-, -N(R ^q )-Ak1-Ak2-C(=O)-, -N( R ^q )-Ak1-Ak2-N(R ^q )C(=O)-, -O-Ak1-N(R ^q )-Ak2-N(R ^q )C(=O)-, -S-Ak1- O-Ak2-C(=O)-, -O-Ak1-S-Ak2-C(=O)-, -N(R ^q )-Ak1-O-Ak2-S(=O) ₂ -, -O -Ak1-O-Ak2-S(=O) ₂ -, -N(R ^q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, the right side is connected to ring B;

Or L1 is selected from -N(R ^q )-Ak1-O-Ak2-C(=O)N(R ^q )-, -O-Ak1-N(R ^q )-Ak2-C(=O)N(R ^q )-, -O-Ak1-OC(=O)N(R ^q )-, the right side is connected with ring B;

L4 is selected from -Ak3-O-K1-C(=O)-, -Ak3-N(R ^q )-K1-C(=O)-, -Ak3-N(R ^q )-K1-C(=O )-, the right side is connected with ring B;

Ring E is selected from benzene ring or pyridine;

Y is selected from -NHC(=O)-, -C(=O)NH-, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, -NHCH ₂ -, -NHCH ₂ CH ₂ -, -CH ₂ NH-, -CH ₂ CH ₂ NH-, -NHC(=O)CH ₂ -, -CH ₂ C(=O)NH-;

Or Y is selected from O, -N(CH ₃ )C(=O)-, -C(=O)N(CH ₃ )-, -CH ₂ C(=O)NH-, -CH ₂ C(=O )N( _CH3 )-;

Or Y is selected from -N(CH ₂ CH ₃ )C(=O)-, -N(CH(CH ₃ ) ₂ )C(=O)-, -N(CH ₂ CH(CH ₃ ) ₂ )C( =O)-, -N(cyclopropyl)C(=O)-, -N(CH ₂ -cyclopropyl)C(=O)-, -C(=O)N(CH ₂ CH ₃ )- , -C(=O)N(CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(cyclopropyl)- , -C(=O)N(CH ₂ -cyclopropyl)-;

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； Or each Y is independently selected from -C(=O)N(CD ₃ )-, -C(=O)N(CH ₂ -oxetanyl)-, -C(=O)N(CH ₂ - Oxolane)-, -C(=O)N(CH ₂ -azetidinyl)-, -C(=O)N(CH ₂ -pyrrolidinyl)-, -C(=O) N(CH ₂ -cyclopentyl)-, -C(=O)N(CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH(CH ₂ CH ₃ ) ₂ )-,- C(=O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH (CH ₃ )CH ₂ CH ₃ )-, -C(=O)N(n-octyl)-, -C(=S)N(CH ₃ )-, -C(=S)N(CH ₂ CH ₃ )-, -C(=S)N(CH ₂ -cyclopropyl)-,

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;

Or Y is selected from -CH ₂ S(=O) ₂ -;

R ^a2 is selected from H;

W ₁ is selected from N;

The definitions of the remaining groups are the same as any one of the second, third or fourth embodiments of the present invention.

As the sixth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

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，右側與環B連接； L1 is selected from

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，右側與環B連接； L2 is selected from

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，右側與環B連接； L3 selected from

, the right side is connected with ring B;

R ^x are each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, methoxy, Ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy Base, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) Substituents selected from H, F, OH, cyano, methyl, ethyl, methoxy or ethoxy;

R ^a1 is selected from H, F, Cl, Br, I, cyano, CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy , -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R ^a3 is selected from H or methyl;

R ^b are each independently selected from H, F, Cl, Br, I, cyano, OH, =0, methyl, ethyl, propyl or isopropyl;

The definitions of the remaining groups are the same as any one of the second, third, fourth or fifth embodiments of the present invention.

As the seventh embodiment of the present invention, the compound represented by the following general formula (II-a), (II-b), (II-c) or its stereoisomer, deuterated product, solvate, prodrug, metabolites, pharmaceutically acceptable salts or co-crystals,

(II-a)

(II-b)

(II-a)

(II-b)

(II-c)

(II-c)

Y is selected from -NHC(=O)-, -C(=O)NH-, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -CH ₂ CH ₂ -, -CH ₂ O-, -CH _{2 CH2O-} , _{-OCH2CH2- ;}

Or Y is selected from O, -N(CH ₃ )C(=O)-, -C(=O)N(CH ₃ )-, -CH ₂ C(=O)NH-, -CH ₂ C(=O )N( _CH3 )-;

Or Y is selected from -N(CH ₂ CH ₃ )C(=O)-, -N(CH(CH ₃ ) ₂ )C(=O)-, -N(CH ₂ CH(CH ₃ ) ₂ )C( =O)-, -N(cyclopropyl)C(=O)-, -N(CH ₂ -cyclopropyl)C(=O)-, -C(=O)N(CH ₂ CH ₃ )- , -C(=O)N(CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(cyclopropyl)- , -C(=O)N(CH ₂ -cyclopropyl)-;

、

； Or each Y is independently selected from -C(=O)N(CD ₃ )-, -C(=O)N(CH ₂ -oxetanyl)-, -C(=O)N(CH ₂ - Oxolane)-, -C(=O)N(CH ₂ -azetidinyl)-, -C(=O)N(CH ₂ -pyrrolidinyl)-, -C(=O) N(CH ₂ -cyclopentyl)-, -C(=O)N(CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH(CH ₂ CH ₃ ) ₂ )-,- C(=O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH (CH ₃ )CH ₂ CH ₃ )-, -C(=O)N(n-octyl)-, -C(=S)N(CH ₃ )-, -C(=S)N(CH ₂ CH ₃ )-, -C(=S)N(CH ₂ -cyclopropyl)-,

,

;

Or Y is selected from -CH ₂ S(=O) ₂ -;

X ₁ , X ₂ , X ₃ , and X ₄ are each independently selected from N, CR ^x , and X ₁ , X ₂ , X ₃ , and X ₄ contain at most 2 Ns;

R ^x are each independently selected from H, F, Cl, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , cyclopropyl;

The definitions of the remaining groups are the same as any one of the second, third, fourth, fifth or sixth embodiments of the present invention.

As the eighth embodiment of the present invention, the compound represented by the above general formula (II-a), (II-b), (II-c) or its stereoisomer, deuterium, solvate, prodrug, metabolic product, pharmaceutically acceptable salt or co-crystal,

或者

，右側與環B連接； L from

or

, the right side is connected with ring B;

、

、

、

，右側與環B連接； or L from

,

,

,

, the right side is connected with ring B;

、

、

、

，右側與環B連接； L from

,

,

,

, the right side is connected with ring B;

Preferably, X ₁ is selected from N, X ₂ is selected from CH, X ₃ is selected from CH, CF, CCl, CCN or CCF ₃ , X ₄ is selected from CH or N;

The definitions of the remaining groups are the same as those in any one of the seventh embodiment of the present invention.

。 The present invention relates to the compound shown below or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the following structures:

.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from O, S, S(=O), S (=O) ₂ , S(=O) ₂ N(R ^y ), N(R ^y ), C _1-4 alkylene, -OC _1-3 alkylene-, -C _1-3 alkylene O-, -C _1-3 alkylene S-, -C _1-3 alkylene S(=O)-, -C _1-3 alkylene S(=O) ₂ -, -N(R ^y ) C _1-3 alkylene-, -C _1-3 alkylene N(R ^y )-, said alkylene is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4 ) selected from H, halogen, =O, =S, OH, cyano, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl replaced by substituents.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from O, N(R ^y ), C _{1- 3} alkylene, -OC _1-2 alkylene-, -C _1-2 alkylene O-, -C _1-2 alkylene S-, -C _1-2 alkylene S(=O) ₂ -, -N(R ^y )C _1-2 alkylene-, -C _1-2 alkylene N(R ^y )-, said alkylene is optionally further replaced by 0 to 4 (for example 0 , 1, 2, 3 or 4) selected from H, halogen, =O, =S, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy , The substituent of C _3-6 cycloalkyl is substituted.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from O, N(R ^y ), -N( R ^y )C(=O)-, -C(=O)N(R ^y )-, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, - OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, -CH ₂ S-, -CH ₂ CH ₂ S-, -CH ₂ S(=O) ₂ -, -CH ₂ CH ₂ S(=O) ₂ -, -N(R ^y )CH ₂ -, -N(R ^y )CH ₂ CH ₂ -, -CH ₂ N(R ^y )-, -CH ₂ CH ₂ N(R ^y ) -, -N(R ^y )C(=O)CH ₂ -, -CH ₂ C(=O)N(R ^y )-, the CH ₂ is optionally further replaced by 0 to 2 (such as 0, 1 or 2) selected from H, =O, =S, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl Substituents are substituted.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from O, -NHC(=O)-, - C(=O)NH-, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, -NHCH ₂ -, -NHCH ₂ CH ₂ -, -CH ₂ NH-, -CH ₂ CH ₂ NH-, -NHC(=O)CH ₂ -, -CH ₂ C(=O)NH -.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from O, -NHC(=O)-, - _C ( ₌ O)NH- _, -CH2CH2CH2-, _{-OCH2- , -CH2CH2- , -CH2O- ,} -CH2CH2O-, _{-OCH2CH2- .}

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from O, -N(CH ₃ )C(= O)-, -C(=O)N( _CH3 )-, _-CH2C (=O)NH-, _-CH2C (=O)N( _CH3 )-.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from -N(CH ₂ CH ₃ )C(= O)-, -N(CH(CH ₃ ) ₂ )C(=O)-, -N(CH ₂ CH(CH ₃ ) ₂ )C(=O)-, -N(cyclopropyl)C(= O)-, -N(CH ₂ -cyclopropyl)C(=O)-, -C(=O)N(CH ₂ CH ₃ )-, -C(=O)N(CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(cyclopropyl)-, -C(=O)N(CH ₂ -cyclopropyl )-.

、

。 The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), each Y is independently selected from -C(=O)N( CD ₃ )-, -C(=O)N(CH ₂ -oxetanyl)-, -C(=O)N(CH ₂ -oxolyl)-, -C(=O)N (CH ₂ -azetidinyl)-, -C(=O)N(CH ₂ -pyrrolidinyl)-, -C(=O)N(CH ₂ -cyclopentyl)-, -C(= O)N(CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH(CH ₂ CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH(CH ₃ )CH ₂ CH ₃ )-, -C(= O)N(n-octyl)-, -C(=S)N(CH ₃ )-, -C(=S)N(CH ₂ CH ₃ )-, -C(=S)N(CH ₂ -ring Propyl)-,

,

.

The present invention relates to some embodiments of the general formula (I), (II), (II-a), (II-b) or (II-c), each Y is independently selected from Y selected from -CH ₂ S( =O) ₂ -.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Ry ^each independently selected from H, C _1-6 alkane group or C _3-6 cycloalkyl group, said alkyl or cycloalkyl group is optionally further selected from 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, 3 to 8 membered heterocyclic group or C _3-6 cycloalkyl substituent, the heterocyclic group Contains 1 to 3 heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R ^y are each independently selected from H, C _1-4 alkane group or C _3-6 cycloalkyl group, said alkyl or cycloalkyl group is optionally further selected from 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 3 to 8 membered heterocyclic group or C _3-6 cycloalkyl substituent, the heterocyclic group Contains 1 to 3 heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R ^y each independently selected from H, methyl, ethyl , propyl, isopropyl, butyl, third butyl, second butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl Base, isopropyl, butyl, third butyl, second butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further replaced by 0 to 4 (such as 0, 1 , 2, 3 or 4) selected from H, deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 3 to 8 membered heterocyclyl or C _3-6 cycloalkyl substituents, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R ^y each independently selected from H, methyl, ethyl , propyl, isopropyl, butyl, third butyl, second butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl Base, isopropyl, butyl, third butyl, second butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further replaced by 0 to 4 (such as 0, 1 , 2, 3 or 4) selected from H, deuterium, F, Cl, Br, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, propyl, butyl, methoxy, ethoxy, Substituents of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolyl, azetidinyl, pyrrolidinyl.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R ^y are each independently selected from H, C _1-4 alkane base.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R ^y each independently selected from H, methyl, ethyl .

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), each R ^y is independently selected from CD ₃ ;

The present invention relates to some embodiments of general formula (I), ring A is selected from C _6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclic group, said heteroaryl or heterocyclic The group contains 1 to 5 (eg 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I), ring A is selected from 3(2H)-pyridazinone or 2(1H)-pyridinone.

選自

或

。 The present invention relates to some embodiments of general formula (I),

selected from

or

.

選自

。 The present invention relates to some embodiments of general formula (I),

selected from

.

選自

。 The present invention relates to some embodiments of general formula (I),

selected from

.

選自

、

、

。 The present invention relates to some embodiments of general formula (I),

selected from

,

,

.

選自

、

、

、

； The present invention relates to some embodiments of general formula (I),

selected from

,

,

,

;

The present invention relates to some embodiments of general formula (II-a), (II-b) or (II-c), X ₁ , X ₂ , X ₃ , X ₄ are each independently selected from N, CR ^x , X ₁ , X ₂ , X ₃ , and X ₄ contain at most 2 Ns (at most 2 of X ₁ , X ₂ , X ₃ , and X ₄ are N).

The present invention relates to some embodiments of general formula (I), (II), ring X is selected from C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 carbocyclic or 5-10 membered heterocyclic The said heteroaryl or heterocyclic group contains 1 to 5 (eg 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (II-a), (II-b) or (II-c), X ₁ is selected from N, X ₂ is selected from CH, X ₃ is selected from CH, CF, CCl, CCN or CCF ₃ , X ₄ is selected from CH or N.

The present invention relates to some embodiments of general formula (I), (II), ring X is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, said heteroaryl or heterocyclic The group contains 1 to 5 (eg 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I), (II), ring X is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazole , pyrrolyl, pyrazolyl or imidazolyl.

The present invention relates to some embodiments of general formula (II), W ₁ is selected from N or C(R ^a4 ).

The present invention relates to some embodiments of general formula (II), W ₁ is selected from N or CH.

The present invention relates to some embodiments of general formula (II), W ₁ is selected from N.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R ^x , R ^a are each independently selected from H, halogen, Cyano, OH, =O, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -SO ₂ -C _1-6 alkyl, -C(=O)C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 carbocycle or -(CH ₂ ) _q -3 to 12 membered heterocycle, said -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle are optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H , halogen, OH, cyano, =O, NH ₂ , NH(C _1-6 alkyl), N(C _1-6 alkyl) ₂ , C _1-6 alkyl, halogen substituted C _1-6 alkane Substituent group, C _1-6 alkoxy group, C _3-6 cycloalkyl group or 3 to 10 membered heterocycle containing 1 to 3 (for example 1, 2 or 3) selected Heteroatoms from O, S, N.

The present invention relates to some embodiments of general formula (II), (II-a), (II-b) or (II-c), R ^a1 , R ^a2 , R ^a4 are each independently selected from R ^a .

The present invention relates to some embodiments of general formula (II), (II-a), (II-b) or (II-c), R ^a1 , R ^a2 , R ^a4 are each independently selected from H, halogen, cyanide radical, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -SO ₂ -C _1-6 alkane group, -C(=O)C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 carbocycle or -(CH ₂ ) _q -3 to 12-membered heterocycle, the -CH ₂ - , alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH , cyano, =O, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl or substituents of 3 to 10 membered heterocycles Substituted, said heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.

In some embodiments of the present invention related to general formula (II), R ^a3 is selected from H, C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 carbocycle or -(CH ₂ ) _q -3 to 12-membered heterocyclic ring, the -CH ₂ -, alkyl, carbocyclic or heterocyclic ring is optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano C _1-6 alkyl, C _1-6 alkyl substituted by halogen, C _1-6 alkoxy, C _3-6 cycloalkyl or substituents of 3 to 10 membered heterocyclic rings, said A heterocycle contains 1 to 3 (eg 1 , 2 or 3) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formula (II), R ^a3 is selected from H, C _1-4 alkyl, and said alkyl is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4) Substituents selected from H, halogen, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl .

The present invention relates to some embodiments of the general formula (II), R ^a3 is selected from H, methyl, ethyl, propyl, isopropyl, and the methyl, ethyl, propyl or isopropyl is optionally C _{1-4 alkyl, C 1-4 further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C 1-4 alkyl ,} halogen Substituents of alkoxy and C _3-6 cycloalkyl are substituted.

In some embodiments of the present invention related to general formula (II), R ^a2 is selected from H, F, Cl, Br, I, cyano, CF ₃ , CHF ₂ , CH ₂ F, methyl, methoxy, ring Propyl.

The present invention relates to some embodiments of general formula (II), R ^a3 is selected from H or methyl.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R ^x , R ^a1 , R ^a2 , R ^a4 are each independently Selected from H, halogen, cyano, OH, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkylthio, -SO ₂ -C _1-4 alkyl, -C(=O)C _1-4 alkyl, -(CH ₂ ) _q -C _3-6 carbocycle or -(CH ₂ ) _q -3 to 6 membered heterocycle, The -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle are optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, =O, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or 3 to 6 Substituted by a substituent of a heterocyclic ring containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), each of R ^x , R ^a1 , and R ^a2 is independently selected from H , F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, - SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl C 1-4 alkyl, cyclohexyl optionally further substituted by 0 to 4 (for example 0 _, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C _1-4 alkyl, halogen Substituents of radical, C _1-4 alkoxy, C _3-6 cycloalkyl.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), each R ^x is independently selected from H, F, Cl, Br , I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH _3. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, OH, cyano, methyl, Ethyl, methoxy or ethoxy substituents.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), each R ^x is independently selected from H, F, Cl, cyano radical, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C (=O) _CH2CH3 , _cyclopropyl .

The present invention relates to some embodiments of general formula (II), (II-a), (II-b) or (II-c), R ^a1 is selected from H, F, Cl, Br, I, cyano, CF _3. CHF ₂ , CH ₂ F, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl , cyclopentyl or cyclohexyl.

The present invention relates to some embodiments of general formula (II), (II-a), (II-b) or (II-c), R ^a1 is selected from H, F, Cl, Br, I, cyano, CF _3. Methyl.

The present invention relates to some embodiments of general formula (II), R ^a2 is selected from H.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), ring B is selected from 4 to 11 membered nitrogen-containing heterocycles, C _4-10 carbon rings.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), ring B is selected from 4 to 7 membered monocyclic nitrogen-containing heterocycles , 5-11-membered spiro nitrogen-containing heterocycle, 5-11-membered parallel nitrogen-containing heterocycle, 5-11-membered bridging nitrogen-containing heterocycle or C _4-7 monocyclic carbocycle.

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

。 The present invention relates to some embodiments of general formula (I), (II), ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl ,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

.

選自

、

、

、

、

、

、

、

、

、

、

，左側與L連接。 The present invention relates to some embodiments of general formula (I), (II),

selected from

,

,

,

,

,

,

,

,

,

,

, the left side is connected with L.

The present invention relates to some embodiments of general formula (I), (II), R ^b each independently selected from H, halogen, cyano, OH, =0, C _1-6 alkyl, C _1-6 alkoxy group, -(CH ₂ ) _q -C _3-6 cycloalkyl, said -CH ₂ -, alkyl, alkoxy or cycloalkyl is optionally further replaced by 0 to 4 (for example 0, 1, 2 , 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy or C _3-6 cycloalkane The substituent of the group is substituted.

The present invention relates to some embodiments of the general formula (I), (II), each R ^b is independently selected from H, halogen, cyano, OH, =0, C _1-4 alkyl, C _1-4 alkoxy group, -(CH ₂ ) _q -C _3-6 cycloalkyl, said -CH ₂ -, alkyl, alkoxy or cycloalkyl is optionally further replaced by 0 to 4 (for example 0, 1, 2 , 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkane The substituent of the group is substituted.

The present invention relates to some embodiments of general formula (I), (II), R ^b each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propane Base or isopropyl, said methyl, ethyl, propyl or isopropyl is optionally further selected from 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyanide Substituents of radical, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl.

The present invention relates to some embodiments of general formula (I), (II), R ^b each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propane base or isopropyl.

The present invention relates to some embodiments of the general formula (I), W is selected from a bond, C _1-3 alkylene or Q2, and the alkylene shown is optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4) Substituents selected from H, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy.

The present invention relates to some embodiments of general formula (I), W is selected from a bond.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L is selected from L1, L2 or L3.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L1 is selected from -Q1-Ak1-Q2-Ak2-Q3- , the right side is connected with ring B.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L1 is selected from -N(R ^q )-Ak1-O- Ak2-C(=O)-, -O-Ak1-O-Ak2-C(=O)-, -O-Ak1-N(R ^q )-Ak2-C(=O)-, -N(R ^q )-Ak1-N(R ^q )-Ak2-C(=O)-, -N(R ^q )-Ak1-O-Ak2-N(R ^q )C(=O)-, -O-Ak1-O -Ak2-N(R ^q )C(=O)-, -N(R ^q )-Ak1-Ak2-C(=O)-, -N(R ^q )-Ak1-Ak2-N(R ^q )C (=O)-, -O-Ak1-N(R ^q )-Ak2-N(R ^q )C(=O)-, -S-Ak1-O-Ak2-C(=O)-, -O- Ak1-S-Ak2-C(=O)-, -N(R ^q )-Ak1-O-Ak2-S(=O) ₂ -, -O-Ak1-O-Ak2-S(=O) ₂ - , -N(R ^q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, the right side is connected to ring B.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), or L1 is selected from -N(R ^q )-Ak1-O -Ak2-C(=O)N(R ^q )-, -O-Ak1-N(R ^q )-Ak2-C(=O)N(R ^q )-, -O-Ak1-OC(=O) N(R ^q )-, the right side is connected with ring B.

，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L1 is selected from

, the right side is connected with ring B.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L1 is selected from -NH-Ak1-O-Ak2-C( =O)-, -O-Ak1-O-Ak2-C(=O)-, -N(CH ₃ )-Ak1-O-Ak2-C(=O)-, -O-Ak1-NH-Ak2- C(=O)-, -O-Ak1-N(CH ₃ )-Ak2-C(=O)-, -N(CH ₃ )-Ak1-NH-Ak2-C(=O)-, -NH- Ak1-NH-Ak2-C(=O)-, -S-Ak1-O-Ak2-C(=O)-, -O-Ak1-S-Ak2-C(=O)-, -NH-Ak1- O-Ak2-S(=O) ₂ -, -O-Ak1-O-Ak2-S(=O) ₂ -, -NH-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, right side Connect with ring B.

，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L2 is selected from

, the right side is connected with ring B.

，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L2 is selected from

, the right side is connected with ring B.

或

，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L2 is selected from

or

, the right side is connected with ring B.

或

，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L3 is selected from

or

, the right side is connected with ring B.

、

、

、

、

、

、

或

，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L3 is selected from

,

,

,

,

,

,

or

, the right side is connected with ring B.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), L4 is selected from -Ak3-Q4-Ak4-K1-Q5- K2-Ak5-Q6- or -Ak3-Q4-Ak4-K1-Q5-, the right side is connected to ring B.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L4 is selected from -Ak3-O-K1-C(=O )-, -Ak3-N(R ^q )-K1-C(=O)-, -Ak3-N(R ^q )-K1-C(=O)-, the right side is connected to ring B.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L4 is selected from -Ak3-O-K1-C(=O )-, -Ak3-NH-K1-C(=O)-, -Ak3-N(CH ₃ )-K1-C(=O)-, the right side is connected to ring B.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), Ak1 and Ak2 are each independently selected from C _1-4 alkylene Base, C _2-4 alkenylene, C _2-4 alkynylene, said Ak1 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k1 , said Ak2 is optionally Further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k2 .

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Ak1, Ak2 are each independently selected from C _1-3 alkylene Group, C _2-3 alkenylene, C _2-3 alkynylene, said Ak1 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k1 , said Ak2 is optionally Further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k2 .

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), Ak1 and Ak2 are each independently selected from methylene, ethylene A group, a propylene group, a vinylidene group, a propenylene group, an ethynylene group, a propynylene group, the Ak1 is optionally further substituted by 0 to 4 (such as 0, 1, 2, 3 or 4) R ^k1 , The Ak2 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) ^Rk2 .

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Ak3, Ak4, Ak5 are each independently selected from a bond, C _{1 -4} alkylene, C _2-4 alkenylene, C _2-4 alkynylene, the Ak3 is optionally further substituted by 0 to 4 (for example 0, 1, 2, 3 or 4) R ^k3 , the The Ak4 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k4 , and the Ak5 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k5 replaced.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Ak3, Ak4, Ak5 are each independently selected from a bond, C _{1 -3} alkylene, C _2-3 alkenylene, C _2-3 alkynylene, said Ak3 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k3 , the The Ak4 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k4 , and the Ak5 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k5 replaced.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Ak3, Ak4, Ak5 are each independently selected from the group consisting of bond, methylene group, ethylene group, propylene group, vinylidene group, propenylene group, ethynylene group, propynylene group, the Ak3 is optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k3 is substituted, the Ak4 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k4 , and the Ak5 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k5 substitution.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), K1 or K2 are selected from C _1-2 alkylene, C _3-10 carbon ring or 3 to 12-membered heterocyclic ring, said alkylene group is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k6 , said carbocyclic or heterocyclic The ring is optionally further surrounded by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, -C _1-6 alkyl-OC _{1-6 alkyl, -OC 1-6 alkyl} -OC _1- Substituents of ₆ alkyl, -OC _3-8 carbocycle, C _3-8 carbocycle, 4 to 10 membered heterocycle, the heterocycle contains 1 to 3 (eg 1, 2 or 3) A heteroatom selected from O, S, N.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), K1 or K2 are selected from C _1-2 alkylene, C _3-6 carbon ring or 3 to 7-membered heterocyclic ring, said alkylene is optionally further substituted by 0 to 4 (for example 0, 1, 2, 3 or 4) R ^k6 , said carbocyclic or heterocyclic The ring is optionally further surrounded by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OC _{1-4 alkyl, -OC 1-4 alkyl} -OC _1- Substituents of ₄ alkyl, -OC _3-6 carbocycle, C _3-6 carbocycle, 4 to 7-membered heterocycle, the heterocycle contains 1 to 3 (such as 1, 2 or 3) A heteroatom selected from O, S, N.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), K1 or K2 is selected from methylene, ethylene, ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, piperazine, morpholine, oxetanyl, oxolyl, oxygen Heterocyclohexyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine, the methylene and ethylene groups are optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^k6 , the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, piperazine, morpholine, oxetanyl, oxa Cyclopentyl, oxanyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano radical, NH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkane Substituents of -OC _1-4 alkyl, -OC _1-4 alkyl -OC _1-4 alkyl, -OC _3-6 carbocycle, C _3-6 carbocycle, 4 to 7-membered heterocycle , the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), R ^k1 , R ^k2 , R ^k3 , R ^k4 , R ^k5 , R ^k6 , R ^L1 , R ^L2 are each independently selected from H, halogen, cyano, OH, =O, NH ₂ , NHC _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, -OC _3-6 carbocycle, C _3-6 carbocycle or 4 to 7 membered heterocycle, said The alkyl, alkenyl, alkynyl, alkoxy, carbocyclic or heterocyclic ring is optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, -OC _3-8 carbocycle, Substituents of C _3-8 carbon rings and 4 to 10 membered heterocyclic rings, the heterocyclic rings contain 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), R ^k1 , R ^k2 , R ^k3 , R ^k4 , R ^k5 , R ^k6 , R ^L1 , R ^L2 are each independently selected from H, halogen, cyano, OH, =O, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _{1- 4} alkyl, C _1-4 alkoxy, C _3-6 carbocyclic or 4 to 7 membered heterocyclic, said alkyl, alkoxy, carbocyclic or heterocyclic optionally further surrounded by 0 to 4 ( For example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, Substituents of C _3-6 carbocycles and 4 to 6-membered heterocycles, the heterocycles contain 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S and N.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), R ^k1 , R ^k2 , R ^k3 , R ^k4 , R ^k5 , R ^k6 , R ^L1 , R ^L2 are each independently selected from H, F, Cl, Br, I, cyano, OH, =O, NH ₂ , NH(CH ₃ ), N(CH ₃ ) ₂ , methyl , ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetane Butyl, oxolane, oxanexyl, pyridine, phenyl, the methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetyl, oxolyl, oxanexyl, pyridine, phenyl are optionally further replaced by 0 to 4 ( For example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, Substituents of C _3-6 carbocycles and 4 to 6-membered heterocycles, the heterocycles contain 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S and N.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 , R ^k3 and R ^k3 , R ^k4 and R ^k4 , R ^k5 and R ^k5 , R ^k6 and R ^k6 are directly connected to form a C _3-6 carbon ring or a heterocycle with 4 to 7 members, and the carbocycle Or the heterocycle is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, C _1-6 alkyl, halogen substituted C _{1- 6} alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl substituents, the heterocycle contains 1 to 3 (eg 1, 2 or 3) selected from O, S, N heteroatoms.

The present invention relates to some embodiments of general formula (I), (II), (II-a), R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 , R ^k3 and R ^k3 , R ^k4 Direct connection with R ^k4 , R ^k5 and R ^k5 , R ^k6 and R ^k6 to form a C _3-6 carbon ring (such as C ₃ , C ₄ , C ₅ or C ₆ ) or 4 to 7 members (such as 4, 5, 6 or 7 member) heterocycle, said carbocycle or heterocycle is optionally further 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents, the heterocycle contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Q1, Q5 are each independently selected from O, S, N( R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O), C(=O)O, OC(=O), S(=O) , S(=O) ₂ , S(=O) ₂ N(R ^q ), N(R ^q )S(=O) ₂ , N(R ^q )C(=O)N(R ^q ), N( R ^q )C(=O)N(R ^q ).

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Q1, Q5 are each independently selected from O, S, N( R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O), S(=O) ₂ .

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), ring E is selected from C _3-6 carbocycle or 4 to 7 A membered heterocyclic ring, said heterocyclic ring contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), ring E is selected from C _3-6 carbocycle or 4 to 6 A membered heterocyclic ring, said heterocyclic ring contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), ring E is selected from phenyl or 5-6 membered heteroaryl , the heteroaryl group contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), ring E is selected from benzene ring or pyridine.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R ^q are each independently selected from H, C _1-6 alkane group or C _3-6 cycloalkyl group, said alkyl or cycloalkyl group is optionally further selected from 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, halogen, CF ₃ , OH, Substituents of cyano, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy.

The present invention relates to some embodiments of general formula (I), (II), (II-a), R ^q are each independently selected from H, C _1-4 alkyl, and said alkyl is optionally further replaced by O to 4 (e.g. 0, 1, 2, 3 or 4) substituents selected from H, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy replace.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R ^q are each independently selected from H, methyl, ethyl .

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R ^q is directly connected with R ^k1 or R ^k2 to form 4 to A 7-membered heterocycle, which is optionally further surrounded by 0 to 4 (eg 0, 1, 2, 3 or 4) members selected from H, halogen, =O, OH, cyano, C _1-6 alkane C _1-6 alkyl group, C _1-6 alkoxy group, C _3-6 cycloalkyl substituent substituted by halogen, said heterocycle contains 1 to 3 (such as 1, 2 or 3 a) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R ^q and R ^k1 , R ^q and R ^k2 are directly connected to form 4 to 7-membered heterocycle, which is optionally further represented by 0 to 4 (eg 0, 1, 2, 3 or 4) members selected from H, halogen, =O, OH, cyano, C _{1- 4} alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R ^q and R ^k1 , R ^q and R ^k2 are directly connected to form 4 to 7-membered heterocyclic ring, the heterocyclic ring is optionally further 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, methyl, Ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl substituents are substituted, and the heterocycle contains 1 to 3 (eg 1, 2 or 3) selected from O, S, N heteroatoms.

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，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L1 is selected from

,

,

,

,

,

,

,

,

,

,

,

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,

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,

,

,

,

,

,

, the right side is connected with ring B.

、

、

、

、

、

、

，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L1 is selected from

,

,

,

,

,

,

, the right side is connected with ring B.

或者

，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L is selected from

or

, the right side is connected with ring B.

、

、

、

，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L is selected from

,

,

,

, the right side is connected with ring B.

、

、

、

，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L is selected from

,

,

,

, the right side is connected with ring B.

、

、

、

、

、

、

、

、

，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L2 is selected from

,

,

,

,

,

,

,

,

, the right side is connected with ring B.

