Process for the preparation of pyrimidine compounds and their use

Abstract

The application discloses a preparation method and application of a pyrimidine compound, and belongs to the field of medicines. The structural general formula of the compound is shown as formula I. The application also provides the use of the compounds in the preparation and manufacture of medicines or pharmaceutical compositions for treating, preventing acute or chronic diseases and disorders, including but not limited to cancer. Therefore, the compound of the application can be used for manufacturing anticancer medicines.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to a method for preparing a class of pyrimidine compounds and their application as anticancer agents. Background Technology

[0002] The kinesin superfamily plays a crucial role in cell mitosis. Among them, subprotein 18A, a member of the kinesin subfamily, regulates the distribution and division of spindle microtubules by influencing microtubule-based movement and microtubule dynamics during mitosis (PANS, October 23, 2017, 114(45)E9539-E9548), and plays an important role in tumorigenesis, proliferation, differentiation, and metastasis. This subprotein is abnormally highly expressed in numerous cancer cells, including breast cancer, colorectal cancer, ovarian cancer, head and neck cancer, lung cancer, liver cancer, and malignant glioma (Cancer Cell Int. 2020 Apr 15;20:113, Front. Genet., 08 April 2022, IUBMB Life 2019, 71, 942-955, Medicine). , 99(4):pe19011, January 2020), and also plays an important role in the autoimmune system (Biomolecules 2023, 13(2), 326). In addition, studies have found that this subprotein plays an important role in maintaining the stability of cancer cell chromosomes, and is essential for the proliferation of aneuploid cancer cells, but not for the survival of normal euploid somatic cells (Nature 590,486–491, 2021, Nat Commun 11, 1113,2021, Nature Cancer, volume 5, pages66–84, 2024). Based on the above findings, selective inhibition of this subprotein may be an anticancer therapy with broad therapeutic potential and safety. Currently, there are no drugs based on this target on the market worldwide. Therefore, the development of selective inhibitors of this subprotein is of great significance for meeting the clinical needs of patients. Summary of the Invention

[0003] The object of this invention is to provide a new class of compounds and their stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates and solvates, prodrugs or deuterated derivatives. These compounds possess regulatory activity against members of the kinin subfamily, and in particular, inhibitory activity against the kinin subfamily member 18A subprotein. To this end, the invention also provides the use of these compounds in the preparation and manufacture of medicaments or pharmaceutical compositions for the treatment or prevention of acute or chronic diseases and disorders (including but not limited to cancer) mediated by this subprotein. Therefore, the compounds of this invention can be used in the manufacture of anticancer drugs.

[0004] The first aspect of the present invention is to provide a class of compounds and their stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates and solvates, prodrugs or deuterated derivatives.

[0005] The compounds provided by this invention have the general structural formula as shown in Formula I:

[0006]

