CN119661557A

CN119661557A - Disubstituted nitrogen-containing five-membered heteroaryl compounds as kinase inhibitors and uses thereof

Info

Publication number: CN119661557A
Application number: CN202411836512.1A
Authority: CN
Inventors: 蔡遂雄; 田野; 王晓珠
Original assignee: Impact Therapeutics Inc
Current assignee: Impact Therapeutics Inc
Priority date: 2023-12-15
Filing date: 2024-12-12
Publication date: 2025-03-21

Abstract

本发明涉及作为激酶抑制剂的二取代含氮五元杂芳基化合物及其应用。本发明的二取代含氮五元杂芳基化合物的化学结构如式A所示。本发明的化合物是CHK1抑制剂。因此，本发明的化合物可用于治疗癌症。 The present invention relates to a disubstituted nitrogen-containing five-membered heteroaryl compound as a kinase inhibitor and its application. The chemical structure of the disubstituted nitrogen-containing five-membered heteroaryl compound of the present invention is shown in formula A. The compound of the present invention is a CHK1 inhibitor. Therefore, the compound of the present invention can be used to treat cancer.

Description

Disubstituted nitrogen-containing five-membered heteroaryl compounds as kinase inhibitors and uses thereof

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a disubstituted nitrogenous five-membered heteroaryl compound serving as a kinase inhibitor and application thereof.

Background

The process of eukaryotic cell growth and proliferation is to produce two identical daughter cells by accurately replicating the genetic information of the mother cells and by mitosis of the chromosomes. This process of proliferation, division of cells is known as the cell cycle and includes the entire process of cells starting from the completion of one division to the completion of the next division. The cell cycle includes four phases, the G1 phase of massive synthesis of postmitotic proteins, RNA, etc., the S phase of DNA replication, the G2 phase of pre-mitotic preparation and the M phase of mitotic cell. To ensure the integrity and correctness of genetic material in cells, a complex and precise signal path is provided in the cells to monitor DNA damage and respond accordingly, such as DNA repair, cell cycle test points, apoptosis, etc., and the signal path network is called DNA-damage response (DDR).

When DNA damage occurs, the cell cycle checkpoint will be activated by blocking the cell from entering the S phase by the G1/S phase checkpoint, delaying the S phase progression by the Intra-S phase or S phase checkpoint, and blocking the cell from entering mitosis by the G2/M phase checkpoint (Lobrich M et al, nature REVIEWS CANCER 2007,7 (11): 861-869). In response to DNA damage reactions, there are a number of complex repair pathways that mediate the detection and repair of damaged DNA, and cell cycle checkpoint kinases (CHK 1 and CHK 2) play a very important role in the damage repair signaling pathway of DNA.

The CHK1 protein belongs to the serine/threonine kinase protein (Sanchez Y et al, science,1997,277 (5331):1497-1501) and is a core component of the ATR-CHK1-CDC25C injury response pathway that regulates the G2/M cell cycle checkpoint. Cells activate ATR after recognition of DNA damage signals, phosphorylate multiple serine sites on CHK1, activate CHK1, phosphorylate CDC25 further downstream of CHK1, leading to degradation of CDC25, thereby preventing CDC25 activation of CDK1 and CDK2, inactivating CDK1 and CDK2, and thus preventing cell cycle progression, allowing cells to survive DNA repair (CARRASSA L et al, CELL CYCLE 2011,10 (13): 2121-2128). Thus, targeting CHK1 can interfere with repair of DNA damage, allowing unrepairable DNA damage to accumulate and ultimately lead to cell death.

CHK1 protein kinase is highly expressed in various tumors such as breast cancer, colon cancer, liver cancer, gastric cancer and the like. Some cancer cells are insensitive or resistant to chemotherapy and radiation and other anticancer drugs, often associated with excessive activation of CHK1 (Bao S et al Nature 2006,444 (7120):756-760). The mechanism for promoting tumor cell apoptosis by relieving the blocking effect of CHK1 on cell cycle test points is a hotspot of the current tumor research, and is also a research basis of CHK1 inhibitors.

Various CHK1 kinase inhibitors have been disclosed, for example ,WO2010077758、WO2012064548、WO2013068755、WO2013171470、WO2015120390、WO2017132928、WO2018086546、WO2018086547、WO2021104461、WO2022251502、WO2022114189 and WO2023120696.

However, there remains a need for novel compounds that are potential inhibitors of CHK1 and are beneficial for cancer treatment.

Disclosure of Invention

The present invention provides novel disubstituted nitrogen-containing five membered heteroaryl compounds having structures represented by formulas a and I (including IIa, IIb, IIIa and IIIb), stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, or mixtures thereof, as kinase inhibitors, particularly CHK1 kinase inhibitors.

The invention also provides pharmaceutical compositions comprising an effective amount of a compound of formula a and formula I (including IIa, IIb, IIIa and IIIb), stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically-labeled compounds, or pharmaceutically acceptable salts thereof, or mixtures thereof, for use in treating cancer.

In one embodiment, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers or diluents for treating cancer.

In a specific embodiment, the pharmaceutical composition may further comprise at least one known anticancer drug or a pharmaceutically acceptable salt of the anticancer drug for treating cancer.

The invention also relates to a process for the preparation of novel compounds of the structures of formula a and formula I (including IIa, IIb, IIIa and IIIb), stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts thereof, or mixtures thereof.

Detailed Description

It will be appreciated that the features of the various embodiments described herein may be combined arbitrarily to form the technical solutions herein, and that the definition of the various groups herein applies to any of the embodiments described herein, e.g., the definition of substituents for alkyl groups herein applies to any of the embodiments described herein, unless the embodiment has clearly defined substituents for alkyl groups.

"Hydrogen (H)" as used herein includes the isotopes deuterium (D) and tritium (T) thereof.

Heteroatoms as described herein include oxygen (O), sulfur (S) and nitrogen (N).

"Alkyl" as used herein refers to a straight or branched chain group containing up to ten carbon atoms. Useful alkyl groups include straight or branched chain C _1-10 alkyl groups, preferably C _1-6 alkyl groups. In certain embodiments, the alkyl is a C _1-4 alkyl. Typical C _1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl, which may be optionally substituted.

"Alkylene" as used herein refers to an alkyl group as defined above that is located between and serves to link two other chemical groups. Typical alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

As used herein, "alkenyl" means a straight or branched chain containing from 2 to 10 carbon atoms unless the carbon chain length is otherwise limited, wherein at least two of the carbon atoms in the chain contain a double bond, and C _2-6 alkenyl is preferred. Typical alkenyl groups include vinyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

As used herein, "alkynyl" means a straight or branched chain containing 2 to 10 carbon atoms unless the carbon chain length is otherwise limited, wherein at least two carbon atoms in the chain contain a triple bond between them, and is preferably C _2-6 alkynyl. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 1-butynyl and 2-butynyl.

"Alkoxy" as used herein refers to an oxy group substituted with a C _1-10 alkyl group as described above, preferably a C _1-6 alkyl group or a C _1-4 alkyl group, such as methoxy, ethoxy, and the like. The alkyl groups in the alkoxy groups may be optionally substituted. Substituents for alkoxy groups include, but are not limited to, halogen, amino groups including alkylamino and dialkylamino groups, and carboxyl groups (including ester groups thereof).

"Amino" as described herein may be represented by-NR ^′R^″, wherein R ^′ and R ^″ are each independently hydrogen, optionally substituted C _1-10 alkyl, Optionally substituted C _3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl, preferably R ^′ and R ^″ are each independently H, optionally substituted C _1-4 alkyl, Optionally substituted C _3-6 cycloalkyl or optionally substituted 5 membered heteroaryl, or R ^′ and R ^″ together with the N to which they are attached form an optionally substituted nitrogen containing heterocyclyl or nitrogen containing heteroaryl, such as a 4 to 7 membered nitrogen containing heterocyclyl or nitrogen containing heteroaryl, optionally containing one or more (e.g. 2, 3) further heteroatoms selected from O, N and S. Preferred amino groups include-NH ₂、–NHR^′ and-NHR ^″ wherein R ^′ and R ^″ are each independently optionally substituted C _1-4 alkyl, an optionally substituted C _3-6 cycloalkyl group and an optionally substituted 3-6 membered heterocyclyl group.

As used herein, "oxo" refers to = O.

As used herein, "aryl" refers to an aryl group as such or as part of another group, which is a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms. Aryl groups may be substituted with one or more substituents described herein.

Useful aryl groups include C _6-14 aryl groups, preferably C _6-10 aryl groups. Typical C _6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylene and fluorenyl.

"Carbocyclyl" as used herein includes cycloalkyl and partially saturated carbocyclyl groups. Useful cycloalkyl groups are C _3-8 cycloalkyl groups, such as C _3-6 cycloalkyl or C _3-4 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Useful partially saturated carbocyclic groups include cycloalkenyl groups such as C _3-8 cycloalkenyl, C _3-6 cycloalkenyl, or C _3-4 cycloalkenyl groups, e.g., cyclopentenyl, cycloheptenyl, and cyclooctenyl. The carbocyclic group may be substituted with one or more substituents described herein.

Useful halogen or halogen groups include fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

Acyl is a functional group containing a carbonyl group (carbon-oxygen double bond, -C (O) -), useful acyl groups include C _1-6 acyl, or C _1-3 acyl, such as acetyl. The acyl group may be optionally substituted with a group selected from the group consisting of halogen, amino, and aryl, wherein the amino and aryl groups may be optionally substituted. When substituted with halogen, the number of halogen substituents may be in the range of 1 to 5. Examples of the substituted acyl group include chloroacetyl group, pentafluorobenzoyl group and the like. When substituted with an amino group, the amino group may be substituted with one or 2 substituents as described herein.

Useful acyl groups include C _1-6 acyl groups, such as acetyl. The acyl group may be optionally substituted with a group selected from the group consisting of halogen, amino, and aryl, wherein amino and aryl are optionally substituted. When substituted with halogen, the number of halogen substituents may be in the range of 1 to 5. Examples of the acyl group substituted with halogen include chloroacetyl group, pentafluorobenzoyl group and the like. When substituted with an amino group, the amino group may be substituted with 1 or 2 substituents as described herein. In some embodiments, the aminoacyl is-C (O) -NR ^′R^″, wherein R ^′ and R ^″ are each independently hydrogen, optionally substituted C _1-10 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, preferably R ^′ and R ^″ are each independently H, optionally substituted C _1-4 alkyl, optionally substituted C _3-6 cycloalkyl, and optionally substituted 3-6 membered heterocyclyl.

Herein, sulfonyl refers to R-S (=o) ₂ -, wherein R may be, for example, alkyl as described herein. Herein, C _1-4 sulfonyl refers to sulfonyl where R is C _1-4 alkyl.

As used herein, "heterocyclyl" refers to a saturated or partially saturated 3-7 membered monocyclic group, 7-12 membered bicyclic group, 11-14 membered tricyclic group, including spiro, parallel and bridged cyclic groups, which consists of carbon atoms and 1-4 heteroatoms selected from O, N, S. In some embodiments, both the heteroatom nitrogen and sulfur in the heterocyclyl may be optionally oxidized, and the nitrogen may also be optionally quaternized. Heterocyclic groups also include fused heterocycles of any of the heterocyclic rings defined above in the bicyclic ring system fused to a benzene ring. If the resulting compound is stable, the carbon or nitrogen atom of the heterocycle may be substituted. The heterocyclyl may be substituted with one or more substituents described herein.

Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, 1, 4-diazepanyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetrahydroisoquinolyl, dihydropyrrolopyrazinyl, dihydrofuranpyridinyl, dioxapyridinyl, dihydrodioxinpyridinyl, dihydropyridoxazinyl, pyridooxazinyl, tetronoyl, and tetramoyl, which groups may be substituted with one or more substituents described herein.

"Heteroaryl" as used herein refers to groups containing 5 to 14, preferably 5 to 10, ring atoms and having 6, 10 or 14 pi electrons in common on the ring system. The ring atoms contained in the heteroaryl group are carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen, sulfur. Heteroaryl groups may be substituted with one or more substituents described herein.