，右側與環B連接。 In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), L3 is selected from

, the right side is connected with ring B.

The present invention relates to some embodiments of general formulas (I) and (II), q are each independently selected from 0, 1, 2, 3 or 4.

The present invention relates to some embodiments of general formula (I), (II), a is selected from 0, 1, 2, 3 or 4.

The present invention relates to some embodiments of general formula (I), (II), b is selected from 0, 1, 2, 3 or 4.

The present invention relates to some embodiments of general formula (I), (II), x is selected from 0, 1, 2, 3 or 4.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), s1 is selected from 0, 1, 2, 3 or 4.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), s2 is selected from 0, 1, 2, 3 or 4.

In some embodiments of the present invention related to general formula (I), (II), (II-a), (II-b) or (II-c), s3 is selected from 0, 1, 2, 3 or 4.

The present invention relates to a pharmaceutical composition, including any of the above compounds or their stereoisomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and pharmaceutically acceptable carriers.

The present invention relates to any of the above-mentioned compounds or their stereoisomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals used in the preparation of drugs for treating diseases related to PARP7 activity or expression For use in , preferably, the disease is selected from tumors.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include ¹² C, ¹³ C and ¹⁴ C, and the isotopes of hydrogen include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes include ¹⁴ N and ¹⁵ N, the isotopes of fluorine include ¹⁷ F and ¹⁹ F, the isotopes of chlorine include ³⁵ Cl and ³⁷ Cl, and the isotopes of bromine include ⁷⁹ Br and ⁸¹ Br.

"Halogen" means F, Cl, Br or I.

"Halogen substituted" refers to F, Cl, Br or I substitution, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 substituents selected from F, Cl, Br Or substituted by a substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is referred to simply as "halo".

"Alkyl" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to an alkyl group of 1 to 20 carbon atoms, an alkyl group of 1 to 8 carbon atoms, an alkyl group of 1 to 6 An alkyl group of carbon atoms, an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; where alkyl appears herein, its definition is consistent with this definition. Alkyl groups can be monovalent, divalent, trivalent or tetravalent.

"Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) replace. Non-limiting examples include -X(CH ₂ )vX(CH ₂ )vX(CH ₂ )vH (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, and the heteroatom includes but is not limited to N , O or S, and at least one X is selected from heteroatoms, and N or S in heteroatoms can be oxidized into various oxidation states). Heteroalkyl groups can be monovalent, divalent, trivalent or tetravalent.

"Alkylene" refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH ₂ ) _v - (v is an integer from 1 to 10), examples of alkylene include but not Limited to methylene, ethylene, propylene and butylene, etc.

"Heteroalkylene" refers to a substituted or unsubstituted alkylene group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) substitutions. Non-limiting examples include -X(CH ₂ )vX(CH ₂ )vX(CH ₂ )v-, v is an integer from 1 to 5, each X is independently selected from a bond, N, O or S, and at least 1 X is selected from N, O or S.

"Cycloalkyl" means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclo Heptyl etc. As used herein, cycloalkyl is as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent or tetravalent.

"Heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 atoms selected from N, O or The heteroatoms of S, the selectively substituted N and S in the ring of heterocycloalkyl can be oxidized into various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include ring Oxyethyl, aziridyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2 H -pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl , piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent

"Alkenyl" means a substituted or unsubstituted straight and branched unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain including but not limited to 2 to 10 1, 2 to 6, or 2 to 4 carbon atoms, alkenyl examples include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-but Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 -pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octene base, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-Hexadiene, etc.; alkenyl groups appearing in this text have the same definition as this one. Alkenyl groups can be monovalent, divalent, trivalent or tetravalent.

"Alkynyl" means a substituted or unsubstituted straight and branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to Including 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1 -Butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butyne Base, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5- Hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, divalent, trivalent or Quadrivalent.

"Alkoxy" means a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, Cyclopropoxy and cyclobutoxy.

、

、

、

或

。「碳環基」或「碳環」可以是一價、二價、三價或四價。 "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a single ring with 3 to 8 members, a ring with 4 to 12 members Bicyclic or 10- to 15-membered tricyclic ring system, the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring is optionally a monocyclic, bridged or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,

,

,

,

or

. A "carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

、

、

、

、

、

、

、

、

、

、

、

、

或

。「雜環基」或「雜環」可以是一價、二價、三價或四價。 "Heterocyclic group" or "heterocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a single ring with 3 to 8 members, a ring with 4 to 12 members Bicyclic or 10- to 15-membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, the ring optional of heterocyclyl Substituted N and S can be oxidized into various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom. The heterocyclic group can be connected to an aromatic ring or a non-aromatic ring. The heterocyclic group can be a monocyclic ring, a parallel ring, a bridged ring or a spiro ring. Non-limiting examples Including oxiranyl, aziridyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxo Hexacyclyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholine base, thiomorpholinyl, 1,3-dithianyl, dihydrofuryl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl , tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl , benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazine Base, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxa spiro[3.3]heptyl,

,

,

,

,

,

,

,

,

,

,

,

,

or

. "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"Spiro ring" or "spiro ring group" refers to a polycyclic group that shares one atom (called spiro atom) between substituted or unsubstituted monocyclic rings. The number of ring atoms in the spiro ring system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any can contain 0 to 5 heteroatoms selected from N, O or S(=O) _n . Non-limiting examples include:

。「螺環」或「螺環基」可以是一價、二價、三價或四價。

. A "spirocycle" or "spirocyclyl" may be monovalent, divalent, trivalent or tetravalent.

、

、

、 "Acyl ring" or "annyl ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more ( including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain from 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to be selected from N, S(=O) _n or O, n being 0, 1 or 2). The number of ring atoms in the double ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

,

,

,

「並環」或「並環基」可以是一價、二價、三價或四價。

"Alkyl" or "alkyl" may be monovalent, divalent, trivalent or tetravalent.

、

、

、

、

、立方烷、金剛烷。「橋環」或「橋環基」可以是一價、二價、三價或四價。 "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly connected, which may contain 0 or more double bonds, and any ring in the ring system It may contain 0 to 5 groups selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) _n or O, wherein n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12 or 5 to 10. Non-limiting examples include

,

,

,

,

, Cubane, Adamantane. A "bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

"Carbospiro", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" whose ring system consists only of carbon atoms. The definitions of "carbospirocycle", "spirocyclic carbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing in this article are consistent with spirocycle.

"Carbocyclyl", "paracyclic carbocyclyl", "carbocyclyl" or "carbocyclyl" refers to a "carbocyclyl" whose ring system consists only of carbon atoms. The definition of "carbocyclyl", "paracyclic carbocyclyl", "paracarbocyclyl" or "carbocyclyl" used herein is consistent with that of bicyclic.

"Carbobridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged cycloyl" refers to a "bridged ring" whose ring system consists only of carbon atoms. The definitions of "carbon bridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged ring" appearing in this article are consistent with those of bridged ring.

"Heterocyclic group", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to "heterocyclic group" or "heterocyclic group" of a monocyclic ring system, and the heterocyclic group, "monocyclic heterocyclic group" appearing herein group" or "heteromonocyclic group", the definition of which is consistent with that of heterocycle.

"Heterocyclyl", "heterocyclyl", "heterocyclic heterocyclyl" or "heterocyclyl" refers to "heterocyclyl" containing heteroatoms. The definition of heterocyclic ring, "heterocyclic group", "heterocyclic heterocyclic group" or "heterocyclic group" used herein is consistent with that of parallel ring.

"Heterospiro", "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" that contains heteroatoms. The definition of heterospirocycle, "heterospirocyclyl", "spirocyclic heterocyclyl" or "heterospirocyclyl" used herein is consistent with that of spirocycle.

"Heterobridged ring", "heterobridged ring group", "bridged ring heterocyclyl" or "heterobridged ring group" refers to a "bridged ring" that contains heteroatoms. The definition of heterobridged ring, "heterobridged ring group", "bridged ring heterocyclic group" or "heterobridged ring group" used herein is consistent with bridged ring.

「芳基」或「芳環」可以是一價、二價、三價或四價。當為二價、三價或四價時，連接位點位於芳基環上。 "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a single ring or fused rings. The number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples include benzene, naphthalene,

"Aryl" or "aromatic ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

和

。本文中出現的雜芳基，其定義與本定義一致。雜芳基可以是一價、二價、三價或四價。當為二價、三價或四價時，連接位點位於雜芳基環上。 "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S (= O) n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples include

and

. Where heteroaryl appears herein, its definition is consistent with this definition. Heteroaryl groups can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the heteroaryl ring.

"5-membered ring and 5-membered heteroaromatic ring" refers to a fused heteroaryl ring with 5 and 5 members, and at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N), the entire group is aromatic, and non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolopyrrole ring, pyrazolofuran ring, pyrrolothiophene ring, pyrazolothiophene ring.

"5 and 6-membered heteroaromatic ring" refers to a fused heteroaromatic ring with 5 and 6 members, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N) , the entire group is aromatic, and non-limiting examples include benzo 5-membered heteroaryl rings, 6-membered heteroaryl rings, and 5-membered heteroaryl rings.

"Substituted" or "substituted" means substituted with one or more (including but not limited to 2, 3, 4 or 5) substituents including but not limited to H, F, Cl, Br, I , Alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro Cyclic group, paracyclic group, hydroxyalkyl group, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m - C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -ene -R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR ^b R ^c and other groups, wherein R ^b and R ^c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoro Methanesulfonyl, as an option, R ^b and R ^c can form a five- or six-membered cycloalkyl or heterocyclic group, and R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, Cycloalkyl, heterocyclyl, carbonyl, ester, endocyclyl, spirocyclyl or alkynyl.

"Containing 1 to 5 heteroatoms selected from O, S, and N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, and N.

"Substituted by 0 to X substituents" means substituted by 0, 1, 2, 3...X substituents, X is selected from any integer between 1 and 10. For example, "substituted by 0 to 4 substituents" means substituted by 0, 1, 2, 3 or 4 substituents. For example, "substituted by 0 to 5 substituents" means substituted by 0, 1, 2, 3, 4 or 5 substituents. For example, "the heterobridged ring is optionally further substituted by 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H or F base replaced.

Rings with X-Y members (X is selected from integers less than Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) include X+1, X+2, X+3, X+4....Y members ring. Rings include heterocycles, carbocycles, aryls, aryls, heteroaryls, cycloalkyls, heteromonocycles, heteroheterocycles, heterospirocycles or heterobridged rings. For example, "4-7 membered heterocyclic ring" refers to 4-membered, 5-membered, 6-membered or 7-membered heterocyclic rings, and "5-10-membered heterocyclic ring" refers to 5-membered, 6-membered, 7-membered, 8-membered heterocyclic rings. , 9-membered or 10-membered heterocyclic ring.

"Optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example: "Alkyl optionally substituted by F" means that the alkyl group may but not necessarily be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention maintains the biological effectiveness and characteristics of free acid or free alkali, and said free acid is mixed with non-toxic inorganic alkali or organic Alkaline, the free alkali is a salt obtained by reacting with a non-toxic inorganic acid or organic acid.

"Pharmaceutical composition" refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals and A mixture formed by other chemical components, wherein "other chemical components" refer to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.

Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). Proper dosage and suitable duration and frequency of administration will be determined by factors such as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient and the method of administration. Optimal dosages can be determined using experimental models and/or clinical trials.

In some embodiments, the methods involve administering from about 0.1 μg to about 500 mg of at least one compound of the invention per kg body weight of the subject. Doses of from about 10 μg to about 200 mg of the compounds disclosed herein are more commonly used, depending on the physiological response of the subject. For example, the dose of the compound described in the application for the treatment and/or prevention of diseases as described in the application is about 0.001 to about 1 mg/kg body weight of the subject/day, such as about 0.001 mg, about 0.002 mg , about 0.005mg, about 0.010mg, about 0.015mg, about 0.020mg, about 0.025mg, about 0.050mg, about 0.075mg, about 0.1mg, about 0.15mg, about 0.2mg, About 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight/day. In some embodiments, the dosage of a compound described herein for use in the described methods is from about 1 to about 1000 mg/kg body weight/day of the subject being treated, about 1 mg, about 2 mg, about 5 mg, about 10 mg, About 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

"Carrier" means a material that does not produce significant irritation to an organism and that does not abrogate the biological activity and properties of the administered compound.

"Excipient" means an inert substance added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders agents and disintegrants.

"Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups of the compounds of the present invention, which modifications can be removed by routine manipulation or in vivo to obtain the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

"Co-crystal" refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bond or other non-covalent bonds, wherein the pure state of API and CCF are homogeneous at room temperature. It is a solid and there is a fixed stoichiometric ratio between the components. Eutectic is a kind of multi-component crystal, including two-membered eutectic formed between two neutral solids, and multi-membered eutectic formed between neutral solid and salt or solvate.

"Animal" is meant to include mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.

"Stereoisomers" refer to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.

"Tautomer" refers to a functional group isomer produced by a certain atom in a molecule moving rapidly at two positions, such as keto-enol isomerization and amide-imino alcohol isomerization.

"Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or circumstance may but not necessarily occur, and that the description includes the circumstances in which the event or circumstance occurs and the circumstances in which it is not what happened. For example, "heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group, and cases where the heterocyclyl group is not substituted with an alkyl group Condition.

"IC ₅₀ " is the concentration of drug or inhibitor required to inhibit a given biological process (or a component of that process such as an enzyme, receptor, cell, etc.) by half.

The following examples illustrate the technical solution of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.

Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument, and the measuring solvent is deuterated dimethyl sulfide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD ), the internal standard is tetramethylsilane (TMS);

For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

The determination of HPLC uses Agilent 1260DAD high performance liquid chromatography (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

TLC silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used in thin-layer chromatography (TLC) are 0.15 mm-0.20 mm, and the specifications of TLC separation and purification products are 0.4 mm. -0.5 mm;

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

In order to accomplish the purpose of the present invention, according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in chemical literature, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aisha (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anaiji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd. company etc.

DMSO: Dimethylsulfone; DMA: Dimethylacetamide; Solutol: Polyethylene glycol-15-hydroxystearate; PEG400: Polyethylene glycol 400; 20%SBE-β-CD: Sulphobutyl Saline: normal saline; MC: methylcellulose solution; CO ₂ : carbon dioxide; MeOH: methanol; DEA: diethylamine; DIPEA: N,N-diisopropylethylamine: DMF : N,N-Dimethylformamide;

HATU: CAS 148893-10-1;

PyBOP: CAS 128625-52-.

Example 1 : 5-(((S)-1-(3- Oxo -3-((R)-3-( Trifluoromethyl )-6a,7,9,10- Tetrahydropyrazino [1,2-d] pyrido [3,2-b][1,4] Oxazine -8(6H)- base ) Propoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- ketone ( compound 1)

5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2- b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

The first step: (3R)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1c )

tert-butyl (3R)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

At room temperature, 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1a) (2.00g, 8.83mmol) was added to DMF (20 mL), and (3R)-3-(hydroxy tert-butyl methyl)piperazine-1-carboxylate (1.91 g, 8.83 mmol) and DIPEA (3.42 g, 26.49 mmol). The mixture was stirred overnight at room temperature. Add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 10:1) to obtain (3R)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoro Methyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester ( 1c ) (3.50 g, 97%).

LCMS m/z = 351.1 [M-55] ⁺ .

The second step: (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4 ]oxazine-8(6H)-tert-butyl carboxylate (1d)

tert-butyl (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylate

(3R)-3-(Hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1c) (1.0 g, 2.46 mmol) was added to DMF (20 ml) solution, NaH (0.34 g, 8.5 mmol) was added. The mixture was reacted at 40°C for 16 hours. Cool, add water (10 mL) to quench the reaction, extract with ethyl acetate (10 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v)=10:1) to obtain (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine a[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-tert-butyl carboxylate (1d) (0.5 g, 56%).

LCMS m/z =360.2[M+1] ⁺ .

The third step: (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b] Trifluoroacetate salt of [1,4]oxazine (1e)

(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine trifluoroacetate

(R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine -8(6H)-tert-butylcarboxylate (1d) (0.37g, 1.03 mmol) was dissolved in DCM (4 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3 ,2-b][1,4]oxazine trifluoroacetate salt (1e) (380 mg, 100%) was used directly in the next step.

LCMS m/z =260.2[M+1] ⁺ .

The fourth step: (R)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridyl[3,2-b][ 1,4]oxazin-8(6H)-yl)prop-2-en-1-one ( 1f )

(R)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl )prop-2-en-1-one

(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1, 4] The trifluoroacetic acid salt of oxazine (1e) (380 mg, 1.02 mmol) was dissolved in dichloromethane (4 mL), then acrylic anhydride (0.15 g, 1.22 mmol) and triethylamine (0.31 mg, 3.06 mmol), the mixture was reacted at 20°C for 24h, and the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v)=10:1) to obtain (R) -1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridyl[3,2-b][1,4]oxazine- 8(6H)-yl)prop-2-en-1-one ( 1f ) (0.3 g, 94%).

LCMS m/z = 314.1 [M+1] ⁺ .

The fifth step: ((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2 -d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)carbamate tert-butyl ester ( 1g )

tert-butyl ((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2- b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)carbamate

(R)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridyl[3,2-b][1,4 ]oxazin-8(6H)-yl)prop-2-en-1-one ( 1f ) (300 mg, 0.96 mmol) was dissolved in acetonitrile (1.8 mL), then N-Boc-L-alaninol was added (0.87 g, 5 mmol) and cesium carbonate (0.42 mg, 1.29 mmol), the mixture was reacted at 20°C for 48h. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v) = 10:1) to obtain ((S)-1-(3-oxo Generation-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1, 4] Oxazin-8(6H)-yl)propoxy)propan-2-yl)carbamate tert-butyl ester ( 1 g ) (0.34 g, 72%).

LCMS m/z = 489.2 [M+1] ⁺ .

The sixth step: 3-((S)-2-aminopropoxy)-1-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1 ,2-d]pyridyl[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one (1h) hydrochloride

3-((S)-2-aminopropoxy)-1-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][ 1,4]oxazin-8(6H)-yl)propan-1-one hydrochloride

((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridine And[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)carbamate tert-butyl ester ( 1g )(0.34g, 0.7 mmol ) was added to HCl/dioxane (4 mL, 4N), and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain 3-((S)-2-aminopropoxy)-1-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro Pyrazino[1,2-d]pyridyl[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one (1h) hydrochloride (230 mg, 77%), used directly in the next step.

LCMS m/z = 389.3 [M+1] ⁺ .

The seventh step: 2-(4-methoxybenzyl)-5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a, 7,9,10-Tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2- base)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ( 1j )

2-(4-methoxybenzyl)-5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2- d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

3-((S)-2-aminopropoxy)-1-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2- d]pyridyl[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one (1h) hydrochloride (0.18g, 0.42 mmol) was dissolved in acetonitrile (3 mL), add 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (0.13 g, 0.42 mmol) and triethylamine (127.26 mg, 1.26mmol), the mixture was stirred at room temperature for 24 h. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was subjected to prep-TLC (developing solvent: petroleum ether: ethyl acetate=1:2) to obtain 2-(4-methoxybenzyl)-5-(( (S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido [3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H) - Ketone ( 1j ) (130 mg, 46%).

LCMS m/z = 671.3 [M+1] ⁺ .

The eighth step: 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[ 1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl ) Pyridazin-3(2H)-one ( compound 1 )

5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2- b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

2-(4-methoxybenzyl)-5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9 ,10-Tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino )-4-(trifluoromethyl)pyridazin-3(2H)-one ( 1j ) (0.13g, 0.19 mmol) was dissolved in trifluoroacetic acid (5 mL), and trifluoromethanesulfonic acid (0.14 g, 0.95 mmol). The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in methanol, and DIPEA was added dropwise to adjust the pH to 8-9. After concentration under reduced pressure, the residue was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, and the preparative column model was XBridge@Prep C ₁₈ , inner diameter × length = 19mm × 250mm). Preparation method: The crude product was dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia water). Gradient elution method: Acetonitrile was eluted from 10% gradient to 55% (flow rate: 12 mL/min; elution time 17 min) to obtain 5-(((S)-1-(3-oxo-3-(( R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8 (6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ( Compound 1 ) (10 mg, 9.37%).

LCMS m/z =551.2[M+1] ⁺ .

Example 2 : 5-(((S)-1-(3- Oxo -3-((S)-3-( Trifluoromethyl )-6a,7,9,10- Tetrahydropyrazino [1,2-d] pyrido [3,2-b][1,4] Oxazine -8(6H)- base ) Propoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- ketone ( compound 2)

5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2- b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

The first step: (3S)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2c )

tert-butyl (3S)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

At room temperature, 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1a) (2.00g, 8.83mmol) was added to DMF (20 mL), and (3S)-3-(hydroxy tert-butyl methyl)piperazine-1-carboxylate (1.91 g, 8.83 mmol) and DIPEA (3.42 g, 26.49 mmol). The mixture was stirred overnight at room temperature. Add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 10:1) to obtain (3S)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoro Methyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester ( 2c ) (3.00 g, 83%).

LCMS m/z = 351.1 [M-55] ⁺ .

The second step: (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4 ]Oxazine-8(6H)-tert-butyl carboxylate (2d)

tert-butyl (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylate

(3S)-3-(Hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2c) (1.0 g, 2.46 mmol) was added to DMF (20 ml) solution, NaH (0.34 g, 8.5 mmol) was added. The mixture was reacted at 40°C for 16 hours. Cool, add water (10 mL) to quench the reaction, extract with ethyl acetate (10 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v)=10:1) to obtain (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine a[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-tert-butyl carboxylate (2d) (0.54 g, 61%).

LCMS m/z =360.2[M+1] ⁺ .

The third step: (S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b] Trifluoroacetate salt of [1,4]oxazine (2e)

(S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine trifluoroacetate

(S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine -8(6H)-tert-butylcarboxylate (2d) (0.56g, 1.42 mmol) was dissolved in DCM (4 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain (S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3 ,2-b][1,4]Oxazine trifluoroacetate salt (2e) (530 mg, 100%) was used directly in the next step.

LCMS m/z = 260.1 [M+1] ⁺ .

The fourth step: (S)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridyl[3,2-b][ 1,4]oxazin-8(6H)-yl)prop-2-en-1-one ( 2f )

(S)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl )prop-2-en-1-one

(S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1, 4] The trifluoroacetic acid salt of oxazine (2e) (530 mg, 1.42 mmol) was dissolved in dichloromethane (4 mL), and then acrylic anhydride (0.21 g, 1.69 mmol) and triethylamine (430 mg, 4.26 mmol), the mixture was reacted at 20°C for 24h, and the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v)=10:1) to obtain (S) -1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridyl[3,2-b][1,4]oxazine- 8(6H)-yl)prop-2-en-1-one ( 2f ) (0.34 g, 76%).

LCMS m/z = 314.1 [M+1] ⁺ .

The fifth step: ((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2 -d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)carbamate tert-butyl ester ( 2g )

tert-butyl ((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2- b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)carbamate

(S)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridyl[3,2-b][1,4 ]oxazin-8(6H)-yl)prop-2-en-1-one ( 2f ) (278 mg, 0.89 mmol) was dissolved in acetonitrile (1.4 mL), then N-Boc-L-alaninol was added (0.78 g, 4.44 mmol) and cesium carbonate (376 mg, 1.16 mmol), the mixture was reacted at 20°C for 48h. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v) = 10:1) to obtain ((S)-1-(3-oxo Generation-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1, 4] Oxazin-8(6H-yl)propoxy)propan-2-yl)carbamate tert-butyl ester ( 2 g ) (0.28 g, 64%).

LCMS m/z = 489.3 [M+1] ⁺ .

The sixth step: 3-((S)-2-aminopropoxy)-1-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1 ,2-d]pyridyl[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one (2h) hydrochloride

3-((S)-2-aminopropoxy)-1-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][ 1,4]oxazin-8(6H)-yl)propan-1-one hydrochloride

((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridine And[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)carbamate tert-butyl ester ( 2g )(0.28g, 0.57 mmol ) was added to HCl/dioxane (4 mL, 4N), and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain 3-((S)-2-aminopropoxy)-1-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro Pyrazino[1,2-d]pyridyl[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one (2h) hydrochloride (180 mg, 74%), used directly in the next step.

LCMS m/z = 389.1 [M+1] ⁺ .

The seventh step: 2-(4-methoxybenzyl)-5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a, 7,9,10-Tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2- base)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ( 2j )

2-(4-methoxybenzyl)-5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2- d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

3-((S)-2-aminopropoxy)-1-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2- d]pyridyl[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one (2h) hydrochloride (0.14g, 0.36 mmol) was dissolved in acetonitrile (3 mL), add 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (0.12 g, 0.36 mmol) and triethylamine (109.08 mg, 1.08mmol), the mixture was stirred at room temperature for 24 h. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was subjected to prep-TLC (developing solvent: petroleum ether: ethyl acetate=1:2) to obtain 2-(4-methoxybenzyl)-5-(( (S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido [3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H) - Ketone ( 2j ) (106 mg, 44%).

LCMS m/z = 671.3 [M+1] ⁺ .

The eighth step: 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[ 1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl ) Pyridazin-3(2H)-one ( compound 2 )

5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2- b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

2-(4-methoxybenzyl)-5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9 ,10-Tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino )-4-(trifluoromethyl)pyridazine-3(2H-one ( 2j ) (0.11g, 0.16 mmol) was dissolved in trifluoroacetic acid (5 mL), trifluoromethanesulfonic acid (0.12g, 0.80 mmol). The mixture was stirred and reacted at room temperature for 1 h. After the reaction solution was concentrated under reduced pressure, the crude product was obtained. The crude product was dissolved in methanol, and DIPEA was added dropwise to adjust the pH to 8-9. After concentrating under reduced pressure, the residue was subjected to Pre -HPLC purification (instrument and preparative column: use Waters 2767 to prepare the liquid phase, the preparative column model is XBridge@Prep C ₁₈ , inner diameter×length=19mm×250mm). Preparation method: the crude product is dissolved in DMF and filtered with a 0.45 μm membrane Filter to prepare sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient extraction method: acetonitrile gradient from 10% to 55% (flow rate: 12 mL/min; extraction time 17 min ) to obtain 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1, 2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridium Azin-3(2H)-one ( Compound 2 ) (12 mg, 13%).

LCMS m/z =551.2[M+1] ⁺ .

Example 3 : 5-(((2S)-1-(3- Oxo -3-(3-( Trifluoromethyl )-6,7,7a,8,10,11- Hexahydro -9H- pyrazino [1,2-d] pyrido [3,2-b][1,4] Oxazepine -9- base ) Propoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- ketone ( compound 3)

5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[ 3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

The first step: 3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (3b)

tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate

Under ice-cooling, tert-butyl 3-(2-methoxy-2-oxyethyl)piperazine-1-carboxylate (3a) (1.00g, 3.87mmol) was added to THF (10 mL), and LiAlH ₄ (0.11 g, 2.90 mmol). The mixture was stirred under ice bath for 2h. Add water (0.11 mL), 2N NaOH (0.11 mL) and water (0.33 mL) sequentially to quench the reaction, add ethyl acetate (20 mL) and anhydrous MgSO ₄ (2g), stir the mixture for 1 h, filter, and concentrate the filtrate under reduced pressure tertiary butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (3b) (1.00 g, 89%) was obtained, which was directly used in the next step.

LCMS m/z = 231.2 [M+1] ⁺ .

The second step: (3-(2-hydroxyethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3c)

tert-butyl 3-(2-hydroxyethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

At room temperature, 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (0.98 g, 4.33 mmol) was added to DMF (10 mL), and 3-(2-hydroxyethyl)piperazine was added - tert-butyl 1-carboxylate (3b) (1.00 g, 4.33 mmol) and DIPEA (1.68 g, 12.99 mmol). The mixture was stirred overnight at room temperature. Add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v)=10:1) to obtain ((3-(2-hydroxyethyl)-4-(3-nitro-5-(trifluoro Methyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3c) (0.64 g, 35%).

LCMS m/z = 365.1 [M-55] ⁺ .

The third step: 3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][ 1,4] tert-butyl oxazepine-9-carboxylate (3d)

tert-butyl 3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9- carboxylate

((3-(2-hydroxyethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3c) (0.63 g, 1.55mmol) was added to DMF (10 ml) solution, and NaH (0.19 g, 4.65 mmol) was added. The mixture was reacted at 40°C for 16 hours. Cooled, water (10 mL) was added to quench the reaction, ethyl acetate (10 mL x 2) extraction, combined organic phase, organic phase washed with saturated brine, filtered after drying over anhydrous sodium sulfate, obtained crude product after filtrate was concentrated under reduced pressure. Crude product was separated and purified through preparative column (petroleum ether: ethyl acetate (v/v )=10:1) to get 3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2- b] Tert-butyl [1,4]oxazepine-9-carboxylate (3d) (0.5 g, 86%).

LCMS m/z = 374.2 [M+1] ⁺ .

The fourth step: 3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][ 1,4] Trifluoroacetate salt of oxazepine (3e)

3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine trifluoroacetate

(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1, 4] Tert-butyl oxazepine-9-carboxylate (3d) (0.45g, 1.21 mmol) was dissolved in DCM (4 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 h. Directly The reaction solution was concentrated under reduced pressure to obtain 3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2- b] The trifluoroacetate salt of [1,4]oxazepine (3e) (470 mg, 100%) was used directly in the next step.

LCMS m/z = 274.1 [M+1] ⁺ .

The fifth step: 1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2- b][1,4]Oxazepin-9-yl)prop-2-en-1-one ( 3f )

1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9- yl)prop-2-en-1-one

3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4 ] The trifluoroacetate salt of oxazepine (3e) (460 mg, 1.19 mmol) was dissolved in dichloromethane (4 mL), then acrylic anhydride (0.15 g, 1.19 mmol) and triethylamine (601 mg, 5.95 mmol), the mixture was reacted at 20°C for 24h, and the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v)=10:1) to obtain 1-( 3-(Trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4] Oxazepin-9-yl)prop-2-en-1-one ( 3f ) (0.36 g, 92%).

LCMS m/z = 328.1 [M+1] ⁺ .

The sixth step: (2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1 ,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)tert-butyl carbamate ( 3g )

tert-butyl ((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[ 3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)carbamate

1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][ 1,4]Oxazepin-9-yl)prop-2-en-1-one ( 3f ) (350 mg, 1.07 mmol) was dissolved in acetonitrile (1.8 mL), then N-Boc-L-alanine was added Alcohol (0.94 g, 5.35 mmol) and cesium carbonate (452 mg, 1.39 mmol), the mixture was reacted at 20°C for 48h. The reaction solution was directly filtered, the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v) = 10:1) to obtain ((2S)-1-(3-oxo Substituent-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b] [1,4]Oxazepin-9-yl)propoxy)propan-2-yl)tert-butyl carbamate ( 3 g ) (0.33 g, 61%).

LCMS m/z = 503.2 [M+1] ⁺ .

The seventh step: 3-((S)-2-aminopropoxy)-1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazine [1,2-d]pyridin[3,2-b][1,4]oxazepin-9-yl)propan-1-one (3h) hydrochloride

3-((S)-2-aminopropoxy)-1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2 -b][1,4]oxazepin-9-yl)propan-1-one hydrochloride

((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2 -d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)tert-butyl carbamate ( 3g ) (0.3 g, 0.6 mmol ) was added to HCl/dioxane (4 mL, 4 N ), and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain 3-((S)-2-aminopropoxy)-1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro -9H-pyrazino[1,2-d]pyridin[3,2-b][1,4]oxazepin-9-yl)propan-1-one (3h) hydrochloride (260 mg, 98%), used directly in the next step.

LCMS m/z = 403.1 [M+1] ⁺ .

The eighth step: 2-(4-methoxybenzyl)-5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a, 8,10,11-Hexahydro-9H pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2- Base)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ( 3I )

2-(4-methoxybenzyl)-5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[ 1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

3-((S)-2-aminopropoxy)-1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1 ,2-d]pyridin[3,2-b][1,4]oxazepin-9-yl)propan-1-one (3h) hydrochloride (0.16 g, 0.36 mmol) was dissolved in acetonitrile (3 mL), add 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (0.11g, 0.36 mmol) and triethylamine (109.08 mg, 1.08mmol), the mixture was stirred at room temperature for 24 h. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was subjected to prep-TLC (developing solvent: petroleum ether: ethyl acetate=1:2) to obtain 2-(4-methoxybenzyl)-5-(( (2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H pyrazino[1,2-d] Pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H) - Ketone ( 3I ) (100 mg, 41%).