[0007] R 1 Selected from groups ZR 6 Z is independently selected from C0 6-alkylene , C0 6-alkylene NR 7 C0 6-alkylene , C0 6-alkylene NR 7 SO2 C0 6-alkylene , C0 6-alkylene SO2NR 7 C0 6-alkylene , C0 6-alkylene NR 7 SO2NR 7 C0 6-alkylene , C0 6-alkylene NR 7 SO2NR 7 C(=O) O C0 6-alkylene , C0 6-alkylene NR 7 S(=O) (=NH) C0 6-alkylene , C0 6-alkylene S(=O) (=NH) C0 6-alkylene , C0 6-alkylene S C0 6-alkylene , C0 6-alkylene S(=O) C0 6-alkylene , C0 6-alkylene SO2 C0 6-alkylene , C0 6-alkylene O C0 6-alkylene , P , C0 6-alkylene P(=O)(R 7 ) , C0 6-alkylene P(=O)2、 C0 6-alkylene (C=O) C0 6-alkylene , C0 6-alkylene (C=O) O C0 6-alkylene , C0 6-alkylene (C=O)NR 7 C0 6-alkylene , C0 6-alkylene NR 7 (C=O) C0 6-alkylene or C(=N OH) ; or the group ZR 6 for N = S (= O) (R 6 )2, where two R 6 Alternatively, they can be combined with the carbon atoms to which they are attached to form saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic rings containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S. Among them, R 6 Hydrogen, halogen, hydroxyl, cyano, R 6a or R 6b ; R 7 For hydrogen, R 7a or R 7b ; R 3 Selected from hydrogen, halogen, cyano, C1 8-alkyl, OC1 8-alkyl, C1 4-Halogenated Alkyl Groups OR 3a , OR 3b , C0 6-alkylene (C=O)N(C0 6-alkyl)2, C0 6-alkylene SO2N(C0 6-alkyl)2, R 3a or R 3b ; and R 3 and R 4 They can combine with their respective attached carbon atoms to form saturated or partially saturated 5- or 6-membered monocyclic rings fused with benzene rings or heteroaromatic rings; wherein the 5- or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, and further, wherein the hydrogen on the 5- or 6-membered monocyclic ring is substituted by 0, 1, 2, or 3 groups selected from: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OR a , OC1 4-Hydroalkyl, -CN, NR a R b Or oxygenation; R 4 Selected from hydrogen, halogen, cyano, 5 6-membered heteroaryl, phenyl, SR a , SF5, nitro, hydroxyl, C1 8-alkyl, C3 8-cycloalkyl, C3 8-Halogenated cycloalkyl group, C3 with at least two deuterated hydrogen atoms on the carbon atom. 8-Halogenated cycloalkyl, C1 4. Haloalkyl group, C1 with at least two hydrogens on the carbon atom deuterated 4-Halogenated Alkyl Groups OC1 8 alkyl groups, with at least two hydrogen atoms on the carbon atom being deuterated. OC1 8-alkyl, OC3 8-cycloalkyl group, with at least two hydrogen atoms on the carbon atom replaced by deuterium. OC3 8-cycloalkyl, OC1 8-Hydroalkyl, OC3 8-Halogenated cycloalkyl groups NR a R b , NR a C(O)R b , C(O)NR a R b , OC(O)R a , C(O)R a , P(O)R a R b , C(O)OR a , S(O)R a , S(O)2R a and S(O)2NR a R b R 4aor R 4b The hydrogen atoms on the 5-6 heteroaryl group and the phenyl group are substituted by 0, 1, 2, or 3 groups selected from the following: halogen, C1... 6-alkyl, C1 4-Halogenated Alkyl Groups OR a , OC1 4-Hydroalkyl, CN, NR a R b Or oxidized; or alternatively, and R 3 With R 4 They can combine with their respective attached carbon atoms to form saturated or partially saturated 5- or 6-membered monocyclic rings fused with benzene rings or heteroaromatic rings; wherein the 5- or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, and further, wherein the hydrogen on the 5- or 6-membered monocyclic ring is substituted by 0, 1, 2, or 3 groups selected from: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OR a , OC1 4-Hydroalkyl, -CN, NR a R b Or oxygenation; R 5 Halogen or group Y R 8 , where Y is C0 7-alkylene , C3 7-cycloalkylene , C0 6-alkylene NR 9 C0 6-alkylene , C0 6-alkylene NR 9 C3 7-cycloalkylene , C0 6-alkylene O C0 6-alkylene , C0 6-alkylene O C3 7-cycloalkylene , C0 6-alkylene S C0 6-alkylene , C0 6-alkylene S C3 7-cycloalkylene , C0 6-alkylene S(=O) C0 6-alkylene , C0 6-alkylene S(=O) C3 7-cycloalkylene , C0 6-alkylene S(=O)2 C0 6-alkylene , C0 6-alkylene S(=O)2 C3 7-cycloalkylene , C0 6-alkylene SO2NR 9 C0 6-alkylene , C0 6-alkylene SO2NR 9 C3 7-cycloalkylene , C0 6-alkylene S(=O) (=NH) , C0 6-alkylene NR 9 SO2 C0 6-alkylene , C0 6-alkylene NR 9 SO2 C3 7-cycloalkylene , C0 6-alkylene NR 9 SO2NR 9 C0 6-alkylene , C0 6-alkylene NR 9 SO2NR 9 C3 7-cycloalkylene , C0 6-alkylene C(=O) C0 6-alkylene , C0 6-alkylene C(=O) C3 7-cycloalkylene , C0 6-alkylene NR 9 C(=O) C0 6-alkylene , C0 6-alkylene NR 9 C(=O) C3 7-cycloalkylene , C0 6-alkylene (C=O)NR 9 C0 6-alkylene or C0 6-alkylene C(=O) O C0 6-alkylene ;or Y R 8 for N = S (= O) (R 8 )2, where two R 8 Alternatively, they can be combined with the carbon atoms to which they are attached to form saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic rings containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S. Among them, R 8 Hydrogen, halogen, cyano, R 8a or R 8b ; R 9 For hydrogen, R 9a or R 9b ; Ring A is a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms; R 3a R 4a R 6a R 7a R 8a R 9a Each of the following groups is independently selected: saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, wherein the hydrogen atom on the carbon atom is substituted by 0, 1, 2, or 3 groups selected from: halogen, cyano, amino, C1 6-alkyl, C3 6-cycloalkyl, C1 6-Hydroalkyl, C3 6-Halogenated cycloalkyl groups OR a , OC1 6-Hydroalkyl, C(=O)R b , C(=O)OR a , C(=O)NR a R b , C(=NR a )NR a Rb , OC(=O)R b , OC(=O)NR a R b , OC2 6-alkylene NR a R b , OC2 6-alkylene OR a , SR a , S(=O)R b , S(=O)2R b , S(=O)2NR a R b , NR a R b , N(R a )C(=O)R b , N(R a )C(=O)OR b , N(R a )C(=O)NR a R b , N(R a )C(=NR a )NR a R b , N(R a )S(=O)2R b , N(R a )S(=O)2NR a R b , NR a C2 6-alkylene NR a R b , NR a C2 6-alkylene OR a , C1 6-alkylene NR a R b , C1 6-alkylene ORa , C1 6-alkylene N(R) a )C(=O)R b , C1 6-alkylene OC(=O)R b , C1 6-alkylene C(=O)NR a R b , C1 6-alkylene C(=O)OR a R 10 And oxygenation; R 3b R 4b R 6b R 7b R 8b R 9b C1 groups that are independently substituted by 0, 1, 2, 3, 4, or 5 groups selected from the following groups. 6-alkyl, C3 6-cycloalkyl groups: deuterium, halogen, cyano, C1 6-alkyl, C3 6-cycloalkyl, C1 6-Hydroalkyl, C1 6-Halogenated cycloalkyl groups C0 6NR a R b , OR a , C(=O)OR a And saturated, partially saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic rings; R 10 Independently selected from the group consisting of: saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, wherein the hydrogen atoms are substituted by 0, 1, 2, or 3 groups selected from: halogen, cyano, amino, C1 6-alkyl, C1 6-Hydroalkyl, OR a , OC1 6-Hydroalkyl, C(=O)R b , C(=O)OR a , C(=O)NR a R b , C(=NR a )NR a R b , OC(=O)R b , OC(=O)NR a R b , OC2 6alkyleneNR a R b , OC2 6alkyleneOR a , SR a , S(=O)R b , S(=O)2R b , S(=O)2NR a R b , NR a R b , N(R a )C(=O)R b , N(R a )C(=O)OR b , N(R a )C(=O)NR a R b , N(R a )C(=NR a )NR a R b , N(R a )S(=O)2R b , N(R a )S(=O)2NR a R b , NR a C2 6alkyleneNR a R b , NR a C2 6-alkylene OR b , C1 6-alkylene NR a R b , C1 6-alkylene OR a , C1 6-alkylene N(R) a )C(=O)R b , C1 6-alkylene OC(=O)R b , C1 6-alkylene C(=O)NR a R b , C1 6-alkylene C(=O)OR a And oxygenation; R 2 Choose from the following groups: hydrogen,