Useful heteroaryl groups include thienyl (phenylthio), benzo [ d ] isothiazol-3-yl, benzo [ b ] thienyl, naphtho [2,3-b ] thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromene, xanthenyl, thioxoanthryl (phenoxanthiinyl), pyrrolyl, imidazolyl, pyrazolyl, pyridinyl (including but not limited to 2-pyridinyl, 3-pyridinyl and 4-pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolinyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β -carbolinyl, phenanthridinyl, acridinyl, naphthyridinyl (hetero) phenyl, cinnolinyl phenanthroline, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, tetrahydropyridopyrimidine, tetrahydropenta [ c ] pyrazol-3-yl, benzisoxazolyl such as 1, 2-benzisoxazol-3-yl, benzimidazolyl, 2-oxindole, thiadiazyl, 2-oxo-benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, furanopyridinyl, oxazolopyridinyl, triazolopyridinyl, tetrahydropyridopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, and pharmaceutical compositions containing them triazolopyrazinyl, thienoquinolinyl, furoquinolinyl, thiazoloquinolinyl, pyrazoloquinolinyl, pyrroloquinolinyl, imidazoquinolinyl, oxazoloquinolinyl, and the like. When heteroaryl groups contain nitrogen atoms in the ring, such nitrogen atoms may be in the form of N-oxides, such as pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

Herein, unless otherwise indicated, when substituted, an alkyl, alkenyl, alkynyl, alkoxy, amino, acyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl group described in any embodiment herein may each be substituted with one or more (e.g., 1,2, 3, or 4) substituents selected from the group consisting of halogen, hydroxy, carboxyl, amino, nitro, cyano, C _1-6 amido, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 acyl, C _6-10 aryl, C _3-8 cycloalkyl, heteroaryl, heterocyclyl, and carbonyl, and the like, as defined herein. Wherein the substituents themselves may also be optionally substituted. More preferred substituents include, but are not limited to, halogen, hydroxy, cyano, amino, C _1-6 alkoxy, C _1-6 alkyl, and C _1-6 acyl.

It is to be understood that in the various embodiments herein, when the substituent is a carbocyclyl, heterocyclyl, aryl or heteroaryl group, the number of such carbocyclyl, heterocyclyl, aryl or heteroaryl groups as substituents is typically 1.

Specifically, the present invention provides a compound, stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically-labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, as shown in formula I:

Wherein a ₁ is selected from N and CR ₁;

A ₂ is selected from N and C;

q is selected from NR _a, O and S;

the Z ₁ ring is selected from optionally substituted heteroaryl and optionally substituted heterocyclyl;

cy is selected from optionally substituted heteroaryl and optionally substituted heterocyclyl, and when Cy is When D ₁、D₂ and D ₃ are each independently selected from N and CR ₉, and at least one of D ₁ and D ₃ is N;

R ₁ is selected from hydrogen, halogen, optionally substituted alkyl, and optionally substituted alkoxy;

R ₉ and R ₁₅ are each independently selected from hydrogen, halogen, optionally substituted C _1-4 alkyl, and optionally substituted C _1-4 alkoxy;

R _a is hydrogen and optionally substituted C _1-4 alkyl.

In the formula A and formula I and each structural formula, when each alkyl, alkoxy and acyl in each group definition are substituted, the substituent groups can be independently selected from deuterium, cyano, hydroxyl, nitro, amino (-NR ^′R^″), aryl, heteroaryl, halogen and the like, the number of the substituent groups can be independently 1,2, 3,4 or 5, R ^′ and R ^″ are defined as the text, and R ^′ and R ^″ are preferably independently H or C _1-4 alkyl. For example, substituted alkyl groups can be deuterated alkyl groups, hydroxyalkyl groups, dihydroxyalkyl groups, alkylaminoalkyl groups, dialkylaminoalkyl groups, aralkyl groups, heteroarylalkyl groups, haloalkyl groups, and the like. It will be appreciated that when the substituents are aryl, heteroaryl, cyano and nitro, the number of substituents is typically 1, and when the substituents are, for example, halogen, up to 5 halogen groups can be present depending on the carbon chain length of the alkyl and alkoxy groups, exemplary such substituents being trifluoromethyl and pentafluoroethyl and the like. In some embodiments, each alkyl, alkoxy, acyl group in the definition of each group in formulas a and I and each formula of the present invention is optionally substituted with 1,2, 3,4, or 5 substituents selected from deuterium, hydroxy, nitro, amino, and halogen.

In the formula A and the formula I and each structural formula, when each cycloalkyl, heterocyclic group, aryl and heteroaryl in the group definition is substituted, the number of the substituents can be 1,2,3,4 or 5 independently, and each substituent can be independently selected from halogen, hydroxy, carboxyl, amino, nitro, cyano, C _1-6 amido, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 acyl, C _6-10 aryl, C _3-8 cycloalkyl, heteroaryl, heterocyclyl and carbonyl, preferably selected from halogen, hydroxy, cyano, amino, C _1-6 alkoxy, c _1-6 alkyl and C _1-6 acyl. The C _1-6 -amido, C _1-6 -alkoxy, C _1-6 -alkyl, C _1-6 -acyl radicals can in each case optionally also be substituted by 1, 2. 3,4 or 5 substituents selected from cyano, hydroxy, nitro, amino, aryl, heteroaryl and halogen. The C _6-10 aryl, C _3-8 cycloalkyl, heteroaryl, heterocyclyl groups may each optionally also be substituted with 1, 2, 3, 4 or 5 groups selected from halogen, hydroxy, carboxy, amino, nitro, cyano, C _1-6 amido, C _1-6 alkoxy, substituents for C _1-6 alkyl, C _1-6 acyl and carbonyl.

In one or more embodiments of the compounds of formula a and formula I, R ₁ is hydrogen, halogen, optionally substituted C _1-4 alkyl or optionally substituted C _1-4 alkoxy. Further, R ₁ is H, halogen, halo C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, halo C _1-4 alkoxy or hydroxy substituted C _1-4 alkoxy.

In one or more embodiments of the compounds of formulas A and I, A ₁ is N or CR ₁, wherein R ₁ is hydrogen, halogen, optionally substituted C _1-4 alkyl, or optionally substituted C _1-4 alkoxy, and in one or more embodiments, A ₁ is N, CH or CF, preferably, A ₁ is N.

In one or more embodiments of the compounds of formula a and formula I, a ₁ is N and a ₂ is C.

In one or more embodiments of the compounds of formula a and formula I, R _a is hydrogen.

In one or more embodiments of the compounds of formula a and formula I, Q ₁ is NH or O, preferably Q is NH.

In one or more embodiments of the compounds of formulas A and I, the Z ₁ ring is an optionally substituted 5-6 membered heteroaryl or an optionally substituted 5-10 membered heterocyclyl, preferably the Z ₁ ring is an optionally substituted 5-6 membered heteroaryl or an optionally substituted 5-10 membered heterocyclyl (preferably 5-6 membered heterocyclyl) with A ₂ being C. the 5-6 membered heteroaryl is preferably a nitrogen containing heteroaryl, such as a heteroaryl containing 1 or 2 nitrogen atoms, optionally also containing 1 or 2 heteroatoms selected from O and S. Preferably, a ₂ in the Z ₁ ring is C and the Z ₁ ring is a 5-6 membered heteroaryl group containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S. The 5-10 membered heterocyclic group is preferably a nitrogen-containing heterocyclic group such as a heterocyclic group containing 1 or 2 nitrogen atoms, optionally further containing 1 or 2 hetero atoms selected from O and S. Preferably, a ₂ in the Z ₁ ring is C and the Z ₁ ring is a 5-10 membered heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S. In some embodiments, the 5-10 membered heterocyclyl is a 7-10 membered spiro heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S, preferably wherein a ₂ is C. When the 5-6 membered heteroaryl and 5-10 membered heterocyclyl are substituted, the number of substituents may be 1, 2, 3 or 4, and may be selected from halogen, cyano, =o, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkoxy, optionally substituted C _3-8 cycloalkyl and optionally substituted heterocyclyl. In some embodiments, the optionally substituted C _1-6 alkyl as a substituent for the Z ₁ ring is optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclyl, and amino (-NR 'R'), wherein, preferably, the heterocyclyl is a nitrogen and/or oxygen containing 4-10 membered heterocyclyl, preferably a nitrogen and/or oxygen containing 4-7 membered heterocyclyl, such as azetidinyl, Oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and the like, the heterocyclyl being preferably substituted with 1,2, 3 or 4 groups selected from halogen, hydroxy, cyano, C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy, Halogenated C _1-4 alkoxy, optionally substituted C _3-4 cycloalkyl (e.g. optionally substituted with 1, 2 or 3 groups selected from halogen, C _3-4 cycloalkyl of C _1-4 alkyl and haloC _1-4 alkyl) and optionally substituted C _1-3 acyl (e.g., haloC _1-3 acyl), R 'and R' are as defined herein, preferably each independently selected from hydrogen, C _1-4 alkyl and halogenated C _1-4 alkyl. In some embodiments, the optionally substituted C _3-8 cycloalkyl as a substituent of the Z ₁ ring is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxy, cyano, C _1-4 alkyl, halo C _1-4 alkyl, Substituents for C _1-4 alkoxy and halo C _1-4 alkoxy. In some embodiments, the optionally substituted heterocyclyl as a substituent of the Z ₁ ring may be a 4-10 membered monocyclic or bicyclic heterocyclyl, a 7-10 membered spiroheterocyclyl, or a 7-10 membered bridged heterocyclyl, each of which may be optionally substituted with 1,2, 3, or 4 substituents selected from halogen, hydroxy, cyano, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, optionally substituted C _3-4 cycloalkyl (e.g., optionally substituted with 1, 2 or 3 groups selected from halogen, C _3-4 cycloalkyl of C _1-4 alkyl and haloC _1-4 alkyl) and optionally substituted C _1-3 acyl (e.g., haloC _1-3 acyl), preferably the heterocyclyl is a 4-10 membered monocyclic or bicyclic heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, 7-10 membered spirocyclic heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms or 7-10 membered bridged cyclic heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 6-azabicyclo [3.1.1] hept-3-yl and 2-azaspiro [3.3] hept-6-yl, etc.

In one or more embodiments of the compounds of formulas a and I,Selected from the following groups:

Preferably, the method comprises the steps of, The method comprises the following steps:

More preferably still the use of a polymer, The method comprises the following steps:

Wherein, represents the connection position of the group and the amino group on the 5 membered heteroaryl containing Q of the compound, B ₁ and B ₂ are each independently selected from N and CR ₂, wherein each R ₂ is independently selected from hydrogen, Halogen, cyano, optionally substituted C _1-4 alkyl and optionally substituted C _1-4 alkoxy, preferably each R ₂ is independently hydrogen, fluoro, chloro, cyano, methyl or deuteromethyl, R ₃ is selected from hydrogen, Optionally substituted C _1-4 alkyl and optionally substituted C _3-4 cycloalkyl, preferably hydrogen, Methyl or deuteromethyl, R ₄ and R ₅ are each independently selected from hydrogen and optionally substituted C _1-4 alkyl, or R ₄ and R ₅ form with the attached C a C _3-4 cycloalkyl, preferably R ₄ and R ₅ are each independently hydrogen or methyl, or R ₄ and R ₅ form with the attached C a cyclopropyl, R ₆ and R ₇ are each independently selected from optionally substituted 4-10 membered mono-or bicyclic heterocyclyl, a, Optionally substituted 7-10 membered spirocyclic heterocyclyl, optionally substituted 7-10 membered bridged cyclic heterocyclyl and optionally substituted C _1-6 alkyl.