LCMS m/z = 685.2 [M+1] ⁺ .

The ninth step: 5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyridine Azino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethane base) pyridazin-3(2H)-one ( compound 3 )

5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[ 3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

2-(4-methoxybenzyl)-5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10 ,11-Hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl) Amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ( 3I ) (0.1 g, 0.15 mmol) was dissolved in trifluoroacetic acid (5 mL), trifluoromethanesulfonic acid (0.14 g , 0.95 mmol). The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in methanol, and DIPEA was added dropwise to adjust the pH to 8-9. After concentration under reduced pressure, the residue was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, and the preparative column model was XBridge@Prep C ₁₈ , inner diameter × length = 19mm × 250mm). Preparation method: The crude product was dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia water). Gradient extraction method: acetonitrile was extracted from 10% gradient to 55% (flow rate: 12 mL/min; extraction time 17 min) to obtain 5-(((2S)-1-(3-oxo-3-(3 -(Trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxo Azapin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ( Compound 3 ) (10 mg, 11.8%).

LCMS m/z = 565.0 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (s, 1H), 8.17-8.12 (m, 1H), 7.93-7.88 (m, 1H), 7.34 (s, 1H), 6.29-6.20 (m , 1H), 4.35-4.19 (m, 2H), 4.18-4.08 (m, 1H), 4.06-3.96 (m, 1H), 3.91-3.76(m, 2H), 3.75-3.31 (m, 8H), 2.59 -2.51 (m , 2H), 2.18-2.00 (m, 1H), 1.95-1.83 (m 1H), 1.19-1.10 (m, 3H).

Example 4 : (R)-8-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazine [1,2-a] pyridine [3,2-e] pyrazine -6(6aH)- ketone ( compound 4)

(R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

The first step: 1-tert-butyl 3-methyl(3R)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxylic acid Esters ( 4c )

1-Tert-butyl-3-methyl-(3R)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxylate

At room temperature, 2-chloro-3-nitro-5-(trifluoromethyl)pyridine ( 4a ) (2.00g, 8.83mmol) was added to DMF (20 mL), and then (3R)-piperazine- tert-butyl-1-carboxylate-3-methylcarboxylate ( 4b ) (2.16 g, 8.83 mmol) and DIPEA (3.42 g, 26.49 mmol). The mixture was stirred overnight at room temperature. Add water (40 mL) to quench the reaction, extract with ethyl acetate (40 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v)=10:1) to obtain 1-tert-butyl 3-methyl (3R)-4-(3-nitro-5-( Trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxylate ( 4c ) (2.70 g, 70%).

LCMS m/z = 379.1 [M-55] ⁺ .

The second step: tertiary butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1, 2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d )

Tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e] pyrazine-8-carboxylate

At room temperature, 1-tert-butyl 3-methyl(3R)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxy Ester ( 4c ) (1.0 g, 2.30 mmol) was dissolved in anhydrous methanol (20 mL), and then 10% palladium on carbon (200 mg) was added. After hydrogen replacement three times, the reaction was carried out at room temperature for 16 hours. After drying and filtering, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 4:1) to obtain tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5 ,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ) (380 mg, 44%).

LCMS m/z = 317.1 [M-55] ⁺ .

The third step: (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine- 6(6aH)-ketone ( 4e ) hydrochloride

(R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride

At room temperature, tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1 ,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ) (100 mg, 0.27 mmol) was dissolved in 1,4-dioxane (5 mL) solution, and then Add hydrogen chloride-1,4-dioxane solution (4.0 M, 10 mL, 40 mmol) and react at room temperature for 4 hours. After the reaction, the solvent was concentrated under reduced pressure to obtain (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3, 2-e] Hydrochloride salt of pyrazin-6(6aH)-one ( 4e ) (83.0 mg, 100%).

LCMS m/z = 273.1 [M+1] ⁺ .

The fourth step: 5-{[(2S)-1-hydroxypropan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2 ,3-Dihydropyridazin-3-one ( 4g )

5-{[(2S)-1-hydroxypropan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

At room temperature, 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one ( 4f )( 15.0 g, 47.07 mmol) and (2S)-2-aminopropan-1-ol (5.40 g, 71.9 mmol) were dissolved in anhydrous acetonitrile (100 mL), and then DIPEA (30.0 g, 233 mmol) was added. The reaction was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure. Add water (50 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, dry and filter, and concentrate the filtrate under reduced pressure to obtain 5-{[(2S)-1-hydroxypropan-2-yl]amino} - 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one ( 4 g ) (16.5 g, 98%).

LCMS m/z = 358.2 [M+1] ⁺ .

The fifth step: Methyl-3-[(2S)-2-[(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl)amino]propoxy]propionate ( 4h )

Methyl-3-[(2S)-2-[(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoate

At room temperature, 5-{[(2S)-1-hydroxypropan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)- 2,3-Dihydropyridazin-3-one ( 4 g ) (13.5 g, 37.82 mmol) and prop-2-enoic acid methyl ester (33 g, 378.2 mmol) were dissolved in acetonitrile solution (90 mL), then carbonic acid was added Cesium (13.6 g, 41.60 mmol), stirred at room temperature for 48 hours. After the reaction was completed, after the solvent was removed by concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V)=7: 3) to obtain methyl-3-[(2S)-2-[ (1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy] Propionate ( 4h ) (6.0 g, 36%).

LCMS m/z = 444.2 [M+1] ⁺ .

Step 6: Methyl-3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy ]propionate ( 4i )

Methyl-3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoate

At room temperature, methyl-3-[(2S)-2-[(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1 ,6-dihydropyridazin-4-yl)amino]propoxy]propionate ( 4h ) (6.0 g, 13.5 mmol) was dissolved in trifluoroacetic acid (30 mL), and trifluoromethanesulfonic acid ( 5 mL), and then stirred at room temperature for 2 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure to obtain methyl-3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4- base) amino] propoxy] propionate ( 4i ) was used directly in the next reaction without further purification.

LCMS m/z = 324.1 [M+1] ⁺ .

The seventh step: 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid ( 4j )

3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoic acid

At room temperature, methyl-3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy The crude product of propionate ( 4i ) was dissolved in a mixed solution of methanol (30 mL) and water (30 mL), adjusted to pH = 7~8 with lithium hydroxide monohydrate, and then added lithium hydroxide monohydrate (1.14 g, 27 mmol), stirred at room temperature for 16 hours. After the reaction, adjust the pH to about 5 with 2M aqueous hydrochloric acid in an ice-water bath, filter, and concentrate the filtrate under reduced pressure to obtain a residue, which is separated and purified by silica gel column chromatography (dichloromethane:methanol (V/V)= 15:1) to 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propane Acid ( 4j ) (2.5 g, 60%).

LCMS m/z = 310.1 [M+1] ⁺ .

The eighth step: (R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyridine Azin-6(6aH)-one ( compound 4 )

(R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

At room temperature, 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propane Acid ( 4j ) (50 mg, 0.16 mmol) and (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3 ,2-e]pyrazin-6(6aH)-one ( 4e ) hydrochloride (49 mg, 0.16 mmol) was dissolved in DMF (5 mL), DIPEA (83 mg, 0.64 mmol) and HATU (46 mg, 0.12 mmol), react at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (elution time 15min). After lyophilization, (R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyridine Azin-6(6aH)-one ( Compound 4 ) (10 mg, 11%).

LCMS m/z = 564.2 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 10.93 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.16 (d, 1H), 6.31- 6.20 (m, 1H), 4.85-4.44 (m, 2H), 4.27-3.96 (m, 3H), 3.74-3.63 (m, 2H), 3.49 (d, 2H), 3.27-3.06 (m, 1H), 2.82-2.59 (m, 4H), 1.16 (d, 3H).

Example 5 : 5- methyl -8-(3-((S)-1-(6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) pyrrolidine -2- base ) Methoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazine [1,2-a] pyridine [3,2-e] pyrazine -6(6aH)- ketone ( compound 5)

5-Methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

The first step: [(2S)-pyrrolidin-2-yl]methanol hydrochloride ( 5b )

[(2S)-pyrrolidin-2-yl]methanol hydrochloride

To a solution of (2S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate ( 5a ) (14.50 g, 72.05 mmol) in 1,4-dioxane (60 mL) was added hydrogen chloride 1,4-dioxane solution (60 mL, 4 N), reacted at room temperature for 16 h, and concentrated under reduced pressure to remove the solvent to obtain the hydrochloride salt of [(2S)-pyrrolidin-2-yl]methanol ( 5b ) (9.91 g, 100%).

LCMS m/z = 101.7[M+1] ⁺ .

The second step: 5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl) -2,3-Dihydropyridazin-3-one ( 5c )

5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

5-Chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (17.66 g, 55.42 mmol), [(2S)-Pyrrolidin-2-yl]methanol hydrochloride ( 5b ) (9.91 g, 72.05 mmol), DIPEA (28.65 g, 221.68 mmol) were added to acetonitrile (150 mL) successively, and reacted at room temperature for 2 h, after the reaction was completed, ethyl acetate (500 mL) was added to dilute the reaction solution, then the reaction solution was washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain 5-[( 2S)-2-(Hydroxymethyl)pyrrolidin-1-yl]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridine Azin-3-one ( 5c ) (20.77 g, 98%).

LCMS m/z = 384.2[M+1] ⁺ .

The third step: 3-{[(2S)-1-(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-di Methyl hydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propionate ( 5d )

Methyl 3-{[(2S)-1-(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy } propanoate

At room temperature, to 5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl )-2,3-dihydropyridazin-3-one ( 5c ) (16.40 g, 42.78 mmol) and methyl acrylate (36.83 g, 427.80 mmol) in acetonitrile (100 mL) were added cesium carbonate (15.33 g, 47.06 mmol). After reacting at room temperature for 48 h, filter, and concentrate the filtrate under reduced pressure to obtain a residue, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 1: 1) to obtain 3-{[(2S) -1-(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidine- Methyl 2-yl]methoxy}propionate ( 5d ) (12.65 g, 63%).

LCMS m/z = 470.2 [M+1] ⁺ .

The fourth step: 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methanol Methyl oxy}propionate ( 5e )

Methyl 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propanoate

At room temperature, 3-{[(2S)-1-(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6- Dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propionic acid methyl ester ( 5d ) (12.65 g, 26.95 mmol) was dissolved in trifluoroacetic acid (100 mL), then trifluoroform was added Sulfonic acid (5 mL), react at room temperature for 2 h. Concentrate under reduced pressure to remove the reaction solvent to give 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2- The crude product of methyl]methoxy}propionate ( 5e ) was directly used in the next reaction without further purification.

LCMS m/z = 350.0 [M+1] ⁺ .

The fifth step: 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methanol Oxy}propionic acid ( 5f )

3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propanoic acid

3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy} Methyl propionate ( 5e ) was dissolved in a mixed solution of methanol (60 mL) and water (60 mL), adjusted to pH=7~8 with lithium hydroxide monohydrate, and then added lithium hydroxide monohydrate (1.70 g , 40.41 mmol), reacted at room temperature for 16 h. After the reaction, use 2M aqueous hydrochloric acid to adjust the pH to about 5, filter, and concentrate the filtrate under reduced pressure to obtain a residue, which is separated and purified by silica gel column chromatography (methanol: dichloromethane (V/V) = 1: 15) to obtain 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propane Acid ( 5f ) (4.1 g, 45.39%).

LCMS m/z = 336.2 [M+1] ⁺ .

The sixth step: tert-butyl-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1 ,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 5g )

Tert-butyl-(R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3, 2-e]pyrazine-8-carboxylate

At room temperature, tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1 ,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ) (200 mg, 0.54 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to 0 ℃, slowly added hydrogenation Sodium (60%, 93 mg, 2.32 mmol). After stirring at 0°C for 10 minutes, iodomethane (232 mg, 1.62 mmol) was added, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, slowly add saturated ammonium chloride solution to quench the reaction under an ice-water bath, add 10 mL of water, and extract with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 7: 3) to obtain tert-butyl-5-methyl-6-oxo-3-(trifluoromethyl)-5 ,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 5g ) (155 mg, 74%).

LCMS m/z = 331.1 [M-55] ⁺ .

Step 7: 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3,2-e]pyrazine -6(6aH)-ketone ( 5h ) hydrochloride

5-Methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride

At room temperature, tert-butyl-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 5g ) (155 mg, 0.40 mmol) was dissolved in 1,4-dioxane (5 mL) solution, Add hydrogen chloride-1,4-dioxane solution (4.0 M, 10 mL, 40 mmol) and react at room temperature for 4 hours. After the reaction, the solvent was concentrated under reduced pressure to obtain 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3 , 2-e]pyrazin-6(6aH)-one ( 5h ) hydrochloride (130 mg, 100%).

LCMS m/z = 287.1 [M+1] ⁺ .

The eighth step: 5-methyl-8-(3-((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrole Alk-2-yl)methoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3, 2-e]pyrazin-6(6aH)-one ( Compound 5 )

5-Methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

At room temperature, 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl] Methoxy}propionic acid ( 5f ) (63 mg, 0.19 mmol) and 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2 -a]pyridin[3,2-e]pyrazin-6(6aH)-one ( 5h ) hydrochloride (62 mg, 0.19 mmol) was dissolved in DMF (5 mL), and DIPEA (120 mg, 0.95 mmol) and HATU (54 mg, 0.14 mmol) and stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (elution time 15min). After lyophilization, 5-methyl-8-(3-((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrole was obtained Alk-2-yl)methoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3, 2-e]pyrazin-6(6aH)-one ( Compound 5 ) (25 mg, 22%).

LCMS m/z = 604.2 [M+1] ⁺ .

Example 6 : 5- methyl -8-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazine [1,2-a] pyridine [3,2-e] pyrazine -6(6aH)- ketone ( compound 6)

5-Methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

At room temperature, 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propane Acid ( 4j ) (50 mg, 0.16 mmol) and 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[ 3,2-e] The hydrochloride salt of pyrazin-6(6aH)-one ( 5h ) (50 mg, 0.16 mmol) was dissolved in DMF (5 mL), and DIPEA (83 mg, 0.64 mmol) was added thereto and HATU (46 mg, 0.12 mmol) and stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (elution time 15min). After lyophilization, 5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e] Pyrazin-6(6aH)-one ( Compound 6 ) (15 mg, 17%).

LCMS m/z = 578.2 [M+1] ⁺ .

Example 7 : 5-(((S)-1-(3- Oxo -3-((R)-3-( Trifluoromethyl )-6,7,7a,8,10,11- Hexahydro -9H- pyrazino [1,2-d] pyrido [3,2-b][1,4] Oxazepine -9- base ) Propoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2 H )- ketone ( compound 7-1)

5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9 H -pyrazino[1,2 -d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3( 2H )-one

5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9 H - Pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoro Methyl) pyridazin-3(2 H )-one ( compound 7-2 )

5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9 H -pyrazino[1,2 -d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3( 2H )-one

Compound 3 was purified by SFC on AD column (instrument and preparative column: Waters 150 mgm was used, and the preparative column model was DAICEL CHIRALPAK AD (250mm×30mm, 10μm)). Preparation method: Compound 3 was dissolved in ethanol and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO ₂ and B for EtOH (0.1%NH ₃ •H ₂ O). Gradient extraction method: 30% phase B (flow rate: 120mL/min; extraction time 2.5min), after lyophilization to obtain compound 7-1 and compound 7-2 .

Analysis method (instrument and preparative column: high performance liquid chromatography-normal phase chromatography, preparative column model: CHIRALPAKAD-H (4.6×250mm, 5um)) mobile phase system: n-hexane-isopropanol (80:20), 1.0ml/min.

The retention time T=16.489 min is Example 7-A (Example 7-A is one of the structures of Compound 7-1 and Compound 7-2 ).

LCMS m/z = 565.3 [M+1] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.09-8.05 (m, 1H), 7.94-7.90 (m, 1H), 7.28-7.25(m, 1H), 4.38-4.25 (m, 2H), 4.18- 4.02 (m, 2H), 3.97-3.45 (m, 10H), 2.74-2.57 (m, 2H), 2.22-2.08 (m, 1H), 2.03-1.90 (m, 1H), 1.27-1.18 (m, 3H ).

The retention time T=19.522min is Example 7-B (Example 7-B is one of the structures of compound 7-1 and compound 7-2 ).

LCMS m/z = 565.3 [M+1] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.10-8.06 (m, 1H), 7.93 (s, 1H), 7.28-7.24(m, 1H), 4.39-4.25(m, 2H), 4.20-4.01 ( m, 2H), 3.98-3.45 (m, 10H), 2.74-2.58 (m, 2H), 2.22-2.08 (m, 1H), 2.03-1.90 (m, 1H), 1.24 (d, 3H).

Example 8 : 5-((S)-2-((3- Oxo -3-((S)-3-( Trifluoromethyl )-6a,7,9,10- tetrahydropyrazine [1,2-d] pyridine [3,2-b][1,4] Oxazine -8(6H)- base ) Propoxy ) methyl ) pyrrolidine -1- base )-4-( Trifluoromethyl ) pyrazine -3(2H)- ketone ( compound 8)

5-((S)-2-((3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2- b][1,4]oxazin-8(6H)-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

Compound 8 is represented by (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4] Oxazine-8(6H)-tert-butyl carboxylate ( 2d ) and 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridium Oxyzin-4-yl) pyrrolidin-2-yl] methoxy} propionic acid ( 5f ) as raw material, referring to the synthetic method of Example 4, to obtain 5-((S)-2-((3-oxo- 3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]pyridine[3,2-b][1,4]oxazine -8(6H)-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyrazin-3(2H)-one ( compound 8 ).

LCMS m/z = 577.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.34 (s, 1H), 8.08-8.06 (m, 1H), 8.00 (s, 1H), 7.28 (d, 1H), 4.58-4.37 (m, 4H ), 4.06-3.92 (m, 2H), 3.71-3.58 (m, 2H), 3.56-3.36 (m, 4H), 3.25-3.17(m,1H),3.16-2.38(m, 5H), 2.14-2.02 (m, 1H), 1.95-1.81 (m, 1H), 1.71-1.56 (m, 2H).

Example 9 : (R)-8-(3-(((S)-1-(6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) pyrrolidine -2- base ) Methoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- Pyridazine [1,2-a] Pyridazine [3,2-e] Pyridazine -6(6aH)- ketone ( compound 9)

(R)-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

Compound 9 as (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3,2-e]pyrazine-6 (6aH)-Kone hydrochloride ( 4e ) and 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Pyrrolidin-2-yl]methoxy}propionic acid ( 5f ) as raw material, referring to the synthetic method of Example 4, to obtain (R)-8-(3-(((S)-1-(6-oxo -5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propionyl)-3-(trifluoromethyl)-7, 8,9,10-Tetrahydro-5H-pyridazin[1,2-a]pyridazin[3,2-e]pyridazin-6(6aH)-one ( Compound 9 ).

LCMS m/z = 590.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41-12.28 (m, 1H), 11.01-10.86 (m, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.16 (d, 1H) ), 4.86-4.42 (m, 3H), 4.27-3.91 (m, 2H), 3.73-3.58 (m, 2H), 3.56-3.46(m, 2H), 3.45-3.37 (m, 1H), 3.26-3.02 (m, 2H), 2.83-2.54 (m, 4H), 2.14-2.01 (m, 1H), 1.94-1.82 (m, 1H), 1.72-1.55(m, 2H).

Example 10 : (S)-8-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6a H )- ketone ( compound 10)

(S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5 H -pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6a H )-one

The first step: (S)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl-3-methyl carboxylate ( 10c )

1-(tert-butyl)3-methyl (S)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxylate

At room temperature, 2-chloro-3-nitro-5-(trifluoromethyl)pyridine ( 1a ) (2.00g, 8.83mmol) was added to DMF (20 mL), and (3S)-piperazine-1 - tert-butyl formate-3-methyl carboxylate ( 10b ) (2.16 g, 8.83 mmol) and DIPEA (3.42 g, 26.49 mmol). The mixture was stirred overnight at room temperature. Add water (40 mL) to quench the reaction, extract with ethyl acetate (40 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 10:1) to obtain (S)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl ) tert-butyl piperazine-1-carboxylate-3-methylcarboxylate ( 10c ) (3.50 g, 91%).

LCMS m/z = 379.1 [M-55] ⁺ .

The second step: (S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8 H -pyrazino[1,2-a] tert-butyl pyrido[3,2-e]pyrazine-8-carboxylate (10d)

tert-butyl (S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine -8-carboxylate

(S)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl-3-carboxylic acid methyl ester ( 10c ) (3.5 g, 8.06 mmol) was added to a solution of MeOH (50 ml), Pd/C (0.35 g) was added. The mixture was reacted at room temperature under hydrogen atmosphere for 16 hours. Filter and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 10:1) to obtain (S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7 ,9,10-Hexahydro- 8H -pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester (10d) (1.3 g, 43% ).

LCMS m/z = 317.1 [M-55] ⁺ .

The third step: ((S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro- 5H -pyrazino[1,2-a]pyrido[3,2-e ] The hydrochloride salt of pyrazin-6(6a H )-one (10e)

(S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5 H -pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6a H )-one hydrochloric acid

(S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8 H -pyrazino[1,2-a]pyrido[ 3,2-e]pyrazine-8-carboxylic acid tert-butyl ester (10d) (240 mg, 0.64 mmol) was dissolved in HCl/dioxane (5 mL, 4M, 20 mmol), and the mixture was heated at room temperature The reaction was stirred for 2 h. Concentrate under reduced pressure to remove the solvent to give the crude product ((S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro- 5H -pyrazino[1,2-a]pyrido[ 3,2-E]pyrazin-6( 6aH )-one (10e) hydrochloride (180 mg, 90%) was used directly in the next step.

LCMS m/z = 273.1 [M+1] ⁺ .

The fourth step: (S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro- 5H -pyrazino[1,2-a]pyrido[3,2- e] pyrazin-6(6a H )-one ( compound 10 )

(S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5 H -pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6a H )-one

(((S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro- 5H -pyrazino[1,2-a]pyrido[3,2-E]pyr The hydrochloride (49 mg, 0.16 mmol) of azin-6(6a H )-one (10e) was dissolved in DMF (2 mL), and 3-[(2S)-2-[(6-oxo-5 -(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoic acid (4j) (50 mg, 0.16 mmol), HATU (46 mg, 0.12 mmol) and DIPEA (103 mg, 0.8 mmol), the mixture was reacted at 20°C for 2 h, added water (10 mL) to quench the reaction, extracted with ethyl acetate (10 mL x 2), combined the organic phases, washed the organic phases with saturated brine, and anhydrous sulfuric acid Natrium dried and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, and the preparative column model was XBridge@Prep C ₁₈ , inner diameter × length=19mm × 250mm). Preparation method: the crude product is dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient extraction method: acetonitrile by 10% gradient Elution to 55% (flow rate: 12 mL/min; extraction time 17 min) to obtain (S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl )-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro- 5H -pyridine Azino[1,2-a]pyrido[3,2-e]pyrazin-6(6a H )-one ( compound 10 ) (10 mg, 11%).

LCMS m/z = 564.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (s, 1H), 10.92 (s, 1H), 8.12 (s, 1H), 7.93-7.86 (m, 1H), 7.16 (d, 1H), 6.31-6.21(m, 1H), 4.87-4.41(m, 2H), 4.29-3.93(m, 3H), 3.76-3.60(m, 2H), 3.49(d, 2H), 3.26-3.04(m, 1H ), 2.84-2.57 (m, 4H), 1.16 (d, 3H).

Example 11 : (S)-5- methyl -8-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6a H )- ketone ( compound 11)

(S)-5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5 H -pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6a H )-one

The first step: (S)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8 H -pyrazino[1 ,2-a]pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester ( 11a )

tert-butyl (S)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2 -e]pyrazine-8-carboxylate

At room temperature, (S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8 H -pyrazino[1,2-a ]pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester (10d) (1.00 g, 2.69 mmol) was added to DMF (10 mL), and K ₂ CO ₃ (1.10 g, 8.07 mmol) was added and _CH3I (1.91 g, 13.45 mmol). The mixture was stirred overnight at room temperature. Add water (40 mL) to quench the reaction, extract with ethyl acetate (40 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v)=10:1) to obtain (S)-5-methyl-6-oxo-3-(trifluoromethyl)-5, 6,6a,7,9,10-hexahydro- 8H -pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester ( 11a ) (0.33 g, 32%).

LCMS m/z = 331.1 [M-55] ⁺ .

The second step: (S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro- 5H -pyrazino[1,2-a]pyrido[3 ,2-e]pyrazin-6(6a H )-one (11b) hydrochloride

(S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5 H -pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6a H ) -one hydrochloric acid

(S)-5-Methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a ]pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester (11a) (120 mg, 0.31 mmol) was dissolved in HCl/dioxane (5 mL, 4M, 20 mmol), and the mixture The reaction was stirred at room temperature for 2 h. Concentrate under reduced pressure to remove the solvent to obtain the crude product (S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a] The hydrochloride salt of pyrido[3,2-e]pyrazin-6-( 6aH )-one (11b) (100 mg, 99%) was used directly in the next step.

LCMS m/z =287.2[M+1] ⁺ .

The third step: (S)-5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine- 4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro- 5H -pyrazino[1,2-a]pyrido [3,2-e]pyrazin-6(6a H )-one ( compound 11 )

(S)-5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5 H -pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6a H )-one

(S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e ]pyrazin-6( 6aH )-one (11b) hydrochloride (48 mg, 0.15 mmol) was dissolved in DMF (2 mL), then 3-[(2S)-2-[(6-oxo Dioxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoic acid (4j) (46 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol ) and DIPEA (58 mg, 0.45 mmol), the mixture was reacted at 20°C for 2 h, quenched by adding water (10 mL), extracted with ethyl acetate (10 mL x 2), combined the organic phases, and washed the organic phases with saturated brine , dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used for preparative liquid phase, the preparative column model was XBridge@Prep C ₁₈ , inner diameter×length=19mm×250mm). Preparation method: The crude product was dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia water). Gradient elution method: gradient elution of acetonitrile from 10% to 55% (flow rate: 12 mL/min; elution time 17 min) to obtain ((S)-5-methyl-8-(3-((S)- 2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro- 5H -pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6-( 6aH )-one ( compound 11 )( 10 mg, 11%).

LCMS m/z = 578.3 [M+1] ⁺ .

Example 12 : (S)-8-(3-(((S)-1-(6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) pyrrolidine -2- base ) Methoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6a H )- ketone ( compound 12) trifluoroacetate

(S)-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5 H -pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6a H )-one trifluoroacetate

(((S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro- 5H -pyrazino[1,2-a]pyrido[3,2-e]pyr The hydrochloride salt of azin-6-( 6aH )-one (10e) (49 mg, 0.16 mmol) was dissolved in DMF (2 mL), and then (3-{[(2S)-1-(6-oxo Substitute-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propionic acid (5f) (54 mg, 0.16 mmol), HATU ( 61 mg, 0.16 mmol) and DIPEA (103 mg, 0.8 mmol), react the mixture at 20°C for 2 h, add water (10 mL) to quench the reaction, extract with ethyl acetate (10 mL x 2), combine the organic phases, and use Wash with saturated brine, filter after drying over anhydrous sodium sulfate, and obtain the crude product after the filtrate is concentrated under reduced pressure. The crude product is purified through Pre-HPLC (instrument and preparative column: adopt Waters 2767 to prepare the liquid phase, and the preparative column model is Sunfire@Prep C ₁₈ , 5 μm, inner diameter × length = 19mm × 250mm). Preparation method: the crude product is dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 1% trifluoroacetic acid) .Gradient extraction method: acetonitrile was extracted from 5% gradient to 50% (flow rate: 15 mL/min; extraction time 15min), and lyophilized to obtain (S)-8-(3-(((S)-1- (6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propionyl)-3-(trifluoromethyl base)-7,8,9,10-tetrahydro- 5H -pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6( 6aH )-one ( compound 12 ) trifluoroacetate (10 mg, 9%).

LCMS m/z = 590.3 [M+1] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.16-8.07 (m, 2H), 7.19 (s, 1H), 5.10-4.50 (m, 3H), 4.46-4.00(m, 2H), 3.87-3.58( m,4H),3.52-3.40 (m, 1H), 3.39-3.34(m,1H),3.29-3.15 (m, 1H), 2.91-2.60 (m, 4H), 2.28-2.15 (m, 1H), 2.02-1.90 (m, 1H), 1.79-1.60 (m, 2H).

Example 13 : (S)-5- methyl -8-(3-(((S)-1-(6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) pyrrolidine -2- base ) Methoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6a H )- ketone ( compound 13) trifluoroacetate

(S)-5-methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy) propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5 H -pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6a H )-one trifluoroacetate

(S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e ]pyrazin-6-(6a H )-one (11b) hydrochloride (48 mg, 0.15 mmol) was dissolved in DMF (2 mL), then 3-{[(2S)-1-(6- Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propanoic acid (5f) (50 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol) and DIPEA (58 mg, 0.45 mmol), the mixture was reacted at 20°C for 2 h, quenched with water (10 mL), extracted with ethyl acetate (10 mL x 2), combined organic phases, organic The phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used for preparative liquid phase, the preparative column model was Sunfire@Prep C ₁₈ , 5 μm, inner diameter×length=19mm×250mm). Preparation method: The crude product was dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 1% trifluoroacetic acid). Gradient extraction method: acetonitrile was extracted from 5% gradient to 50% (flow rate: 15 mL/min; extraction time 15min), and lyophilized to obtain (S)-5-methyl-8-(3-(((S )-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propionyl)-3- (Trifluoromethyl)-7,8,9,10-tetrahydro-5 H -pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6-(6a H )- Trifluoroacetate salt of ketone ( Compound 13 ) (10 mg, 9%).

LCMS m/z = 604.4[M+1] ⁺ .

Example 14 : 5-((S)-2-((3- Oxo -3-((R)-3-( Trifluoromethyl )-6a,7,9,10- Tetrahydropyrazino [1,2-d] pyrido [3,2-b][1,4] Oxazine -8(6 H )- base ) Propoxy ) methyl ) pyrrolidine -1- base )-4-( Trifluoromethyl ) Pyridazine -3(2 H )- ketone ( compound 14) trifluoroacetate

5-((S)-2-((3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2- b][1,4]oxazin-8(6H)-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate

Compound 14 is represented by (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4] Oxazine-8(6H)-tert-butyl carboxylate (1d) and 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine -4-yl) pyrrolidin-2-yl] methoxy} propionic acid (5f) is the synthetic method of starting material reference example 10, obtains 5-((S)-2-((3-oxo- 3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4] Oxazin-8( 6H )-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3( 2H )-one ( compound 14 ) tri Fluoroacetate.

LCMS m/z =577.4[M+1] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 (d, 1H), 8.00 (s, 1H), 7.18 (s, 1H), 4.65-4.50 (m, 3H), 4.43-4.33 (m, 1H) , 4.10-3.97 (m, 2H), 3.82-3.59 (m, 4H), 3.55-3.32 (m, 3H), 3.29-2.51(m, 5H), 2.29-2.14 (m, 1H), 2.01-1.91 ( m, 1H), 1.79-1.59 (m, 2H).

Example 15 : (5-((2S)-2-((3- Oxo -3-(3-( Trifluoromethyl )-6,7,7a,8,10,11 Hexahydro -9H- pyrazino [1,2-d] pyrido [3,2-b][1,4] Oxazepine -9- base ) Propoxy ) methyl ) pyrrolidine -1- base )-4-( Trifluoromethyl ) Pyridazine -3(2H ) - ketone ( compound 15) trifluoroacetate

5-((2S)-2-((3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[ 3,2-b][1,4]oxazepin-9-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2 H )-one trifluoroacetate

Compound 15 is represented by 3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1 ,4] Oxazepine-9-carboxylic acid tert-butyl ester (3d) and 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine Oxyzin-4-yl) pyrrolidin-2-yl] methoxy} propionic acid (5f) is the synthetic method of starting material reference example 10, obtains (5-((2S)-2-((3-oxo Substituent-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9 H -pyrazino[1,2-d]pyrido[3,2-b ][1,4]Oxazepin-9-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3( 2H) -one ( compound 15 ) trifluoroacetate.