[0008] or R 2 C2 substituted with 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of the following. 8. Alkyl groups: Halogen, Cyano, Amino, C1 6-alkyl, C1 6-Hydroalkyl, C3 6-Halogenated cycloalkyl groups OR a , NR a R b , C(=O)OR a , OC1 4-Halogenated alkyl or R 11n ; or R 2 A phenyl or an unsaturated 5-membered monocyclic phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups selected from the group consisting of: halogen, cyano, amino, C1 6-alkyl, C1 6-Hydroalkyl, OR a , NR a R b , C(=O)OR a , OC1 4-Halogenated alkyl or R 11n The 5-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S. R 11a R 11b R 11c R 11d R 11e R 11f R 11g R 11h R 11i R 11j R 11k R 11l R 11m Each of these elements is independently hydrogen, halogen, hydroxyl, or R. 11o or R 11p ; Alternatively, R 11a and R 11b Yes, R 11c and R 11d Yes, R 11e and R 11f Yes, R 11g and R 11h Yes, R 11i and R 11j and R 11k and R 11l Each pair can independently combine with its respective attached carbon atom to form a screw-in connection to R. 2 A saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring; wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further, wherein the 3-, 4-, 5-, or 6-membered monocyclic ring is substituted by 0, 1, 2, or 3 groups selected from: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OR a , OC1 4-Hydroalkyl, CN, NR a R b Or oxidized; or alternatively, R 11a and R 11b Yes, R 11c and R 11d Yes, R 11e and R 11f Yes, R 11g and R 11h Yes, R 11i and R 11j Yes, and R11k and R 11l Each pair in the pair can independently combine to form a double bond; The R 11n and R 11o The carbon atoms that can be connected to them and the saturated monocyclic rings in which they reside can form 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered saturated bicyclic rings; or alternative R... 11n and R 11o It can be independently selected from saturated, partially saturated, or unsaturated 3-membered, 4-membered, 5-membered, 6-membered, and 7-membered monocyclic rings or 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered bicyclic rings; wherein the monocyclic or bicyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further, wherein the monocyclic or bicyclic ring is substituted by 0, 1, 2, 3, or 4 groups selected from: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OR a , OC1 4-Hydroalkyl, CN, C(=O)OR a , C(=O)R b , C(=O)NR a R b , C(=NR a )NR a R b , OC(=O)R b , OC(=O)NR a R b , OC2 6-alkylene NR a R b , NR a R b , OC2 6OR a , SR a , S(=O)R b , S(=O)2R b , S(=O)2NR a R b , NRa C(=O)R b , NR a C (=O)OR b , NR a C (=O)NR a R b , NR a C(=NR a )NR a R b , NR a S(=O)2NR b , NR a S(=O)2NR a R b , R a C2 6-alkylene NR a R b , NR a C2 6-alkylene OR a , C1 6-alkylene NR a R b , C1 6-alkylene OR a , C1 6-alkylene OC(=O)R b , C1 6-alkylene NR a C(=O)R b , C1 6-alkylene NR a C(=O)NR a R b , C1 6-alkylene C(=O)OR a Or oxygenation; R 11p It can be independently selected from 0, 1, 2, 3, 4 or 5 elements selected from halogens, C1 4-Hydroalkyl, CN, C(=O)OR a , OR a , OC1 4-Halogenated alkyl or NR a R b C1 with substituent group 8-alkyl; R a It can be independently selected from H and R. b -C(O)R b -P(O)(OR) b )2, -P(O)(ONa)2, -CH2P(O)(OR b )2、 -CH2P(O)(ONa)2; R b Independently selected from C1 6-alkyl, C3 7. Cycloalkyl, phenyl, or benzyl, wherein the C1 6-alkyl, C3 The hydrogen atom on the 7-cycloalkyl group is substituted by not less than two deuterium groups or by 0, 1, 2, or 3 substituents selected from the following: halogen, hydroxyl, ... OC1 6-alkyl, NH2, NHC1 6-alkyl, OC(=O)C1 6-alkyl or N(C1 6-alkyl)C1 6-alkyl, 5-6-membered heteroaryl; and the phenyl or benzyl group is substituted by 0, 1, 2 or 3 substituents selected from the following: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OH、 OC1 6-alkyl, NH2, NHC1 6-alkyl, OC(=O)C1 6-alkyl or N(C1 6-alkyl)C1 6-alkyl, 5-6-membered heteroaryl.

[0009] In some preferred embodiments of the present invention, the compounds represented by Formula I, their stereoisomers, tautomers, and pharmaceutically acceptable salts, hydrates and solvates, prodrugs, or deuterated derivatives, have the following structures:

[0010] Among them, R 1 R 2 R 3 R 4 R 5 The definition of ring A is as described above; In some preferred embodiments of the present invention, R 1 for ZR 6 Z and R 6 As described in Solution 1 of this invention.

[0011] Z is selected from C0 6-alkylene NHC0 6-alkylene , C0 6-alkylene NHSO2 C0 6-alkylene , C0 6-alkylene SO2NHC0 6-alkylene , C0 6-alkylene S(=O) (=NH) C0 6-alkylene , C0 6-alkylene SO2 C0 6-alkylene ; Preferably, Z is NH , NHSO2 , SO2NH , S(=O) (=NH) , SO2 , CH2SO2 ; Ideally, Z is NHSO2 , SO2NH ; The R6 Selected from halogens, hydroxyl groups, R 6a Or R 6b ;where R 6a Selected from: saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic rings containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, or substituted by 0, 1, 2, or 3 groups selected from: halogen, hydroxyl, C1 6-alkyl, C1 6-Haloalkyl; R 6b For independent C1 substitution by 0, 1, 2, 3, 4 or 5 of the following groups 6-alkyl, C3 6-cycloalkyl groups: deuterium, halogen, hydroxyl, C1 6-alkyl groups, and saturated, partially saturated or unsaturated 3-, 4-, 5-, or 6-membered monocyclic rings; preferably, the 3-, 4-, 5-, or 6-membered monocyclic rings are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl in sequence. Ideally, R 6 Selected from: C1 6-alkyl, C3 6-cycloalkyl, C1 6-alkylene C3 6-cycloalkyl, 4 6-membered heterocyclic alkyl, C1 6-cycloalkylene C1 6-alkyl or C1 6-alkylene 4 6-membered heterocyclic alkyl; the C1 6-alkyl, C3 6-cycloalkyl or 4-cycloalkyl The 6-membered heterocyclic alkyl group may optionally be substituted with a substituent selected from the following: deuterium, F, Cl, hydroxyl, methyl, ethyl, propyl, butyl; More preferably, the R 6 Selected from methyl, ethyl, tert-butyl, CH2CH2OH, CH2CD2OH, CD2CD2OH, CD2CH2OH, , , , CH2F, , , Cyclopropyl, -cyclopropylene-CH3, CH2 Cyclopropyl , , , , Tetrahydrofuranyl, cyclopentyl, oxetyl, aziridine, or 1,3,4 Oxazinyl alkyl.

[0012] The best R 6 Selected from methyl, ethyl, CH2CH2OH, CH2CD2OH, CD2CD2OH, CD2CH2OH; In some preferred embodiments, R 2 Selected from:

[0013] The R 11a R 11b R 11c R 11d R 11e R 11f R 11g R 11h R 11i and R 11j R 11m Each of these elements is independently hydrogen, halogen, hydroxyl, or C1. 6-alkyl or C1 4-Halogenated alkyl; or R 11a and R 11b They combine with their respective attached carbon atoms to form screw-on R 2 A saturated ternary, quaternary, or quinary monocyclic ring; wherein the ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; or alternatively, R 11a and R 11b Yes, R 11c and R 11d Yes, R 11e and R 11f Yes, R 11g and R 11h Yes, R 11i and R 11j Each pair in the pair can independently combine to form a double bond; the R 11a R 11b R 11c R 11d R 11e R 11f R 11g R 11h R 11iR 11j R 11m Each pair in the formula is independently selected from hydrogen, halogen, and R. 11o or R 11p ; The R 11o The carbon atoms that can be connected to them and the saturated monocyclic rings they belong to form 6-membered, 7-membered, 8-membered, 7-membered, 10-membered, 11-membered, and 12-membered saturated bicyclic rings; or alternative R... 11o It can be independently selected from saturated, partially saturated, or unsaturated 3-membered, 4-membered, 5-membered, 6-membered, and 7-membered monocyclic rings or 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered bicyclic rings; wherein the monocyclic or bicyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further, wherein the monocyclic or bicyclic ring is substituted by 0, 1, 2, 3, or 4 groups selected from: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OR a , OC1 4-Hydroalkyl, CN, C(=O)OR a , C(=O)R b , C(=O)NR a R b , C(=NR a )NR a R b , OC(=O)R b , OC(=O)NR a R b , OC2 6-alkylene NR a R b , NR a R b , OC2 6OR a , SR a , S(=O)R b , S(=O)2R b , S(=O)2NR a R b , NRa C(=O)R b , NR a C(=O)OR b , NR a C (=O)NR a R b , NR a C(=NR a )NR a R b , NR a S(=O)2NR b , NR a S(=O)2NR a R b , R a C2 6-alkylene NR a R b , NR a C2 6-alkylene OR a , C1 6-alkylene NR a R b , C1 6-alkylene OR a , C1 6-alkylene OC(=O)R b , C1 6-alkylene NR a C(=O)R b , C1 6-alkylene NR a C(=O)NR a R b , C1 6-alkylene C(=O)OR a Or oxygenation; R 11p It can be independently selected from 0, 1, 2, 3, 4 or 5 elements selected from halogens, C1 4-Hydroalkyl, CN, C(=O)OR a , OR a , OC1 4-Halogenated alkyl or NR a R b C1 with substituent group 8-alkyl; R a It can be independently selected from H or R. b ; R b Independently selected from C1 6. Alkyl, phenyl, or benzyl, wherein the C1 The 6-alkyl group is substituted with 0, 1, 2, or 3 of the following substituents: halogen, hydroxyl, ... OC1 6-alkyl, NH2, NHC1 6-alkyl, OC(=O)C1 6-alkyl or N(C1 6-alkyl)C1 6-alkyl; and the phenyl or benzyl group is substituted with 0, 1, 2, or 3 substituents selected from the following: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OH、 OC1 6-alkyl, NH2, NHC1 6-alkyl, OC(=O)C1 6-alkyl or N(C1 6-alkyl)C1 6-alkyl group.

[0014] The preferred group is described above. Selected from:

[0015] The preferred group is described above. Selected from: ; The preferred group is described above. Selected from: ; The preferred group is described above. Selected from:

[0016] The preferred group is described above. Selected from:

[0017] The preferred embodiment of the group R is... 2 Selected from: ; In some preferred embodiments of the present invention, R 5 Halogen or group Y R 8 Where Y is a chemical bond, -NH-, NH C1 6-alkylene , NH C3 6-cycloalkylene , O C0 6-alkylene , O C3 6-cycloalkyl , S C0 6-alkylene , S C3 6-cycloalkylene R 8 A saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, wherein the hydrogen atom on the carbon atom is substituted by 0, 1, 2, or 3 groups selected from: halogen, cyano, C1 6-alkyl, C3 6-cycloalkyl, C1 6-Hydroalkyl, C3 6-Halogenated cycloalkyl groups.

[0018] In some preferred embodiments of the present invention, R 5 It is a saturated 5- or 6-membered monocyclic ring, wherein each ring contains 0, 1, or 2 N atoms and 0 or 1 O atom, and wherein each ring is substituted by 0, 1, 2, or 3 groups selected from the following: halogen, cyano, C1 6-alkyl, C1 6-Hydroalkyl, hydroxyl, O C0 6-alkyl , O C3 6-cycloalkyl R 15 And oxygenation.

[0019] In some preferred embodiments described in this invention, R 5 for: a) Group Y R 8a Where Y is a chemical bond or a chemical bond. S(=O) (=NH) And R 8a The ring is morpholine, piperidinyl or aziridine, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazine, tetrahydrofuranyl, wherein each ring is independently substituted by 0, 1, 2 or 3 methyl, F, CF3, OH, OCHF2, CN or oxo groups; b) Group Y R 8b , where Y is SO2NH , O NH ; and R 8b It is a tert-butyl group substituted with 0, 1, 2 or 3 OH groups; Or in some preferred embodiments of the present invention, R 5 for SO2NH tert-butyl group, -SO2 tert-butyl group or NH tert-butyl OH group.

[0020] Furthermore, in another preferred embodiment of the present invention, R 5 Selected from:

[0021]

[0022]

[0023] .

[0024] Among them, the best R 5 Selected from:

[0025] In some preferred embodiments of the present invention, the preferred R 3 Selected from hydrogen, halogen, methoxy, per-deuterated methoxy, cyano, or methyl; In some preferred embodiments of the present invention, the preferred R 4 Selected from: -NO2, halogen, cyano, SF5, -C 3-6 Alkyl, -C 3-6 cycloalkyl, -OC 1-4 Alkyl, deuterated-OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl groups, deuterated-OC 1-4 Halogenated alkyl groups, -OC 3-6 cycloalkyl, -OC 3-6 Halogenated cycloalkyl groups, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl groups, -SC 3-6 cycloalkyl, -SC 3-6 Halogenated cycloalkyl, NR a R b , pyrrole, pyrazole, imidazole, methylpyrazole, trifluoromethylpyrazole, thiazole, oxazole, isoxazole; In some preferred embodiments of the present invention, R 3 and R 4 They can combine with their respective attached carbon atoms to form saturated or partially saturated 5- or 6-membered monocyclic rings fused with benzene rings or heteroaromatic rings; wherein the 5- or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, and further, wherein the 5- or 6-membered monocyclic ring is substituted by 0, 1, 2, or 3 groups selected from: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OR a , OC1 4-Hydroalkyl, -CN, NR a R b Or oxygenation; Better, R 3 and R 4 The saturated or partially saturated 5- or 6-membered monocyclic rings fused with the benzene ring or heteroaromatic rings, formed by combining with their respective attached carbon atoms, are selected from the following structures, wherein the hydrogen on the 5- or 6-membered monocyclic ring can be replaced by methyl or F:

[0026] Preferred ring A is selected from pyrrole, pyrazole, imidazole, triazole, furan, oxazole, oxadiazole, thiophene, thiazole, thiadiazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine; More preferably, cyclic A is selected from triazole, pyrazole, oxazole, oxadiazole, thiazole, and thiadiazole; In a preferred embodiment of the present invention, the compound represented by Formula I is any one of the following compounds:

[0027] Another aspect of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a diluent and / or an excipient, and a compound of Formula I of the present invention, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, a prodrug or a deuterated derivative thereof as an active ingredient.