In one or more embodiments of the compounds of formulas A and I, each of the 4-10 membered monocyclic or bicyclic heterocyclyl, 7-10 membered spirocyclic heterocyclyl and 7-10 membered bridged heterocyclyl in the definition of R ₆ and R ₇ may optionally be substituted with 1, 2, 3 or 4 substituents selected from halogen, hydroxy, cyano, C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, optionally substituted C _3-4 cycloalkyl (e.g., C _3-4 cycloalkyl optionally substituted with 1, 2 or 3 substituents selected from halogen, C _1-4 alkyl and halo C _1-4 alkyl) and optionally substituted C _1-3 acyl (e.g., halo C _1-3 acyl), preferably the 4-10 membered monocyclic or bicyclic heterocyclyl, 7-10 membered spirocyclic heterocyclyl and 7-10 membered bridged heterocyclyl are 4-10 membered monocyclic or bicyclic heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, and 7-10 membered oxetanyl, 1-or 3-membered spiroheterocyclyl, 1-6-membered spiroheterocyclyl, 3-membered spiroheterocyclyl and 3-membered 1-membered spiroheterocyclyl, 3-membered 1-or 6-membered spiroheterocyclyl, and the like.

In one or more embodiments of the compounds of formulas A and I, the optionally substituted C _1-6 alkyl in the definition of R ₆ and R ₇ is optionally substituted with 1,2,3 or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclyl and amino (-NR ' R '), preferably the heterocyclyl is a nitrogen and/or oxygen containing 4-10 membered heterocyclyl, preferably nitrogen and/or oxygen containing 4-7 membered heterocyclyl, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl, and the like, the heterocyclyl is preferably substituted with 1,2,3 or 4 substituents selected from halogen, hydroxy, C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy and halo C _1-4 alkoxy, and R ' are as defined herein, preferably each independently selected from hydrogen, C _1-4 alkyl and halo C _1-4 alkyl.

In one or more embodiments of the compounds of formula a and formula I, R ₆ is selected from the following groups:

Wherein R ₈ is selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 cycloalkyl and optionally substituted C _1-3 acyl, preferably hydrogen, C _1-4 alkyl, deuterated C _1-4 alkyl, cyclopropyl or C _1-3 acyl.

In one or more embodiments of the compounds of formula a and formula I, R ₇ is selected from the following groups:

In one or more embodiments of the compounds of formula a and formula I, cy is optionally substituted 5-12 membered heteroaryl or optionally substituted 9-12 membered heterocyclyl. Preferably, cy is a 9-12 membered bicyclic heteroaryl or 9-12 membered bicyclic heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms. When the heteroaryl and heterocyclyl groups are substituted, the number of substituents may be 1,2, 3 or 4, and the substituents may be selected from = O, halogen, optionally substituted C _1-4 alkyl (e.g. halo C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _1-4 alkoxy (e.g. halo C _1-4 alkoxy or deuterated C _1-4 alkoxy). Preferably, the substituents of the heteroaryl and heterocyclyl are independently selected from =o, halogen and C _1-4 alkoxy.

In one or more embodiments of the compounds of formula a and formula I, cy is:

Wherein represents the position of attachment of said group to the remainder of the compound; Represents a single bond or a double bond, D ₁、D₂ and D ₃ are each independently selected from N and CR ₉, wherein R ₉ is selected from the group consisting of =O, Hydrogen, halogen, Optionally substituted C _1-4 alkyl (e.g., halogenated C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _1-4 alkoxy (e.g., halogenated C _1-4 alkoxy or deuterated C _1-4 alkoxy), preferably hydrogen, =o, fluorine, Methoxy or deutero methoxy, E ₁ and E ₂ are each independently selected from C and N and are not simultaneously N, X ₁ and X ₂ are each independently selected from O, S, NR ₁₀ and CR ₁₁R₁₂, wherein R ₁₀ is selected from hydrogen, Optionally substituted C _1-4 alkyl (e.g., halogenated C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _3-5 cycloalkyl (e.g., optionally substituted with 1, 2 or 3 are selected from halogen, C _3-5 cycloalkyl of C _1-4 alkyl and haloC _1-4 alkyl), R ₁₁ and R ₁₂ are each independently selected from hydrogen, Optionally substituted C _1-4 alkyl (e.g. halo C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _1-4 alkoxy (e.g. halo C _1-4 alkoxy or deuterated C _1-4 alkoxy), or R ₁₁ and R ₁₂ form with the attached C a C _3-4 cycloalkyl group, Y is selected from C=O, Y is selected from C=C, C=s and CR ₁₃R₁₄, wherein R ₁₃ and R ₁₄ are each independently selected from hydrogen, Optionally substituted C _1-4 alkyl (e.g. halo C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _1-4 alkoxy (e.g. halo C _1-4 alkoxy or deuterated C _1-4 alkoxy), or R ₁₃ and R ₁₄ form with the attached C a C _3-4 cycloalkyl group, preferably Y is c=o, and the Z ₂ ring is selected from optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl.

In one or more embodiments of the compounds of formulas A and I, E ₁ or E ₂ is N,Is a single bond, in one or more embodiments, E ₁ and E ₂ are both C,Is a double bond.

In one or more embodiments of the compounds of formulas a and I, the Z ₂ ring is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, optionally substituted C _1-4 alkyl (e.g., halo C _1-4 alkyl or deuterated C _1-4 alkyl), and optionally substituted C _1-4 alkoxy (e.g., halo C _1-4 alkoxy or deuterated C _1-4 alkoxy). In one or more embodiments, the Z ₂ ring is a nitrogen-and/or oxygen-containing 5-6 membered heteroaryl or an oxygen-and/or nitrogen-containing 5-6 membered heterocyclyl.

Wherein, represents the position of attachment of the group to the remainder of the compound.

In one or more embodiments of the compounds of formula a and formula I, cy is optionally substituted 5-6 membered nitrogen containing heteroaryl. The heteroaryl group, when substituted, may have 1,2, 3 or 3 substituents, and may be selected from halogen, optionally substituted C _1-4 alkyl (e.g., halogenated C _1-4 alkyl or deuterated C _1-4 alkyl), and optionally substituted C _1-4 alkoxy (e.g., halogenated C _1-4 alkoxy or deuterated C _1-4 alkoxy). In one or more embodiments, cy is:

Wherein, represents the connection position of the group and the rest of the compound, D ₁、D₂ and D ₃ are each independently selected from N and CR ₉, at least one of D ₁ and D ₃ is N, R ₉ is selected from hydrogen, Halogen, halogen, Optionally substituted C _1-4 alkyl (e.g., halogenated C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _1-4 alkoxy (e.g., halogenated C _1-4 alkoxy or deuterated C _1-4 alkoxy), preferably hydrogen, Fluorine, methoxy or deuterated methoxy, R ₁₅ is selected from hydrogen, halogen, Optionally substituted C _1-4 alkyl (e.g., halogenated C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _1-4 alkoxy (e.g., halogenated C _1-4 alkoxy or deuterated C _1-4 alkoxy), preferably fluoro, difluoromethyl, methoxy or deuterated methoxy.

In one or more embodiments of the compounds of formulas a and I, when Cy is substituted, the substituents are selected from halogen, optionally substituted C _1-4 alkyl (e.g., halo C _1-4 alkyl or deuterated C _1-4 alkyl), and optionally substituted C _1-4 alkoxy (e.g., halo C _1-4 alkoxy or deuterated C _1-4 alkoxy), preferably fluoro, difluoromethyl, methoxy or deuterated methoxy.

One group of preferred compounds of formulae a and I of the present invention is represented by formula II (including formulae IIa and IIb) or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically-labeled compounds, or pharmaceutically acceptable salts thereof, or mixtures thereof:

Wherein the D ₁、D₂、D₃、E₁、E₂、Q、X₁、X₂、Y、Z₁ ring and Z ₂ ring are as described in any one of the embodiments of formula I;

represents a single bond or a double bond.

In one or more embodiments of the compounds of formula II, Q is NH or O, preferably Q is NH.

In one or more embodiments of the compounds of formula II, the Z ₁ ring is an optionally substituted 5-6 membered heteroaryl or an optionally substituted 5-10 membered heterocyclyl (preferably 5-6 membered heterocyclyl). The 5-6 membered heteroaryl is preferably a nitrogen containing heteroaryl, such as a heteroaryl containing 1 or 2 nitrogen atoms, optionally also containing 1 or 2 heteroatoms selected from O and S. The 5-10 membered heterocyclic group is preferably a nitrogen-containing heterocyclic group such as a heterocyclic group containing 1 or 2 nitrogen atoms, optionally further containing 1 or 2 hetero atoms selected from O and S. in some embodiments, the 5-10 membered heterocyclyl is a 7-10 membered spiro heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S. When the 5-6 membered heteroaryl and 5-10 membered heterocyclyl are substituted, the number of substituents may be 1, 2, 3 or 4, and may be selected from halogen, cyano, =o, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkoxy, optionally substituted C _3-8 cycloalkyl and optionally substituted heterocyclyl. In some embodiments, the optionally substituted C _1-6 alkyl as a substituent for the Z ₁ ring is optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclyl, and amino (-NR 'R'), wherein, preferably, the heterocyclyl is a nitrogen and/or oxygen containing 4-10 membered heterocyclyl, preferably a nitrogen and/or oxygen containing 4-7 membered heterocyclyl, such as azetidinyl, Oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and the like, the heterocyclyl being preferably substituted with 1,2, 3 or 4 groups selected from halogen, hydroxy, cyano, C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy, Halogenated C _1-4 alkoxy, optionally substituted C _3-4 cycloalkyl (e.g. optionally substituted with 1, 2 or 3 groups selected from halogen, C _3-4 cycloalkyl of C _1-4 alkyl and haloC _1-4 alkyl) and optionally substituted C _1-3 acyl (e.g., haloC _1-3 acyl), R 'and R' are as defined herein, preferably each independently selected from hydrogen, C _1-4 alkyl and halogenated C _1-4 alkyl. In some embodiments, the optionally substituted C _3-8 cycloalkyl as a substituent of the Z ₁ ring is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxy, cyano, C _1-4 alkyl, halo C _1-4 alkyl, Substituents for C _1-4 alkoxy and halo C _1-4 alkoxy. In some embodiments, the optionally substituted heterocyclyl as a substituent of the Z ₁ ring may be a 4-10 membered monocyclic or bicyclic heterocyclyl, a 7-10 membered spiroheterocyclyl, or a 7-10 membered bridged heterocyclyl, each of which may be optionally substituted with 1,2, 3, or 4 substituents selected from halogen, hydroxy, cyano, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, optionally substituted C _3-4 cycloalkyl (e.g., optionally substituted with 1, 2 or 3 groups selected from halogen, C _3-4 cycloalkyl of C _1-4 alkyl and haloC _1-4 alkyl) and optionally substituted C _1-3 acyl (e.g., haloC _1-3 acyl), preferably the heterocyclyl is a 4-10 membered monocyclic or bicyclic heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, 7-10 membered spirocyclic heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms or 7-10 membered bridged cyclic heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 6-azabicyclo [3.1.1] hept-3-yl and 2-azaspiro [3.3] hept-6-yl, etc.

In one or more embodiments of the compounds of formula II,Selected from the following groups:

Wherein, represents the connection position of the group and the amino group on the 5 membered heteroaryl containing Q of the compound, B ₁ and B ₂ are each independently selected from N and CR ₂, wherein each R ₂ is independently selected from hydrogen, Halogen, cyano, optionally substituted C _1-4 alkyl and optionally substituted C _1-4 alkoxy, preferably each R ₂ is independently hydrogen, fluoro, chloro, cyano, methyl or deuteromethyl, R ₃ is selected from hydrogen, Optionally substituted C _1-4 alkyl and optionally substituted C _3-4 cycloalkyl, preferably hydrogen, methyl or deuteromethyl, R ₄ and R ₅ are each independently selected from hydrogen and optionally substituted C _1-4 alkyl, or R ₄ and R ₅ form with the attached C _3-4 cycloalkyl, preferably R ₄ and R ₅ are each independently hydrogen or methyl, or R ₄ and R ₅ form with the attached C cyclopropyl, R ₆ and R ₇ are each independently selected from optionally substituted 4-10 membered monocyclic or bicyclic ring, Optionally substituted 7-10 membered spirocyclic heterocyclyl, optionally substituted 7-10 membered bridged cyclic heterocyclyl and optionally substituted C _1-6 alkyl.