LCMS m/z = 591.3 [M+1] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ8.14-8.05(m, 2H), 7.43-7.30(m, 1H), 4.64-4.51 (m, 1H), 4.44-4.27 (m, 2H), 4.22 -4.08 (m, 1H), 3.96-3.75 (m, 5H), 3.74-3.52 (m, 5H), 3.46-3.34 (m, 2H), 2.68-2.49 (m, 2H), 2.28-2.09 (m, 2H), 2.07-1.91 (m, 2H), 1.79-1.58 (m, 2H).

Example 16 : 9-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,7a,8,9,10,11- Hexahydropyrazino [1,2-d] pyrido [3,2-b][1,4] Diazepines -6(5H)- ketone ( compound 16)

9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,7a ,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one

The first step: 3-(2-methoxy-2-oxyethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid Tributyl ester ( 16c )

Tert-butyl 3-(2-methoxy-2-oxoethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

At room temperature, 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (16a) (1.50g, 6.62mmol) was added to DMF (20 mL), and 3-(2-methoxy tert-butyl-2-oxyethyl)piperazine-1-carboxylate (3a) (2.16 g, 8.83 mmol) and DIPEA (3.42 g, 26.49 mmol). The mixture was stirred overnight at room temperature. Add water (40 mL) to quench the reaction, extract with ethyl acetate (40 mL x 2), combine the organic phases, wash the organic phase with saturated brine (40 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure A crude product was obtained. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v)=8:1) to obtain 3-(2-methoxy-2-oxyethyl)-4-(3-nitro-5 -(Trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester ( 16c ) (2.4 g, 81%).

LCMS m/z = 393.1 [M-55] ⁺ .

The second step: 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-3-(2-methoxy-2-oxyethyl)piperazine-1-carboxylic acid third Butyl ester (16d)

Tert-butyl 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylatte

3-(2-methoxy-2-oxyethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester ( 16c ) (3.2 g, 7.14 mmol) was added to a solution of MeOH (50 ml), Pd/C (0.35 g) was added. The mixture was reacted at room temperature under hydrogen atmosphere for 16 hours. Filter and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v)=5:1) to obtain 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-3-( tert-butyl 2-methoxy-2-oxyethyl)piperazine-1-carboxylate (16d) (2.2 g, 75%).

LCMS m/z = 419.2 [M +1] ⁺ .

The third step: tert-butyl-6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11 hexahydropyrazino[1,2-d]pyrido[3 ,2-b][1,4]diaza-9-(5H)-carboxylate ( 16e )

Tert-butyl 6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine-9( 5H)-carboxylate

At room temperature, 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-3-(2-methoxy-2-oxyethyl)piperazine-1-carboxylic Butyl ester (16d) (2.20 g, 5.26 mmol) was added to DMF (20 mL) and potassium carbonate (2.20 g, 15.94 mmol) was added. The mixture was stirred overnight at room temperature. Add water (40 mL) to quench the reaction, extract with ethyl acetate (40 mL x 3), combine the organic phases, wash the organic phase with saturated brine (40 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure A crude product was obtained. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v)=4:1) to obtain 3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazine A[1,2-d]pyrido[3,2-B][1,4]diazepin-6(5H)-one ( 16e ) (1.3 g, 65%).

LCMS m/z = 331.1 [M-55] ⁺ .

The fourth step: 3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-B][1,4 ] The hydrochloride salt of diazapin-6(5H)-one (16f)

3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one hydrochloric acid

(3-(Trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-B][1,4]di Aza-6(5H)-one ( 16e ) (170 mg, 0.44 mmol) was dissolved in HCl/dioxane (5 mL, 4M, 20 mmol), and the mixture was stirred at room temperature for 2 h. Reduced pressure Concentration to remove the solvent gave the crude product 3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-B][ 1,4] The hydrochloride salt of diazepin-6(5H)-one (16f) (130 mg, 92%) was used directly in the next step.

LCMS m/z =287.2[M+1] ⁺ .

The fifth step: 9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy )propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1 ,4] Diazapin-6(5H)-one ( compound 16 )

9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,7a ,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one

3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-B][1,4]diazepine Hetero-6(5H)-one (16f) hydrochloride (55 mg, 0.17 mmol) was dissolved in DMF (2 mL), and 3-[(2S)-2-[(6-oxo-5- (Trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoic acid (4j) (50 mg, 0.16 mmol), HATU (45.6 mg, 0.12 mmol) and DIPEA ( 103.2 mg, 0.8 mmol), the mixture was reacted at 20°C for 2 h. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used for preparative liquid phase, the preparative column model was Sunfire@Prep C ₁₈ , 5 μm, inner diameter×length=19mm×250mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient extraction method: acetonitrile was extracted from 5% gradient to 50% (flow rate: 15 mL/min; extraction time 15min), and 9-(3-((S)-2-((6-oxo) Substitute-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,7a,8, 9,10,11-Hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one ( Compound 16 ) (10 mg, 11%).

LCMS m/z = 578.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (s, 1H), 9.85 (s, 1H), 8.40 (s, 1H), 7.91 (s, 1H), 7.49 (d, 1H), 6.30- 6.18 (m, 1H), 4.41-4.30 (m, 1H), 4.18-4.08 (m, 1H), 3.97-3.83 (m 2H), 3.77-3.58 (m, 3H), 3.49 (d, 2H), 3.28 -3.15 (m, 1H), 3.12-2.90 (m, 2H), 2.82-2.54 (m, 3H), 2.46-2.34 (m, 1H), 1.16 (d, 3H).

Example 17 : 9-(3-(((S)-1-(6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) pyrrolidine -2- base ) Methoxy ) Propyl )-3-( Trifluoromethyl )-7,7a,8,9,10,11- Hexahydropyrazino [1,2-d] pyrido [3,2-b][1,4] Diazepines -6(5H)- ketone ( compound 17)

9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl) -7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one

(((S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro- 5H -pyrazino[1,2-a]pyrido[3,2-e]pyr The hydrochloride salt of azin-6-(6a H )-one (16f) (55 mg, 0.17 mmol) was dissolved in DMF (3 mL), and then (S)-3-((1-(6-oxo -5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoic acid (5f) (55 mg, 0.17 mmol), HATU (61 mg, 0.16 mmol) and DIPEA (105 mg, 0.8 mmol), the mixture was reacted at 20°C for 2 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, and the preparative column model was Sunfire@Prep C ₁₈ , 5μm, inner diameter×length=19mm×250mm). Preparation method: filter the reaction solution with a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient extraction method : Acetonitrile was eluted from 5% gradient to 50% (flow rate: 15 mL/min; elution time 15min), and 9-(3-(((S)-1-(6-oxo-5- (Trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propionyl)-3-(trifluoromethyl)-7,7a,8 ,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one ( compound 17 ) (12 mg , 12%).

LCMS m/z = 604.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.32 (s, 1H), 9.85 (s, 1H), 8.43-8.39 (m, 1H), 8.00 (s, 1H), 7.49 (d, 1H), 4.59-4.46(m, 1H), 4.41-4.26(m, 1H), 3.95-3.84(m, 2H), 3.76-3.59(m, 3H), 3.57-3.45(m, 2H), 3.44-3.35(m , 1H), 3.25-2.55 (m, 7H), 2.47-2.34 (m, 1H), 2.14-2.02 (m, 1H), 1.96-1.84 (m, 1H), 1.72-1.57 (m, 2H).

Example 18 : 5- methyl -9-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,7a,8,9,10,11- Hexahydropyrazino [1,2-d] pyrido [3,2-b][1,4] Diazepines -6(5H)- ketone ( compound 18)

5-methyl-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one

The first step: tertiary butyl 5-methyl-6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d ]pyrido[3,2-B][1,4]diazepine 9(5H)-tert-butyl carboxylate ( 18a )

Tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4] diazepine-9(5H)-carboxylate

At room temperature, tert-butyl-6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[ 3,2-B][1,4]diaza-9-(5H)-carboxylate ( 16e ) (300 mg, 0.78 mmol) was added to DMF (5 mL), K ₂ CO ₃ (321 mg , 2.33 mmol) and CH ₃ I (133 gm , 0.93 mmol). The mixture was stirred overnight at room temperature. Add water (15 mL) to quench the reaction, extract with ethyl acetate (20 mL x 3), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v)=5:1) to obtain tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-6, 7,7a,8,10,11-Hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine 9(5H)-carboxylate tertiary butyl ester ( 18a ) (150 mg, 50%).

LCMS m/z = 345.2 [M-55] ⁺ .

The second step: 5-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-B ][1,4]diazepin-6(5H)-one (18b) hydrochloride

5-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)- one

The tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido [3,2-B][1,4]diazepine 9(5H)-tert-butyl carboxylate ( 18a ) (150 mg, 0.38 mmol) was dissolved in HCl/dioxane (4 mL, 4M, 16 mmol), the mixture was stirred at room temperature for 2 h. Concentrate under reduced pressure to remove the solvent to give the crude product 5-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[ The hydrochloride salt of 3,2-B][1,4]diazepin-6(5H)-one (18b) (110 mg, 87%) was used directly in the next step.

LCMS m/z =301.2[M+1] ⁺ .

The third step: 5-methyl-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Amino)propoxy)propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2 -b][1,4]diazepin-6(5H)-one ( compound 18 )

5-methyl-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one

5-Methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1 ,4] The hydrochloride salt of diazepin-6(5H)-one (18b) (55 mg, 0.15 mmol) was dissolved in DMF (3 mL), then 3-[(2S)-2-[(6 -Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoic acid (4j) (50 mg, 0.16 mmol), HATU (45.6 mg, 0.12 mmol) and DIPEA (103.2 mg, 0.8 mmol), the mixture was reacted at 20°C for 2 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, the preparative column model was Sunfire@Prep C ₁₈ , 5 μm, inner diameter×length=19mm×250mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient extraction method: acetonitrile was extracted from 5% gradient to 50% (flow rate: 15 mL/min; extraction time 15min), and 5-methyl-9-(3-((S)-2- ((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7 ,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine-6(5H)-one ( compound 18 ) (12 mg, 14%).

LCMS m/z = 592.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.49 (s, 1H), 8.01 (d, 1H), 7.91 (s, 1H), 6.30-6.19 (m, 1H), 4.46-4.29 (m, 1H), 4.21-4.07 (m, 1H), 4.00-3.85 (m, 1H), 3.84-3.44 (m, 6H), 3.24 (s, 3H), 3.11-2.84 (m, 2H ), 2.80-2.54 (m, 4H), 2.43-2.32 (m, 1H), 1.16 (d, 3H).

Example 19 : 5- methyl -9-(3-(((S)-1-(6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) pyrrolidine -2- base ) Methoxy ) Propyl )-3-( Trifluoromethyl )-7,7a,8,9,10,11- Hexahydropyrazino [1,2-d] pyrido [3,2-b][1,4] Diazepines -6(5H)- ketone ( compound 19)

5-methyl-9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3 -(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one

5-Methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-B][1 ,4] The hydrochloride salt of diazepin-6(5H)-one (18b) (55 mg, 0.15 mmol) was dissolved in DMF (3 mL), then (S)-3-((1-(6 -oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoic acid (5f) (55 mg, 0.17 mmol), HATU (61 mg, 0.16 mmol) and DIPEA (105 mg, 0.8 mmol), the mixture was reacted at 20°C for 2 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, the preparative column model was Sunfire@Prep C ₁₈ , 5 μm, inner diameter×length=19mm×250mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient extraction method: acetonitrile was extracted from 5% gradient to 50% (flow rate: 15 mL/min; extraction time 15min), and lyophilized to obtain (5-methyl-9-(3-(((S)-1 -(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propionyl)-3-(trifluoro Methyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diaza-6(5H) - Ketone ( Compound 19 ) (14 mg, 15%).

LCMS m/z = 618.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.32 (s, 1H), 8.52-8.47 (m, 1H), 8.03-7.99 (m, 2H), 4.57-4.48 (m, 1H), 4.43-4.29 (m, 1H), 3.95-3.85 (m, 1H), 3.83-3.74 (m, 1H), 3.68-3.47 (m, 5H), 3.44-3.38 (m, 1H), 3.26-2.69(m, 8H) , 2.65-2.53 (m, 2H), 2.46-2.35 (m, 1H), 2.13-2.03 (m, 1H), 1.94-1.85 (m, 1H), 1.72-1.59 (m, 2H).

Example 20 : 9-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-7,7a,9,10,11- Hexahydro -6H- pyrazino [1,2-d] pyrido [3,2-b][1,4] Oxazepine -3- Formaldehyde ( compound 20)

9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-7,7a,8,9,10 ,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile

The first step: (4-(5-cyano-3-nitropyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (20b)

Tert-butyl 4-(5-cyano-3-nitropyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate

At room temperature, 6-chloro-5-nitropyridine-3-carbonitrile ( 20a ) (1 g, 5.45 mmol) was dissolved in DMF (10 mL), and 3-(2-hydroxyethyl)piperazine was added - Tert-butyl 1-carboxylate (3b) (1.26 g, 5.45 mmol) and DIPEA (2.11 g, 16.35 mmol). The mixture was stirred overnight at room temperature. Add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v)=10:1) to obtain (4-(5-cyano-3-nitropyridin-2-yl)-3-(2- hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (20b) (1 g, 48%).

LCMS m/z = 322.2 [M-55] ⁺ .

The second step: 3-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4] tertiary butyl oxazepine-9-carboxylate (20c)

Tert-butyl 3-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylate

(4-(5-cyano-3-nitropyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (20b) (0.5 g, 1.32 mmol) Dissolve in DMF (10 ml), add K ₂ CO ₃ (540 mg, 3.97 mmol). The mixture was reacted at 100°C for 16 hours. Cooled to room temperature, quenched with water (10 mL), ethyl acetate (10 mL x 2) extraction, combined organic phase, organic phase washed with saturated brine, filtered after drying over anhydrous sodium sulfate, obtained crude product after filtrate was concentrated under reduced pressure. Crude product was separated and purified through preparative column (petroleum ether: ethyl acetate (v/v )=10:1) to get 3-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1 ,4] tert-butyl oxazepine-9-carboxylate (20c) (0.23 g, 53%).

LCMS m/z = 275.1 [M-55] ⁺ .

The third step: 3-cyano-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4] Oxazepine (20d) hydrochloride

3-cyano-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepinehydrochloric acid

3-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine - Tert-butyl-9-carboxylate (20c) (120 mg, 0.36 mmol) was dissolved in HCl/dioxane (5 mL, 4M, 20 mmol), and the mixture was stirred at room temperature for 2 h. Concentrate under reduced pressure to remove the solvent to give 3-cyano-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1 ,4] The hydrochloride salt of oxazepine (20d) (96 mg, 100%) was directly used in the next step.

LCMS m/z =231.2[M+1] ⁺ .

The fourth step: 9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy )propionyl)-7,7a,9,10 ,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3 -Formonitrile ( Compound 20 )

9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-7,7a,8,9,10 ,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile

(3-cyano-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazone Hetero (20d) hydrochloride (48 mg, 0.18 mmol) was dissolved in DMF (2 mL), and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)- 1,6-Dihydropyridazin-4-yl)amino]propoxy]propanoic acid (4j) (46 mg, 0.18mmol), HATU (51 mg, 0.14 mmol) and DIPEA (70 mg, 0.54 mmol), The mixture was reacted at 20°C for 2 h, quenched by adding water (10 mL), extracted with ethyl acetate (10 mL x 2), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was decompressed After concentration, the crude product was obtained. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, and the preparative column model was XBridge@Prep C ₁₈ , inner diameter×length=19mm×250mm). Preparation method: crude The product is dissolved in DMF, and is filtered with a 0.45 μm filter membrane, and is prepared into a sample solution.Mobile phase system: acetonitrile/water (containing 0.05% ammoniacal liquor).Gradient extraction method: acetonitrile is extracted to 55% by 10% gradient (flow rate: 12 mL/min; extraction time 17 min) to obtain 9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4 -yl)amino)propoxy)propionyl)-7,7a,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1 ,4] Oxazepine-3-carbonitrile ( Compound 20 ) (10 mg, 12%).

LCMS m/z =522.2[M+1] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.14-8.11 (m, 1H), 7.95-7.90 (m, 1H), 7.30-7.27 (m, 1H), 4.39-4.08 (m, 4H), 4.01- 3.44 (m, 10H), 2.70-2.59 (m, 2H), 2.22-2.07 (m, 1H), 2.04-1.91 (m, 1H), 1.28-1.18 (m, 3H).

Example twenty one : 9-(3-(((S)-1-(6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) pyrrolidine -2- base ) Methoxy ) Propyl )-7,7a,8,9,10,11- Hexahydro -6H- pyrazino [1,2-d] pyrido [3,2-b][1,4] Oxazepine -3- Formaldehyde ( compound twenty one)

9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-7,7a,8 ,9,10,11-hexahydro-6 H -pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile

(3-cyano-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazone Hetero (20d) hydrochloride (48 mg, 0.18 mmol) was dissolved in DMF (2 mL), and then 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl) -1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propionic acid (5f) (60 mg, 0.18 mmol), HATU (68 mg, 0.18 mmol) and DIPEA (70 mg, 0.54 mmol), the mixture was reacted at 20°C for 2 h, quenched by adding water (10 mL), extracted with ethyl acetate (10 mL x 2), combined the organic phases, washed with saturated brine, and dried over anhydrous sodium sulfate After filtering, the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, and the preparative column model was XBridge@Prep C ₁₈ , inner diameter × length=19mm × 250mm ). Preparation method: the crude product is dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient extraction method: acetonitrile is extracted by 10% gradient to 55% (flow rate: 12 mL/min; extraction time 17 min) to obtain 9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6- Dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propionyl)-7,7a,8,9,10,11-hexahydro- 6H -pyrazino[1,2 -d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile ( Compound 21 ) (10 mg, 10%).

LCMS m/z =548.2[M+1] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.15-8.12 (m, 1H), 8.11-8.09 (m, 1H), 7.30 (d, 1H), 4.61-4.50 (m, 1H), 4.41-4.32 ( m, 1H), 4.31-4.23 (m, 1H), 4.22-4.13 (m, 1H), 4.02-3.47 (m, 10H), 3.46-3.32 (m, 2H), 2.65-2.49 (m, 2H), 2.26-2.08 (m, 2H), 2.04-1.89 (m, 2H), 1.79-1.59 (m, 2H).

Example twenty two : (R)-5- methyl -8-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyridine [3,2-e] pyrazine -6(6aH)- Ketones (compounds twenty two )

(R)-5-Methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

The first step: tertiary butyl-(R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyridine Azino[1,2-a]pyridin[3,2-e]pyrazine-8-carboxylate ( 22a )

Tert-butyl-(R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3, 2-e]pyrazine-8-carboxylate

At room temperature, tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1 ,2-a]pyridine[3,2-e]pyrazine-8-carboxylate ( 4d ) (16.0 g, 43.0 mmol) was dissolved in DMF (150 mL), then potassium carbonate (17.82 g, 128.9 mmol) was added ), methyl iodide (18.43 g, 128.9 mmol), and reacted at room temperature for 16 hours. After the reaction was completed, 300 mL of water was added and extracted with ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 7: 3) to obtain tert-butyl-(R)-5-methyl-6-oxo-3-(trifluoroform base)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridin[3,2-e]pyrazine-8-carboxylate ( 22a )( 12.5 g, 75%).

LCMS m/z = 331.1 [M-55] ⁺ .

The second step: (R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridin[3,2 -e] hydrochloride of pyrazin-6(6aH)-one ( 22b )

(R)-5-Methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride

At room temperature, tert-butyl-(R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H- Pyrazino[1,2-a]pyridin[3,2-e]pyrazine-8-carboxylate ( 22a ) (12.5 g, 32.4 mmol) dissolved in 1,4-dioxane (50 mL) , then added hydrogen chloride-1,4-dioxane solution (4.0 M, 150 mL, 600 mmol), and reacted at room temperature for 16 hours. After the reaction, the solvent was concentrated under reduced pressure to obtain (R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2- a] Hydrochloride salt of pyridin[3,2-e]pyrazin-6(6aH)-one ( 22b ) (10.3 g, 87%).

LCMS m/z = 287.1 [M+1] ⁺ .

The third step: (R)-5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine- 4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridin[3 ,2-e]pyrazin-6(6aH)-one ( compound 22 )

(R)-5-Methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

At room temperature, 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propane acid ( 4j ) (8.5 g, 27.56 mmol) and (R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2 -a]pyridin[3,2-e]pyrazin-6(6aH)-one ( 22b ) hydrochloride (10.0 g, 27.84 mmol) was dissolved in DMF (100 mL), and DIPEA (18.0 g, 139.2 mmol) and HATU (10.6 g, 27.84 mmol). React at room temperature for 3 hours. After the reaction, add 200 mL of water and extract with ethyl acetate (250 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (dichloromethane: methanol (v/v) = 95: 5) to obtain (R)-5-methyl-8-(3-((S)-2-((6-oxo Substitute-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9, 10-Tetrahydro-5H-pyrazino[1,2-a]pyridin[3,2-e]pyrazin-6(6aH)-one ( Compound 22 ) (14.0 g, 87%).

LCMS m/z = 578.2 [M+1] ⁺ .

Example twenty three : 5- methyl -8-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- Dipyrazine [1,2-a:2',3'-e] pyrazine -6(6aH)- Ketones (compounds twenty three )

5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one

The first step: 1-tert-butyl 3-methyl(3R)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate ( 23b )

1-tert-butyl 3-methyl (3R)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate

2-Chloro-5-(trifluoromethyl)pyrazine ( 23a ) (1.00 g, 5.48 mmol), 1-(tert-butyl)3-methyl(R)-piperazine-1,3-di Carboxylate (2.01 g, 8.22 mmol), DIPEA (2.12 g, 16.44 mmol) were sequentially added to dimethylsulfone (15 mL), and reacted at 100 °C for 16 h. After the reaction was completed, cooled to room temperature, and the reaction solution was Pour it into water (150 mL), extract with ethyl acetate (30 mL x 3), combine the organic phases, backwash the organic phase with saturated brine (30 mL x 3), dry over anhydrous sodium sulfate, filter with suction, and reduce the filtrate to Concentrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 2: 1) to obtain 1-tert-butyl 3-methyl(3R)-4-(5-(trifluoromethyl )pyrazin-2-yl)piperazine-1,3-dicarboxylate ( 23b ) (900 mg, 42%).

LCMS m/z = 335.0 [M-55] ⁺ .

The second step: 1-tert-butyl 3-methyl(3R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylic acid Esters ( 23c )

1-tert-butyl 3-methyl (3R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate

To 1-tert-butyl 3-methyl(3R)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate ( 23b ) (500 mg , 1.28 mmol) in DMF (5 mL) was added N-chlorobutanediimide (188 mg, 1.41 mmol), and reacted at room temperature for 16 h. After the reaction, the reaction solution was poured into water (50 mL ), extracted with ethyl acetate (20 mL x 3), combined the organic phases, backwashed the organic phase with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered with suction, and concentrated the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 3: 1) to obtain 1-tert-butyl 3-methyl(3R)-4-(3-chloro-5-( Trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate ( 23c ) (396 mg, 73%).

LCMS m/z = 369.0 [M-55] ⁺ .

The third step: tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-dipyrazine[1, 2-a:2',3'-e]pyrazine-8-carboxylate ( 23d )

Tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-dipyrazino[1,2-a:2',3'-e]pyrazine -8-carboxylate

To 1-tert-butyl 3-methyl(3R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate ( 23c ) (348 mg, 0.82 mmol) in ethanol (7 mL), sequentially added methylamine hydrochloride (277 mg4.1 mmol), DIPEA (1.06 g, 8.2 mmol). Reaction was carried out at 100°C for 16 h. After the reaction was completed and cooled to room temperature, the reaction solution was concentrated under reduced pressure to obtain a residue, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 5 : 1) Obtain tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-dipyrazine[1, 2-a: 2',3'-e]pyrazine-8-carboxylate ( 23d ) (265 mg, 83%).

LCMS m/z = 332.1 [M-55] ⁺ .

The fourth step: 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazine[1,2-a:2',3'-e]pyridine Hydrochloride of oxazin-6(6aH)-one ( 23e )

5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one hydrochloride

The tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-dipyrazine[1,2-a :2',3'-e]pyrazine-8-carboxylate ( 23d ) (150 mg, 0.39 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (5mL, 4 N), room temperature Reaction for 1 h, after the reaction was completed, concentrated under reduced pressure to obtain 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazine[1,2-a:2 ',3'-e] The hydrochloride salt of pyrazin-6(6aH)-one ( 23e ) (130 mg) crude product was used directly in the next step.

The fifth step: 5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazine[1,2-a:2',3'-e ]pyrazin-6(6aH)-one ( compound 23 )

5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one

5-Methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazine[1,2-a:2',3'-e]pyrazine-6 (6aH)-ketone ( 22e ) hydrochloride (60 mg, crude product), 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-di Hydropyridazin-4-yl)amino]propoxy]propanoic acid (4j) (65 mg, 0.21 mmol), HATU (80 mg, 0.21 mmol) and DIPEA (140 mg, 1.05 mmol) were sequentially added to DMF (2 mL), react at room temperature for 1 h. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used for preparative liquid phase, the preparative column model was Sunfire@Prep C ₁₈ , 5 μm, inner diameter×length=19mm×250mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient elution method: Acetonitrile was eluted from 5% to 50% gradient (flow rate: 15 mL/min; elution time 15min), and 5-methyl-8-(3-((S)-2- ((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7 ,8,9,10-Tetrahydro-5H-dipyrazin[1,2-a:2',3'-e]pyrazin-6(6aH)-one ( compound 23 )(30 mg,25%) .

LCMS m/z = 579.1 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 6.30-6.20(m, 1H), 4.91-4.53(m, 1H ), 4.53- 3.98(m, 4H), 3.75-3.62 (m, 2H), 3.49 (d, 2H), 3.43-3.04(m, 4H), 2.91-2.81 (m, 1H), 2.77-2.56(m , 3H), 1.16 (d, 3H).

Example twenty four : 5- methyl -8-(3-(((S)-1-(6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) pyrrolidine -2- base ) Methoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- Dipyrazine [1,2-a:2',3'-e] pyrazine -6(6aH)- ketone ( compound twenty four )

5-methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one

Compound 24 as 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazine[1,2-a:2',3'-e]pyrazine -6(6aH)-one ( 22e ) hydrochloride and 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4 -yl)pyrrolidin-2-yl]methoxy}propionic acid ( 5f ) as raw material, referring to the synthesis method of Example 22, to obtain 5-methyl-8-(3-(((S)-1-( 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propionyl)-3-(trifluoromethyl )-7,8,9,10-tetrahydro-5H-dipyrazin[1,2-a:2′,3′-e]pyrazin-6(6aH)-one ( compound 24 ).

LCMS m/z = 605.2 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.32 (s, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 4.93 - 3.96 (m, 5H), 3.73 - 3.59 (m, 2H ), 3.57-3.46 (m, 2H), 3.46-3.03 (m, 6H), 2.91-2.80 (m, 1H), 2.77-2.53 (m, 3H), 2.15-2.00 (m, 1H), 1.97-1.79 (m, 1H), 1.72-1.55(s, 2H).

Example 25 : 5-(((S)-1-(3- Oxo -3-((R)-3-( Trifluoromethyl )-6a,7,9,10- Tetrahydrodipyrazine [2,3-b:1',2'-d][1,4] Oxazine -8(6H)- base ) Propoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- Ketones (compounds 25 )

5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'- d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

The first step: (R)-3-(hydroxymethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester ( 25b )

tert-butyl (R)-3-(hydroxymethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylate

2-Chloro-5-(trifluoromethyl)pyrazine ( 25a ) (1.00 g, 5.48 mmol), (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.42 g, 6.58 mmol), DIPEA (1.42 g, 10.96 mmol) were sequentially added to dimethyl sulfide (10 mL), reacted at 100°C for 16 h, after the reaction was completed, cooled to room temperature, and the reaction solution was poured into water ( 150 mL), extracted with ethyl acetate (30 mL x 3), combined the organic phases, backwashed the organic phase with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered with suction, and concentrated the filtrate under reduced pressure to obtain a residue things. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 2: 1) to obtain (R)-3-(hydroxymethyl)-4-(5-(trifluoromethyl)pyridine ( 25b ) (1.77 g, 89%).

LCMS m/z = 363.2 [M+1] ⁺ .

Second step: (R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester ( 25c )

tert-butyl (R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

To (R)-3-(hydroxymethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester ( 25b ) (200 mg, 0.55 mmol) in DMF (2 mL) was added N-chlorobutanediimide (81 mg, 0.61 mmol), and reacted at room temperature for 16 h. After the reaction, the reaction solution was poured into water (20 mL) , extracted with ethyl acetate (20 mL x 3), combined the organic phases, backwashed the organic phase with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered with suction, and concentrated the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 3: 1) to obtain (R)-4-(3-chloro-5-(trifluoromethyl)pyrazine-2- tert-butyl)-3-(hydroxymethyl)piperazine-1-carboxylate ( 25c ) (110 mg, 50%).

LCMS m/z = 341.1 [M-55] ⁺ .

The third step: (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazine[2,3-b:1',2'-d][1,4] Oxazine-8(6H)-tert-butyl carboxylate ( 25d )

Tert-butyl (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazine-8(6H)-carboxylate

To (R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester ( 25c )( Add potassium carbonate (116 mg, 0.84 mmol) to a DMF (2 mL) solution of 110 mg, 0.28 mmol), and react at 100°C for 16 h. After the reaction, cool to room temperature, and pour the reaction solution into water (20 mL ), extracted with ethyl acetate (20 mL x 3), combined the organic phases, backwashed the organic phase with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered with suction, and concentrated the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 3: 1) to obtain (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodi Pyrazine[2,3-b:1',2'-d][1,4]oxazine-8(6H)-tert-butyl carboxylate ( 25d ) (61 mg, 60%).

LCMS m/z =361.2[M+1] ⁺ .

The fourth step: (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrodipyrazine[2,3-b:1',2'-d][ 1,4] Hydrochloride of oxazine ( 25e )

(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazine hydrochloride

(R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazine[2,3-b:1',2'-d][1,4]oxazine- 8(6H)-tert-butyl carboxylate ( 25d ) (61 mg, 0.17 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (5 mL, 4 N), reacted at room temperature for 1 h, and the reaction was completed Afterwards, concentrated under reduced pressure to obtain (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrodipyrazine[2,3-b:1',2'-d ][1,4]Oxazine ( 25e ) hydrochloride (53 mg) crude product was directly used in the next reaction.

LCMS m/z = 261.1 [M+1] ⁺ .

The fifth step: 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazine[ 2,3-b:1',2'-d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl) Pyridazin-3(2H)-one ( compound 25 )

5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'- d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrodipyrazine[2,3-b:1',2'-d][1,4 ]oxazine ( 25e ) hydrochloride (53 mg, crude product), 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridium Oxyzin-4-yl)amino]propoxy]propanoic acid (4j) (56 mg, 0.18 mmol), HATU (68 mg, 0.18 mmol) and DIPEA (116 mg, 0.90 mmol) were sequentially added to DMF (2 mL), React at room temperature for 1 h. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used for preparative liquid phase, the preparative column model was Sunfire@Prep C ₁₈ , 5 μm, inner diameter×length=19mm×250mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient extraction method: Acetonitrile was extracted from 5% gradient to 50% (flow rate: 15 mL/min; extraction time 15min), and 5-(((S)-1-(3-oxo-3 -((R)-3-(Trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazine[2,3-b:1',2'-d][1,4]oxazine -8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ( compound 25 ) (30 mg, 30%).

LCMS m/z =552.2[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (s, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 6.32 - 6.18 (m, 1H), 4.66-4.54 (m, 1H ), 4.53-4.33 (m, 2H), 4.24 - 3.98 (m, 3H), 3.75-3.61 (m, 3H), 3.49 (d, 2H), 3.24-2.73 (m, 3H), 2.66 - 2.58 (m , 2H), 1.15 (d, 3H).