[0028] Another aspect of the invention provides the use of the compound of Formula I, or its stereoisomers, tautomers, and pharmaceutically acceptable salts, hydrates and solvates, prodrugs or deuterated derivatives, or the above-described pharmaceutical compositions, as an inhibitor of the kinin subfamily member 18A subprotein, or in the preparation of medicaments for the treatment and / or prevention of diseases associated with this subprotein.

[0029] The diseases associated with the kinin subfamily member 18A subprotein include cancer, psoriasis, atopic dermatitis, other autoimmune diseases, or proliferative disorders of inflammatory bowel disease.

[0030] Cancers that should be mentioned include mesothelioma, neuroblastoma, rectal cancer, colon cancer, the familiar adenomatous polyposis and hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, nasal cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, and urinary tract cancer. Melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma.

[0031] Autoimmune diseases that should be mentioned include rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, mixed connective tissue disease, dermatomyositis, polymyositis, Reiter's syndrome, autoimmune lymphoproliferative syndrome, multiple sclerosis, myasthenia gravis, and encephalomyelitis.

[0032] Inflammatory bowel diseases that should be mentioned include ulcerative colitis or Crohn's disease.

[0033] Another aspect of the invention provides a method for treating, modulating, or preventing diseases mediated by the subprotein, comprising administering to a subject a therapeutically effective amount of a compound of the invention as shown in Formula I-1 or I-2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt, hydrate, or solvate thereof, a prodrug, a deuterated derivative thereof, or a pharmaceutical composition thereof.

[0034] Through extensive and in-depth research, the inventors discovered that the compound prepared according to Formula I unexpectedly possesses significant inhibitory activity against the 18A subprotein of the kinin subfamily, which can treat diseases or symptoms mediated by this subprotein. It exhibits excellent pharmacokinetic properties, high safety, and high drugability.

[0035] Compound Synthesis The preparation methods of the compounds of the present invention are described in detail below, but these specific methods do not constitute any limitation on the present invention. The compounds described above can be synthesized using standard synthetic techniques or well-known techniques in combination with the methods described herein. Furthermore, the solvents, temperatures, and other reaction conditions mentioned herein can be varied. The starting materials used for the synthesis of the compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using well-known techniques and starting materials. General methods for the preparation of compounds can be modified by using appropriate reagents and conditions that introduce different groups into the molecular formulas provided herein.

[0036] On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to those explained below. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0037] Terminology Definitions and Explanations Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures shall fall within the scope of this application specification.

[0038] Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0039] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this application, unless specifically stated otherwise, the singular is used to include the plural. It must be noted that unless clearly stated otherwise, the singular form used in this specification and claims includes the plural form of the referred to. It should also be noted that unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0040] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg, "Advanced Organic Chemistry 4th Edition," Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR, UV / VIS spectroscopy, and pharmacological methods, are used. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art, based on the descriptions in the various summary and more specific references cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0041] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2. As used in this article or , indicating the linkage site of the group. As used in this article, "R1", "R", etc. 1 The meanings of "R1" and "R2" are the same and can be used interchangeably. The meanings of other symbols, such as "R2", are similarly defined.

[0042] The chapter headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter. All references or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0043] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0044] The numerical ranges described in this application specification and claims, when interpreted as "integers," should be understood to include the two endpoints of the range and every integer within that range. For example, "integers from 1 to 6" should be understood to include every integer of 0, 1, 2, 3, 4, 5, and 6.

[0045] In this application, "saturated, partially saturated or unsaturated" includes substituents saturated with hydrogen, substituents that are completely unsaturated with hydrogen, and substituents that are partially saturated with hydrogen.

[0046] In this application, the term "halogen" refers to fluorine, chlorine, bromine, or iodine, either alone or as part of other substituents.

[0047] As used herein, the term "cyano" refers to, either alone or as part of other substituents. CN.

[0048] As used herein, the term "amino" refers to, either alone or as part of other substituents. NH2.

[0049] As used herein, the term "alkyl" refers, alone or as part of other substituents, to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by single bonds. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Alkyl groups may also be isotopic isomers of naturally abundant alkyl groups rich in carbon and / or hydrogen isotopes (i.e., deuterium or tritium).

[0050] Term "C" α β "Alkyl" refers to an alkyl group containing a minimum of α and a maximum of β carbon atoms in a branched, linear, or any combination of these three relationships, where α and β represent integers. It can also be represented by "C". α C β The alkyl group is indicated by the form "alkyl". Alkyl groups described in this section may also contain one or two double or triple bonds. The designation of C0 alkyl indicates a direct bond. For example, C0... 6-alkyl groups include straight bonds, C1 6-alkyl groups (e.g., C1, C2, C3, C4, C5, C6 alkyl groups); C1 Examples of 6-alkyl groups include, but are not limited to, the following:

[0051] "Benzo group" alone or in combination refers to a divalent group C4H4=, one of which is represented as CH=CH CH=CH When it attaches to another ring at an adjacent position, it forms a benzene ring, such as tetrahydronaphthalene and indole.

[0052] The term "C" refers to the use of the term alone or as part of other substituents. α β "Halogenated alkyl" refers to an alkyl group as described above, wherein any number (at least one) of the hydrogen atoms attached to the alkyl chain are replaced by fluorine, chlorine, bromine or iodine.

[0053] When used alone or as part of other substituents, the term "alkoxy" refers to a group. O R Q , where R Q "alkyl" as defined above.

[0054] When used alone or as part of other substituents, the term "oxo" refers to the substitution of two hydrogens on the methylene group by oxygen, that is, the methylene group is replaced by a carbonyl group, denoted as =O.

[0055] The term "thio" refers to the substitution of two hydrogen atoms on the methylene group by sulfur, either alone or as part of other substituents, and is represented by =S.