In one or more embodiments of the compounds of formula II, each of the 4-10 membered monocyclic or bicyclic heterocyclyl, 7-10 membered spirocyclic heterocyclyl and 7-10 membered bridged heterocyclyl in the definition of R ₆ and R ₇ may optionally be substituted with 1, 2, 3 or 4 substituents selected from halogen, hydroxy, cyano, C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, optionally substituted C _3-4 cycloalkyl (e.g., C _3-4 cycloalkyl optionally substituted with 1, 2 or 3 substituents selected from halogen, C _1-4 alkyl and halo C _1-4 alkyl) and optionally substituted C _1-3 acyl (e.g., halo C _1-3 acyl), preferably the 4-10 membered monocyclic or bicyclic heterocyclyl, 7-10 membered spirocyclic heterocyclyl and 7-10 membered bridged heterocyclyl are 4-10 membered monocyclic or bicyclic heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, 7-membered spirocyclic heterocyclyl and 1-or 2 membered oxacyclic heterocyclyl [ 1-or 2 membered oxacycloalkyl ] and 1-6-membered spiroheterocyclyl, 3.6-membered spiroheterocyclyl, 7-10 membered spiroheterocyclyl, 7-membered spiroheterocyclyl and 7-10 membered spiroheterocyclyl, 5-or 3-membered spiroheterocyclyl, and the like.

In one or more embodiments of the compounds of formula II, the optionally substituted C _1-6 alkyl in the definition of R ₆ and R ₇ is optionally substituted with 1,2, 3 or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclyl and amino (-NR ' R '), preferably the heterocyclyl is a nitrogen and/or oxygen containing 4-10 membered heterocyclyl, preferably a nitrogen and/or oxygen containing 4-7 membered heterocyclyl, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl and the like, the heterocyclyl is preferably substituted with 1,2, 3 or 4 substituents selected from halogen, hydroxy, C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy and halo C _1-4 alkoxy, and R ' are as defined herein, preferably each is independently selected from hydrogen, C _1-4 alkyl and halo C _1-4 alkyl.

In one or more embodiments of the compound of formula II, R ₆ is selected from the following groups:

In one or more embodiments of the compound of formula II, R ₇ is selected from the following groups:

In one or more embodiments of the compound of formula II, D ₁、D₂ and D ₃ are each independently selected from N and CR ₉, wherein R ₉ is selected from hydrogen, halogen, optionally substituted C _1-4 alkyl (e.g., halogenated C _1-4 alkyl or deuterated C _1-4 alkyl), and optionally substituted C _1-4 alkoxy (e.g., halogenated C _1-4 alkoxy or deuterated C _1-4 alkoxy). In one or more embodiments, R ₉ is hydrogen, fluoro, methoxy, or deuterated methoxy.

In one or more embodiments of the compounds of formula II, E ₁ and E ₂ are each independently selected from C and N, and are not both N. In one or more embodiments, E ₁ or E ₂ is N,Is a single bond, in one or more embodiments, E ₁ and E ₂ are both C,Is a double bond.

In one or more embodiments of the compound of formula II, X ₁ and X ₂ are each independently selected from O, S, NR ₁₀ and CR ₁₁R₁₂, wherein R ₁₀ is selected from hydrogen, Optionally substituted C _1-4 alkyl (e.g., halogenated C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _3-5 cycloalkyl (e.g., optionally substituted with 1, 2 or 3 are selected from halogen, C _3-5 cycloalkyl of C _1-4 alkyl and haloC _1-4 alkyl), R ₁₁ and R ₁₂ are each independently selected from hydrogen, Optionally substituted C _1-4 alkyl (e.g. halo C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _1-4 alkoxy (e.g. halo C _1-4 alkoxy or deuterated C _1-4 alkoxy), or R ₁₁ and R ₁₂ form with the attached C a C _3-4 cycloalkyl group. In one or more embodiments, X ₁ and X ₂ are each independently selected from O and S,Is a single bond. In one or more embodiments, X ₁ and X ₂ are each independently selected from NR ₁₀ and CR ₁₁R₁₂,Is a single bond or a double bond, R ₁₀ is preferably hydrogen, methyl, deuterated methyl or cyclopropyl, R ₁₁ and R ₁₂ are preferably hydrogen, or R ₁₁ and R ₁₂ form cyclopropyl with the attached C.

In one or more embodiments of the compound of formula II, Y is selected from c= O, C =s and CR ₁₃R₁₄, wherein R ₁₃ and R ₁₄ are each independently selected from hydrogen, optionally substituted C _1-4 alkyl (e.g., halo C _1-4 alkyl or deuterated C _1-4 alkyl), and optionally substituted C _1-4 alkoxy (e.g., halo C _1-4 alkoxy or deuterated C _1-4 alkoxy), or R ₁₃ and R ₁₄ form with the attached C a C _3-4 cycloalkyl. In one or more embodiments, Y is c=o or c=s. In one or more embodiments, R ₁₃ and R ₁₄ are each independently selected from hydrogen, methyl, or R ₁₃ and R ₁₄ form cyclopropyl with the attached C.

In one or more embodiments of the compounds of formula II, the Z ₂ ring is selected from optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl. In some embodiments, the Z ₂ ring is optionally substituted with 1,2, 3, or 4 substituents selected from halogen, optionally substituted C _1-4 alkyl (e.g., halogenated C _1-4 alkyl or deuterated C _1-4 alkyl), and optionally substituted C _1-4 alkoxy (e.g., halogenated C _1-4 alkoxy or deuterated C _1-4 alkoxy). In one or more embodiments, the Z ₂ ring is a nitrogen-and/or oxygen-containing 5-6 membered heteroaryl or an oxygen-and/or nitrogen-containing 5-6 membered heterocyclyl.

In one or more embodiments of the compounds of formula II, whenWhen substituted, the number of substituents may be 1,2, 3 or 4, and may be selected from halogen, optionally substituted C _1-4 alkyl (e.g. halogenated C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _1-4 alkoxy (e.g. halogenated C _1-4 alkoxy or deuterated C _1-4 alkoxy), preferably fluoro, difluoromethyl, methoxy or deuterated methoxy.

One group of preferred compounds of formulae a and I of the present invention is represented by formula III (including formulae IIIa and IIIb) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically-labeled compound, or pharmaceutically acceptable salt thereof, or a mixture of same:

wherein ,B₁、R₂、R₆、D₁、D₂、D₃、E₁、E₂、X₁、X₂ and Y are as described in any of the preceding embodiments;

represents a single bond or a double bond.

In one or more embodiments of the compound of formula III, B ₁ is selected from N and CR ₂, wherein R ₂ is selected from hydrogen, halogen, cyano, optionally substituted C _1-4 alkyl (e.g., halogenated C _1-4 alkyl or deuterated C _1-4 alkyl), and optionally substituted C _1-4 alkoxy (e.g., halogenated C _1-4 alkoxy or deuterated C _1-4 alkoxy). In one or more embodiments, R ₂ is hydrogen, fluoro, chloro, cyano, methyl, or deuterated methyl.

In one or more embodiments of the compounds of formula III, each of the 4-10 membered monocyclic or bicyclic heterocyclyl, 7-10 membered spiroheterocyclyl and 7-10 membered bridged heterocyclyl in the definition of R ₆ may optionally be substituted with 1, 2, 3 or 4 substituents selected from halogen, hydroxy, cyano, C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, optionally substituted C _3-4 cycloalkyl (e.g., C _3-4 cycloalkyl optionally substituted with 1, 2 or 3 substituents selected from halogen, C _1-4 alkyl and halo C _1-4 alkyl) and optionally substituted C _1-3 acyl (e.g., halo C _1-3 acyl), preferably the 4-10 membered monocyclic or bicyclic heterocyclyl, 7-10 membered spiroheterocyclyl and 7-10 membered bridged heterocyclyl are 4-10 membered monocyclic or bicyclic heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, 7-10 membered heterocyclyl containing 1-or 2 nitrogen atoms and optionally 1-2 membered nitrogen atoms, 3-membered heterocyclyl [ 1-6.6-membered spiroheterocyclyl, 3-membered heteroaryl, 3-membered spiroheterocyclyl, 3-6-membered spiroheterocyclyl, 5-membered spiroheterocyclyl, 7-10 membered spiroheterocyclyl, etc.

In one or more embodiments of the compounds of formula III, the optionally substituted C _1-6 alkyl in the definition of R ₆ is optionally substituted with 1,2,3 or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclyl and amino (-NR ' R '), wherein preferably the heterocyclyl is a nitrogen and/or oxygen containing 4-10 membered heterocyclyl, preferably a nitrogen and/or oxygen 4-7 membered heterocyclyl, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl, and the like, the heterocyclyl preferably being substituted with 1,2,3 or 4 substituents selected from halogen, hydroxy, cyano, C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy and halo C _1-4 alkoxy, and R ' are as defined herein, preferably each independently selected from hydrogen, C _1-4 alkyl and halo C _1-4 alkyl.

In one or more embodiments of the compound of formula III, R ₆ is selected from the following groups:

In one or more embodiments of the compound of formula III, D ₁、D₂ and D ₃ are each independently selected from N and CR ₉, wherein R ₉ is selected from hydrogen, halogen, optionally substituted C _1-4 alkyl (e.g., halogenated C _1-4 alkyl or deuterated C _1-4 alkyl), and optionally substituted C _1-4 alkoxy (e.g., halogenated C _1-4 alkoxy or deuterated C _1-4 alkoxy). In one or more embodiments, R ₉ is hydrogen, fluoro, methoxy, or deuterated methoxy.

In one or more embodiments of the compounds of formula III, E ₁ and E ₂ are each independently selected from C and N, and are not both N. In one or more embodiments, E ₁ or E ₂ is N,Is a single bond, in one or more embodiments, E ₁ and E ₂ are both C,Is a double bond.

In one or more embodiments of the compound of formula III, X ₁ and X ₂ are each independently selected from O, S, NR ₁₀ and CR ₁₁R₁₂, wherein R ₁₀ is selected from hydrogen, Optionally substituted C _1-4 alkyl (e.g., halogenated C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _3-5 cycloalkyl (e.g., optionally substituted with 1, 2 or 3 are selected from halogen, C _3-5 cycloalkyl of C _1-4 alkyl and haloC _1-4 alkyl), R ₁₁ and R ₁₂ are each independently selected from hydrogen, Optionally substituted C _1-4 alkyl (e.g. halo C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _1-4 alkoxy (e.g. halo C _1-4 alkoxy or deuterated C _1-4 alkoxy), or R ₁₁ and R ₁₂ form with the attached C a C _3-4 cycloalkyl group. In one or more embodiments, X ₁ and X ₂ are each independently selected from O and S,Is a single bond. In one or more embodiments, X ₁ and X ₂ are each independently selected from NR ₁₀ and CR ₁₁R₁₂,Is a single bond or a double bond, R ₁₀ is preferably hydrogen, methyl, deuterated methyl or cyclopropyl, R ₁₁ and R ₁₂ are preferably hydrogen, or R ₁₁ and R ₁₂ form cyclopropyl with the attached C.

In one or more embodiments of the compound of formula III, Y is selected from c= O, C =s and CR ₁₃R₁₄, wherein R ₁₃ and R ₁₄ are each independently selected from hydrogen, optionally substituted C _1-4 alkyl (e.g., halo C _1-4 alkyl or deuterated C _1-4 alkyl), and optionally substituted C _1-4 alkoxy (e.g., halo C _1-4 alkoxy or deuterated C _1-4 alkoxy), or R ₁₃ and R ₁₄ form with the attached C a C _3-4 cycloalkyl. In one or more embodiments, Y is c=o or c=s. In one or more embodiments, R ₁₃ and R ₁₄ are each independently selected from hydrogen, methyl, or R ₁₃ and R ₁₄ form cyclopropyl with the attached C.