Example 26 : 5-(((S)-1-(3- Oxo -3-((S)-3-( Trifluoromethyl )-6a,7,9,10- Tetrahydrodipyrazine [2,3-b:1',2'-d][1,4] Oxazine -8(6H)- base ) Propoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- Ketones (compounds 26 )

5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'- d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Compound 26 uses 2-chloro-5-(trifluoromethyl)pyrazine ( 25a ) and (S)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl as raw materials, refer to Example 25 The synthetic method of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazine [2,3-b:1',2'-d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl ) pyridazin-3(2H)-one ( compound 26 ).

LCMS m/z =552.2[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (s, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 6.29 - 6.21 (m, 1H), 4.67-4.32 (m, 3H ), 4.26 - 3.98 (m, 3H), 3.77 - 3.61 (m, 3H), 3.49 (d, 2H), 3.22-2.68 (m, 3H), 2.66 - 2.57 (m, 2H), 1.15 (d, 3H ).

Example 27 : (R)-5- Ethyl -8-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazine [1,2-a] pyridine [3,2-e] pyrazine -6(6aH)- Ketones (compounds 27 )

(R)-5-ethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

The first step: (R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1, 2-a]pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester ( 27b )

Tert-butyl (R)-5-ethyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2 -e]pyrazine-8-carboxylate

At room temperature, (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a] Pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester ( 4d ) (100 mg, 0.27 mmol), potassium carbonate (112 mg, 0.81 mmol) was added to DMF (2 mL), then added Iodoethane (84 mg, 0.54 mmol). React at room temperature for 16 h. After the reaction, pour the reaction solution into water (20 mL), extract with ethyl acetate (20 mL x 3), combine the organic phases, and use saturated brine (20 mL x 3) for the organic phases. Backwash, dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 3: 1) to obtain (R)-5-methyl-6-oxo-3-(trifluoromethyl)-5 ,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester ( 27b )( 120 mg, 100%).

LCMS m/z = 345.1 [M-55] ⁺ .

The second step: (R)-5-ethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2- e] hydrochloride of pyrazin-6(6aH)-one ( 27c )

(R)-5-ethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride

(R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a ]pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester ( 27b ) (120 mg, 0.30 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (5 mL, 4 N) , reacted at room temperature for 1 h, after the reaction, concentrated under reduced pressure to remove the solvent to obtain (R)-5-ethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyridine The crude hydrochloride salt of azin[1,2-a]pyridin[3,2-e]pyrazin-6(6aH)-one ( 27c ) (100 mg) was used directly in the next step.

LCMS m/z = 301.1 [M+1] ⁺ .

The third step: (R)-5-ethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine- 4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3, 2-e]pyrazin-6(6aH)-one ( compound 27 )

(R)-5-ethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

(R)-5-Ethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyridine Hydrochloride salt of azin-6(6aH)-one ( 27c ) (91 mg, crude product), 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1, 6-Dihydropyridazin-4-yl)amino]propoxy]propanoic acid (4j) (84 mg, 0.27 mmol), HATU (100 mg, 0.27 mmol) and DIPEA (170 mg, 1.35 mmol) were sequentially added to DMF (2 mL), react at room temperature for 1 h. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used for preparative liquid phase, the preparative column model was Sunfire@Prep C ₁₈ , 5 μm, inner diameter×length=19mm×250mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient elution method: Acetonitrile was eluted from 5% to 50% gradient (flow rate: 15 mL/min; elution time 15min), and (R)-5-ethyl-8-(3-((S )-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl base)-7,8,9,10-tetrahydro-5H-pyrazin[1,2-a]pyridin[3,2-e]pyrazin-6(6aH)-one ( Compound 27 ) (40 mg, 25%).

LCMS m/z =592.2[M+1] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.14 (d, 1H), 7.92 (d, 1H), 7.43 (s, 1H), 5.15 - 4.58 (m, 2H), 4.55 - 3.93 (m, 5H) , 3.86 - 3.72 (m, 2H), 3.64-3.57 (m, 1H), 3.54-3.46 (m, 1H), 3.28-2.62 (m, 5H), 1.29-1.19 (m, 6H).

Example 28 : (R)-5- Cyclopropylmethyl -8-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazine [1,2-a] pyridine [3,2-e] pyrazine -6(6aH)- Ketones (compounds 28 )

(R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl) -3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

The first step: (R)-5-cyclopropylmethyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino [1,2-a]pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester ( 28b )

tert-butyl (R)-5-(cyclopropylmethyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3 ,2-e]pyrazine-8-carboxylate

At room temperature, (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a] Pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester ( 4d ) (100 mg, 0.27 mmol), potassium carbonate (112 mg, 0.81 mmol) was added to DMF (2 mL), then added (Iodomethyl)cyclopropane (74 mg, 0.41 mmol). React at room temperature for 16 h. After the reaction, pour the reaction solution into water (20 mL), extract with ethyl acetate (20 mL x 3), combine the organic phases, and use saturated brine (20 mL x 3) for the organic phases. Backwash, dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 3: 1) to obtain (R)-5-cyclopropylmethyl-6-oxo-3-(trifluoromethyl )-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester ( 28b ) (120 mg, 100%).

LCMS m/z = 427.2[M+1] ⁺ .

The second step: (R)-5-cyclopropylmethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3 ,2-e]pyrazin-6(6aH)-one ( 28c ) hydrochloride

(R)-5-(cyclopropylmethyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH) -one hydrochloride

(R)-5-Cyclopropylmethyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1, 2-a]pyrido[3,2-e]pyrazine-8-carboxylate tert-butyl ester ( 28b ) (120 mg, 0.28 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (5mL, 4 N), reacted at room temperature for 1 h, after the reaction, concentrated under reduced pressure to remove the solvent to obtain (R)-5-cyclopropylmethyl-3-(trifluoromethyl)-7,8,9,10 - Tetrahydro-5H-pyrazine[1,2-a]pyridin[3,2-e]pyrazin-6(6aH)-one ( 28c ) hydrochloride (100 mg, crude product), used directly Next step.

LCMS m/z = 327.1 [M+1] ⁺ .

The third step: (R)-5-cyclopropylmethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro Pyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine [3,2-e]pyrazin-6(6aH)-one ( compound 28 )

(R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl) -3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

(R)-5-Cyclopropylmethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3,2- e] hydrochloride (98 mg, crude product) of pyrazin-6(6aH)-one ( 28c ), 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl) -1,6-dihydropyridazin-4-yl)amino]propoxy]propanoic acid (4j) (84 mg, 0.27 mmol), HATU (100 mg, 0.27 mmol) and DIPEA (170 mg, 1.35 mmol) Add to DMF (2 mL) successively, and react at room temperature for 1 h. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used for preparative liquid phase, the preparative column model was Sunfire@Prep C ₁₈ , 5 μm, inner diameter×length=19mm×250mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (flow rate: 15 mL/min; elution time 15 min), and (R)-5-cyclopropylmethyl-8-(3- ((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-( Trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazin[1,2-a]pyridin[3,2-e]pyrazin-6(6aH)-one ( Compound 28 )( 40 mg, 24%).

LCMS m/z = 618.2[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 6.30-6.17 (m, 1H), 4.90-4.42 (m, 2H), 4.36 - 3.86 (m, 5H), 3.75-3.63 (m, 2H), 3.49 (d, 2H), 3.25-3.09 (m, 1H), 2.87 - 2.58 (m, 4H) , 1.15 (d, 3H), 1.11-0.99 (m, 1H), 0.53-0.26 (m, 4H).

Example 29 : 5-(((2S)-1-(3- oxygen -3-(3-( Trifluoromethyl )-5,6,6a,7,9,10- Hexahydro -8H- pyrazino [1,2-a][1,8] naphthyridine -8- base ) Propoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- Ketones (compounds 29 )

5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1 ,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

The first step: 1-benzyl 4-(tert-butyl)2-(hydroxymethyl)piperazine-1,4-dicarboxylate ( 29b )

benzyl 4-(tert-butyl)2-(hydroxymethyl)piperazine-1,4-dicarboxylate

At room temperature, 1-benzyl 4-(tert-butyl) 2-methyl-piperazine-1,2,4-tricarboxylate ( 29a ) (5.3 g, 14.01 mmol) was dissolved in THF (30 mL), EtOH (30 mL), NaBH ₄ (0.79 g, 21.02 mmol) and LiCl (0.89 g, 21.02 mmol) were added, the mixture was stirred at room temperature overnight, and the reaction solution was poured into water (50 mL), Extract with ethyl acetate (50 mL x 3), combine the organic phases, backwash the organic phase with saturated brine (30 mL x 3), dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (30%EA in PE) to obtain: (4-(tert-butyl)2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid 1-benzyl ester ( 29b ) (3 g, 61%).

LCMS m/z = 251.1 [M-99] ⁺ .

The second step: 1-benzyl 4-(tert-butyl)2-formylpiperazine-1,4-dicarboxylate ( 29c )

1-benzyl 4-(tert-butyl)2-formylpiperazine-1,4-dicarboxylate

(4-(tert-butyl)2-(hydroxymethyl)piperazine-1,4-dicarboxylate 1-benzyl ester ( 29b ) (3.9 g, 11.13 mmol) was dissolved in DCM (60 mL), add Dess-Martin oxidant (4.96 g, 11.69 mmol), and react under ice bath for 4 hours. After the reaction is complete, add water to quench the reaction, extract with ethyl acetate (50 mL x 3), combine the organic phases, organic phase Backwash with saturated brine (30 mL x 3), dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue is separated and purified by silica gel column chromatography (20% EA in PE) to obtain: 1-benzyl 4-(tert-butyl)2-formylpiperazine-1,4-dicarboxylate ( 29c ) (3 g, 77%).

LCMS m/z = 293.1 [M-55] ⁺ .

The third step: 1-benzyl 4-(tert-butyl) 2-vinylpiperazine-1,4-dicarboxylate ( 29d )

1-benzyl 4-(tert-butyl)2-vinylpiperazine-1,4-dicarboxylate

At room temperature, methyltriphenylphosphine bromide (4.61 g, 12.91 mmol) was dissolved in THF (60 mL), replaced with nitrogen three times, the mixture was cooled to -78 °C, and n-BuLi (6.88 mL , 10.33 mmol, 1.5 M), the dropwise addition was completed, stirred at this temperature for 1h, added 1-benzyl 4-(tert-butyl) 2-formylpiperazine-1,4-dicarboxylate ( 29c ) (3 g, 8.61 mmol), react at -78°C for 2h. Add water to quench the reaction, extract with ethyl acetate (50 mL x 3), combine the organic phases, backwash the organic phase with saturated brine (30 mL x 3), dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue . The residue was separated and purified by silica gel column chromatography (15%EA in PE) to obtain: 1-benzyl 4-(tert-butyl)2-vinylpiperazine-1,4-dicarboxylate ( 29d ) (1.8 g , 60%).

LCMS m/z = 247.2 [M-99] ⁺ .

The fourth step: 1-benzyl 4-(tert-butyl)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1,4 -Dicarboxylate ( Compound 29e )

1-benzyl 4-(tert-butyl)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1,4-dicarboxylate

Dissolve 1-benzyl 4-(tert-butyl)2-vinylpiperazine-1,4-dicarboxylate ( 29d ) (200 mg, 0.58 mmol) in DMF (6 mL) at room temperature , adding 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine (210 mg, 0.87 mmol), K ₂ CO ₃ (240 mg, 1.74 mmol), Xphos (110 mg, 0.23 mmol) and Pd( OAc) ₂ (26 mg, 0.12 mmol). Nitrogen was replaced 3 times, stirred overnight at 100 °C, quenched with water, extracted with ethyl acetate (10 mL x 3), combined the organic phases, backwashed with saturated brine (10 mL x 3), anhydrous sodium sulfate Dry, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (30%EA in PE) to obtain: 1-benzyl 4-(tert-butyl)-2-(2-(2-hydroxyl-5-(trifluoromethyl)pyridine- 3-yl)vinyl)piperazine-1,4-dicarboxylate ( compound 29e ) (38 mg, 13%) was cast in 9 pots in parallel, and a total of 340 mg was obtained.

LCMS m/z = 452.0 [M-55] ⁺ .

Step 5: tertiary butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate ( compound 29f )

Tert-butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate

At room temperature, 1-benzyl 4-(tert-butyl)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1, 4-dicarboxylate ( compound 29e ) (150 mg, 0.3 mmol) was dissolved in MeOH (5 mL), added Pd/C (15 mg), stirred at room temperature overnight, filtered, and concentrated to obtain 3-(2-( 2-Hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester ( compound 29f ) (100 mg, crude product) was directly injected into the next step without further purification . A total of 200 mg was obtained by throwing two pots in parallel.

LCMS m/z=376.2[M+1] ⁺ .

The sixth step: 3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridine-8- Tertiary butyl carboxylate ( compound 29g )

Tert-butyl 3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridine-8-carboxylate

At room temperature, tert-butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate ( compound 29f ) (110 mg , 0.29 mmol) was dissolved in DMSO (5 mL), and PyBOP (150 mg, 0.29 mmol) and DIPEA (37 mg, 0.29 mmol) were added. Stir overnight at 60 ^o C, add water to quench the reaction, extract with ethyl acetate (10 mL x 3), combine the organic phases, backwash the organic phase with saturated brine (10 mL x 3), dry over anhydrous sodium sulfate, and suction filter, The filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (10%EA in PE) to obtain: 3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a][1,8]naphthyridine-8-carboxylate tert-butyl ester ( compound 29g ) (80 mg, 77%).

LCMS m/z = 358.2 [M+1] ⁺ .

The seventh step: 3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine ( compound 29h ) hydrochloride

3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine hydrochloride

At room temperature, 3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridine-8 - Tertiary butyl carboxylate ( compound 29g ) (80 mg, 0.22 mmol) was dissolved in hydrogen chloride/1,4-dioxane solution (4.0 M, 2 mL, 8 mmol), and reacted at room temperature until the reaction was complete. Concentrate under reduced pressure to remove the solvent to obtain 3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine The hydrochloride salt of ( compound 29h ) (65.0 mg, crude product) was used directly in one step without further purification.

LCMS m/z = 258.2 [M+1] ⁺ .

The eighth step: 5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine And[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ( compound 29 )

5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1 ,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

At room temperature, 3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine ( compound 29h ) hydrochloride (65 mg, crude product) and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4- base)amino]propoxy]propionic acid ( 4j ) (68 mg, 0.22 mmol) was dissolved in DMF (2 mL), and DIPEA (85 mg, 0.66 mmol) and HATU (84 mg, 0.22 mmol) were added thereto The reaction was then stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (elution time 15min). After lyophilization, 5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine And[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ( Compound 29 ) (80 mg, yield 66%)

LCMS m/z=549.2[M+1] ⁺ .

Example 30 : 5-(((S)-1-(3- Oxo -3-((S)-3-( Trifluoromethyl )-5,6,6a,7,9,10- Hexahydro -8H- pyrazino [1,2-a][1,8] naphthyridine -8- base ) Propoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- ketone ( compound 30a)

5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2- a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyridine Azino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)- Ketone ( Compound 30b )

5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2- a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Compound 29 (70 mg, 0.13 mmol) was purified by SFC on AD column (instrument and preparative column: Waters 150 mgm was used, and the preparative column model was Chiralpak Column). Preparation method: Compound 29 was dissolved in acetonitrile to prepare a sample solution. Mobile phase system: A for CO ₂ and B for MeOH (0.1%NH ₃ •H ₂ O). Gradient extraction method: 30% phase B (flow rate: 110mL/min; extraction time 3.3min), after lyophilization to obtain compound P1 (20mg) and compound P2 (33.6mg) .

Analysis method (instrument and preparative column: SHIMADZULC-30AD sf, preparative column model: Chiralpak AD-3 50×4.6mm ID mobile phase system: A for CO ₂ and B for MeOH (0.05%DEA), 3.0ml/min.

The retention time T=2.03 min is compound P1 (compound P1 is one of the structures of compound 30a and compound 30b ).

LCMS m/z = 549.2 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.46-10.25 (m, 1H), 8.25 (s, 1H), 7.65 (s, 1H), 7.43-7.32 (m, 1H), 5.88-5.70 (m, 1H ), 5.03-4.83 (m, 1H), 4.72-4.55 (m, 1H), 3.99-3.78 (m, 4H), 3.71-3.61 (m, 1H), 3.54-3.45(m, 1H), 3.44-2.77 (m, 5H), 2.73-2.42 (m, 3H), 2.19-2.04 (m, 1H), 1.81-1.71 (m, 1H), 1.30 (d, 3H).

The retention time T=2.245min is compound P 2 (compound P 2 is one of the structures of compound 30a and compound 30b ).

LCMS m/z = 549.2 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.34 (s, 1H), 8.25 (s, 1H), 7.66 (s, 1H), 7.44-7.32 (m, 1H), 5.90-5.70 (m, 1H), 5.03-4.83 (m, 1H), 4.73-4.54 (m, 1H), 3.99-3.76 (m, 4H), 3.71-3.57 (m, 1H), 3.56-3.45(m, 1H), 3.44-2.77 (m , 5H), 2.73-2.45 (m, 3H), 2.23-2.04 (m, 1H), 1.81-1.68 (m, 1H), 1.30 (d, 3H).

Example 31 : 5-((S)-1-(3-((R)-5- methyl -6- Thio -3-( Trifluoromethyl )-5,6,6a,7,9,10- Hexahydro -8H- pyrazine [1,2-a] pyridine [3,2-e] pyrazine -8- base )-3- Oxypropoxy -2- base ) Amino )-4-( Trifluoromethyl ) pyrazine -3(2H)- Ketones (compounds 31 )

5-(((S)-1-(3-((R)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

The first step: (R) -3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridyl[3,2-e]pyrazine -6(6aH)-one hydrochloride ( 31a )

(R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

At room temperature, tert-butyl (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1, 2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ) (2 g, 5.38 mmol) was dissolved in 1,4-dioxane (30 mL) solution, and added Hydrogen chloride/1,4-dioxane solution (4.0 M, 30 mL, 40 mmol), react at room temperature for 4 hours. After the reaction, the solvent was concentrated under reduced pressure to obtain (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridyl[3, 2-e] The hydrochloride salt of pyrazin-6(6aH)-one ( 31a ) (1.46 g, crude product) was used directly in the next step.

LCMS m/z = 273.1[M+1] ⁺ .

The second step: 2-(trimethylsilyl)ethyl(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H- Pyrazine[1,2-a]pyridin[3,2-e]pyrazine-8-carboxylate ( 31b )

2-(trimethylsilyl)ethyl (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2- e]pyrazine-8-carboxylate

At room temperature, (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridyl[3,2-e]pyridine Azin-6(6aH)-one ( 31a ) hydrochloride (1.46 g, crude product), N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (1.4 g, 5.38 mmol ), triethylamine (1.76 g, 16.13 mmol) were dissolved in tetrahydrofuran (50 mL), and reacted at room temperature for one hour. Add water (50 mL) to quench the reaction, extract with ethyl acetate (50 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v) = 8:1) to obtain 2-(trimethylsilyl)ethyl(R)-6-oxo-3-(trifluoro Methyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyridin[3,2-e]pyrazine-8-carboxylate ( 31b )( 1.9 g, 85%).

LCMS m/z = 415.1 [M −1 ] ⁻ .

The third step: 2-(trimethylsilyl)ethyl(R)-6-thio-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H- Pyrazine[1,2-a]pyridin[3,2-e]pyrazine-8-carboxylate ( compound 31c )

2-(trimethylsilyl)ethyl (R)-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2- e]pyrazine-8-carboxylate

At room temperature, 2-(trimethylsilyl)ethyl(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H -pyrazine[1,2-a]pyridin[3,2-e]pyrazine-8-carboxylate ( 31b ) (3.4 g, 8.17 mmol) and Lawson's reagent (6.8 g, 16.83 mmol) dissolved in THF (100 mL), stirred at 60°C for 3 hours. After the reaction was completed, the crude product was obtained after concentration under reduced pressure. The crude product was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v) = 8:1) to obtain 2-(trimethylsilyl)ethyl(R)-6-thio-3-(trifluoro Methyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyridin[3,2-e]pyrazine-8-carboxylate ( compound 31c ) (1.95 g, 55%).

LCMS m/z = 431.1 [M −1 ] ⁻ .

The fourth step: 2-(trimethylsilyl)ethyl(R)-5-methyl-6-sulfanyl-3-(trifluoromethyl)-5,6,6a,7,9,10- Hexahydro-8H-pyrazine[1,2-a]pyridin[3,2-e]pyrazine-8-carboxylate ( 31d )

2-(trimethylsilyl)ethyl (R)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[ 3,2-e]pyrazine-8-carboxylate

At room temperature, 2-(trimethylsilyl)ethyl(R)-6-thio-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H -pyrazine[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylate ( compound 31c ) (300 mg, 0.69 mmol), methyl iodide (200 mg, 1.39 mmol) in DMF (5 mL), potassium carbonate (288 mg, 2.08 mmol) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, saturated brine (20 mL) was added, and ethyl acetate was added for extraction (20 mLx2). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 8: 1) to obtain 2-(trimethylsilyl)ethyl(R)-5-methyl-6-thio- 3-(Trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylic acid Ester ( 31d ) (261 mg, 85%).

LCMS m/z = 447.1 [M+1] ⁺ .

The fifth step: (R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3,2- e] pyrazine-6(6aH)-thione ( 31e )

(R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH)-thione

At room temperature, 2-(trimethylsilyl)ethyl(R)-5-methyl-6-sulfanyl-3-(trifluoromethyl)-5,6,6a,7,9,10 - Hexahydro-8H-pyrazine[1,2-a]pyridin[3,2-e]pyrazine-8-carboxylate ( 31d ) (261 mg, 0.59 mmol) was dissolved in THF (3 mL) , and then added tetrabutylammonium fluoride-tetrahydrofuran solution (1.0 M, 3 mL, 3.00 mmol), and reacted at room temperature for 4 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to obtain a crude product, which was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v) = 1:8) to obtain (R)-5-methyl-3-( Trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3,2-e]pyrazine-6(6aH)-thione ( 31e )( 87 mg, 49%).

LCMS m/z = 303.1 [M +1] ⁺ .

The sixth step: 5-((S)-1-(3-((R)-5-methyl-6-sulfanyl-3-(trifluoromethyl)-5,6,6a,7,9, 10-Hexahydro-8H-pyrazine[1,2-a]pyridin[3,2-e]pyrazin-8-yl)-3-oxopropoxy-2-yl)amino)-4-(tri Fluoromethyl)pyrazin-3(2H)-one ( Compound 31 )

5-(((S)-1-(3-((R)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

At room temperature, 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propane acid ( 4j ) (81 mg, 0.26 mmol) and (R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2- a]pyridine[3,2-e]pyrazine-6(6aH)-thione ( 31e ) (80 mg, 0.26 mmol) was dissolved in DMF (3 mL), and DIPEA (102 mg, 0.79 mmol ) and HATU (101 mg, 0.26 mmol) and stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (elution time 15min). After lyophilization, 5-((S)-1-(3-((R)-5-methyl-6-sulfanyl-3-(trifluoromethyl)-5,6,6a,7,9, 10-Hexahydro-8H-pyrazine[1,2-a]pyridin[3,2-e]pyrazin-8-yl)-3-oxopropoxy-2-yl)amino)-4-(tri Fluoromethyl)pyrazin-3(2H)-one ( Compound 31 ) (20 mg, 12%).

LCMS m/z = 594.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (s, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.52 - 7.48 (m, 1H), 6.31 - 6.19 (m, 1H ), 4.70 - 4.58 (m, 2H), 4.50 - 4.34 (m, 1H), 4.21 - 4.09 (m, 1H), 4.04 - 3.87 (m, 1H), 3.73 - 3.60 (m, 2H), 3.57-3.45 (m, 2H), 3.43 - 3.05 (m, 1H), 2.93 - 2.56 (m, 4H), 2.51 (s, 3H), 1.15 (d, 3H).

Example 32 : 5-((S)-1-(3-((R)-3- chlorine -5- methyl -6- Thio -5,6,6a,7,9,10- Hexahydro -8H- pyrazine [1,2-a] pyridine [3,2-e] pyrazine -8- base )-3- Oxypropoxy ) propane -2- base ) Amino )-4-( Trifluoromethyl ) pyrazine -3(2H)- Ketones (compounds 32 )

5-(((S)-1-(3-((R)-3-chloro-5-methyl-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1, 2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Compound 32 is synthesized from 2,5-dichloro-3-nitropyridine and (3R)-piperazine-1-carboxylate-3-butyl-3-methylcarboxylate ( 4b ) as starting materials, referring to the synthesis of Example 31 method to obtain 5-((S)-1-(3-((R)-3-chloro-5-methyl-6-sulfanyl-5,6,6a,7,9,10-hexahydro-8H -pyrazin[1,2-a]pyridin[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl) Pyrazin-3(2H)-one ( Compound 32 )

LCMS m/z = 560.1 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (s, 1H), 7.96-7.85 (m, 2H), 7.40 (d, 1H), 6.34-6.16 (m, 1H), 4.65-4.42 (m , 2H), 4.39-4.24 (m, 1H), 4.20-4.07 (m, 1H), 4.00-3.83 (m, 1H), 3.76-3.60 (m, 2H), 3.54-3.44 (m, 2H), 3.35 -3.04 (m,1H), 2.86-2.55 (m,4H), 2.49 (s,3H) , 1.15 (d, 3H).

Example 33 : (R)-5- Isobutyl -8-(3 -((S)-2 -((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-E] pyrazine -6-(6aH)- Ketones (compounds 33 )

(R)-5-isobutyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

The first step: tertiary butyl (R)-5-isobutyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyridine Azino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 33a )

tert-butyl-(R)-5-isobutyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3, 2-e]pyrazine-8-carboxylate

At room temperature, tert-butyl (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1, 2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ) (110 mg, 0.30 mmol), iodoisobutane (83 mg, 0.45 mmol) was dissolved in DMF (5 mL ), potassium carbonate (210 mg, 0.91 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, saturated brine (20 mL) was added, and ethyl acetate was added for extraction (20 mLx2). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v) = 8: 2) to obtain tertiary butyl (R)-5-isobutyl-6-oxo-3-(trifluoromethyl base)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 33a ) (100 mg, 78%).

LCMS m/z = 373.1 [M-55] ⁺ .

The second step: (R)-5-isobutyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3 ,2-e]pyrazin-6(6aH)-one hydrochloride ( 33b )

(R)-5-isobutyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride

At room temperature, (R)-5-isobutyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 33a ) (100 mg, 0.23 mmol) was dissolved in 1,4-dioxane (3 mL) solution, Add hydrogen chloride/1,4-dioxane solution (4.0 M, 3 mL, 40 mmol) and react at room temperature for 4 hours. After the reaction, concentrated under reduced pressure to obtain (R)-5-isobutyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a ]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride ( 33b ) (80 mg, 96%) crude product.

LCMS m/z = 329.2[M+1] ⁺ .

The third step: (R)-5-isobutyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine -4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido [3,2-E]pyrazin-6-(6aH)-one ( Compound 33 )

(R)-5-isobutyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

At room temperature, 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propane Acid ( 4j ) (66 mg, 0.22 mmol) and (R)-5-isobutyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1, 2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride ( 33b ) (80 mg, 0.22 mmol) was dissolved in DMF (3 mL), and DIPEA ( 142 mg, 1.10 mmol) and HATU (84 mg, 0.22 mmol) and stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (elution time 15min). After lyophilization, (R)-5-isobutyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine -4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido [3,2-E]pyrazin-6-(6aH)-one ( Compound 33 ) (20 mg, 12%).

LCMS m/z = 620.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.55 (s, 1H), 6.30-6.19 (m, 1H), 4.89- 4.45 (m, 2H), 4.31 - 3.98 (m, 3H), 3.95 - 3.78 (m, 2H), 3.75-3.62 (m, 2H), 3.49 (d, 2H), 3.28-3.09 (m, 1H ), 2.87-2.59 (m, 4H), 1.97-1.85 (m, 1H), 1.15 (d, 3H), 0.98-0.77 (m, 6H).

Example 34 : (R)-5- Isopropyl -8-(3-((S)-2-((6- oxygen -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6aH)- Ketones (compounds 34 )

(R)-5-isopropyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

Compound 34 was converted to tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ) and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1 , 6-dihydropyridazin-4-yl) amino] propoxyl] propionic acid ( 4j ) as raw material, refer to the synthetic method of Example 33 to obtain (R)-5-isopropyl-8-(3- ((S)-2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl) Fluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( compound 34 ) .

LCMS m/z = 606.2 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.22 (s, 1H), 7.90 (s, 1H), 7.66-7.55 (m, 1H), 6.32-6.18 (m, 1H ), 4.86 - 4.47 (m, 2H), 4.39-4.30 (m, 1H), 4.29 - 3.85 (m, 3H), 3.77-3.60 (m, 2H), 3.49 (d, 2H), 3.25 - 3.09 (m , 1H), 2.86 - 2.54 (m, 4H), 1.63-1.24 (m, 6H), 1.15 (d, 3H).

Example 35 : (6aR)-5-( Oxetane -2- methyl group )-8-(3-((S)-2-((6- oxygen -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6aH)- Ketones (compounds 35 )

(6aR)-5-(oxetan-2-ylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

The first step: (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridine Benzyl[3,2-e]pyrazine-8-carboxylate ( 35a )

benzyl (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8 -carboxylate

At room temperature, (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e] Pyrazin-6(6aH)-one ( 10e ) (4 g, 11.59 mmol) was dissolved in THF (40 mL), K ₂ CO ₃ (4.81 g, 34.77 mmol) and H ₂ O (10 mL) were added, and the mixture Stir for 5 min, slowly add benzyl chloroformate (1.21 g, 15.20 mmol) under ice cooling, after the reaction is complete, pour the reaction solution into water (150 mL), extract with ethyl acetate (50 mL x 3), combine organic phase, the organic phase was backwashed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 5: 1) to obtain: (R)-6-oxo-3-(trifluoromethyl)-5,6,6a , Benzyl 7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 35a ) (4 g, 85%) .

LCMS m/z = 407.1 [M+1] ⁺ .

The second step: (6aR)-5-(oxetan-2-ylmethyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexa Hydrogen-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylic acid benzyl ester ( 35b )

Benzyl (6aR)-5-(oxetan-2-ylmethyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido [3,2-e]pyrazine-8-carboxylate

At room temperature, ( 35a ) (0.25 g, 0.62 mmol) and 2-iodomethyloxetane (0.25 g, 1.24 mmol) were dissolved in DMF (2 mL), and potassium carbonate (0.26 g, 1.86 mmol) was added ), reacted at room temperature for 36 hours. After the reaction was complete, ethyl acetate (20 mL x 2) was added, washed with water (5 mL x 3), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a residue. the remains. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 5: 1) to obtain: (6aR)-5-(oxetan-2-ylmethyl)-6-oxo -3-(Trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8 - Benzyl carboxylate ( 35b ) (0.3 g, 100%).

LCMS m/z = 477.3 [M+1] ⁺ .

The third step: (6aR)-5-(oxetan-2-ylmethyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( 35c )

(6aR)-5-(oxetan-2-ylmethyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin- 6(6aH)-one

At room temperature, (6aR)-5-(oxetan-2-ylmethyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10 -Benzyl hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 35b ) (0.30 g, 0.62 mmol) was dissolved in methanol (8 mL ), replaced with nitrogen three times, added palladium carbon (45 mg), replaced with hydrogen three times, and reacted at room temperature for 4 hours. After the reaction was complete, filter with diatomaceous earth, combine the filtrates, and concentrate under reduced pressure to obtain the crude product (6aR)-5-(oxetan-2-ylmethyl)-3-(trifluoromethyl)-7 ,8,9,10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( 35c ) (210 mg, crude product) , was directly used in the next step without further purification.

LCMS m/z = 343.1 [M+1] ⁺ .