[0056] When used alone or as part of other substituents, the term "cycloalkyl" or "carbocycloyl" refers to a cyclic alkyl group. The term "m" n-membered cycloalkyl" or "C m C n "Cycloalkyl" should be understood as referring to a saturated, unsaturated, or partially saturated carbon ring having m to n atoms. For example, "3 "15-membered cycloalkyl" or "C3" C 15 "Cycloalkyl" refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6, or 3 to 5 carbon atoms, and may contain 1 to 4 rings. "8-membered cycloalkyl" contains 5 Eight carbon atoms. Includes monocyclic, bicyclic, tricyclic, spirocyclic, or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as decahydronaphthalene. The cycloalkyl group may be substituted with one or more substituents. In some embodiments, the cycloalkyl group may be a cycloalkyl group fused with an aryl or heteroaryl group. The term "C3" is used. "C6 cycloalkyl" should be understood as representing a saturated monovalent monocyclic or bicyclic hydrocarbon ring with 3 to 6 carbon atoms, including fused or bridged polycyclic systems. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0057] "Bicyclic" refers to a group having two connecting rings. A bicyclic ring can be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, one, two, or three heteroatoms, such as N, O, or S). Both rings can be aliphatic (e.g., naphthane and norbornane), aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetrahydronaphthalene). Bicyclic rings include (a) spirocyclic compounds, where the two rings share only one single atom (the spiro atom, which is usually a quaternary carbon). Examples of spirocyclic compounds include, but are not limited to: , It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0058] (b) Fused bicyclic compounds in which the two rings share two adjacent atoms. In other words, the rings share a single covalent bond, meaning the bridgehead atoms are directly connected (e.g., α-covalent bonds). (Cephane and naphthane). Examples of fused bicyclic compounds include, but are not limited to:

[0059] (c) Bridged bicyclic compounds, wherein the two rings share three or more atoms and are separated by a bridge containing at least one atom. For example, norbornane, also known as bicyclic [2.2.1]heptane, can be considered as a pair of cyclopentane rings, each ring sharing three of its five carbon atoms. Examples of bridged bicyclic compounds include, but are not limited to:

[0060] When used alone or as part of other substituents, the term "heterocyclic alkyl" refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, O, S, and P. The term "3..." "8-membered heterocyclic group" or "3-membered heterocyclic group" "8-membered heterocyclic alkyl" should be understood to mean a monocyclic, bicyclic, or tricyclic ring having 3 to 8 atoms, wherein the heteroatoms are preferably N, O, and S. It should be understood that when the total number of S and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. Examples of heterocyclic alkyl groups include, but are not limited to: tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiaranyl.

[0061] The term "5- or 6-membered heteroaryl" should be understood as having 5 or 6 ring atoms—and containing 1 Five aromatic cyclic groups, each independently selected from N, O, and S heteroatoms, preferably 1 Three aromatic ring groups—independently selected from N, O, and S heteroatoms. Examples of heteroaryl groups include, but are not limited to: thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.

[0062] NR, whether alone or as part of other substituents a R b Groups can It exists in the form of R, or it may include R within it. a and R b The groups together form a ring, which optionally contains N, O, or S atoms, and may also include, for example: .

[0063] When used alone or as part of other substituents, the group N(C) α β Alkyl)C α β Alkyl groups (where α and β are as defined above) include two of their carbon atoms. α β Alkyl groups together form substituents of a ring (optionally containing N, O, or S atoms), and include, for example: .

[0064] The term "inert solvent" includes, but is not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, etc. N Methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, chloroform, 1,2 Dichloroethane, acetonitrile, N,N dimethylformamide, N,N Dimethylacetamide, dioxane, or combinations thereof.

[0065] The compounds described herein include intermediates that can be used to prepare the compounds described herein, containing reactive functional groups (e.g., but not limited to carboxyl, hydroxyl, and amino moieties), and also their protected derivatives. A “protected derivative” is a compound in which one or more reactive sites are blocked by one or more protecting groups (also called protecting groups). Suitable carboxyl protecting groups include benzyl, tert-butyl, etc., and isotopes, etc. Suitable amino and amide protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable hydroxyl protecting groups include trimethylsilyl, benzyl, etc. Other suitable protecting groups are well known to those skilled in the art.

[0066] In this application, "optional" or "arbitrary" means that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or not substituted, and the description includes both substituted and unsubstituted aryl groups.

[0067] This application includes a list of categories (sometimes referred to as Markush groups) using the phrases “selected from…and…” and “for…or…”. When this language is used in this application, unless otherwise stated, it is intended to include the group as a whole, any individual member thereof, or any subgroup thereof. The use of this language is for shorthand purposes only and is not intended to limit the removal of individual elements or subgroups as needed.

[0068] In this application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, to the extent of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0069] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are also considered in this invention. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or can be used for the identification, characterization, or purification of the compounds of this invention.

[0070] The term "amine salt" refers to the product obtained by neutralizing an alkyl primary amine, secondary amine, or tertiary amine with an acid. The acid includes the inorganic or organic acids described in this application.

[0071] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0072] Depending on the choice of raw materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation of light induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0073] When the bonds to chiral carbons in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbons and the enantiomerically pure compounds and mixtures thereof derived therefrom are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114. 120. Use wedge keys and dashed keys to represent the absolute configuration of the center of a solid.

[0074] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form; attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0075] In this application, "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0076] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or animal use.

[0077] The term "solvent" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or nonstoichiometric solvent bound by intermolecular noncovalent forces, and when the solvent is water, it is a hydrate.

[0078] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; this modification can be performed conventionally or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.

[0079] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium. 2 H), tritium ( 3 H), iodine 125 ( 125 I) or C 14( 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0080] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0081] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of this invention is administered to the mammal (such as a human) requiring treatment, wherein the dose administered is a pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1-2000 mg, preferably 5-1000 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are within the scope of a skilled physician's expertise.

[0082] The term "treatment" and other similar synonyms used in this article include the following meanings: (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it; (ii) To suppress a disease or symptom, that is, to curb its development; (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or (iv) To alleviate the symptoms caused by the disease or condition.

[0083] The reaction temperature and time for each step can be selected appropriately based on the solvent, starting materials, and reagents. After each reaction step is completed, the target compound can be separated and purified from the reaction system using common methods such as filtration, extraction, recrystallization, washing, and silica gel column chromatography. Alternatively, the target compound can proceed directly to the next reaction step without separation or purification, provided it does not affect the subsequent reaction. Detailed Implementation

[0084] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0085] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0086] This application has the following definitions: Symbols or units: IC 50 The half-maximum inhibitory concentration (MCC) refers to the concentration at which half of the maximum inhibitory effect is achieved. M: mol / L, for example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol / L. N: Equivalent concentration, for example, 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution. h: hours min: minutes Reagents: TEA: Triethylamine DCM: Dichloromethane DMAP: 4-Dimethylaminopyridine DMF: N,N -Dimethylformamide DMSO: Dimethyl sulfoxide DIPEA: N,N -Diisopropylethylamine Test method: LC-MS: Liquid chromatography-mass spectrometry NMR: Nuclear Magnetic Resonance Spectroscopy Preparation of intermediates: Synthesis of intermediate 6-(2-{4-[6-(4,4-difluorohexahydropyridin-1-yl)-4-methylpyrimidin-2-yl]-1,2,3-triazacyclopentan-1-yl}-5-iodophenyl)-6-azaspiro[2,5]octane (IM1):