In one or more embodiments of the compounds of formula III, the Z ₂ ring is selected from optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl. In some embodiments, the Z ₂ ring is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, optionally substituted C _1-4 alkyl (e.g., halogenated C _1-4 alkyl or deuterated C _1-4 alkyl), and optionally substituted C _1-4 alkoxy (e.g., halogenated C _1-4 alkoxy or deuterated C _1-4 alkoxy). In one or more embodiments, the Z ₂ ring is a nitrogen-and/or oxygen-containing 5-6 membered heteroaryl or an oxygen-and/or nitrogen-containing 5-6 membered heterocyclyl.

In one or more embodiments of the compound of formula III,Selected from the following groups:

In one or more embodiments of the compound of formula III, whenWhen substituted, the number of substituents may be 1,2, 3 or 4, and may be selected from halogen, optionally substituted C _1-4 alkyl (e.g. halogenated C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _1-4 alkoxy (e.g. halogenated C _1-4 alkoxy or deuterated C _1-4 alkoxy), preferably fluoro, difluoromethyl, methoxy or deuterated methoxy.

It will be appreciated that while the A₁、A₂、B₁、B₂、Cy、R₆、D₁、D₂、D₃、E₁、E₂、X₁、X₂、Y、Z₁ ring and Z ₂ ring of formulae A and I (including formulae IIa, IIb, IIIa and IIIb), respectively, have been described above, the features described may be combined in any desired manner to form the different ranges of compounds of formulae A and I (including formulae IIa, IIb, IIIa and IIIb) of the present invention. For example, in some embodiments of the compounds of formulas A and I (including formulas IIa, IIb, IIIa and IIIb) of the present invention.

Preferred examples of compounds of formula a and formula I (including formulas IIa, IIb, IIIa and IIIb) include, but are not limited to:

or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof.

Some of the compounds of the present invention may exist as stereoisomers, including optical isomers. The present invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as individual enantiomers which may be separated according to methods well known to those skilled in the art.

Examples of pharmaceutically acceptable salts in the present invention include inorganic and organic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate, and inorganic and organic base salts with bases such as sodium hydroxy, TRIS (hydroxymethyl) aminomethane (TRIS, tromethamine) and N-methylglucamine.

Examples of prodrugs of the compounds of the present invention include simple esters of carboxylic acid containing compounds (e.g., esters obtained by condensation with C _1-4 alcohols according to methods known in the art), esters of hydroxyl containing compounds (e.g., esters obtained by condensation with C _1-4 carboxylic acid, C _3-6 diacid or anhydrides thereof such as succinic anhydride and fumaric anhydride according to methods known in the art), imines of amino containing compounds (e.g., imines obtained by condensation with C _1-4 aldehyde or ketone according to methods known in the art), carbamates of amino containing compounds such as those described by Leu et al (J. Med. Chem.42:3623-3628 (1999)) and Greenwald et al (J. Med. Chem.42:3657-3667 (1999)), aldols or ketals of alcohol containing compounds (e.g., those obtained by condensation with chloromethylmethyl ether or chloromethylethyl ether according to methods known in the art).

The compounds of the present invention may be prepared using methods known to those skilled in the art or by the novel methods of the present invention. Specifically, the compounds of the present invention having the formulas A and I can be prepared as shown in the reaction examples in scheme 1. Under the catalysis of t-BuOLi, 1- (1, 5-naphthyridin-4-yl) ethane-1-ketone reacts with CS ₂、CH₃ I to obtain 3, 3-bis (methylthio) -1- (1, 5-naphthyridin-4-yl) prop-2-en-1-one. 3, 3-bis (methylthio) -1- (1, 5-naphthyridin-4-yl) prop-2-en-1-one is reacted with 4- (3-amino-7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylic acid tert-butyl ester under NaH catalysis to give the product 4- (7-fluoro-3- ((1- (methylthio) -3- (1, 5-naphthyridin-4-yl) -3-oxoprop-1-en-1-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylic acid tert-butyl ester. Under the catalysis of AcOH, 4- (7-fluoro-3- ((1- (methylthio) -3- (1, 5-naphthyridin-4-yl) -3-oxo-prop-1-en-1-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylic acid tert-butyl ester is reacted with N ₂H₄·H₂ O to obtain the product 4- (3- ((5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) amino) -7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylic acid tert-butyl ester. 4- (3- ((5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) amino) -7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylic acid tert-butyl ester is reacted with TFA to give the target compound N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine.

Synthesis of tert-butyl 4- (3-amino-7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylate tert-butyl 4- (3-chloro-7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylate was reacted with benzhydrylamine under the catalysis of Pd ₂(dba)₃, BINAP and Cs ₂CO₃ to give the product tert-butyl 4- (3- ((diphenylmethylene) amino) -7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylate. The 4- (3- ((diphenylmethylene) amino) -7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylic acid tert-butyl ester is reacted with NH ₂ OH-HCl and NaOAc to obtain the product 4- (3-amino-7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylic acid tert-butyl ester.

Reaction scheme 1

Other related compounds may be prepared in a similar manner. For example, the target compound N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine can be prepared by replacing tert-butyl 4- (3-amino-7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylate with tert-butyl 4- (3-amino-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylate. Replacement of tert-butyl 4- (3-amino-7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylate with tert-butyl 4- (3-amino-7-cyano-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylate gives the target compound 3- ((5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) amino) -5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazine-7-carbonitrile. The target compound N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (1-methylpiperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine was prepared by substituting 7-fluoro-5- (1-methylpiperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine for tert-butyl 4- (3-amino-7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-carboxylate.

An important aspect of the present invention is the discovery that compounds of formula a and formula I (including formulas IIa, IIb, IIIa and IIIb) are kinase inhibitors, particularly CHK1 kinase inhibitors. Thus, the compounds of formula a and formula I (including formulas IIa, IIb, IIIa and IIIb) or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, or mixtures thereof, are useful for treating diseases, disorders, and conditions associated with, or for the manufacture of a medicament for treating diseases, disorders, and conditions associated with, high intrinsic DNA damage or damage during CHK1 continuous activation or DNA replication.

In the present invention, diseases, disorders and conditions associated with high intrinsic DNA damage or injury during continuous activation or DNA replication of CHK1 include cancer. The cancer may be a solid tumor or hematological tumor including, but not limited to, liver cancer, melanoma, hodgkin's disease, non-hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, wilms 'tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myelogenous leukemia, primary brain cancer, malignant melanoma, stomach cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides granulation zhong, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myelogenous leukemia, hairy cell leukemia, rhabdomyosarcoma, kaposi's sarcoma, genitourinary system tumor disease, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenal cancer, skin cancer, and prostate cancer. Preferably, the cancer is associated with high intrinsic DNA damage or injury during continuous activation of CHK1 or DNA replication, the term "associated" means that it plays a role in the occurrence and progression of cancer, such as resulting in the occurrence of cancer, and/or promoting the development or metastasis of cancer.

Accordingly, the present invention provides a method of treating or preventing diseases, disorders and conditions associated with high intrinsic DNA damage or injury during continuous activation of CHK1 or DNA replication, comprising administering to a subject in need thereof an effective amount of a compound of formula a and formula I (including formulas IIa, IIb, IIIa and IIIb), stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts thereof, or mixtures thereof, or a pharmaceutical composition containing an effective amount of a compound of formula a and formula I (including formulas IIa, IIb, IIIa and IIIb), stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts thereof, or mixtures thereof. In the present invention, the subject includes mammals, more specifically, humans.

In practicing the methods of treatment of the present invention, an effective amount of the pharmaceutical formulation is administered to a patient having one or more of these symptoms. The pharmaceutical formulations contain therapeutically effective concentrations of the compounds of formula a and formula I (including formulas IIa, IIb, IIIa and IIIb) formulated for oral, intravenous, topical, or topical administration for the treatment of cancer and other diseases. The amount administered is an amount effective to ameliorate or eliminate one or more of the conditions. For the treatment of a particular disease, an effective amount is an amount of drug sufficient to ameliorate or in some way alleviate symptoms associated with the disease. Such amounts may be administered as a single dose or may be administered according to an effective treatment regimen. The amount administered may be such that the disease is cured, but is generally administered to ameliorate the symptoms of the disease. Repeated doses are generally required to achieve the desired symptomatic improvement.

In another embodiment, a pharmaceutical composition is provided comprising a compound of formula a and formula I (including formulas IIa, IIb, IIIa and IIIb) of the invention, stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, or mixtures thereof, as an inhibitor of CHK1, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention relates to a pharmaceutical composition effective for treating cancer comprising a compound of formula a and formula I of the present invention, a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically-labeled compound, or a pharmaceutically acceptable salt thereof, or a mixture of same, as an inhibitor of CHK1, together with at least one known anticancer drug or pharmaceutically acceptable salt of an anticancer drug. The at least one known anticancer drug or pharmaceutically acceptable salt thereof includes other anticancer drugs related to DNA damage and repair mechanism, including PARP inhibitors olaparib, niraparib, rucaparib, talazoparib and Senaparib, HDAC inhibitors vorinostat, luo Mi digin, panobinostat and belinostat, and the like. the at least one known anticancer agent or pharmaceutically acceptable salt thereof further includes other anticancer agents associated with the cell division assay site including CDK4/6 inhibitors such as palbociclib, ATM inhibitors, ATR inhibitors, wee1 inhibitors and the like. Other known anticancer agents useful in anticancer combination therapy include, but are not limited to, alkylating agents such as busulfan, marflange, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin and carboplatin, topoisomerase I inhibitors such as camptothecins, irinotecan and topotecan, topoisomerase II inhibitors such as doxorubicin, epirubicin, aclacinomycin, mitoxantrone, methylhydroxy ellipticine and Ming topotecan, RNA/DNA antimetabolites such as 5-azacytidine, gemcitabine, 5-fluorouracil and methotrexate, DNA antimetabolites such as 5-fluoro-2' -deoxyuridine, Fludarabine is used as a carrier, nelarabine, cytarabine, pralatrexed, pemetrexed, hydroxyurea and thioguanine; anti-mitotic agents such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, and docetaxel, antibodies such as monoclonal antibodies, panitumumab, anti-certolizumab, nivolumab, pembrolizumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, oxybutyramimab You Tuozhu, ofatuzumab, rituximab, alemtuzumab, temozolomab, toximomab, rituximab, darimumab, erltuzumab, T-DM1, Ofatumumab, dinutuximab, blinatumomab, yiprinim, althamine, herceptin and Metronidazole, kinase inhibitors such as imatinib, gefitinib, erlotinib, octenib, afatinib, ceritinib, ai Leti, crizotinib, erlotinib, lapatinib, sorafenib, regafinib, vemurafenib, dabrafenib, aflavin, sunitinib, nilotinib, dasatinib, bosutinib, platinib, ibrutinib, cabatinib, lenvatinib, vande, trametinib, carbitinib, axitinib, temsirolimus, vandalteib, triamcinolone acetonide, temsirolimus, and pharmaceutical compositions containing them, idelalisib, pazopanib, tec cancer and everolimus. Other known anticancer drugs that may be used in anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenicum, zoledronic acid, bortezomib, carfilzomib, ixazomib, valmod gem, sonideji, dieldalem, salmetemine, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2) and Sipueucel-T (prostate cancer therapeutic vaccine).

In practicing the methods of the invention, the compounds of the invention and at least one known anticancer agent can be administered together as a single pharmaceutical composition. Alternatively, the compounds of the invention may be administered separately from at least one known anticancer agent. In one embodiment, the compound of the invention and at least one known anticancer agent are administered at about the same time, i.e., all agents are administered simultaneously or sequentially, so long as the compound reaches therapeutic concentrations in the blood at the same time. In another embodiment, the compound of the invention and at least one known anticancer agent are administered according to respective dosage regimens, so long as the compound reaches a therapeutic concentration in the blood.