The fourth step: (6a R)-5-(oxetane-2-ylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl )-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine And[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( Compound 35 )

(6aR)-5-(oxetan-2-ylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

At room temperature, (6aR)-5-(oxetan-2-ylmethyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino [1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( 35c ) (210 mg, 0.61 mmol) and 3-[(2S)-2-[(6-oxo Dioxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoic acid ( 4j ) (188 mg, 0.61 mmol) was dissolved in DMF (5 mL) , to which DIPEA (240 mg, 1.83 mmol) and HATU (230 mg, 0.61 mmol) were added respectively and stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (elution time 15min). (6aR)-5-(oxetan-2-ylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl) -1,6-Dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino [1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( Compound 35 ) (20 mg, 5%)

LCMS m/z=634.3[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d6 ) δ 12.42 (s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.82 (d, 1H), 6.32-6.19 (m, 1H), 4.97 -3.96 (m, 10H), 3.76 - 3.60 (m, 2H), 3.49 (d, 2H), 3.28-2.59 (m, 7H), 1.15 (d, 3H).

Example 36 : (R)-5-( methyl -d3)-8-(3-((S)-2-((6- oxygen -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6aH)- Ketones (compounds 36 )

(R)-5-(methyl-d3)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

Compound 34 was converted to tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ) and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1 ,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid ( 4j ) as raw material, refer to the synthesis method of Example 33 to obtain (R)-5-(methyl-d ₃ )-8 -(3-((S)-2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)- 3-(Trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( compound 36 ).

LCMS m/z = 581.3 [M+1] ⁺ .

1H NMR (400 MHz, DMSO- d6 ) δ 12.41 (s, 1H), 8.19 (s, 1H), 7.94-7.85 (m, 1H), 7.53-7.40 (m, 1H), 6.31-6.19 (m, 1H ), 4.90-4.46 (m, 2H), 4.31-3.99 (m, 3H),3.77-3.62 (m, 2H), 3.49 (d, 2H), 3.28-3.04 (m, 1H), 2.86-2.58 (m , 4H), 1.15 (d, 3H).

Example 37 : (R)-5-((1- Methylcyclopropyl ) methyl )-8-(3-((S)-2-((6- oxygen -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino )) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6aH)- Ketones (compounds 37 )

(R)-5-((1-methylcyclopropyl)methyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

The first step: (R)-5-((1-methylcyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10- tert-butyl hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 37a )

Tert-butyl(R)-5-((1-methylcyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2- a]pyrido[3,2-e]pyrazine-8-carboxylate

At room temperature, (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a] Pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester ( 4d ) (150 mg, 0.40 mmol) was added to ultra-dry THF (15 mL), followed by 1-methylcyclopropanemethanol (38 mg, 0.44mmol) and triphenylphosphine (115 mg, 0.44 mmol), replaced with nitrogen three times, and slowly added diethyl azodicarboxylate (77 mg, 0.44mmol). The mixture was stirred overnight at room temperature. Add water (30 mL) to quench the reaction, extract with ethyl acetate (30 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 8:1) to obtain (R)-5-((1-methylcyclopropyl)methyl)-6-oxo- 3-(Trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8- Tertiary butyl carboxylate ( 37a ) (70 mg, 40%).

LCMS m/z = 385.1 [M-55] ⁺ .

The second step: (R)-5-((1-methylcyclopropyl)methyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( 37b ) hydrochloride

(R)-5-((1-methylcyclopropyl)methyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin -6(6aH)-one hydrochloride

At room temperature, (R)-5-((1-methylcyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10 - Tert-butyl hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 37a ) (70 mg, 0.16 mmol) dissolved in 1, Add hydrogen chloride/1,4-dioxane solution (4.0 M, 3 mL, 40 mmol) to the 4-dioxane (3 mL) solution, and react at room temperature for 4 hours. After the reaction, the solvent was concentrated under reduced pressure to obtain (R)-5-((1-methylcyclopropyl)methyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro -5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( 37b ) hydrochloride (60 mg, crude product).

LCMS m/z = 341.1[M+1] ⁺ .

The third step: (R)-5-((1-methylcyclopropyl)methyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl) -1,6-Dihydropyridazin-4-yl)amino))propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine And[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( Compound 37 )

(R)-5-((1-methylcyclopropyl)methyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

At room temperature, 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propane Acid ( 4j ) (49 mg, 0.16 mmol) and (R)-5-((1-methylcyclopropyl)methyl)-3-(trifluoromethyl)-7,8,9,10-tetra Hydrogen-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( 37b ) hydrochloride (60 mg, crude product) was dissolved in DMF (3 mL), to which were added DIPEA (103 mg, 0.80 mmol) and HATU (61 mg, 0.16 mmol) and then stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (elution time 15min). After lyophilization, (R)-5-((1-methylcyclopropyl)methyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl) -1,6-Dihydropyridazin-4-yl)amino))propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine a[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( Compound 37 ) (20 mg, 15%).

LCMS m/z = 632.2 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.69 (s, 1H), 6.31-6.19 (m, 1H), 4.90-4.40 (m, 2H), 4.34-3.94 (m, 5H), 3.76-3.62 (m, 2H), 3.49 (d, 2H), 3.27-3.10 (m, 1H), 2.86-2.59 (m, 4H ), 1.15 (d, 3H), 0.91 (s, 3H), 0.55-0.45 (m, 2H), 0.33-0.24 (m, 2H).

Example 38 : 1-(((R)-6- oxygen -8-(3-((S)-2-((6- oxygen -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-6,6a,7,8,9,10- Hexahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -5- base ) methyl ) Cyclopropane -1- Nitrile (compound 38 )

1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) propanoyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane -1-carbonitrile

The first step: 1-(iodomethyl)cyclopropane-1-carbonitrile ( 38b )

1-(iodomethyl)cyclopropane-1-carbonitrile

At room temperature, 1-(hydroxymethyl)cyclopropanecarbonitrile ( 38a ) (1.00 g, 10.30 mmol), triphenylphosphine (3.24 g, 12.36 mmol) and imidazole (0.84 g, 12.36 mmol) were added to di In methyl chloride (30 mL), nitrogen was replaced three times, and iodine (2.61 g, 10.30 mmol) was added slowly. The mixture was stirred overnight at room temperature. The reaction was quenched by adding water (30 mL), extracted with dichloromethane (30 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=12:1) to obtain 1-(iodomethyl)cyclopropane-1-carbonitrile ( 38b ) (1.50 g, 75%).

The second step: (R)-5-((1-cyanocyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10- tert-butyl hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 38c )

Tert-butyl(R)-5-((1-cyanocyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2- a]pyrido[3,2-e]pyrazine-8-carboxylate

At room temperature, (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a] Pyrido[3,2-e]pyrazine-8-carboxylate tert-butyl ester ( 4d ) (110 mg, 0.30 mmol) was added to DMF (5 mL), followed by 1-(iodomethyl)cyclopropane -1-carbonitrile ( 38b ) (93 mg, 0.45mmol) and potassium carbonate (210 mg, 0.91 mmol), the mixture was stirred overnight at room temperature. Add saturated brine (30 mL) to quench the reaction, extract with ethyl acetate (30 mL x 2), combine the organic phases, wash the organic phase with saturated brine (30 mL x 3), dry over anhydrous sodium sulfate and filter, the filtrate The crude product was obtained after concentration under reduced pressure. The crude product was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v) = 8:1) to obtain (R)-5-((1-cyanocyclopropyl)methyl)-6-oxo- 3-(Trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8- Tertiary butyl carboxylate ( 38c ) (100 mg, 74%).

LCMS m/z = 396.1 [M-55] ⁺ .

The third step: (R)-1-((6-oxo-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2- a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile ( 38d )hydrochloride

(R)-1-((6-oxo-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e] pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile hydrochloride

At room temperature, (R)-5-((1-cyanocyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10 - Tert-butyl hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 38c ) (100 mg, 0.22 mmol) dissolved in 1, Add hydrogen chloride/1,4-dioxane solution (4.0 M, 3 mL, 40 mmol) to the 4-dioxane (3 mL) solution, and react at room temperature for 4 hours. After the reaction, the solvent was concentrated under reduced pressure to obtain (R)-1-((6-oxo-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyridine azino[1,2-a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile ( 38d ) hydrochloride (85 mg, crude product).

LCMS m/z = 352.1[M+1] ⁺ .

The fourth step: 1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine Azin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile ( compound 38 )

1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) propanoyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane -1-carbonitrile

At room temperature, 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propane Acid ( 4j ) (68 mg, 0.22 mmol) and (R)-1-((6-oxo-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H- Pyrazino[1,2-a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile ( 38d ) hydrochloride (85 mg, crude product) In DMF (3 mL), DIPEA (142 mg, 1.10 mmol) and HATU (84 mg, 0.22 mmol) were added thereto, and the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (elution time 15min). After lyophilization, 1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine) Azin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile ( Compound 38 ) (20 mg, 14%).

LCMS m/z = 643.1 [M+1]+.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.25 (s, 1H), 7.90 (s, 2H), 6.34-6.17 (m, 1H), 4.91-4.42 (m, 2H ), 4.37-3.98 (m, 5H), 3.77-3.62 (m, 2H), 3.49 (d, 2H), 3.27-3.10 (m, 1H), 2.90-2.59 (m, 4H), 1.32-1.12 (m , 7H).

Example 39 : 5-(((S)-1-(3-((R)-5-( Cyclopropylmethyl )-3- fluorine -6- Thio -5,6,6a,7,9,10- Hexahydro -8H- pyrazine [1,2-a] pyrido [3,2-e] pyrazine -8- base )-3- Oxopropoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- Ketones (compounds 39 )

5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

The first step: 1-tert-butyl 3-methyl(3R)-4-(5-fluoro-3-nitropyridin-2-yl)piperazine-1,3-dicarboxylate ( 39c )

1-tert-butyl 3-methyl (3R)-4-(5-fluoro-3-nitropyridin-2-yl)piperazine-1,3-dicarboxylate

2-Chloro-5-fluoro-3-nitropyridine ( 39a ) (2.00 g, 11.33 mmol), 1-(tert-butyl) 3-methyl(R)-piperazine-1,3-dicarboxy Ester ( 39b ) (3.32 g, 13.60 mmol), DIPEA (5.00 g, 38.76 mmol) were added to dimethylsulfoxide (15 mL) successively, and reacted at 100°C for 16 h. After the reaction was completed, cool to room temperature, and The reaction solution was poured into water (150 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was combined, and the organic phase was backwashed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 4: 1) to obtain: 1-tert-butyl 3-methyl(3R)-4-(5-fluoro-3- Nitropyridin-2-yl)piperazine-1,3-dicarboxylate ( 39c ) (2.13 g, 49%).

LCMS m/z = 329.1 [M-55] ⁺ .

The second step: (R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2 -e]pyrazine-8-carboxylate tert-butyl ester ( 39d )

tert-butyl (R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8 -carboxylate

At room temperature, 1-tert-butyl 3-methyl(3R)-4-(5-fluoro-3-nitropyridin-2-yl)piperazine-1,3-dicarboxylate ( 39c ) ( 2.13 g, 5.54 mmol) was dissolved in absolute ethanol (30 mL), and then zinc powder (3.62 g, 55.4 mmol) and ammonium chloride (2.96 g, 55.4 mmol) were added. The mixture was stirred and reacted at 60°C for 16 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (40 mL), the organic phase was combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 4:1) to obtain (R)-3-fluoro-6-oxo-5,6,6a,7,9,10 - tert-butyl hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 39d ) (1.30 g, 73%).

LCMS m/z = 321.2 [M-1] ^- .

The third step: (R)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH )-keto hydrochloride ( 39e )

(R)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

At room temperature, (R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3, 2-e] pyrazine-8-carboxylate tert-butyl ester ( 39d ) (1.30 g, 4.03 mmol) was dissolved in 1,4-dioxane (5 mL) solution, and then hydrogen chloride/1,4- Dioxane solution (4.0 M, 10 mL, 40 mmol), react at room temperature for 4 hours. After the reaction, the solvent was concentrated under reduced pressure to obtain (R)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e ]pyrazin-6(6aH)-one ( 39e ) hydrochloride (1.00 g, crude product).

LCMS m/z = 223.1 [M+1] ⁺ .

The fourth step: 2-(trimethylsilyl)ethyl(R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 39f )

2-(trimethylsilyl)ethyl(R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e] pyrazine-8-carboxylate

At room temperature, (R)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6( 6aH)-Kone hydrochloride ( 39e ) (0.30 g, 1.35 mmol) and triethylamine (0.41 g, 4.05 mmol) were dissolved in tetrahydrofuran (10 mL), and N-[2-(trimethylsilyl ) ethoxycarbonyloxy] succinimide (0.35 g, 1.35 mmol). The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the crude product was obtained after concentration under reduced pressure. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 3: 1) to obtain 2-(trimethylsilyl)ethyl(R)-3-fluoro-6-oxo- 5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 39f ) (0.35 g , 71%).

LCMS m/z = 365.2 [M-1] ^-

The fifth step: 2-(trimethylsilyl)ethyl(R)-3-fluoro-6-thio-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 39g )

2-(trimethylsilyl)ethyl(R)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e] pyrazine-8-carboxylate

At room temperature, the third 2-(trimethylsilyl)ethyl(R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyridine Azino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 39f ) (0.35 g, 0.96 mmol) was dissolved in THF (5 mL), and Lawson's reagent was added (0.78 g, 1.92 mmol), and the mixture was reacted at 60°C for 16 hours. After the reaction was completed, the crude product was obtained after concentration under reduced pressure. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 3: 1) to obtain 2-(trimethylsilyl)ethyl(R)-3-fluoro-6-thio- 5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 39g ) (0.20 g , 54%).

Step 6: 2-(trimethylsilyl)ethyl(R)-5-(cyclopropylmethyl)-3-fluoro-6-thio-5,6,6a,7,9,10 - Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 39h )

2-(trimethylsilyl)ethyl(R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[ 3,2-e]pyrazine-8-carboxylate

At room temperature, 2-(trimethylsilyl)ethyl(R)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino [1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 39g ) (110 mg, 0.26 mmol), (iodomethyl)cyclopropane (71 mg, 0.39 mmol) In DMF (5 mL), potassium carbonate (110 mg, 0.78 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, saturated brine (20 mL) was added, and ethyl acetate was added for extraction (20 mLx2). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 6: 1) to obtain 2-(trimethylsilyl)ethyl(R)-5-(cyclopropylmethyl) -3-fluoro-6-thio-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8 - Carboxylate ( 39h ) (70 mg, 62%).

LCMS m/z = 437.2 [M+1] ⁺ .

The seventh step: (R)-5-(cyclopropylmethyl)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3, 2-e]pyrazine-6(6aH)-thione ( 39i )

(R)-5-(cyclopropylmethyl)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH)-thione

At room temperature, 2-(trimethylsilyl)ethyl(R)-5-(cyclopropylmethyl)-3-fluoro-6-thio-5,6,6a,7,9, 10-Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 39h ) (70 mg, 0.16 mmol) was dissolved in THF (3 mL ), and tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 1.5 mL, 1.5 mmol) was added, and reacted at room temperature for 2 hours. After the reaction was completed, saturated brine (20 mL) was added, and ethyl acetate was added for extraction (20 mLx2). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 2: 1) to obtain (R)-5-(cyclopropylmethyl)-3-fluoro-7,8,9,10 - Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH)-thione ( 39i ) (25 mg, 47%).

LCMS m/z = 293.1[M+1] ⁺ .

Step 8: 5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9 ,10-Hexahydro-8H-pyrazine[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino) -4-(trifluoromethyl)pyridazin-3(2H)-one ( compound 39 )

5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

At room temperature, 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propane Acid ( 4j ) (27 mg, 0.09 mmol) and (R)-5-(cyclopropylmethyl)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-6(6aH)-thione ( 39i ) (25 mg, 0.09 mmol) was dissolved in DMF (3 mL), and DIPEA (58 mg, 0.45 mmol) and HATU (34 mg, 0.09 mmol) and stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonium acetate). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (elution time 15min). After lyophilization, 5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9 ,10-Hexahydro-8H-pyrazine[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino) -4-(trifluoromethyl)pyridazin-3(2H)-one ( compound 39 ) (10 mg, 18%).

LCMS m/z = 584.2 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 7.95-7.86 (m, 2H), 7.33 (dd, 1H), 6.33 - 6.18 (m, 1H), 4.64 - 4.34 (m , 2H), 4.25 - 3.82 (m, 3H), 3.75-3.59 (m, 2H), 3.56-3.44 (m, 2H), 3.17 - 2.53 (m, 7H), 1.25 - 1.05 (m, 4H), 0.63 - 0.49 (m, 2H), 0.39 - 0.25 (m, 2H).

Example 40 : (R)-8-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-5- Propyl -3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6aH)- Ketones (compounds 40 )

(R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-5-propyl-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

Compound 40 is represented by tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ), iodopropane and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl )-1,6-dihydropyridazin-4-yl)amino]propoxyl]propionic acid ( 4j ) as raw material, referring to the synthetic method of Example 29, to obtain (R)-8-(3-((S )-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-5-propyl-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one ( compound 40 ).

LCMS m/z = 606.2 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.52 (s, 1H), 6.32-6.15 (m, 1H), 4.93-4.39 (m, 2H), 4.31-3.83 (m, 5H), 3.74 - 3.58 (m, 2H), 3.49 (d, 2H), 3.27-3.04 (m, 1H), 2.88-2.55 (m, 4H ), 1.62-1.43 (m, 2H), 1.15 (d, 3H), 0.88 (t, 3H).

Example 41 : (R)-5- Hinkie -8-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-E] pyrazine -6-(6aH)- Ketones (compounds 41 )

(R)-5-octyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

Compound 41 was converted to tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ) and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1 , 6-dihydropyridazin-4-yl) amino] propoxyl] propionic acid ( 4j ) as raw material, referring to the synthetic method of Example 29, to obtain (R)-5-octyl-8-(3-( (S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl) Fluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6-(6aH)-one ( compound 41 ).

LCMS m/z = 676.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.49 (s, 1H), 6.30-6.18 (m, 1H), 4.92-4.40 (m, 2H), 4.34-3.86 (m, 5H), 3.76-3.61 (m, 2H), 3.49 (d, 2H), 3.26-3.05 (m, 1H), 2.85-2.55 (m, 4H ), 1.58-1.42 (m, 2H), 1.35-1.12 (m, 13H), 0.89-0.79 (m, 3H).

Example 42 : (S)-5-( methyl -D3)-8-(3-((S)-2-((6- oxygen -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6aH)- Ketones (compounds 42 )

(S)-5-(methyl-D ₃ )-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy )propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

Compound 42 was converted to tert-butyl-(S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate ( 10d )deuteromethyl iodide and 3-[(2S)-2-[(6-oxo-5-(trifluoromethane base)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid ( 4j ) as raw material, referring to the synthesis method of Example 11, to obtain (S)-5-(methyl-D ₃ )-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propane Acyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6( 6aH)-ketone ( compound 42 ).

LCMS m/z = 581.3 [M+1] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.14(s, 1H), 7.91 (d, 1H), 7.40 (s, 1H), 5.15 - 4.57 (m, 2H), 4.56-3.92 (m, 3H) , 3.88-3.68 (m, 2H), 3.65-3.46 (m, 2H), 3.27-3.18 (m, 1H), 2.93-2.60 (m, 4H), 1.25 (d, 3H).

Example 43 : 5-(((S)-1-(3-((S)-5- methyl -6- Thio -3-( Trifluoromethyl )-5,6,6a,7,9,10- Hexahydro -8H- pyrazine [1,2-a] pyrido [3,2-e] pyrazine -8- base )-3- Oxopropoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- Ketones (compounds 43 )

5-(((S)-1-(3-((S)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Compound 43 was converted to tert-butyl-(S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate ( 10d ) and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1 , 6-dihydropyridazin-4-yl) amino] propoxy] propionic acid ( 4j ) as raw material, referring to the synthetic method of Example 31, to obtain 5-(((S)-1-(3-(( S)-5-Methyl-6-sulfoxy-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyridine [3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ( Compound 43 ).

LCMS m/z = 594.2 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.14-9.87 (m, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.59-7.51 (m, 1H), 5.83-5.70 (m, 1H ), 5.09-4.53 (m, 2H), 4.41-4.23 (m, 1H), 4.15-3.74 (m, 4H), 3.71-3.59 (m, 1H), 3.56-3.43 (m, 1H), 3.39-3.14 (m, 1H), 2.95-2.72 (m, 2H), 2.71-2.48 (m, 5H), 1.30 (d, 3H).

Example 44 : (R)-5- Cyclopentylmethyl -8-(3-((S)-2-((6- Oxo -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-E] pyrazine -6-(6aH)- Ketones (compounds 44 )

(R)-5-(cyclopentylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl) -3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

Compound 44 was converted to tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate (4 d ), iodomethylcyclopentane and 3-[(2S)-2-[(6-oxo-5- (Trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid ( 4j ) as raw material, refer to the synthesis method of Example 33 to obtain (R)-5-ring Amylmethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy Base) propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine -6-(6aH)-one ( compound 44 ).

LCMS m/z = 646.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.58 (s, 1H), 6.36-6.15 (m, 1H), 4.99 - 4.41 (m, 2H), 4.33 - 3.84(m, 5H), 3.78- 3.60 (m, 2H), 3.49 (d, 2H), 3.27- 3.07 (m, 1H), 2.88- 2.55 (m, 4H ), 2.22- 2.07 (m, 1H), 1.71- 1.39 (m, 6H), 1.31- 1.18 (m, 2H), 1.15 (d, 3H).

Example 45 : (R)-5- Isopentyl -8-(3-((S)-2-((6- oxygen -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino )) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6aH)- Ketones (compounds 45 )

(R)-5-isopentyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

Compound 45 was converted to tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ), isopentyl iodide and 3-[(2S)-2-[(6-oxo-5-(trifluoro Methyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid ( 4j ) as raw material, refer to the synthesis method of Example 33 to obtain (R)-5-isoamyl- 8-(3-((S)-2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino))propoxy)propionyl )-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH) - Ketone ( Compound 45 ).

LCMS m/z = 634.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.44 (s, 1H), 6.30-6.18 (m, 1H), 4.91-4.40 (m, 2H), 4.36-3.90 (m, 5H), 3.76-3.58 (m, 2H), 3.49 (d, 2H), 3.27 - 3.04 (m, 1H), 2.87-2.56 (m, 4H ), 1.68-1.52 (m, 1H), 1.44- 1.33 (m, 2H), 1.15 (d, 3H), 0.97-0.84 (m, 6H).

Example 46 : (R)-5-(2- ethyl butyl )-8-(3-((S)-2-((6- oxygen -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino )) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6aH)- Ketones (compounds 46 )

(R)-5-(2-ethylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

Compound 46 was converted to tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ), 2-ethyl-1-butanol and 3-[(2S)-2-[(6-oxo-5 -(Trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid ( 4j ) as raw material, refer to the synthesis method of Example 37 to obtain (R)-5- (2-Ethylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino ))propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2- e] Pyrazin-6(6aH)-one ( Compound 46 ).

LCMS m/z = 648.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.46 (s, 1H), 6.33-6.17 (m, 1H), 4.94-4.39 (m, 2H), 4.37 - 3.93 (m, 4H), 3.90-3.79 (m, 1H), 3.78-3.61 (m, 2H), 3.49 (d, 2H), 3.25-3.08 (m, 1H ), 2.88-2.55 (m, 4H), 1.62-1.48 (m, 1H), 1.36-1.18 (m, 4H), 1.15 (d, 3H), 0.92-0.76 (m, 6H).

Example 47 : (R)-5-(2- methyl butyl )-8-(3-((S)-2-((6- oxygen -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino )) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6aH)- Ketones (compounds 47 )

(R)-5-(2-methylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

Compound 47 was converted to tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ), 2-methylbutanol and 3-[(2S)-2-[(6-oxo-5-(tri Fluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid ( 4j ) as raw material, refer to the synthesis method of Example 37 to obtain (R)-5-(2- Methylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino))propane Oxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyridine Azin-6(6aH)-one ( compound 47 ).

LCMS m/z = 634.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.51 (s, 1H), 6.31-6.19 (m, 1H), 4.90-4.42 (m, 2H), 4.34-3.78 (m, 5H), 3.76-3.60 (m, 2H), 3.49 (d, 2H), 3.25-3.06 (m, 1H), 2.90-2.58 (m, 4H ), 1.80-1.60 (m, 1H), 1.46-1.28 (m, 1H), 1.22-1.05 (m, 4H), 0.91-0.73 (m, 6H).

Example 48 : (R)-5- Butyl -8-(3-((S)-2-((6- oxygen -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino )) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6aH)- Ketones (compounds 48 )

(R)-5-butyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

Compound 48 was converted to tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ), 1-iodobutane and 3-[(2S)-2-[(6-oxo-5-(tri Fluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid ( 4j ) as raw material, refer to the synthesis method of Example 33 to obtain (R)-5-butyl- 8-(3-((S)-2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino))propoxy)propionyl )-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH) - Ketone ( Compound 48 ).

LCMS m/z = 620.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.51 (s, 1H), 6.37-6.18 (m, 1H), 4.94-4.40 (m, 2H), 4.31-3.91 (m, 5H), 3.81-3.60 (m, 2H), 3.49 (d, 2H), 3.24-3.05 (m, 1H), 2.87-2.60 (m, 4H ), 1.58-1.42 (m, 2H), 1.38-1.25 (m, 2H), 1.15 (d, 3H), 0.99-0.84 (m, 3H).

Example 49 : (R)-5-((S)-2- methyl butyl )-8-(3-((S)-2-((6- oxygen -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino )) Propoxy ) Propyl )-3-( Trifluoromethyl )-7,8,9,10- Tetrahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -6(6aH)- Ketones (compounds 49 )

(R)-5-((S)-2-methylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

Compound 49 was converted to tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ), S-(-)-2-methyl-1-butanol and 3-[(2S)-2-[( 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid ( 4j ) as raw material, referring to the synthesis method of Example 37, to obtain (R)-5-((S)-2-methylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6- Dihydropyridazin-4-yl)amino))propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazin-6(6aH)-one ( Compound 49 ).

LCMS m/z = 634.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.50 (s, 1H), 6.32-6.16 (m, 1H), 4.95-4.37 (m, 2H), 4.37-3.76 (m, 5H), 3.74-3.59 (m, 2H), 3.49(d, 2H), 3.28-3.06 (m, 1H), 2.89-2.56 (m, 4H ), 1.76-1.60 (m, 1H), 1.47-1.32 (m, 1H), 1.26-1.08 (m, 4H), 0.97-0.75 (m, 6H).

Example 50 : (R)-5-( Cyclopropylmethyl )-8-(3-((S)-2-((6- oxygen -5-( Trifluoromethyl )-1,6- Dihydropyridazine -4- base ) Amino ) Propoxy ) Propyl )-6- Thio -6,6a,7,8,9,10- Hexahydro -5H- pyrazino [1,2-a] pyrido [3,2-e] pyrazine -3- Nitrile (compound 50 )

(R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl) -6-thioxo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-3-carbonitrile

Compound 50 was synthesized with 6-chloro-5-nitronicotinonitrile and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4- base)amino]propoxy]propanoic acid ( 4j ), (iodomethyl)cyclopropane and tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a , 7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate ( 4d ) as raw material, refer to Example 39 Synthetic method, obtain (R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-di Hydropyridazin-4-yl)amino)propoxy)propionyl)-6-thioxo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a ]pyrido[3,2-e]pyrazine-3-carbonitrile ( compound 50 ).

LCMS m/z = 591.2 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (s, 1H), 8.29 (d, 1H), 7.90 (s, 1H), 7.59 (d, 1H), 6.33-6.19 (m, 1H), 4.77-4.31 (m, 3H), 4.24-3.88 (m, 2H), 3.77-3.62 (m, 2H), 3.55-3.45 (m, 2H), 3.44-3.01 (m, 3H), 2.94-2.56 (m , 4H), 1.22-1.04 (m, 4H), 0.61-0.50 (m, 2H), 0.37-0.27 (m, 2H).

Example 51 : 5-(((S)-1-(3- Oxo -3-((R)-3-( Trifluoromethyl )-5,6,6a,7,9,10- Hexahydro -8H- pyridine [1,6-a:2,3-b'] Dipyrazine -8- base ) Propoxy ) propane -2- base ) Amino )-4-( Trifluoromethyl ) pyrazine -3(2H)- ketone ( compound 51)

5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6- a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

The first step: 5-(trifluoromethyl)pyrazin-2-ol ( 51b )

5-(trifluoromethyl)pyrazin-2-ol

2-Chloro-5-(trifluoromethyl)pyrazine (2.00 g, 10.96 mmol) ( 51a ) was dissolved in tetrahydrofuran (10 mL), and sodium hydroxide (0.88 g, 21.92 mmol) in water (4 mL) was added ) solution, heated to 70°C for 3 h. After the reaction, the pH was adjusted to 6-7 with hydrochloric acid solution (2 M) in an ice-water bath. Then extract with ethyl acetate (20 mL x 3), combine the organic phases, backwash with saturated brine (20 mL x 2), dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain 5-(trifluoromethyl) Pyrazin-2-ol ( 51b ) (1.60 g, 89%).

LCMS m/z = 165.0 [M+1] ⁺ .

The second step: 3-bromo-5-(trifluoromethyl)pyrazin-2-ol ( 51c )

3-bromo-5-(trifluoromethyl)pyrazin-2-ol

Under an ice-water bath, bromine (7.80 g, 48.81 mmol) was slowly added dropwise to a solution of 5-(trifluoromethyl)pyrazin-2-ol ( 51b ) (1.40 g, 8.53 mmol) in DMF (15 mL). After dropping, keep the temperature for 3 h. After the reaction, the reaction solution was slowly added to ice water (100 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, and the organic phase was backwashed with saturated brine (20 mL x 2), anhydrous sulfuric acid Dry over sodium, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue is separated and purified by a preparative column (methanol:dichloromethane (v/v)=1:25) to obtain 3-bromo-5-(trifluoromethyl) Pyrazin-2-ol ( 51c ) (1.40 g, 68%).

LCMS m/z =240.9[M-1] ^-

The third step: 1-benzyl 4-(tert-butyl)(R)-2-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)vinyl)piperazine -1,4-dicarboxylate ( 51d )

1-benzyl 4-(tert-butyl)(R)-2-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)vinyl)piperazine-1,4-dicarboxylate

At room temperature, 1-benzyl 4-(tert-butyl)(R)-2-vinylpiperazine-1,4-dicarboxylate (200 mg, 0.58 mmol, dissolved in (S)-3- (Hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester as raw material (prepared according to WO2007146066) was dissolved in DMF (12 mL), and 3-bromo-5-(trifluoromethyl)pyrazine-2- Alcohol ( 51c ) (211 mg, 0.87 mmol), potassium carbonate (240 mg, 1.74 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (111 mg, 0.23 mmol ) and palladium acetate (26 mg, 0.12 mmol). Nitrogen was replaced three times, and the reaction was carried out at 100 °C for 16 h. After the reaction, add water (40 mL) and ethyl acetate (40 mL), filter with Celite, and separate the filtrate, extract the aqueous phase with ethyl acetate (40 mL x 2), combine the organic phases, and wash the organic phase with saturated Backwash with brine (20 mL x 2), dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (tetrahydrofuran:dichloromethane (v/v)=15:85) to obtain 1-benzyl 4-(tert-butyl)(R)-2-(2-(3-hydroxy -6-(trifluoromethyl)pyrazin-2-yl)vinyl)piperazine-1,4-dicarboxylate ( 51d ) (100 mg, 34%).

LCMS m/z = 453.0 [M-55] ⁺ .

The fourth step: (R)-3-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester ( 51e )

tert-butyl (R)-3-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)ethyl)piperazine-1-carboxylate

At room temperature, 1-benzyl 4-(tert-butyl)(R)-2-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)vinyl)piper Oxyzine-1,4-dicarboxylate ( 51d ) (150 mg, 0.29 mmol) was dissolved in MeOH (10 mL), ammonia water (mass fraction 25%-28%, 0.1 mL), palladium carbon (20 mg, 10%), after hydrogen replacement, react at room temperature under hydrogen atmosphere for 16 h, after the reaction, filter with Celite, and concentrate the filtrate under reduced pressure to obtain (R)-3-(2-(3-hydroxy-6-(tri Fluoromethyl)pyrazin-2-yl)ethyl)piperazine-1-carboxylate tert-butyl ester ( 51e ) (110 mg) crude product was used directly in the next step.

LCMS m/z=377.2[M+1] ⁺ .