[0087] Step 1: Synthesis of 2-chloro-6-(4,4-difluorohexahydropyridin-1-yl)-4-methylpyrimidine (IM1-2) 2,6-Dichloro-4-methylpyrimidine (IM1-1) (2.0 g, 12.3 mmol), 4,4-difluorohexahydropyridine hydrochloride (1.94 g, 12.3 mmol), and DIPEA (3.94 g, 30.7 mmol) were successively placed in 30 mL of tetrahydrofuran solution and stirred overnight at room temperature. After the reaction was complete, an appropriate amount of water was added to the reaction system, and the reaction mixture was extracted three times with dichloromethane. The organic layer was collected and washed twice with saturated brine. The organic layer was then dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 3:1) to give a white solid 2-chloro-6-(4,4-difluorohexahydropyridin-1-yl)-4-methylpyrimidine (2.3 g, yield 76%). 1 H NMR (400 MHz, DMSO- d 6) δ 6.86 (s, 1H), 3.80 – 3.64 (m, 4H), 2.25 (s, 3H), 2.09 – 1.86 (m, 4H). Step 2: Synthesis of 6-(4,4-difluorohexahydropyridin-1-yl)-4-methyl-2-[(trimethylsilyl)ethynyl]pyrimidine (IM1-3) Compound IM1-2 (2.47 g, 10.0 mmol), trimethylsilylacetylene (1.96 g, 20.0 mmol), cuprous iodide (0.19 g, 1.0 mmol), and bis(tribenzylphosphine)palladium dichloride (0.35 g, 0.5 mmol) were added to a mixed solvent of TEA and DMF (TEA:DMF = 1:1, 20 mL). The mixture was stirred and heated to 100 °C overnight under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with ethyl acetate (100 mL), and washed with water (80 mL × 2 times). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3.3 g of 6-(4,4-difluorohexahydropyridin-1-yl)-4-methyl-2-[(trimethylsilyl)acetylene]pyrimidine black solid product, which was directly used in the next reaction.

[0088] Step 3: Synthesis of 4-(4,4-difluorohexahydropyridin-1-yl)-2-ethynyl-6-methylpyrimidine (IM1-4) Potassium carbonate (7.3 g, 53.0 mmol) was added to a methanol (100 mL) solution of compound IM1-3 (3.3 g, 10.6 mmol). After stirring at room temperature for 3 hours, the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was directly purified by silica gel column chromatography to give the product 4-(4,4-difluorohexahydropyridin-1-yl)-2-ethynyl-6-methylpyrimidine (2.1 g, brown solid). MS (ESI): m / z 238.1 [M+1] + .

[0089] Step 4: Synthesis of 6-(2-{4-[6-(4,4-difluorohexahydropyridin-1-yl)-4-methylpyrimidin-2-yl]-1,2,3-triazacyclopentan-1-yl}-5-iodophenyl)-6-azaspiro[2.5]octane (IM1) L-proline (42 mg, 0.28 mmol) and cuprous iodide (53 mg, 0.28 mmol) were added to a mixture of 3 mL of glycerol and IM1-4 (0.13 g, 0.56 mmol) obtained in the previous step and 6-(2-azido-5-iodophenyl)-6-azaspiro[2.5]octane (0.10 g, 0.28 mmol). The mixture was stirred at room temperature for 5 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (50 mL) and washed with water (30 mL × 2 times). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 50 mg of the target product, a yellow solid of 6-(2-{4-[6-(4,4-difluorohexahydropyridin-1-yl)-4-methylpyrimidin-2-yl]-1,2,3-triazacyclopentanyl-1-yl}-5-iodophenyl)-6-azaspiro[2.5]octane. MS (ESI): m / z 592.1 [M+1] + .

[0090] Example 1: N Preparation of -(4-{4-[4-(4,4-difluorohexahydropyridin-1-yl)-6-methylpyrimidin-2-yl]-1,2,3-triazacyclopentan-1-yl}-3-(6-azaspiro[2.5]oct-6-yl)phenyl)-2-hydroxyethanesulfonamide (compound 1)

[0091] Intermediate IM1 (50 mg, 0.084 mmol), 2-hydroxy-1-sulfonamide (21 mg, 0.168 mmol), cuprous iodide (32 mg, 0.168 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (24 mg, 0.168 mmol), and potassium phosphate (53 mg, 0.252 mmol) were added to a 3 mL DMF solution. The reaction mixture was stirred and heated to 90 °C for 3 hours. After the reaction was complete, the reaction mixture was cooled and diluted with 50 mL of ethyl acetate. The organic phase was washed with water (30 mL × 2 times), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target product. N -(4-{4-[4-(4,4-difluorohexahydropyridin-1-yl)-6-methylpyrimidin-2-yl]-1,2,3-triazacyclopentan-1-yl}-3-(6-azaspiro[2.5]oct-6-yl)phenyl)-2-hydroxyethanesulfonamide (10 mg, off-white solid). 1 H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H),7.21 (s, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.42 (s, 1H), 5.34 (s, 1H), 4.25 – 4.07(m, 2H), 3.89 (s, 4H), 3.42 – 3.28 (m, 2H), 2.84 – 2.67 (m, 4H), 2.49 (s,3H), 2.27 – 2.15 (m, 1H), 2.04 (dd, J = 12.7, 7.0 Hz, 4H), 1.33 (s, 4H), 0.26 (s, 4H). Table 1 shows the synthesis of the following compounds using different starting materials, referencing the synthetic method of compound 1.

[0092] Example 2: Compound Inhibition of Tumor Cell Proliferation Assay Compound inhibition assay of OVCAR-3 cell proliferation: OVCAR was used in the assay. 3. (Zhejiang Meisen) Cells were seeded in T75 culture flasks and cultured in Advanced RPMI 1640 medium containing 10% FBS for subsequent culture and seeding in 96-well plates for cell proliferation assays. OVCAR3 cells in the logarithmic growth phase were used to prepare a cell density of 6 × 10⁻⁶ cells / well using medium containing 2% FBS. 4 100 µL of cell suspension per well was seeded into each well of a 96-well plate. The edge wells were filled with sterile water, and the plate was incubated in an incubator (37°C, 5% CO2) for about 24 h. On the second day after cell seeding, drug treatment began. 100 µL of serially diluted test compound solutions (starting concentration of 10 μM for each drug, diluent: DMSO, dilution ratio: 1:5, 9 dilution points for each drug) were added to the cell wells. A blank control group and a solvent (DMSO) control group were also set up. 100 µL of serum-free medium was added to the blank control group, and 100 µL of DMSO solution diluted to the same volume as the drug treatment group was added to the solvent control group. Each group was divided into 3 replicates. The drugs were incubated for 96 h. On the fourth day, plate testing was performed. After aspirating the original liquid from the wells, 100 µL of pre-prepared serum-free medium containing 10% CCK-8 (Tongren Chemical CK04) stock solution was added to each well. The plates were incubated for 1.5 h, and the absorbance of each well was measured using a Thermofisher Multistan FC microplate reader.