Another embodiment of the invention is a bioconjugate comprising a compound of the invention effective as a kinase inhibitor to inhibit a tumor. The bioconjugates of the invention comprise or consist of a compound according to the invention and at least one known therapeutically active antibody, such as herceptin or rituximab, or a growth factor, such as EGF or FGF, or a cytokine, such as interleukin 2 or 4, or any molecule capable of binding to the cell surface. The antibodies and other molecules can deliver the compounds to their targets, making them potent anticancer drugs. The bioconjugate can also enhance the anticancer effect of a therapeutically active antibody, such as herceptin or rituximab.

Another embodiment of the present invention is directed to a pharmaceutical composition effective for inhibiting tumors comprising a CHK1 inhibitor of formulas a and I (including formulas IIa, IIb, IIIa and IIIb), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, solvate, hydrate or prodrug thereof, in combination with radiation therapy. In this embodiment, the compounds of the invention may be administered at the same time or at different times than the radiation treatment.

Another embodiment of the present invention is directed to a pharmaceutical composition useful for the postoperative treatment of cancer comprising a compound represented by formula a and formula I (including formulas IIa, IIb, IIIa and IIIb), stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, or mixtures thereof. The invention also relates to a method of treatment for surgically resecting a tumor and then treating cancer in the mammal with the pharmaceutical composition of the invention.

The pharmaceutical compositions of the present invention include all pharmaceutical formulations containing a compound of the present invention in an amount effective to achieve its intended purpose. Although the needs of each individual person vary, one skilled in the art can determine the optimal dosage for each part of the pharmaceutical formulation. Typically, the compound, or a pharmaceutically acceptable salt thereof, is administered orally to a mammal daily in an amount of from about 0.0025 to 50 mg/kg body weight. But preferably about 0.01 to 10 mg/kg per kg of oral administration. If a known anticancer drug is also administered, the dosage should be effective to achieve its intended purpose. Optimal dosages of these known anticancer drugs are well known to those skilled in the art.

A unit oral dosage may comprise from about 0.01 to 50mg, preferably from about 0.1 to 10 mg, of a compound of the invention. The unit dose may be administered one or more times per day in one or more tablets containing from about 0.1 to 50mg, conveniently from about 0.25 to 10 mg, of a compound of the invention, a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically-labeled compound, or a pharmaceutically acceptable salt thereof, or a mixture of same.

In the external preparation, the concentration of the compound of the present invention may be about 0.01 to 100 mg per gram of carrier.

The compounds of the present invention may be administered as raw pharmaceutical products. The compounds of the present invention may also be administered as part of a suitable pharmaceutical formulation containing pharmaceutically acceptable carriers, including adjuvants and adjuvants. These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutically acceptable pharmaceutical preparations. Preferred pharmaceutical preparations, in particular those of the oral and preferred administration type, such as tablets, dragees and capsules, as well as solutions suitable for injection or oral administration, contain from about 0.01% to 99%, preferably from about 0.25% to 75%, of the active compound and auxiliary substances.

The scope of the present invention also includes non-toxic pharmaceutically acceptable salts of the compounds of the present invention. The acid addition salts are formed by mixing a non-toxic pharmaceutically acceptable acid solution with a solution of a compound of the present invention. Such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like. Base addition salts are formed by combining a non-toxic pharmaceutically acceptable base solution with a solution of a compound of the invention. Such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris-hydroxymethyl-aminomethane, N-methyl-glucamine, and the like.

The pharmaceutical formulations of the present invention may be administered to any mammal as long as they achieve the therapeutic effect of the compounds of the present invention. Of the most important of these mammals are human and veterinary animals, although the invention is not intended to be so limited.

The pharmaceutical formulations of the present invention may be administered by any route to achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical routes. Alternatively or in parallel, oral administration may be performed. The dosage of the drug will depend on the age, health and weight of the patient, the type of concurrent therapy, the frequency of treatment, and the desired therapeutic benefit.

The pharmaceutical formulations of the present invention may be manufactured in a known manner. For example, by conventional mixing, granulating, tableting, dissolving, or lyophilizing processes. In the manufacture of oral formulations, the mixture may be optionally ground in combination with solid excipients and the active compound. After adding an appropriate amount of auxiliary agent if necessary or desired, the mixture of granules is processed to obtain a tablet or lozenge core.

Suitable auxiliary substances are, in particular, fillers, for example sugars such as lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, for example starch pastes, including maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone. If desired, disintegrating agents can be added, such as the starches mentioned above, as well as carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Adjuvants, in particular flow regulators and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycols. If desired, the lozenge cores may be provided with a suitable coating that resists gastric fluids. For this purpose, concentrated saccharide solutions may be used. This solution may contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. For the preparation of a gastric juice resistant coating, a suitable cellulose solution, such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate, may be used. Dyes or pigments may be added to the coating of the tablet or lozenge cores. For example for identifying or for characterizing combinations of doses of active ingredients.

Other orally acceptable pharmaceutical formulations include compression-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerin or sorbitol. The compression-fit capsules may contain the active compounds in the form of granules, mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, for example oils or liquid paraffin, to which stabilizers may be added.

Formulations suitable for parenteral administration include aqueous solutions of the active compounds, such as solutions of water-soluble salts and alkaline solutions. Furthermore, an oily injection suspension of the appropriate active compound may be administered. Suitable lipophilic solvents or vehicles include oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol 400, or hydrogenated castor oil, or cyclodextrins. The aqueous injection suspension may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and/or dextran. Suspension stabilizers may also be included.

According to one aspect of the invention, the compounds of the invention are formulated for topical and parenteral use and are useful in the treatment of skin cancer.

The external preparation of the present invention can be formulated into oils, creams, emulsions, ointments and the like by preferably using a suitable carrier. Suitable carriers include vegetable or mineral oils, white mineral oils (white soft paraffin), branched fats or oils, animal fats and polymeric alcohols (greater than C ₁₂). Preferred carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. In addition, these external preparations may contain a transdermal penetration enhancer. Examples of such enhancers can be found in U.S. patent nos. 3,989,816 and 4,444,762.

The cream is preferably formulated with a mixture of mineral oil, self-emulsifying beeswax and water, mixed with an active ingredient dissolved in a small amount of oil, such as almond oil. An example of a typical cream includes about 40 parts water, 20 parts beeswax, 40 parts mineral oil and 1 part almond oil.

Ointments may be formulated by mixing a vegetable oil containing the active ingredient, such as almond oil, with warm soft paraffin and then allowing the mixture to cool. A typical example of an ointment includes about 30% almond oil by weight and 70% white soft paraffin by weight.

The invention also relates to the use of the compounds of the invention for the manufacture of a medicament for the treatment of diseases, disorders and clinical conditions associated with high intrinsic DNA damage or injury during continuous CHK1 activation or DNA replication. These medicaments may include the pharmaceutical compositions described above.

The following examples are illustrative, but not limiting, of the methods and formulations of the present invention. Other suitable modifications and improvements in the various conditions and parameters normally encountered in clinical therapy will be apparent to those skilled in the art, all within the spirit and scope of the invention.

Examples

General description of the invention

All reagents were of commercial quality and solvents were dried and purified according to standard methods. Mass spectrometry samples were analyzed using a single quadrupole mass spectrometer (shimadzu 2020) with electrospray. ¹ H NMR spectra were recorded using a Wallace 400MHz nuclear magnetic spectrometer and chemical shifts were recorded as TMS as an internal standard (0.00 ppm) starting from low fields in ppm and coupling constant J values in Hz.

Example 1

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine

A) Preparation of tert-butyl 4- (3- ((diphenylmethylene) amino) -7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylate tert-butyl 4- (3-chloro-7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylate (200 mg,0.564 mmol) was dissolved in toluene (5 mL), and benzhydrylamine (153 mg,0.846 mmol), BINAP (70.2 mg,0.113 mmol), pd ₂(dba)₃ (52 mg,0.056 mmol) and Cs ₂CO₃ (552 mg,1.692 mmol) were added and stirred at 100℃for 16 hours under nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE/ea=3/1) to give the target product (crude, 280mg, yellow solid). MS (ESI) 500.25[ M+H ] ⁺.

B) Preparation of tert-butyl 4- (3-amino-7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylate tert-butyl 4- (3- ((diphenylmethylene) amino) -7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylate (230 mg,0.46 mmol) was dissolved in MeOH (3 mL), NH ₂ OH. HCl (64 mg,0.92 mmol) and NaOAc (75.5 mg,0.92 mmol) were added and stirred at room temperature for 45 min. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (PE/ea=1/1) to give the objective product (120 mg, yellow solid, yield: 77%). MS (ESI) 336.05[ M+H ] ⁺.

C) Preparation of 3, 3-bis (methylthio) -1- (1, 5-naphthyridin-4-yl) prop-2-en-1-one t-BuOLi (1.1 g,14.1 mmol) was dissolved in DMSO (20 mL), 1- (1, 5-naphthyridin-4-yl) ethan-1-one (1.1 g,6.4 mmol) was added at room temperature, CS ₂ (585 mg,7.7 mmol) was slowly added after stirring for 30min, maintaining the reaction temperature below 30 ℃. After stirring at 30℃for 2 hours, meI (1.8 g,12.8 mmol) was slowly added, maintaining the reaction temperature below 30 ℃. The reaction solution was stirred at 30 ℃ for 2 hours. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE/ea=3/1) to give the objective product (980 mg, yellow solid, yield: 55%). MS (ESI): 276.90[ M+H ] ⁺.

D) Preparation of 4- (7-fluoro-3- ((1- (methylsulfanyl) -3- (1, 5-naphthyridin-4-yl) -3-oxoprop-1-en-1-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylic acid tert-butyl ester 4- (3-amino-7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylic acid tert-butyl ester (22 mg,0.08 mol) was dissolved in DMF (3 mL) and NaH (60% purity, 12.7mg,0.32 mmol) was added at 0℃and after stirring for 2 hours room temperature was restored. 3, 3-bis (methylthio) -1- (1, 5-naphthyridin-4-yl) prop-2-en-1-one (26.8 mg,0.08 mmol) was slowly added and after stirring for 15 minutes, it was stirred at 80℃for 2 hours. After completion of the reaction, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE/ea=1/2) to give the objective product (30 mg, yellow solid, yield: 77%). MS (ESI) 564.25[ M+H ] ⁺.

E) Preparation of 4- (3- ((5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) amino) -7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylic acid tert-butyl ester (30 mg,0.053 mol) was dissolved in EtOH (3 mL), acOH (10 mg,0.160 mmol) and N ₂H₄·H₂ O (5.3 mg,0.106 mmol) were added at room temperature and stirred for 3 hours under nitrogen protection at 65 ℃. After the reaction was completed, the reaction solution was concentrated to obtain the objective product (crude product, 30mg, yellow solid). MS (ESI) 530.25[ M+H ] ⁺.

F) Preparation of N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine 4- (3- ((5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) amino) -7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-5-yl) piperidine-1-carboxylic acid tert-butyl ester (30 mg,0.057 mmol) was dissolved in DCM (3 mL), TFA (0.6 mL) was added, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by preparative high performance liquid phase (C18, acetonitrile-water=5-55%, 0.1% formic acid) to give the objective compound (15.8 mg, yellow solid, 2 steps yield: 69%).

The compounds of examples 2-58 were prepared in a similar manner. The results are shown below.