The fifth step: tert-butyl (R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyridine[1,6-a:2,3- b'] dipyrazine-8-carboxylate ( 51f )

tert-butyl (R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazine-8-carboxylate

At room temperature, (R)-3-(2-(3-hydroxyl-6-(trifluoromethyl)pyrazin-2-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester ( 51e ) (110 mg, crude product) was dissolved in dimethylsulfoxide (5 mL), and DIPEA (112 mg, 0.87 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate were added (151 mg, 0.29 mmol). Raise the temperature to 60°C for 1 h. After the reaction, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined, and the organic phase was backwashed with saturated brine (20 mL x 3), anhydrous sodium sulfate Dry, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=15:85) to obtain tert-butyl (R)-3-(trifluoromethyl)-5,6,6a,7 , 9,10-hexahydro-8H-pyridine[1,6-a:2,3-b']dipyrazine-8-carboxylate ( 51f ) (52 mg, 50%, 2-step yield).

LCMS m/z = 303.1 [M-55] ⁺ .

The sixth step: (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyridine[1,6-a:2,3-b']di Hydrochloride of pyrazine ( 51g )

(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,6-a:2,3-b']dipyrazine

At room temperature, tert-butyl(R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyridine[1,6-a:2,3 -b']dipyrazine-8-carboxylate ( 51f ) (87 mg, 0.24 mmol) was dissolved in hydrogen chloride/1,4-dioxane solution (10 mL, 4 M) and reacted at room temperature for 1 h . After the reaction, concentrate under reduced pressure to obtain (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyridine[1,6-a:2,3- b'] The crude product of hydrochloride (71 mg) of dipyrazine ( 51 g ) was directly used in the next reaction.

LCMS m/z = 259.2 [M+1] ⁺ .

The seventh step: 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro -8H-pyridin[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyrazine- 3(2H)-Kone ( Compound 51 )

5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6- a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

At room temperature, (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyridine[1,6-a:2,3-b'] Dipyrazine ( 51g ) hydrochloride (71 mg, crude product) and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridium Oxyzin-4-yl)amino]propoxy]propionic acid ( 4j ) (75 mg, 0.24 mmol) was dissolved in DMF (2 mL), and DIPEA (93 mg, 0.72 mmol) and HATU (91 mg , 0.24 mmol), and then stirred at room temperature for 1 h. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (elution time 15min). After lyophilization, 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro -8H-pyridin[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyrazine- 3(2H)-Kone ( compound 51 ) (55 mg, 42 %, yield over 2 steps).

LCMS m/z = 550.1 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.46-10.19 (m, 1H), 8.26-8.17 (m, 1H), 7.65 (s, 1H), 5.90-5.73(m, 1H), 4.82-4.56 (m , 2H), 4.00-3.79 (m, 4H), 3.69-3.63 (m, 1H), 3.53-3.36 (m, 2H), 3.32-2.48 (m, 7H), 2.29-2.15 (m, 1H), 1.93 -1.77(m, 1H), 1.30(d, 3H).

Example 52 : 5-(((S)-1-(3- Oxo -3-((S)-3-( Trifluoromethyl )-5,6,6a,7,9,10- Hexahydro -8H- pyridine [1,6-a:2,3-b'] Dipyrazine -8- base ) Propoxy ) propane -2- base ) Amino )-4-( Trifluoromethyl ) pyrazine -3(2H)- ketone ( compound 52)

5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6- a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Compound 52 uses 2-chloro-5-(trifluoromethyl)pyrazine and (R)-3-(hydroxymethyl)piperazine-1-tert-butyl carboxylate as raw materials, referring to the synthesis method of Example 51 , to give 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H -pyridin[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyrazine-3( 2H)-Kone ( Compound 52 )

LCMS m/z = 550.3 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.68-10.45 (m, 1H), 8.25-8.16 (m, 1H), 7.65 (s, 1H), 5.88-5.72 (m, 1H), 4.85-4.53 (m , 2H), 4.01-3.77 (m, 4H), 3.70-3.62 (m, 1H), 3.56-3.35 (m, 2H), 3.32-2.49 (m, 7H), 2.29-2.14 (m, 1H), 1.94 -1.76 (m, 1H), 1.31 (d, 3H).

Example 53 : 5-(((S)-1-(3-((S)-5,5- Dioxide -3-( Trifluoromethyl )-6a,7,9,10- tetrahydropyrazine [1,2-d] pyrido [3,2-b][1,4] Thiazide -8(6H)- base )-3- Oxopropoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- ketone ( compound 53)

5-(((S)-1-(3-((S)-5,5-dioxido-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3, 2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

The first step: (S)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester ( compound 53b )

Tert-butyl (S)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

At room temperature, (S)-1-BOC-3-hydroxymethylpiperazine (4.48 g, 20.73 mmol), N,N-diisopropylethylamine (5.36 g, 41.46 mmol) were added to 3-bromo -2-Chloro-5-trifluoromethylpyridine ( 53a ) (5.40g, 20.73 mmol in N,N-dimethylformamide (30 mL) solution, after nitrogen replacement, heated to 100°C for 16 hours After completion of the reaction, cool to room temperature, add ethyl acetate (50 mL) to the reaction solution to dilute the reaction solution, and wash the reaction solution with water (20 mL x 3). The organic phase is concentrated under reduced pressure to obtain a crude product. The crude product Separation and purification by column chromatography (petroleum ether: ethyl acetate (v/v) = 5:3) to obtain (S)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)- Tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate ( 53b ) (3.80 g, 42%).

LCMS m/z = 384.1 [M-55] ⁺ .

The second step: (S)-3-((acetylthio)methyl)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid Tributyl ester ( compound 53c )

Tert-butyl (S)-3-((acetylthio)methyl)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

Under ice-water bath, thioacetic acid (0.79 g, 10.36 mmol) was added to (S)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl) A solution of tert-butyl piperazine-1-carboxylate ( 53b ) (3.80 g, 8.63 mmol), triphenylphosphine (2.72 g, 10.36 mmol), and DEAD (1.80 g, 10.36 mmol) in anhydrous THF (30 mL) middle. After keeping the ice-water bath for 2 hours, the temperature was raised to room temperature for 16 hours. Add silica gel directly to the reaction solution to mix the sample, and separate and purify by column chromatography (petroleum ether: ethyl acetate (v/v) = 10:1) to obtain (S)-3-((acetylthio)methyl) -tert-butyl 4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate ( 53c ) (0.20 g, 5%).

LCMS m/z = 442.0 [M-55] ⁺ .

The third step: (S)-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-4-(tertiary butoxycarbonyl)piperazin-2-yl)methylthio Sodium salt of alcohol ( compound 53d )

Sodium (S)-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-4-(tert-butoxycarbonyl)piperazin-2-yl)methanethiolate

Under ice-water bath, 0.5M sodium ethoxide solution (15 mg, 0.64 mmol, 1.28 mL) was added to (S)-3-((acetylthio)methyl)-4-(3-bromo-5-( Trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester ( 53c ) (0.32 g, 0.64 mmol) in anhydrous tetrahydrofuran (2 mL) solution, then kept at room temperature for 0.5 hours. After the reaction was completed, the direct concentrated dry reaction solution was obtained (S)-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-4-(tertiary butoxycarbonyl)piperazine- 2-yl)methanethiol ( 53d ) sodium salt (300 mg) was carried on to the next step without purification.

LCMS m/z = 431.9 [M-23] ⁺ .

The fourth step: (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4 ]Thiazine-8(6H)-tert-butyl carboxylate ( compound 53e )

Tert-butyl (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-carboxylate

Under nitrogen protection, at room temperature, tris(dibenzylideneacetone)dipalladium (29 mg, 0.032 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (36 mg, 0.063 mmol), N,N-diisopropylethylamine (163 mg, 1.26 mmol) was added to (S)-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl )-4-(tert-butoxycarbonyl)piperazin-2-yl)methanethiol ( 53d ) sodium salt (300 mg) in dry dioxane (2 mL). After replacing nitrogen three times, the temperature was raised to 70° C. for 2 hours. After the reaction was complete, add water (2 mL) to quench the reaction, add ethyl acetate (5 mLx3) to extract, the organic layer was dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative plate (PE:EA (v/v)=5:1) to obtain (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1 ,2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-tert-butyl carboxylate ( 53e ) (100 mg, 41%, 2-step yield).

LCMS m/z = 376.1 [M +1] ⁺ .

The fifth step: (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4 ]thiazine-8(6H)-tert-butyl carboxylate 5,5-dioxide ( compound 53f )

Tert-butyl (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-carboxylate 5,5-dioxide

At room temperature, m-chloroperoxybenzoic acid (219 mg, 1.08 mmol) was added in batches to (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[ 1,2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-tert-butyl carboxylate ( 53e ) (100 mg, 0.27 mmol) mL) solution, keep the reaction at room temperature for 5 hours. After the reaction was complete, add water (2 mL) to quench the reaction, extract with dichloromethane (10 mL×2), dry the organic phase over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by the preparation plate (petroleum ether: ethyl acetate (v/v) = 5:2) to obtain the target product (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro Pyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-tert-butyl carboxylate 5,5-dioxide ( 53f ) (60 mg, 55%).

LCMS m/z = 352.1 [M-55] ⁺ .

The sixth step: (S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b] [1,4] Thiazine 5,5-dioxide ( compound 53g ) hydrochloride

(S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine 5,5-dioxide

At room temperature, (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1, 4] Thiazine-8(6H)-tert-butyl carboxylate 5,5-dioxide ( 53f ) (50 mg, 0.12 mmol) was dissolved in 4N hydrochloric acid dioxane solution (4 mL), and kept The reaction was stirred warmly for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain (S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3, 2-b][1,4]Thiazine 5,5-dioxide ( 53g ) hydrochloride (40 mg), without further purification, was directly used for the next reaction.

LCMS m/z = 308.1 [M +1] ⁺ .

The seventh step: 5-(((S)-1-(3-((S)-5,5-dioxy-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine [1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4 -(trifluoromethyl)pyridazin-3(2H)-one ( compound 53 )

5-(((S)-1-(3-((S)-5,5-dioxido-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3, 2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Add HATU (49 mg, 0.13 mmol) to (S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2- d]pyrido[3,2-b][1,4]thiazine 5,5-dioxide ( 53g ) hydrochloride (40 mg), 3-[(2S)-2-[(6- Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoic acid ( 4j ) (40 mg, 0.13 mmol), N,N-diiso Propylethylamine (17 mg, 0.13 mmol) in N,N-dimethylformamide (2 mL) solution, then kept stirring at room temperature for 1 hour. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, and the preparative column model was Xselect C18, 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia water). Gradient elution method: gradient elution of acetonitrile from 5% to 50% (elution time 15min). After lyophilization, 5-(((S)-1-(3-((S)-5,5-dioxy-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine [1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4 -(trifluoromethyl)pyridazin-3(2H)-one ( Compound 53 ) (25 mg, 34%, yield over 2 steps).

LCMS m/z = 599.2 [M +1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.91 (s, 1H), 8.75 (d, 1H), 8.23 (d, 1H), 7.91 (s, 1H), 6.34-6.19 (m, 1H), 4.88-4.66 (m, 1H), 4.61-4.30 (m, 1H), 4.26-3.85 (m, 4H), 3.76-3.61 (m, 3H), 3.50 (d, 2H), 3.29-3.06 (m, 2H ), 2.93-2.81 (m, 1H), 2.74-2.56 (m, 2H), 1.17(d, 3H).

Example 54 : 5-(((S)-1-(3-((R)-5,5- Dioxide -3-( Trifluoromethyl )-6a,7,9,10- tetrahydropyrazine [1,2-d] pyrido [3,2-b][1,4] Thiazide -8(6H)- base )-3- Oxopropoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- ketone ( compound 54)

5-(((S)-1-(3-((R)-5,5-dioxido-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3, 2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Compound 54 was substituted with 3-bromo-2-chloro-5-trifluoromethylpyridine, (R)-1-Boc-3-hydroxymethylpiperazine and 3-[(2S)-2-[(6-oxo -5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxyl]propionic acid ( 4j ) as raw material, with reference to the synthetic method of Example 53 , to obtain 5-(( (S)-1-(3-((R)-5,5-dioxy-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]pyridine And[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridium Azin-3(2H)-one ( Compound 54 ).

LCMS m/z = 599.1 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.44 (s, 1H), 8.74 (s, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 6.32-6.20 (m, 1H), 4.85-4.67 (m, 1H), 4.59-4.31 (m, 1H), 4.21-3.89 (m, 4H), 3.75-3.63 (m, 3H), 3.49 (d, 2H), 3.29-3.05 (m, 2H ), 2.93-2.81 (m, 1H), 2.71-2.57 (m, 2H), 1.16 (d, 3H)

Example 55 : 5-(((2S)-1-(2- hydroxyl -3- Oxo -3-((R)-3-( Trifluoromethyl )-5,6,6a,7,9,10- Hexahydro -8H- pyrido [1,6-a:2,3-b'] Dipyrazine -8- base ) Propoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- ketone ( compound 55)

、

5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8 H -pyrido [1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

,

Compound 55 as (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyridine[1,6-a:2,3-b']dipyridine Hydrochloride salt of oxazine ( 51g ) and 2-hydroxy-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl )amino)propoxy)propionic acid ( 55a ) (intermediate synthesis is prepared by referring to WO2021087018) as raw material, referring to the synthesis method of Example 51 , to obtain 5-(((2S)-1-(2-hydroxyl-3- Oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro- 8H -pyrido[1,6-a:2,3- b'] dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ( compound 55 ).

LCMS m/z=566.2[M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.47-10.33 (m, 1H), 8.23 (s, 1H), 7.65 (s, 1H), 5.82-5.58 (m, 1H), 4.89-4.50 (m, 3H ), 4.00-3.41 (m, 8H), 3.28-2.58 (m, 5H), 2.32-2.13 (m, 1H), 1.95-1.78 (m, 1H), 1.31 (d, 3H).

Example 56 : 5-(((2S)-1-(2- hydroxyl -3- Oxo -3-((R)-3-( Trifluoromethyl )-5,6,6a,7,9,10- Hexahydro -8H- pyrazine [1,2-a][1,8] naphthyridine -8- base ) Propoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2 H )- ketone ( compound 56) trifluoroacetate

5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8 H -pyrazino [1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2 H )-one trifluoroacetate

The first step: 1-benzyl 4-(tert-butyl)(R)-2-(2-(2-hydroxyl-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine- 1,4-dicarboxylate ( compound 56b )

Benzyl 4-(tert-butyl)(R)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1,4-dicarboxylate

At room temperature, 4-(tert-butyl)(R)-2-vinylpiperazine-1,4-dicarboxylate 1-benzyl ester ( 56a ) (synthesized with reference to patent WO2015013835) (2.5 g, 7.22 mmol) was dissolved in DMF (20 mL), and 3-bromo-2-hydroxy-5-(trifluoromethyl)pyridine (2.62 g, 10.83 mmol), DIPEA (2.80 g, 21.66 mmol), Xphos (1.38 g, 2.89 mmol) and Pd(OAc) ₂ (320 mg, 1.44 mmol ). Nitrogen was replaced 3 times, stirred overnight at 115°C, quenched with water, extracted with ethyl acetate (50 mL x 3), combined the organic phases, backwashed with saturated brine (50 mL x 3), anhydrous sodium sulfate Dry, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (DCM in THF=5-10%) to obtain: 1-benzyl 4-(tert-butyl) (R)-2-(2-(2-hydroxy-5-(tri Fluoromethyl)pyridin-3-yl)vinyl)piperazine-1,4-dicarboxylate ( Compound 56b ) (530 mg, 14%).

LCMS m/z = 452.2 [M-55] ⁺ .

The second step: (R)-tert-butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate ( compound 56c )

Tert-butyl (R)-3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl) piperazine-1-carboxylate

At room temperature, 1-benzyl 4-(tert-butyl)(R)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine -1,4-Dicarboxylate ( Compound 56b ) (1 g, 1.97 mmol) was dissolved in MeOH (5 mL), added Pd/C (100 mg), stirred at room temperature overnight, filtered, and the filtrate was concentrated under reduced pressure Removal of solvent gave (R)-tert-butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate ( compound 56c ) ( 700 mg), without further purification, directly submitted to the next step.

LCMS m/z=376.2[M+1] ⁺ .

The third step: (R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthalene tert-butyl pyridine-8-carboxylate ( compound 56d )

Tert-butyl (R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino [1,2-a][1,8]naphthyridine-8-carboxylate

At room temperature, (R)-tert-butyl 3-(2-(2-hydroxyl-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (compound 56c ) (700 mg, 1.86 mmol) was dissolved in DMSO (15 mL), and PyBOP (970 mg, 1.86 mmol) and DIPEA (720 mg, 5.58 mmol ) were added. Stir overnight at 60°C, add water to quench the reaction, extract with ethyl acetate (10 mL x 3), combine the organic phases, backwash the organic phase with saturated brine (10 mL x 3), dry over anhydrous sodium sulfate, and suction filter. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (10%EA in PE) to obtain (R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ tert-butyl 1,2-a][1,8]naphthyridine-8-carboxylate (compound 56d) (270 mg, 38%, 2-step reaction).

LCMS m/z = 358.2 [M+1] ⁺ .

The fourth step: (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthalene Pyridine (compound 56e) hydrochloride

(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine

At room temperature, (R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8] Tert-butyl naphthyridine-8-carboxylate (compound 56d) (39 mg, 0.11 mmol) was dissolved in hydrogen chloride-1,4-dioxane solution (4.0 M, 2 mL, 8 mmol), and reacted at room temperature to The response is complete. After concentrating under reduced pressure to remove the solvent, (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1, 8] The hydrochloride (36 mg) of naphthyridine (compound 55e) was directly used in the next step without further purification.

LCMS m/z = 258.2 [M+1] +

The fifth step: 5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-(3-(trifluoromethyl)-5,6,6a,7,9, 10-Hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl) Trifluoroacetate salt of pyridazin-3(2H)-one ( compound 56 )

5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate

At room temperature, (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8] Naphthyridine (compound 56e) hydrochloride (36 mg, 0.11 mmol) and 2-hydroxy-3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6 -Dihydropyridazin-4-yl)amino]propoxy]propionic acid (36 mg, 0.11 mmol) was dissolved in DMF (2 mL), and DIPEA (43 mg, 0.33 mmol) and HATU (42 mg, 0.11 mmol) and stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: SHIMADZULC-20AP was used to prepare the liquid phase, and the preparative column model was Phenomenex C18. Preparation method: the reaction solution was filtered with a 0.45 μm filter membrane to prepare a sample solution. Flow Phase system: acetonitrile/water (containing 0.01% trifluoroacetic acid). Gradient extraction method: acetonitrile is extracted from 10%-40% gradient (elution time 10min). After lyophilization, 5-(((2S)-1 -(2-Hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2 -a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 56) Trifluoroacetate (10 mg, 14%, 2-step reaction).

LCMS m/z = 565.3 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ10.94 (s, 1H), 8.26 (s, 1H), 7.76 (s, 1H), 7.50-7.35 (m, 1H), 5.87-5.61 (m, 1H) , 5.10-4.83 (m, 1H), 4.76-4.50 (m, 2H), 3.96-2.59 (m, 13H), 2.30-2.01 (m, 1H), 1.88-1.63 (m, 1H), 1.31 (d, 3H).

Example 56-1 : 5-(((S)-1-((S)-2- hydroxyl -3- Oxo -3-((R)-3-( Trifluoromethyl )-5,6,6a,7,9,10- Hexahydro -8H- pyrazine [1,2-a][1,8] naphthyridine -8- base ) Propoxy ) C -2- base ) Amino )-4-( Trifluoromethyl ) Pyridazine -3(2H)- ketone ( compound 56-1)

5-(((S)-1-((S)-2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro- 8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

5-(((S)-1-((R)-2-Hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9, 10-Hexahydro-8H-pyrazine[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridine Azin-3(2H)-one (compound 56-2)

5-(((S)-1-((R)-2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro- 8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Compound 56 was purified by SFC on AD column (instrument and preparative column: Waters 150 SFC was used, and the preparative column model was Chiralcel Column (250mm*30mm, 10μm)). Preparation method: Compound 56 was dissolved in acetonitrile and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO ₂ and B for MeOH (0.1%NH ₃ •H ₂ O). Gradient elution method: 25% phase B (flow rate: 100mL/min; elution time 2.5min), compound 56-1 and compound 56-2 were obtained after lyophilization.

Analysis method (instrument and preparative column: high performance liquid chromatography - normal phase chromatography, preparative column model: SHIMADZU LC-30AD sf (50×4.6mm, 3um)) mobile phase system: A for CO ₂ and B for MeOH ( 0.05% DEA).

The retention time T=1.341 min (P1) is Example 56-A (Example 56-A is one of the structures of compound 56-1 and compound 56-2).

LCMS m/z = 565.3 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ10.05 (s, 1H), 8.24 (s, 1H), 7.65 (s, 1H), 7.35 (s, 1H), 5.81-5.66 (m, 1H), 5.03 -4.90 (m, 1H), 4.72-4.50 (m, 2H), 3.98- 2.54(m, 13H), 2.17-2.03 (m, 1H), 1.84-1.69 (m, 1H), 1.31 (d, 3H) .

The retention time T=1.531 min (P2) is Example 5 6-B (Example 5 6-B is one of the structures of Compound 5 6-1 and Compound 5 6-2 ).

LCMS m/z=565.3[M+1] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ9.81 (s, 1H), 8.24 (s, 1H), 7.64 (s, 1H), 7.34 (s, 1H), 5.81-5.59 (m, 1H), 5.03 -4.86 (m, 1H), 4.77-4.48 (m, 2H), 3.96- 2.63 (m, 13H), 2.15-1.99 (m, 1H), 1.82-1.67 (m, 1H), 1.31 (d, 3H) .

Embodiment 57 : the synthesis of compound 57-A and compound 57-B

The first step: preparation of compound 57a

3-(Trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4] Oxazepane-9-carboxylic acid tert-butyl ester (3d) was purified by SFC on AD column (instrument and preparative column: Waters 150 AP was used, and the preparative column model was Chiralpak Column). Preparation method: Compound 3d was dissolved in acetonitrile and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO ₂ and B for MeOH (0.1%NH ₃ •H ₂ O). Gradient extraction method: 10% phase B (flow rate: 70mL/min; extraction time 6min), after freeze-drying, compound 3d-Peak-1 and compound 3d-Peak-2 were obtained.

Analysis method (instrument and preparative column: SHIMADZU LC-30AD sfc, preparative column model: Chiralpak AD-3 50×4.6mm ID, 3μm) mobile phase system: A for CO ₂ and B for MeOH (0.05%DEA).

The retention time of compound 3d-Peak-1 is T=0.587 min, which is compound 57a.

LCMS m/z =374.2[M+1] ⁺ .

The retention time of compound 3d-Peak-2 is T=0.677 min.

The second step: the preparation of compound 57b

Compound 57a (0.29 g, 0.77 mmol) was dissolved in HCl/dioxane (10 mL, 4M), and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain the hydrochloride salt of compound 57b (270 mg), which was directly used in the next step.

LCMS m/z = 274.1 [M+1] ⁺ .

The third step: the preparation of compound 57-A

At room temperature, HATU (300 mg, 0.78 mmol) was added to compound 57b hydrochloride (270 mg, 0.78 mmol ), 2-hydroxy-3-((S)-2-((6-oxo-5- (Trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (55a) (250 mg, 0.78 mmol ), DIPEA (300 mg, 0.78 mmol) N, N-dimethylformamide (5 mL) solution, and then kept stirring at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparative column: SHIMADZU LC-20AP was used for preparative liquid phase, and the preparative column model was Phenomenex C18). Preparation method: filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A is 10mM NH ₄ HCO ₃ in H ₂ O; B is acetonitrile. Gradient extraction method: acetonitrile from 25% to 50% (elution time 10min). Compound 57-A was obtained after lyophilization (compound 57 is one of the structures of compound 57-1 and compound 57-2).

LCMS m/z = 581.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.44 (s, 1H), 8.15 (s, 1H), 7.94-7.87 (m, 1H), 7.38–7.32 (m, 1H), 6.33-6.20 (m , 1H), 5.31-5.18 (m, 1H), 4.49-4.38 (m, 1H), 4.35- 4.20 (m, 2H), 4.19-3.58 (m, 8H), 3.58-3.35 (m, 4H), 2.17 -2.01 (m, 1H), 1.99-1.85 (m, 1H), 1.19-1.09 (m, 3H).

Preparation of Compound 57-B

Compound 57-B can be obtained by using compound 3d-Peak-2 as the starting material and referring to the synthesis method of compound 57-A. Compound 57-B is one of the structures of compound 57-1 and compound 57-2.

biological test case

1. NCI-H1373 cell proliferation inhibition

NCI-H1373 cells were purchased from ATCC, culture conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37 ℃, 5% CO ₂ incubator. On the first day, the NCI-H1373 cells in the exponential growth phase were collected and plated on a white 96-well culture plate with a transparent bottom at a density of 500 cells/well. They were cultured overnight in a 5% CO ₂ incubator at 37 °C, and T ₀ wells were plated at the same time. On the second day before adding drugs, aspirate the medium, add 90 µL of fresh medium and 10 µL of compounds of different concentrations to each well, so that the final concentration of DMSO in each well is 0.1%, and culture in a 5% _CO2 incubator at 37 °C for 72 hours , replace the medium and prepare new compounds, and continue culturing for 72 hours. The next day, add the drug and use the CellTiter-Glo kit to detect the T ₀ plate, which is recorded as RLU ₀ . After the incubation, 50 μL of detection solution (Cell Viability Assay, Promega, G7573) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and detected by a microplate reader for chemiluminescence readings. The results were processed according to formula (1), and the cell viability at each concentration of the compound was calculated, and the GI ₅₀ value of the concentration of the compound was calculated when the proliferation rate was 50% using origin9.2 software. RLU _compound is the reading of the drug treatment group, and RLU _control is the mean value of the solvent control group.

Growth % = (RLU _compound -RLU ₀ )/(RLU _control -RLU ₀ )×100% Formula (1) Table 1 Inhibitory effect of compounds on NCI-H1373 cell proliferation serial number Compound number GI ₅₀ (nM) 1 Compound 1 <50nM 2 Compound 2 <50nM 3 Compound 3 <50nM 4 Compound 5 <50nM 5 Compound 6 <50nM 6 Example 7-A <50nM 7 Compound 10 ＜100nM 8 Compound 11 ＜100nM 9 Trifluoroacetate salt of compound 13 <50nM 10 Compound 23 <50nM 11 Compound 25 <50nM 12 Compound 27 ＜20nM 13 Compound 28 <50nM 14 Compound 29 <50nM 15 Compound 31 <50nM 16 Compound 32 <50nM 17 Compound 33 <50nM 18 Compound 34 <50nM 19 Compound 37 <50nM 20 Compound 43 <50nM twenty one Compound 44 <50nM twenty two Compound 48 <50nM twenty three Compound 50 <50nM twenty four Compound 51 <50nM 25 Trifluoroacetate of compound 56 <50nM 26 Compound 57-A <50nM

Conclusion: the compounds of the present invention have cell proliferation inhibitory activity on NCI-H1373 cells. For NCI-H1373 cell proliferation inhibitory activity GI ₅₀ <100nM, for example, compound 28, 31, 43, 51, 56 trifluoroacetate, 57-A for NCI-H1373 cell proliferation inhibitory activity GI ₅₀ value is 5.1 nM, 6 nM, 8 nM, 6 nM, 11 nM, 13 nM.

2. PARP7 enzyme activity test experiment

PARP7 Chemiluminescent Detection Kit was purchased from BPS Bioscience. Dilute the histone solution in the kit 5 times with 1X PBS, transfer 25 μL of histone dilution to a microwell plate, and incubate overnight at 4 °C. After the incubation, the plate was washed 3 times with PBST (0.05% Tween-20), 100 μL of blocking solution was taken into the microwell plate, and incubated at 25 °C for 90 minutes; after the incubation, the plate was washed 3 times with PBST. Take 2.5 μL of different concentrations of compound diluted in test buffer and 12.5 μL of substrate mixed solution (1.25 μL of 10X PARP test buffer; 1.25 μL of 10X PARP test mixture; 10 μL of double distilled water) to the microwell plate. Dilute PARP7 enzyme to 6 ng/μL, transfer 10 μL to a microwell plate, and incubate the reaction system at 25 °C for 60 minutes;

After incubation, the plate was washed 3 times with PBST. Dilute Streptavidin-HRP 50 times with blocking solution, then transfer 25 μL to a microwell plate, and incubate at 25 °C for 30 minutes. After incubation, wash the plate 3 times with PBST, mix ELISA ECL substrate A and substrate B according to 1:1 (v/v), take 50 μL to the microwell plate, and read the chemiluminescence value.

Calculate the inhibition rate according to formula 1, where RLU _sample is the reading value of the compound well, RLU _max is the reading value of the solvent control well, and RLU _min is the reading value of the control well without PARP7 enzyme, using GraphPad Prism software through four parameters (log(inhibitor) vs . response -- Variable slope) for curve fitting and calculation of IC ₅₀ values.

Inhibition% =(1-(RLU _sample -RLU _min )/(RLU _max -RLU _min ))×100% (Formula 1) Table 2. Inhibitory activity of compounds on PARP7 enzyme serial number compound PARP7 IC ₅₀ (nM) 1 Compound 1 ＜100nM 2 Compound 2 ＜100nM 3 Compound 5 ＜100nM 4 Compound 6 ＜100nM 5 Trifluoroacetate salt of compound 13 ＜100nM 6 Compound 33 ＜100nM 7 Compound 51 ＜100nM

Conclusion: The compounds of the present invention have inhibitory effect on PARP7 enzyme, for example, the IC ₅₀ values of compounds 33 and 51 on PARP7 enzyme are 0.88nM and 0.78nM, respectively.

3. MARylation test experiment in NCI-H1373 cells

NCI-H1373 cells were purchased from ATCC, culture conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37 ℃, 5% CO ₂ incubator. On the first day, the NCI-H1373 cells in the exponential growth phase were collected and plated on a white 6-well culture plate with a transparent bottom at a density of 2×10 ⁵ cells/well, and cultured overnight in a 37°C, 5% CO ₂ incubator. The next day, before adding drugs, discard the medium, add 1 mL of fresh medium and 1 mL of different concentrations of compounds to each well, so that the final concentration of DMSO in each well is 0.1%, and incubate at 37 ℃, 5% CO ₂ incubator for 48 hours . After culturing, the cells were collected. Add 35 μL of cell lysate to each tube, lyse on ice for 15 minutes, and vortex during the lysis; centrifuge at 4 °C and 13,000 rpm for 10 minutes, and take the supernatant and store it at low temperature. The BCA detection kit (Beiyuntian, P0009) was used for protein quantification, and the protein concentration of the sample was calculated. Dilute the protein concentration of each tube sample with 0.1×sample buffer to 0.8 mg/mL, take 4 μL of the diluted solution and 1 μL of 5×mix, and mix well; place at 95°C for 5 minutes for protein denaturation. Sample addition was performed according to the WES (ProteinSimple) instructions, in which the dilution ratio of Poly/Mono-ADP Ribose (E6F6A) Rabbit mAb was 1:100, and the dilution ratio of β-Actin (8H10D10) Mouse mAb was 1:400, and tested on the machine. The results were processed according to formula (2), and the MARylation% of each concentration of the compound was calculated, and the IC ₅₀ value was fitted using GraphPad Prism 8 software. Corr.Area _compound is the peak area of the drug treatment group, and Corr.Area _control is the peak area of the solvent control group.

MARylation % =Average（Corr.Area _compound / Corr.Area _control ）×100 Formula (2) Table 3. MARylation inhibitory activity of compounds in NCI-H1373 cells serial number compound PARP7 IC ₅₀ (nM) 1 Compound 51 ＜30nM 2 Compound 57-A ＜30nM Conclusion: The compound of the present invention has inhibitory effect on MARylation in NCI-H1373 cells.