Example 59

Inhibition of CHK1 and CHK2 kinases by the compounds of the invention

Detection of CHK1 kinase inhibition Compounds were diluted in a gradient of DMSO in 384 well plates (LABCYTE, # PP-0200) and diluted compounds were each added to 0.05 μl to 384 well plates (Greiner, # 784075) using an Echo 665 instrument to ensure a final DMSO concentration of 1% (double-multiplexed). Then 2.5. Mu.L of 0.25nM CHK1 enzyme (Carna, # 02-117) solution was added to each well, centrifuged at 1000rpm for 1 min and incubated at 25℃for 10 min. To each well, 2.5. Mu.L of a mixed solution of STK-S1 (1. Mu.M)/ATP (20. Mu.M) was added, and the mixture was centrifuged at 1000rpm for 1 minute and reacted at 25℃for 60 minutes. mu.L of Anti-Eu-STK and SA-XL665 solution (Cisbio, #62ST1 PEC) were then added to each well, centrifuged at 1000rpm for 1 min and incubated at 25℃for 60 min. Finally, signal values of 665nm and 620nm are read on a BMG (PHERAstar FSX) enzyme label instrument and are subjected to ratio. Wells containing 1% DMSO and enzyme served as maximum signal controls and wells containing 1% DMSO and buffer served as minimum signal controls.

Detection of CHK2 kinase inhibition Compounds were diluted in a gradient of DMSO in 384 well plates (LABCYTE, # PP-0200) and diluted compounds were each added to 0.05 μl to 384 well plates (Greiner, # 784075) using an Echo 665 instrument to ensure a final DMSO concentration of 1% (double-multiplexed). Then 2.5. Mu.L of 1nM CHK2 enzyme (Carna, # 02-162) solution was added to each well, centrifuged at 1000rpm for 1 min and incubated at 25℃for 10 min. To each well, 2.5. Mu.L of a mixed solution of STK-S1 (1. Mu.M)/ATP (20. Mu.M) was added, and the mixture was centrifuged at 1000rpm for 1 minute and reacted at 25℃for 60 minutes. mu.L of Anti-Eu-STK and SA-XL665 solution (Cisbio, #62ST1 PEC) were then added to each well, centrifuged at 1000rpm for 1 min and incubated at 25℃for 60 min. Finally, signal values of 665nm and 620nm are read on a BMG (PHERAstar FSX) enzyme label instrument and are subjected to ratio. Wells containing 1% DMSO and enzyme served as maximum signal controls and wells containing 1% DMSO and buffer served as minimum signal controls.

The% inhibition was calculated = (ratio _{Maximum signal contrast} -ratio _{Read of Compounds})/(ratio _{Maximum signal contrast} -ratio _{Minimum signal control}) ×100, where the ratio is the ratio of signal values at 665nm and 620nm wavelengths as described above. Data were analyzed using software xlfit5.5.0 and IC ₅₀ values were obtained by fitting the curve equation y=bottom+ (Top-Bottom)/(1+10 ((LogIC ₅₀ -X) HillSlope)).

Table 1 summarizes the inhibition of CHK1 and CHK2 kinase activity by the compounds (IC ₅₀).

TABLE 1

Remarks:/indicates no detection.

Therefore, the compound has good inhibition effect on CHK1 kinase and good selectivity compared with CHK2 through experimental determination.

Example 60

Inhibition of LoVo growth in human colorectal cancer cells by Compounds of the invention

The human colorectal cancer cells LoVo are cultured and passaged to a good growth state, and are used for experiments when the fusion degree reaches about 90%. Cells were digested with pancreatin, centrifuged at 800rpm for 5min, the supernatant discarded, resuspended in fresh medium (RPMI-1640 medium+10% FBS), counted, seeded into 96 well cell culture plates at 10000 cells/195 μl per well and incubated overnight in a 37℃5% CO ₂ incubator. Serial dilutions of the test compound mother liquor were made in DMSO at 1:3 ratio to 8 concentrations, each concentration was added to 120 μl of medium (25-fold dilution) and mixed by shaking. The cells cultured overnight were taken and 5. Mu.L of the diluted compound (DMSO final concentration 1% by weight) was added, respectively. The plates were placed in a 37℃5% CO ₂ incubator for 3 days, then 20. Mu.L of CCK-8 reagent was added to each well, and the incubation was continued after shaking. After 2h, shake for 5 minutes, put into a multifunctional reader to read the absorbance at 450 nm.

Inhibition ratio% = 100- (OD _{Compounds of formula (I)}-OD_Background)/(OD_DMSO-OD_Background) x 100.

Data were analyzed using software xlfit5.5.0 and IC ₅₀ values were obtained by fitting the curve equation y=bottom+ (Top-Bottom)/(1+10 ++ LogIC 50-X) HillSlope.

Table 2 summarizes the inhibition data (IC ₅₀) of the growth of the human colorectal cancer cells LoVo by the compounds.

TABLE 2

Therefore, the compound has good inhibition effect on LoVo cell growth through experimental determination.

While the invention has been fully described, it will be appreciated by those skilled in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety.

Claims

1. A compound of formula a, a stereoisomer thereof, an isotopically-labeled compound or a pharmaceutically acceptable salt thereof, or a mixture thereof:

Wherein:

A ₁ is selected from N and CR ₁;

A ₂ is selected from N and C;

Q ₁ is selected from NR _a, O, and S;

Q ₂ is selected from NR _a, CH, O, and S;

R _a is independently selected from hydrogen and optionally substituted C _1-4 alkyl.

2. The compound, stereoisomer, isotopically-labeled compound, or pharmaceutically-acceptable salt thereof, or mixture thereof of claim 1, wherein the compound of formula a has a structure represented by formula I:

Wherein a ₁ is selected from N and CR ₁;

A ₂ is selected from N and C;

q is selected from NR _a, O and S;

3. The compound, stereoisomer, isotopically-labeled compound, or pharmaceutically-acceptable salt thereof, or mixture thereof, of claim 1 or 2, wherein:

R ₁ is hydrogen, halogen, optionally substituted C _1-4 alkyl or optionally substituted C _1-4 alkoxy, preferably R ₁ is H, halogen, halogenated C _1-4 alkyl, hydroxy-substituted C _1-4 alkyl, halogenated C _1-4 alkoxy or hydroxy-substituted C _1-4 alkoxy, and/or

A ₁ is N or CR ₁, wherein R ₁ is hydrogen, halogen, optionally substituted C _1-4 alkyl or optionally substituted C _1-4 alkoxy, preferably A ₁ is N, CH or CF, preferably A ₁ is N, A ₂ is C, and/or

Q is NH or O, and/or

R _a is H.

4. The compound, stereoisomer, isotopically-labeled compound, or pharmaceutically-acceptable salt thereof, or mixture thereof, of claim 1 or 2, wherein:

Preferably, the Z ₁ ring is an optionally substituted 5-6 membered heteroaryl or an optionally substituted 5-10 membered heterocyclyl, and preferably, the Z ₁ ring is an optionally substituted 5-6 membered heteroaryl or an optionally substituted 5-10 membered heterocyclyl wherein A ₂ is C;

Preferably, A ₂ in the Z ₁ ring is C and the Z ₁ ring is A5-6 membered heteroaryl group containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S, or A ₂ in the Z ₁ ring is C and the Z ₁ ring is A5-10 membered heterocyclyl group containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S, preferably the 5-10 membered heterocyclyl group is a 7-10 membered spiroheterocyclyl group containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S;

Preferably, the number of substituents is 1,2, 3 or 4 when the 5-6 membered heteroaryl and 5-10 membered heterocyclyl are substituted, selected from halogen, cyano, =o, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkoxy, optionally substituted C _3-8 cycloalkyl and optionally substituted heterocyclyl, preferably the optionally substituted C _1-6 alkyl is optionally substituted with 1, 2.3 or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclyl and-NR' R ", wherein the heterocyclyl is a nitrogen and/or oxygen containing 4-10 membered heterocyclyl, preferably a nitrogen and/or oxygen containing 4-7 membered heterocyclyl, preferably substituted with 1,2,3 or 4 substituents selected from halogen, hydroxy, cyano, C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy, Halogenated C _1-4 alkoxy, optionally substituted C _3-4 cycloalkyl (e.g. optionally substituted with 1, 2 or 3 groups selected from halogen, C _3-4 cycloalkyl of C _1-4 alkyl and haloC _1-4 alkyl) and optionally substituted C _1-3 acyl (e.g., haloC _1-3 acyl), R 'and R' are each preferably independently selected from hydrogen, c _1-4 alkyl and haloC _1-4 alkyl, said optionally substituted C _3-8 cycloalkyl optionally substituted with 1, 2, 3 or 4 groups selected from halogen, hydroxy, cyano, C _1-4 alkyl, Substituted with a substituent selected from the group consisting of halo C _1-4 alkyl, C _1-4 alkoxy and halo C _1-4 alkoxy, said optionally substituted heterocyclyl being a 4-10 membered monocyclic or bicyclic heterocyclyl, a 7-10 membered spiro heterocyclyl or a 7-10 membered bridged heterocyclyl, each of which is optionally substituted with 1, 2.3 or 4 are selected from halogen, hydroxy, cyano, C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, Optionally substituted C _3-4 cycloalkyl (e.g., optionally substituted with 1,2 or 3 groups selected from halogen, C _3-4 cycloalkyl of C _1-4 alkyl and halo C _1-4 alkyl) and optionally substituted C _1-3 acyl (e.g., halo C _1-3 acyl);

Preferably, the said Selected from the following groups:

Wherein, represents the connection position of the group and the amino group on the 5 membered heteroaryl containing Q of the compound, B ₁ and B ₂ are each independently selected from N and CR ₂, wherein each R ₂ is independently selected from hydrogen, Halogen, cyano, optionally substituted C _1-4 alkyl and optionally substituted C _1-4 alkoxy, R ₃ is selected from hydrogen, Optionally substituted C _1-4 alkyl and optionally substituted C _3-4 cycloalkyl, R ₄ and R ₅ are each independently selected from hydrogen and optionally substituted C _1-4 alkyl, or R ₄ and R ₅ together with the attached C form C _3-4 cycloalkyl, R ₆ and R ₇ are each independently selected from optionally substituted 4-10 membered mono-or bicyclic heterocyclyl, Optionally substituted 7-10 membered spirocyclic heterocyclyl, optionally substituted 7-10 membered bridged cyclic heterocyclyl and optionally substituted C _1-6 alkyl.

5. The compound, stereoisomer, isotopically-labeled compound, or pharmaceutically-acceptable salt thereof, or mixture thereof of claim 4 wherein:

Each of the 4-10 membered monocyclic or bicyclic heterocyclyl, 7-10 membered spiroheterocyclyl and 7-10 membered bridged heterocyclyl in the definition of R ₆ and R ₇ is optionally substituted with 1,2, 3 or 4 substituents selected from halogen, hydroxy, cyano, C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, optionally substituted C _3-4 cycloalkyl (e.g., C _3-4 cycloalkyl optionally selected from halogen, C _1-4 alkyl and halo C _1-4 alkyl) and optionally substituted C _1-3 acyl (e.g., halo C _1-3 acyl);

The optionally substituted C _1-6 alkyl in the definition of R ₆ and R ₇ is optionally substituted with 1,2,3 or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclyl and-NR 'R', preferably the heterocyclyl is a nitrogen and/or oxygen containing 4-10 membered heterocyclyl, preferably a nitrogen and/or oxygen containing 4-7 membered heterocyclyl, preferably the heterocyclyl is substituted with 1,2,3 or 4 substituents selected from halogen, hydroxy, C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy and halo C _1-4 alkoxy, R 'and R' are as defined herein, preferably each independently selected from hydrogen, C _1-4 alkyl and halo C _1-4 alkyl;

Preferably, R ₆ is selected from the following groups:

Wherein R ₈ is selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 cycloalkyl and optionally substituted C _1-3 acyl, preferably hydrogen, C _1-4 alkyl, deuterated C _1-4 alkyl, cyclopropyl or C _1-3 acyl;

preferably, R ₇ is selected from the following groups:

6. The compound, stereoisomer, isotopically-labeled compound, or pharmaceutically-acceptable salt thereof, or mixture thereof, of claim 1 or 2, wherein:

(1) Cy is an optionally substituted 5-12 membered heteroaryl or an optionally substituted 9-12 membered heterocyclyl, preferably a 9-12 membered bicyclic heteroaryl or a 9-12 membered bicyclic heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, preferably when Cy is substituted the number of substituents is 1, 2, 3 or 4, the substituents being selected from = O, halogen, optionally substituted C _1-4 alkyl (e.g. halogenated C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _1-4 alkoxy (e.g. halogenated C _1-4 alkoxy or deuterated C _1-4 alkoxy);

Preferably, cy is:

Wherein represents the position of attachment of said group to the remainder of the compound; Represents a single bond or a double bond, D ₁、D₂ and D ₃ are each independently selected from N and CR ₉, wherein R ₉ is selected from the group consisting of =O, Hydrogen, halogen, optionally substituted C _1-4 alkyl and optionally substituted C _1-4 alkoxy, preferably hydrogen, =o, fluorine, Methoxy or deutero methoxy, E ₁ and E ₂ are each independently selected from C and N and are not simultaneously N, X ₁ and X ₂ are each independently selected from O, S, NR ₁₀ and CR ₁₁R₁₂, wherein R ₁₀ is selected from hydrogen, Optionally substituted C _1-4 alkyl and optionally substituted C _3-5 cycloalkyl, R ₁₁ and R ₁₂ are each independently selected from hydrogen, Optionally substituted C _1-4 alkyl and optionally substituted C _1-4 alkoxy, or R ₁₁ and R ₁₂ form with the attached C a C _3-4 cycloalkyl group, Y is selected from C=O, C=s and CR ₁₃R₁₄, wherein R ₁₃ and R ₁₄ are each independently selected from hydrogen, Optionally substituted C _1-4 alkyl (e.g., halo C _1-4 alkyl or deuterated C _1-4 alkyl) and optionally substituted C _1-4 alkoxy, or R ₁₃ and R ₁₄ form with the attached C _3-4 cycloalkyl, preferably Y is C=O, Z ₂ ring is selected from optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl;

Preferably, the method comprises the steps of, Selected from the following groups:

Wherein represents the position of attachment of said group to the remainder of the compound, or

(2) Cy is an optionally substituted 5-6 membered nitrogen containing heteroaryl, preferably when the heteroaryl is substituted, the number of substituents is 1,2,3 or 3, selected from halogen, optionally substituted C _1-4 alkyl and optionally substituted C _1-4 alkoxy;

Preferably, cy is:

wherein, represents the position of attachment of the group to the remainder of the compound, D ₁、D₂ and D ₃ are each independently selected from N and CR ₉, and at least one of D ₁ and D ₃ is N, R ₉ is selected from hydrogen, halogen, optionally substituted C _1-4 alkyl and optionally substituted C _1-4 alkoxy, preferably hydrogen, fluoro, methoxy or deuteromethoxy, R ₁₅ is selected from hydrogen, halogen, optionally substituted C _1-4 alkyl and optionally substituted C _1-4 alkoxy, preferably fluoro, difluoromethyl, methoxy or deuteromethoxy;

7. The compound, stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically-labeled compound, or pharmaceutically acceptable salt thereof, or mixture of same, according to claim 1 or 2, wherein said compound is a compound represented by formula IIa, IIb, IIIa or IIIb below, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically-labeled compound, or pharmaceutically acceptable salt thereof, or mixture of same:

The D ₁、D₂、D₃、E₁、E₂、Q、X₁、X₂、Y、Z₁ ring and Z ₂ ring of formulae IIa and IIb being as defined in any one of claims 1 to 6, and the ,B₁、R₂、R₆、D₁、D₂、D₃、E₁、E₂、X₁、X₂ and Y of formulae IIIa and IIIb being as defined in any one of claims 1 to 6; represents a single bond or a double bond.

8. The compound, stereoisomer, isotopically-labeled compound, or pharmaceutically-acceptable salt thereof, or mixture thereof of claim 1, wherein the compound is selected from the group consisting of:

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (1-methylpiperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

7-fluoro-N- (5- (3-methoxypyridin-4-yl) -1H-pyrazol-3-yl) -5- (1-methylpiperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

7-fluoro-N- (5- (3-methoxypyridin-4-yl) -1H-pyrazol-3-yl) -5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- (piperidin-4-ylmethyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (3-methoxypyridin-4-yl) -1H-pyrazol-3-yl) -5- (piperidin-4-ylmethyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- (pyrrolidin-3-ylmethyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- (azetidin-3-ylmethyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

3- ((5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) amino) -5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazine-7-carbonitrile;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-chloro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-methyl-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- (6-azabicyclo [3.1.1] hept-3-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- (3-azabicyclo [3.1.1] hept-6-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- (2-amino-2-methylpropyl) -7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- (3-amino-3-methylbutyl) -7-fluoro-5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (2-azaspiro [3.3] hept-6-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (tetrahydro-2H-pyran-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (2, 3-dihydrofuro [3,2-b ] pyridin-7-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- ([ 1,3] dioxabicyclo [4,5-b ] pyridin-7-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridin-8-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (3, 4-dihydro-2H-pyrido [3,2-b ] [1,4] oxazin-8-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

7-fluoro-N- (5- (furo [3,2-b ] pyridin-7-yl) -1H-pyrazol-3-yl) -5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

7-fluoro-N- (5- (oxazolo [4,5-b ] pyridin-7-yl) -1H-pyrazol-3-yl) -5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

7-fluoro-N- (5- (oxazolo [5,4-b ] pyridin-7-yl) -1H-pyrazol-3-yl) -5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

7-fluoro-N- (5- (imidazo [1,2-a ] pyridin-8-yl) -1H-pyrazol-3-yl) -5- (1-methylpiperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

7-fluoro-N- (5- (imidazo [1,2-a ] pyridin-8-yl) -1H-pyrazol-3-yl) -5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

4- (3- ((7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-yl) amino) -1H-pyrazol-5-yl) pyrido [2,3-b ] pyrazin-3 (4H) -one;

4- (3- ((7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-yl) amino) -1H-pyrazol-5-yl) -2H-pyrido [3,2-b ] [1,4] oxazin-3 (4H) -one;

n- (5- (2, 3-dihydro-4H-pyrido [3,2-b ] [1,4] oxazin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -1- (1-methylpiperidin-4-yl) -1H-imidazo [4,5-b ] pyrazin-6-amine;

n- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -1- (piperidin-4-yl) -1H-pyrazolo [3,4-b ] pyrazin-6-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -6- (1-methylpiperidin-4-yl) imidazo [1,5-a ] pyrimidin-3-amine;

5- ((5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) amino) -1-methyl-3- (piperidin-4-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyrazin-2-one;

5- ((5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) amino) -3- (piperidin-4-yl) oxazolo [4,5-b ] pyrazin-2 (3H) -one;

5- ((5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) amino) -3- (piperidin-4-yl) thiazolo [4,5-b ] pyrazin-2 (3H) -one;

3' - ((5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) amino) -5' - (piperidin-4-yl) spiro [ cyclopropane-1, 7' -pyrrolo [2,3-b ] pyrazin-6 ' (5 ' H) -one;

n- (5- (1, 6-naphthyridin-8-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (1, 7-naphthyridin-8-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (1, 6-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (1, 7-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (1, 8-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (piperidin-4-ylmethyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (imidazo [1,2-a ] pyridin-8-yl) -1H-pyrazol-3-yl) -5- (piperidin-4-ylmethyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (2, 3-dihydrofuro [3,2-b ] pyridin-7-yl) -1H-pyrazol-3-yl) -5- (piperidin-4-ylmethyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (3, 4-dihydro-2H-pyrido [3,2-b ] [1,4] oxazin-8-yl) -1H-pyrazol-3-yl) -5- (piperidin-4-ylmethyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- ((4-fluoropiperidin-4-yl) methyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- ((3-fluoroazetidin-3-yl) methyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

5- (1, 5-naphthyridin-4-yl) -N- (5- (piperidin-4-ylmethyl) -5H-pyrrolo [2,3-b ] pyrazin-3-yl) isoxazol-3-amine;

n- (7-fluoro-5- (piperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-yl) -5- (1, 5-naphthyridin-4-yl) isoxazol-3-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- ((1-methylpiperidin-4-yl) methyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (7-fluoro-5- (1-methylpiperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-yl) -5- (1, 5-naphthyridin-4-yl) thiazol-2-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -5- ((1- (2, 2-trifluoroethyl) piperidin-4-yl) methyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

n- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (1-methylazetidin-3-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (1-methylpyrrolidin-3-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

N- (5- (1, 5-naphthyridin-4-yl) -1H-pyrazol-3-yl) -7-fluoro-5- ((1-methylazetidin-3-yl) methyl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine;

and N- (5- (2, 3-dihydrofuran [3,2-b ] pyridin-7-yl) -1H-pyrazol-3-yl) -7-fluoro-5- (1-methylpiperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-3-amine.

9. The use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment or prevention of diseases, disorders and conditions associated with high intrinsic DNA damage or injury during continuous activation of CHK1 or DNA replication, preferably wherein the diseases, disorders and conditions are cancer;

Preferably, the cancer is selected from liver cancer, melanoma, hodgkin's disease, non-hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, wilms 'tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myelogenous leukemia, primary brain cancer, malignant melanoma, stomach cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mushroom, granulation zhong, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myelogenous leukemia, hairy cell leukemia, rhabdomyosarcoma, kaposi's sarcoma, genitourinary system tumor, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenal cortex cancer, skin cancer, and prostate cancer;

Preferably, the medicament further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt of the anticancer drug; preferably, the anticancer drug is selected from one or more of the following group: busulfan, marflange, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecine, irinotecan, topotecan, doxorubicin, epirubicin, aclacinomycin, mitoxantrone, methylhydroxy ellipticine, mintopril, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2' -deoxyuridine, fludarabine, nelarabine, cytarabine, pramipexole, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, sapercalcaine, cabazitaxel, docetaxel, monoclonal antibodies, panitumumab, toxaban, drug antibodies nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, oxybutynin You Tuozhu mab, ofatuzumab, rituximab, alemtuzumab, tiimumab, tositumomab, bentuximab, darimumab, erltuzumab, T-DM1, ofatumumab, dinutuximab, blinatumomab, eplimumab, avastin, herceptin, mevalhua, imatinib, gefitinib, erlotinib, olmitinib, afatinib, ceritinib, ai Leti, crizotinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, tematide, everolimus, vorinostat, luo Mi ditin, panobinostat, belinostat, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenicum, zoledronic acid, bortezomib, carfilzomib, ixazomib, valmod gemi, sonideji, dieldolast, salvain, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipueucel-T (prostate cancer therapeutic vaccine), palbociclib, olapanib, niraparib, rucaparib, talazoparib and Senaparib;

Preferably, the medicament is used in combination with radiation therapy.

10. A pharmaceutical composition comprising a compound of any one of claims 1-8 and a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt of said anticancer drug; preferably, the at least one known anticancer drug is selected from the group consisting of: busulfan, malayan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecan, irinotecan, topotecan, doxorubicin, epirubicin, aclacin, mitoxantrone, methylhydroxy ellipticine, mintopypril, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2' -deoxyuridine, fludarabine, nelarabine, cytarabine, prazotinib, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, salbutaline, cabazitaxel, bevacizumab, fluzab, oxob, oxydant, crizotinib, 5-zetimibe, flunix, daclizumab, 5-zetimibe, daclizumab, zetimiben, daclizumab, zetimiben, daclizumab, zetimab, daclix, daclizumab, drug, daclizumab, zetimab, drug-to-the drug-to-be-to-the drug-be-to be-the-be-droxivain-to be-to-be-the-droxivain-to-be-to-the-drug-the-of-drug-of-the-of-the-of- -of-the- -of- -, nilotinib, dasatinib, pazopanib, tecavidine, everolimus, vorinostat, luo Mi desine, panobinostat, belinostat, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenical, zoledronic acid, bortezomib, carfilzomib, ixazomib, verapamil, sonideji, dieldrake, salvamine, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipueucel-T (prostate cancer therapeutic vaccine), palbociclib, olaparib, niraparib, rucaparib, talazoparib and Senaparib.