4. Mouse pharmacokinetic test

1.1 Test animals: male BALB/c mice, 18-20 g, 9/compound. purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

1.2 Experimental design: On the day of the experiment, 36 BALB/c mice were randomly divided into groups according to body weight. One day before administration, fasting without water for 12~14h, and giving food 4h after administration. Dosing Information group quantity Dosing Information male Test substance Dosage (mg/kg) Administration concentration (mg/mL) Administration volume (mL/kg) collect samples Method of administration G1 9 Compound 31 10 1 10 plasma gavage G2 9 Compound 43 10 1 10 plasma gavage G3 9 Compound 33 2.5 0.5 5 plasma vein G4 9 Compound 33 10 1 10 plasma gavage Vehicle for intravenous administration: 5%DMA+5%Solutol+90%Saline; Vehicle for intragastric administration: 5%DMSO+5%Solutol+30%PEG400+60%(20%SBE-β-CD)

Before and after administration, 0.06 ml of blood was collected through the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm, 4 °C for 10 min, and plasma was collected. The time points of intravenous and intragastric blood collection were 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, 24 hours. All samples were stored at -80°C prior to analysis. Table 4. Pharmacokinetic parameters of compounds in mouse plasma test compound Method of administration CL(mL/min/kg) Vd _ss (L/kg) AUC _0-t (hr*ng/mL) F (%) Compound 31 ig (10mg/kg) - - 1572 - Compound 43 ig (10mg/kg) - - 977 - Compound 33 iv (2.5 mg/kg) 80.3 0.671 517 - Compound 33 ig (10mg/kg) - - 1000 48.3 -:not applicable.

Conclusion: Compounds of the invention have higher exposure in mice.

5. Beagle Pharmacokinetic Test

The purpose of the experiment: to administer the test substance to Beagle dogs through a single dose of intravenous and intragastric administration, to determine the concentration of the test substance in the Beagle dog plasma, and to evaluate the pharmacokinetic characteristics of the test substance in the Beagle dog.

Experimental animals: male Beagle dogs, about 8-11 kg, 3 dogs/compound, purchased from Beijing Masi Biotechnology Co., Ltd.

Test method: On the day of the test, 12 Beagle dogs were randomly divided into groups according to body weight. One day before administration, fasting without water for 12~14h, and giving food 4h after administration. Dosing Information group quantity Dosing Information male Test substance Dosage (mg/kg) Administration concentration (mg/mL) Administration volume (mL/kg) collect samples Method of administration G1 3 Compound 33 1 1 1 plasma vein G2 3 Compound 33 5 1 5 plasma gavage G3 3 Compound 51 1 1 1 plasma vein G4 3 Compound 51 5 1 5 plasma gavage

Vehicle for intravenous administration: 5%DMA+5%Solutol+90%Saline; Vehicle for intragastric administration: 0.5%MC

Sampling: Before and after administration, 1 ml of blood was collected from the veins of the extremities and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000rpm for 10min at 4°C to collect plasma.

Blood collection time points: 0, 5, 15, 30min, 1, 2, 4, 6, 8, 10, 12, 24 hours. All samples were stored at -80°C before analysis and detection. Samples were quantitatively analyzed by LC-MS/MS. Table 5 Pharmacokinetic parameters of test compounds in beagle dog plasma test compound Method of administration CL(mL/min/kg) Vd _ss (L/kg) AUC _0-t (hr*ng/mL) F (%) Compound 33 iv (1mg/kg) 5.59 0.514 3091 - Compound 33 ig (5mg/kg) - - 6951 45.0 Compound 51 iv (1mg/kg) 5.96 0.280 3395 - Compound 51 ig (5mg/kg) - - 6129 36.1 -:not applicable.

Conclusion: Compounds 33 and 51 have good PK performance on Beagle dogs.

6. CYP450 Enzyme Inhibition Test

In this test, mixed human liver microsomes were incubated with different concentrations of test compounds (0.05-50 μM) and corresponding probes, and the changes in CYP enzyme activity were measured, and the _IC50 value was calculated to evaluate the effect of test compounds on each Inhibitory potential of CYP enzymes.

The test results showed that compound 51 had basically no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes, and the IC ₅₀ values were all greater than 50 μM.

7. hERG Potassium Channel Action Test

Experimental Platform: Electrophysiological Manual Patch Clamp System

Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

Experimental method: In CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel, the current of hERG potassium channel was recorded by whole-cell patch clamp technique at room temperature. The glass microelectrode is made of a glass electrode blank (BF150-86-10, Sutter) through a drawing machine. The tip resistance after filling the electrode inner liquid is about 2-5 MΩ. Just insert the glass microelectrode into the amplifier probe. Connect to patch clamp amplifier. The clamping voltage and data recording are controlled and recorded by the pClamp 10 software through the computer, the sampling frequency is 10 kHz, and the filtering frequency is 2 kHz. After whole-cell recordings were obtained, the cells were clamped at -80 mV, and the voltage step of the evoked hERG potassium current ( I _hERG ) was given a 2 s depolarization voltage from -80 mV to +20 mV and then repolarized to - 50 mV, return to -80 mV after 1 s. Give this voltage stimulus every 10 s, and start the administration process after confirming that the hERG potassium current is stable (at least 1 minute). Compounds were administered for at least 1 min at each concentration tested and at least 2 cells (n > 2) were tested at each concentration.

Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The degree of inhibition of hERG potassium current (peak hERG tail current evoked at -50 mV) by different compound concentrations was calculated using the following formula:

Inhibition % = [1 – ( I / Io )]×100%

Wherein, Inhibition % represents the inhibitory percentage of the compound to the hERG potassium current, and I and Io represent the amplitudes of the hERG potassium current after and before the drug addition, respectively.

Compound IC ₅₀ was calculated by fitting the following equation using GraphPad Prism 5 software:

Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

Wherein, X is the Log value of the detected concentration of the test substance, Y is the inhibition percentage at the corresponding concentration, Bottom and Top are the minimum and maximum inhibition percentages respectively. Table 6: IC ₅₀ values of the compounds on hERG potassium channel current inhibition compound _IC50 (μM) Compound 51 >20μM

8. Stability of liver microsomes

In this test, canine and human liver microsomes were used as in vitro models to evaluate the metabolic stability of compounds. At 37°C, 1 µM compounds were incubated with the liver microsomes of the above species supplemented with NADPH regeneration system for different times (5, 10, 20, 30, 60 min), and the LC-MS/MS method was used to detect the produced The concentration of the test compound in the sample.

Conclusion: The compounds of the present invention have good stability in liver microsomes.

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Claims (13)

A compound or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the compounds shown in general formula (I), wherein

(I) Y is selected from O, S, S(=O), S(=O) ₂ , S(=O) ₂ N(R ^y ), N(R ^y ), C _1-4 alkylene, - OC _1-3 alkylene-, -C _1-3 alkylene O-, -C _1-3 alkylene S-, -C _1-3 alkylene S(=O)-, -C _{1- 3} alkylene S(=O) ₂ -, -N(R ^y )C _1-3 alkylene- or -C _1-3 alkylene N(R ^y )-, the alkylene is optionally C _1-6 alkyl, C _1-6 alkoxy or C ₃ further substituted by 0 to 4 selected from H, halogen, =O, =S, OH, cyano, C _1-6 alkyl, halogen _-6 cycloalkyl substituents; R ^y each independently selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, the alkyl or cycloalkyl is optionally further 0 to 4 are selected from H, deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, 3 to 8 membered heterocyclyl or C _3-6 cycloalkane The substituent of the group is substituted, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S or N; Ring A is selected from C _6-10 aryl, 5-10 membered heteroaryl or 5- 10-membered heterocyclic group, the heteroaryl or heterocyclic group contains 1 to 5 heteroatoms selected from O, S, N; ring X is selected from C _6-10 aryl, 5-10 membered heteroaryl , C _3-10 carbocycle or 5-10 membered heterocyclic group, said heteroaryl or heterocyclic group contains 1 to 5 heteroatoms selected from O, S or N; R ^x , R ^a each independently Selected from H, halogen, cyano, OH, =O, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio , -SO ₂ -C _1-6 alkyl, -C(=O)C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 carbocycle or -(CH ₂ ) _q -3 to 12 members Heterocycle, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano group, =O, NH ₂ , NH(C _1-6 alkyl), N(C _1-6 alkyl) ₂ , C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 Substituents of alkoxy, C _3-6 cycloalkyl or 3 to 10 membered heterocyclic rings, the heterocyclic rings contain 1 to 3 heteroatoms selected from O, S or N; ring B is selected from 4 to 11-membered nitrogen-containing heterocycle or C _4-10 carbocycle; R ^b are each independently selected from H, halogen, cyano, OH, =O, C _1-6 alkyl, C _1-6 alkoxy or - (CH ₂ ) _q -C _3-6 cycloalkyl, said -CH ₂ -, alkyl, alkoxy or cycloalkyl is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano , NH ₂ , C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy or C _3-6 cycloalkyl substituents; W is selected from bond, C _{1- 3} alkylene or Q2, the alkylene shown is optionally further replaced by 0 to 4 selected from H, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy Substituents of the base are substituted; L is selected from L1, L2 or L3; L1 is selected from -Q1-Ak1-Q2-Ak2-Q3-, and the right side is connected to ring B; L2 is selected from

, the right side is connected to loop B; L3 is selected from

or

, the right side is connected to ring B; L4 is selected from -Ak3-Q4-Ak4-K1-Q5-K2-Ak5-Q6- or -Ak3-Q4-Ak4-K1-Q5-, the right side is connected to ring B; Ak1 and Ak2 are each Independently selected from C _1-4 alkylene, C _2-4 alkenylene or C _2-4 alkynylene, said Ak1 is optionally further substituted by 0 to 4 R ^k1 , said Ak2 is optionally further substituted by 0 to 4 R ^k2 substitutions; Ak3, Ak4, Ak5 are each independently selected from a bond, C _1-4 alkylene, C _2-4 alkenylene or C _2-4 alkynylene, and the Ak3 is optionally further Substituted by 0 to 4 R ^k3 , said Ak4 is optionally further substituted by 0 to 4 R ^k4 , said Ak5 is optionally further substituted by 0 to 4 R ^k5 ; K1 or K2 is selected from C _1-2 alkylene Base, C _3-10 carbocycle or 3 to 12 membered heterocycle, the alkylene group is optionally further substituted by 0 to 4 R ^k6 , and the carbocycle or heterocycle is optionally further substituted by 0 to 4 selected from H, halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halogen substituted C _1-6 alkyl, C _1-6 alkane Oxygen, -C _1-6 alkyl-OC _1-6 alkyl, -OC _1-6 alkyl-OC 1-6 alkyl _{, -OC 3-8 carbocycle, C 3-8 carbocycle ,} 4 to Substituted by a substituent of a 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N; R ^k1 , R ^k2 , R ^k3 , R ^k4 , R ^k5 , R ^k6 , R ^L1 and R ^L2 are each independently selected from H, halogen, cyano, OH, =O, NH ₂ , NHC _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, -OC _3-6 carbocycle, C _3-6 carbocycle or 4 to 7 membered heterocycle, said alkyl, alkenyl Group, alkynyl, alkoxy, carbocycle or heterocycle are optionally further replaced by 0 to 4 members selected from H, halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, Substituents of C _2-6 alkynyl, C _1-6 alkyl substituted by halogen, C _1-6 alkoxy, -OC _3-8 carbocycle, C _3-8 carbocycle or 4 to 10 membered heterocycle Substitution, the heterocycle contains 1 to 3 heteroatoms selected from O, S or N; alternatively, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 , R ^k3 and R ^k3 , R ^k4 and R ^k4 , R ^k5 and R ^k5 , R ^k6 and R ^k6 are directly connected to form a C _3-6 carbon ring or a heterocycle with 4 to 7 members, and the carbocycle or heterocycle is optionally further surrounded by 0 to 4 A substituent selected from H, halogen, =O, OH, cyano, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy or C _3-6 cycloalkyl Substituted, the heterocycle contains 1 to 3 heteroatoms selected from O, S or N; Q1, Q5 are each independently selected from O, S, N(R ^q ), C(=O), C( =O)N(R ^q ), N(R ^q )C(=O), C(=O)O, OC(=O), S(=O), S(=O) ₂ , S(=O ) ₂ N(R ^q ), N(R ^q )S(=O) ₂ , N(R ^q )C(=O)N(R ^q ) or N(R ^q )C(=O)N(R ^q ); Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1; Ring E is selected from a C _3-6 carbon ring or a 4 to 7 member heterocycle, and the heterocycle contains 1 to 3 members selected from O, A heteroatom of S or N; R ^q are each independently selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further selected from 0 to 4 Substituents of H, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy; Alternatively, R ^q is directly connected to R ^k1 or R ^k2 to form A heterocycle with 4 to 7 members, the heterocycle is optionally further substituted _by 0 to 4 C 1-6 alkane selected from H, halogen, =O, OH, cyano, C _1-6 alkyl, halogen Substituent group, C _1-6 alkoxy group or C _3-6 cycloalkyl group, the heterocycle contains 1 to 3 heteroatoms selected from O, S or N; q each independently selected from 0, 1, 2, 3 or 4; a is selected from 0, 1, 2, 3 or 4; b is selected from 0, 1, 2, 3 or 4; x is selected from 0, 1, 2, 3 or 4; s1 is selected from 0, 1, 2, 3 or 4; s2 is selected from 0, 1, 2, 3 or 4; s3 is selected from 0, 1, 2, 3 or 4. According to the compound described in Claim 1 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the compound shown in general formula (II),

(II) W ₁ is selected from N or C(R ^a4 ); ring X is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, and the heteroaryl or heterocyclic group contains 1 to 5 heteroatoms selected from O, S or N; R ^a1 , R ^a2 , and R ^a4 are each independently selected from H, halogen, cyano, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -SO ₂ -C _1-6 alkyl, -C(=O)C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 carbocycle or -(CH ₂ ) _q -3 to 12-membered heterocycle, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Carbocycle or heterocycle is optionally further substituted by 0 to 4 selected from H, halogen, OH, cyano, =0, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy Substituted by radical, C _3-6 cycloalkyl or 3 to 10 membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N; R ^a3 selected from H, C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 carbocycle or -(CH ₂ ) _q -3 to 12 membered heterocycle, the -CH ₂ -, alkyl, carbocycle or heterocycle Optionally further substituted by 0 to 4 selected from H, halogen, OH, cyano, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkane Substituted by a group or a substituent of a 3- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N; the definitions of the remaining groups are the same as those in claim 1. According to the compound described in Claim 2 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, Y is selected from O, N( ^Ry ), _{C1 -3} alkylene, -OC _1-2 alkylene-, -C _1-2 alkylene O-, -C _1-2 alkylene S-, -C _1-2 alkylene S(=O ) ₂ -, -N(R ^y )C _1-2 alkylene- or -C _1-2 alkylene N(R ^y )-, said alkylene is optionally further selected from 0 to 4 Substituents of H, halogen, =O, =S, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl Substituted; Ry ^each independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl, said alkyl or cycloalkyl is optionally further 0 to 4 selected from H, deuterium, Halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 3 to 8-membered heterocyclic group or C _3-6 cycloalkyl substituent, the The heterocyclic group mentioned above contains 1 to 3 heteroatoms selected from O, S or N; R ^x , R ^a1 , R ^a2 , and R ^a4 are each independently selected from H, halogen, cyano, OH, C _1-4 Alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkylthio, -SO ₂ -C _1-4 alkyl, -C(=O) C _1-4 alkyl, -(CH ₂ ) _q -C _3-6 carbocycle or -(CH ₂ ) _q -3 to 6-membered heterocycle, the -CH ₂ -, alkyl, alkenyl, alkyne Alkoxy, alkylthio, carbocycle or heterocycle are optionally further substituted by 0 to 4 C 1- selected from H, halogen, OH, cyano, =O, C _1-4 alkyl, _{halogen 4} alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or 3 to 6 membered heterocyclic substituents, the heterocyclic ring contains 1 to 3 selected from O, S or N Heteroatom; R ^a3 is selected from H or C _1-4 alkyl, and said alkyl is optionally further substituted by 0 to 4 selected from H, halogen, OH, cyano, C _1-4 alkyl, halogen Substituents of C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl; Ring B is selected from 4 to 7 membered monocyclic nitrogen-containing heterocycles, 5-11 membered spiro rings containing Nitrogen-heterocycle, 5-11-membered nitrogen-containing heterocycle, 5-11-membered bridging-ring nitrogen-containing heterocycle, or C _4-7 monocyclic carbocycle; R ^b are each independently selected from H, halogen, cyano, OH , =O, C _1-4 alkyl, C _1-4 alkoxy or -(CH ₂ ) _q -C _3-6 cycloalkyl, the -CH ₂ -, alkyl, alkoxy or ring Alkyl is optionally further substituted with 0 to 4 _C 1-4 alkyl, C _1-4 alkoxy or C selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen _3-6 cycloalkyl substituents are substituted; Ak1 and Ak2 are independently selected from C _1-3 alkylene, C _2-3 alkenylene or C _2-3 alkynylene, and the Ak1 is optionally further Substituted by 0 to 4 R ^k1 , the Ak2 is optionally further substituted by 0 to 4 R ^k2 ; Ak3, Ak4, Ak5 are each independently selected from a bond, C _1-3 alkylene, C _2-3 alkene or C _2-3 alkynylene, the Ak3 is optionally further substituted by 0 to 4 R ^k3 , the Ak4 is optionally further substituted by 0 to 4 R ^k4 , and the Ak5 is optionally further substituted by 0 to 4 R ^k5 is substituted; K1 or K2 is selected from C _1-2 alkylene, C _3-6 carbocycle or 3 to 7-membered heterocyclic ring, and the alkylene is optionally further substituted by 0 to 4 R ^k6 , The carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _1-4 alkyl substituted by halogen, C 1-4 alkoxy, -C _1-4 alkyl-OC _1-4 alkyl, -OC _1-4 alkyl- _{OC 1-4} alkyl, - Substituents of OC _3-6 carbocycle, C _3-6 carbocycle or 4 to 7 membered heterocycle, the heterocycle contains 1 to 3 heteroatoms selected from O, S or N; R ^k1 , R ^k2 , R ^k3 , R ^k4 , R ^k5 , R ^k6 , R ^L1 , R ^L2 are each independently selected from H, halogen, cyano, OH, =O, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocycle or 4 to 7-membered heterocycle, said alkyl, alkoxy, carbocycle or The heterocycle _is optionally further substituted with 0 to 4 C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy, C Substituents of _3-6 carbon rings or 4 to 6 membered heterocyclic rings, said heterocyclic rings contain 1 to 3 heteroatoms selected from O, S or N; alternatively, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 , R ^k3 and R ^k3 , R ^k4 and R ^k4 , R ^k5 and R ^k5 , R ^k6 and R ^k6 are directly connected to form a C _3-6 carbon ring (such as C ₃ , C ₄ , C ₅ or C ₆ ) or a heterocyclic ring with 4 to 7 members (such as 4, 5, 6 or 7 members), the carbocyclic or heterocyclic ring is optionally further replaced by 0 to 4 members selected from H, halogen, =O , OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl substituents, the heterocycle contains 1 to 3 heteroatoms selected from O, S or N; Q1, Q5 are each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O) or S(=O) ₂ ; Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1; ring E is selected from a C _3-6 carbon ring or a 4 to 6-membered heterocycle Ring, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S or N; R ^q are each independently selected from H or C _1-4 alkyl, and the alkyl is optionally further replaced by 0 to 4 substituents selected from H, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy; alternatively, R ^q and R ^k1 , R ^q It is directly connected with R ^k2 to form a heterocyclic ring with 4 to 7 members, and the heterocyclic ring is optionally further substituted by 0 to 4 members selected from H, halogen, =O, OH, cyano, C _1-4 alkyl, halogen Substituents of C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl, the heterocycle contains 1 to 3 heteroatoms selected from O, S or N. According to the compound described in Claim 3 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein, W ₁ is selected from N or CH; Ring X is selected from from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl or imidazolyl; R ^x , R ^a1 , R ^a2 each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, Ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , cyclopropane base, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy , -SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl are optionally further substituted by 0 to 4 selected from H, halogen, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkane Oxygen or C _3-6 cycloalkyl substituents are substituted; R ^a3 is selected from H, methyl, ethyl, propyl or isopropyl, the methyl, ethyl, propyl or isopropyl Optionally further substituted by 0 to 4 selected from H, halogen, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkane Substituents of the group; Y is selected from O, N(R ^y ), -N(R ^y )C(=O)-, -C(=O)N(R ^y )-, -CH ₂ -, - CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, -CH ₂ S-, -CH ₂ CH ₂ S-, -CH ₂ S(=O) ₂ -, -CH ₂ CH ₂ S(=O) ₂ -, -N(R ^y )CH ₂ -, -N(R ^y )CH ₂ CH ₂ - , -CH ₂ N(R ^y )-, -CH ₂ CH ₂ N(R ^y )-, -N(R ^y )C(=O)CH ₂ - or -CH ₂ C(=O)N(R ^y )-, said CH ₂ is optionally further substituted by 0 to 2 selected from H, =O, =S, OH, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _{1- 4} alkoxy or C _3-6 cycloalkyl substituents; R ^y each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, second Butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, second butyl , isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further selected from 0 to 4 H, deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 Substituents of alkyl, C _1-4 alkoxy, 3 to 8 membered heterocyclic group or C _3-6 cycloalkyl, the heterocyclic group contains 1 to 3 selected from O, S or N A heteroatom; Ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,

,

,

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,

or

R ^b are each independently selected from H, F, Cl, Br, I, cyano, OH, =0, methyl, ethyl, propyl or isopropyl, the methyl, ethyl, propyl or isopropyl is optionally further substituted by 0 to 4 selected from H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy Or C _3-6 cycloalkyl substituents are substituted; Ak1, Ak2 are independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene or propynylene , the Ak1 is optionally further substituted by 0 to 4 R ^k1 , and the Ak2 is optionally further substituted by 0 to 4 R ^k2 ; Ak3, Ak4, and Ak5 are each independently selected from a bond, methylene, ethylene , propylene, vinylidene, propenylene, ethynylene or propynylene, said Ak3 is optionally further substituted by 0 to 4 R ^k3 , said Ak4 is optionally further substituted by 0 to 4 R ^k4 Substitution, the Ak5 is optionally further substituted by 0 to 4 R ^k5 ; K1 or K2 is selected from methylene, ethylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , azacyclopentyl, azacyclohexyl, piperazine, morpholine, oxetanyl, oxolyl, oxanyl, benzene ring, pyridine, pyrazine, pyrimidine or pyridazine, the The methylene and ethylene groups are optionally further substituted by 0 to 4 R ^k6 , the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, Azacyclohexyl, piperazine, morpholine, oxetanyl, oxolyl, oxanyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine are optionally further selected from 0 to 4 H, halogen, OH, cyano, NH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy , -C _1-4 alkyl-OC _1-4 alkyl, -OC _1-4 alkyl-OC _1-4 alkyl, -OC _3-6 carbocycle, C _3-6 carbocycle or 4 to 7 members Substituents of heterocyclic rings containing 1 to 3 heteroatoms selected from O, S or N; R ^k1 , R ^k2 , R ^k3 , R ^k4 , R ^k5 , R ^k6 , R ^L1 , R ^L2 are each independently selected from H, F, Cl, Br, I, cyano, OH, =0, NH ₂ , NH(CH ₃ ), N(CH ₃ ) ₂ , methyl, ethyl, propyl, Methoxy, Ethoxy, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Azetidinyl, Azacyclopentyl, Azacyclohexyl, Oxetanyl, Oxolane base, oxanyl, pyridine or phenyl, the methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine Base, azacyclopentyl, azacyclohexyl, oxetanyl, oxolane, oxanyl, pyridine or phenyl are optionally further replaced by 0 to 4 selected from H, halogen, OH, Substituted by cyano, NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocycle or 4 to 6-membered heterocycle, The heterocycle contains 1 to 3 heteroatoms selected from O, S or N; alternatively, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 , R ^k3 and R ^k3 , R ^k4 Direct connection with R ^k4 , R ^k5 and R ^k5 , R ^k6 and R ^k6 to form a C _3-6 carbon ring (such as C ₃ , C ₄ , C ₅ or C ₆ ) or 4 to 7 members (such as 4, 5, 6 or 7-membered) heterocycle, the carbocycle or heterocycle is optionally further substituted by 0 to 4 C 1 selected from H, halogen, =O, OH, cyano, C _1-4 alkyl, _{halogen -4} alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl substituents, the heterocycle contains 1 to 3 heteroatoms selected from O, S or N; Q1, Q5 each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O) or S(=O) ₂ ; Q2, Q3, Q4, Q6 are each independently selected from bonds or Q1; ring E is selected from phenyl or 5-6 membered heteroaryl, and the heteroaryl contains 1 to 3 selected from O, S or N Heteroatoms; R ^q are each independently selected from H, methyl or ethyl; Alternatively, R ^q and R ^k1 , R ^q and R ^k2 are directly connected to form a 4 to 7-membered heterocycle, and the heterocycle is optionally C _1-4 alkyl, C _1-4 alkoxy or C _3-6 ring further substituted by 0 to 4 selected from H, halogen, =O, OH, cyano, C _1-4 alkyl, halogen The substituent of the alkyl group is substituted, and the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S or N. According to the compound described in Claim 4 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein

selected from

,

,

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,

or

, the left side is connected with L; L1 is selected from -N(R ^q )-Ak1-O-Ak2-C(=O)-, -O-Ak1-O-Ak2-C(=O)-, -O-Ak1- N(R ^q )-Ak2-C(=O)-, -N(R ^q )-Ak1-N(R ^q )-Ak2-C(=O)-, -N(R ^q )-Ak1-O- Ak2-N(R ^q )C(=O)-, -O-Ak1-O-Ak2-N(R ^q )C(=O)-, -N(R ^q )-Ak1-Ak2-C(=O )-, -N(R ^q )-Ak1-Ak2-N(R ^q )C(=O)-, -O-Ak1-N(R ^q )-Ak2-N(R ^q )C(=O)- , -S-Ak1-O-Ak2-C(=O)-, -O-Ak1-S-Ak2-C(=O)-, -N(R ^q )-Ak1-O-Ak2-S(=O ) ₂ -, -O-Ak1-O-Ak2-S(=O) ₂ -, -N(R ^q )-Ak1-O-Ak2- or -O-Ak1-O-Ak2-, the right side is connected to ring B or L1 is selected from -N(R ^q )-Ak1-O-Ak2-C(=O)N(R ^q )-, -O-Ak1-N(R ^q )-Ak2-C(=O)N( R ^q )- or -O-Ak1-OC(=O)N(R ^q )-, the right side is connected to ring B; L4 is selected from -Ak3-O-K1-C(=O)-, -Ak3-N( R ^q )-K1-C(=O)-or-Ak3-N(R ^q )-K1-C(=O)-, the right side is connected to ring B; Ring E is selected from benzene ring or pyridine; Y is selected from- NHC(=O)-, -C(=O)NH-, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, - CH ₂ O-, -CH ₂ CH ₂ O-, -NHCH ₂ -, -NHCH ₂ CH ₂ -, -CH ₂ NH-, -CH ₂ CH ₂ NH-, -NHC(=O)CH ₂ -or- CH ₂ C(=O)NH-; or Y is selected from O, -N(CH ₃ )C(=O)-, -C(=O)N(CH ₃ )-, -CH ₂ C(=O) NH- or -CH ₂ C(=O)N(CH ₃ )-; or Y is selected from -N(CH ₂ CH ₃ )C(=O)-, -N(CH(CH ₃ ) ₂ )C(= O)-, -N(CH ₂ CH(CH ₃ ) ₂ )C(=O)-, -N(cyclopropyl)C(=O)-, -N(CH ₂ -cyclopropyl)C(= O)-, -C(=O)N(CH ₂ CH ₃ )-, -C(=O)N(CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(cyclopropyl)- or -C(=O)N(CH ₂ -cyclopropyl)-; or Y is independently selected from -C(=O)N (CD ₃ )-, -C(=O)N(CH ₂ -oxetanyl)-, -C(=O)N(CH ₂ -oxolyl)-, -C(=O) N(CH ₂ -azetidinyl)-, -C(=O)N(CH ₂ -pyrrolidinyl)-, -C(=O)N(CH ₂ -cyclopentyl)-, -C( =O)N(CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH(CH ₂ CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH(CH ₃ )CH ₂ CH ₃ )-, -C( =O)N(n-octyl)-, -C(=S)N(CH ₃ )-, -C(=S)N(CH ₂ CH ₃ )-, -C(=S)N(CH ₂ - Cyclopropyl)-,

,

or Y is selected from -CH ₂ S(=O) ₂ -; R ^a2 is selected from H; W ₁ is selected from N. According to the compound described in Claim 5 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, L1 is selected from

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or

, the right side is connected to loop B; or L1 is selected from

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,

, the right side is connected to loop B; L2 is selected from

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,

, the right side is connected to loop B; L3 is selected from

, the right side is connected to ring B; R ^x are each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, Ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, propyl, isopropyl Base, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl are optionally further selected from 0 to 4 selected from H, F , OH, cyano, methyl, ethyl, methoxy or ethoxy; R ^a1 is selected from H, F, Cl, Br, I, cyano, CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl R ^a3 is selected from H or methyl; R ^b is each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl. The compound according to claim 6 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the general formula (II-a), (II -b) or the compound shown in (II-c),

(II-a)

(II-b)

(II-c) Y is selected from -NHC(=O)-, -C(=O)NH-, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -CH ₂ CH ₂ -, -CH ₂ O -, -CH ₂ CH ₂ O- or -OCH ₂ CH ₂ -; or Y is selected from O, -N(CH ₃ )C(=O)-, -C(=O)N(CH ₃ )-, - CH ₂ C(=O)NH- or -CH ₂ C(=O)N(CH ₃ )-; or Y is selected from -N(CH ₂ CH ₃ )C(=O)-, -N(CH(CH ₃ ) ₂ )C(=O)-, -N(CH ₂ CH(CH ₃ ) ₂ )C(=O)-, -N(cyclopropyl)C(=O)-, -N(CH ₂ - Cyclopropyl)C(=O)-, -C(=O)N(CH ₂ CH ₃ )-, -C(=O)N(CH(CH ₃ ) ₂ )-, -C(=O)N (CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(cyclopropyl)- or -C(=O)N(CH ₂ -cyclopropyl)-; or each Y is independently selected from -C(=O)N(CD ₃ )-, -C(=O)N(CH ₂ -oxetanyl)-, -C(= _O )N(CH 2 -oxetanyl)- , -C(=O)N(CH ₂ -azetidinyl)-, -C(=O)N(CH ₂ -pyrrolidinyl)-, -C(=O)N(CH ₂ -cyclopentyl) base)-, -C(=O)N(CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH(CH ₂ CH ₃ ) ₂ )-, -C(=O)N( CH ₂ CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH(CH ₃ )CH ₂ CH ₃ )-, -C(=O)N(n-octyl)-, -C(=S)N(CH ₃ )-, -C(=S)N(CH ₂ CH ₃ )-, -C(= S)N(CH ₂ -cyclopropyl)-,

or

or Y is selected from -CH ₂ S(=O) ₂ -; X ₁ , X ₂ , X ₃ , and X ₄ are each independently selected from N or CR ^x , and X ₁ , X ₂ , X ₃ , and X ₄ contain at most 2 N; R ^x are each independently selected from H, F, Cl, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, -SO ₂ CH ₃ , - SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ or cyclopropyl; the definitions of other groups are the same as those in Claim 6. According to the compound described in Claim 7 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, L is selected from

or

, the right side is connected to ring B; or L is selected from

,

,

,

, the right side is connected to ring B; or L is selected from

,

,

,

, the right side is connected to ring B; X ₁ is selected from N, X ₂ is selected from CH, X ₃ is selected from CH, CF, CCl, CCN or CCF ₃ , X ₄ is selected from CH or N. According to the compound described in Claim 1 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the following structures:

. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1-9 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co- The crystal, and the pharmaceutically acceptable carrier, optionally contain one or more other chemotherapeutic agents. According to the pharmaceutical composition described in claim 10, wherein the therapeutically effective amount refers to that the pharmaceutical composition is administered at a dose suitable for the disease to be treated (or prevented), for example, at least one of about 0.1 μg to about 50 mg Compound/kg body weight of the subject, preferably from about 10 μg to about 200 mg/kg body weight/day. The compound according to any one of claims 1-9 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is used in the preparation of therapeutic and PARP7 activity Or the application in the medicine of expression related diseases. The use according to claim 12, wherein the disease is selected from tumors.