[0093] Assay for the inhibition of HT-29 cell proliferation by compound: HT-29 cells (purchased from Jinan Bunuo Biotechnology Co., Ltd.) were seeded in T25 culture flasks and cultured for 2 days in RPMI 1640 medium containing 10% FBS, in preparation for subsequent culture and seeding into 96-well plates for cell proliferation assays. HT29 cells in the logarithmic growth phase were harvested and their density adjusted to 2 × 10⁶ cells / well with 2% FBS medium. 4Cells / mL were seeded at 100 µL per well in 96 wells, with the edge wells filled with sterile water. The cell plate was then incubated for 24 h (37°C, 5% CO2). On the second day, drug treatment began. 100 µL of serially diluted test compound solutions (each drug starting at 10 μM, diluted with DMSO at a 1:5 ratio, with nine dilution points for each drug) were added to the culture plate. A DMSO negative control and a blank control (no cell lines seeded, only culture medium added) were also included. After drug addition, the culture plate was incubated for another 96 h (37°C, 5% CO2). On the fourth day, plate analysis was performed. 100 μL of 10% CCK8 (Japan Dojin CK04) reagent was added to each well, and the plate was incubated for 1 h. The absorbance of each well was measured using a Thermofisher Multistan FC microplate reader.

[0094] Cell proliferation inhibition rate (%) = (DMSO group) Compound group) / DMSO group × 100%.

[0095] Experimental results: Cell proliferation assays showed that the compound of this invention significantly inhibited OVCAR. 3 and HT-29 cell proliferation activity.

[0096] Example 3: Inhibition assay of compound activity against kinin subfamily member 18A (KIF18A) subprotein This test used ADP to detect the activity quantification of kinin subfamily member 18A subprotein. The Glo kinase assay kit (Promega Inc) has been completed. A brief description of the procedures is as follows: The reaction system consisted of the analyte, recombinant kinin protein subfamily member 18A subprotein (ICE, working concentration 2.5 nM), ATP (Promega Inc, working concentration 10 μM), and microtubules (Cytoskeleton, 30 μg / mL). The analyte was prepared as a 1.0 mM stock solution with DMSO and serially diluted 3-fold with DMSO, resulting in an initial concentration of 10 μM. 60 μL of the prepared analyte was transferred to a 384 PP dilution plate; 100 nL of the diluted analyte was transferred to a 384 reaction plate (LABCYTE) using ECHO (BECKMAN), and centrifuged at 1000 rpm for 1 minute (ensuring DMSO concentration of 1%, double replicate). Transfer 5 μL of enzyme solution to a 384 detection plate and incubate at 25°C for 10 minutes; transfer 5 μL of ATP solution to the 384 detection plate and incubate at 25°C for 60 minutes; add 5 μL of ADP-Glo ​​Reagent to the 384 detection plate and incubate at 25°C for 40 minutes; add 10 μL of ADP-Glo ​​Detection to the 384 detection plate and incubate at 25°C for 40 minutes; read the RLU (Relative Luminescence Unit) signal using a BMG microplate reader and calculate the inhibition rate.

[0097] Inhibition rate calculation formula: Inhibition rate = (1 (compound group) (Blank group) / (Negative control group) The blank group was multiplied by 100%, and the IC50 of the test compound was calculated in GraphPad Prism8 software based on the inhibition rate of different concentrations of the compound. 50 value.

[0098] Table 3. Inhibitory activity of representative compounds against KIF18A enzyme (IC50) 50 )

[0099] The reference compound is Compound47 from patent WO2023212240Al, and the preparation method is based on the method described in that patent.

[0100] Reference compound structure:

[0101] Experimental results: Enzyme activity results show that the compound of the present invention has significant KIF18A enzyme inhibitory activity.

[0102] Example 4: Rat Pharmacokinetic (PK) Test Male Wistar rats, SPF grade, 200-220g, were used. Three rats were fasted overnight and administered the drug orally via gavage (IG). Three other rats were administered the drug intravenously (IV). Blood samples were collected at 10, 20, 30, 60, 120, 240, 360, and 1440 minutes after drug administration (IG group) and at 2, 5, 10, 20, 30, 60, 120, 240, 360, and 1440 minutes after drug administration (IV group). Whole blood (≥100 μL) was collected via capillary periorbital sampling at these time points and placed in labeled EDTA-K2 anticoagulant tubes. After gently inverting the tubes to thoroughly mix the anticoagulant (EDTA-K2) with the blood, the tubes were immediately placed on wet ice and centrifuged within one hour of collection to separate the plasma. Centrifugation conditions were set at 4°C, 6000 rpm, and 5 minutes. The separated plasma was then placed in labeled EP tubes and stored at -80°C until sample analysis. 40 μL of plasma at each time point was collected, and 10 μL of 50% MeOH-H2O and 10 μL of 20 μg / mL testosterone internal standard solution were added. Then, 190 μL of 0.2% FA (methanol:acetonitrile = 1:1) solution was added and mixed. The mixture was vortexed for 30 s, centrifuged at 4℃ for 10 minutes at 12000 rpm, and 100 μL of the supernatant was collected and mixed with 200 μL of 50% MeOH-H2O. An appropriate amount of the mixture was analyzed by LC-MS / MS. Pharmacokinetic parameters were calculated using WinNonlin based on the plasma drug concentration data at different time points. The Wistar rat PK test showed that the compound of this invention has good pharmacokinetic properties in Wistar rats.

[0103] This application claims the benefit and priority of Chinese Patent 202510419797.7, filed on April 3, 2025. The entire disclosure of that earlier application is incorporated herein by reference.

[0104] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope, and without requiring unnecessary experiments. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including changes made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. The compound represented by Formula I, or its stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates and solvates, prodrugs or deuterated derivatives: R 1 Selected from groups ZR 6 ,in, Z is selected independently C0 6-alkylene , C0 6-alkylene NR 7 C0 6-alkylene , C0 6-alkylene NR 7 SO2 C0 6-alkylene , C0 6-alkylene SO2NR 7 C0 6-alkylene , C0 6-alkylene NR 7 SO2NR 7 C0 6-alkylene , C0 6-alkylene NR 7 SO2NR 7 C(=O) O C0 6-alkylene , C0 6-alkylene NR 7 S(=O) (=NH) C0 6-alkylene , C0 6-alkylene S(=O) (=NH) C0 6-alkylene , C0 6-alkylene S C0 6-alkylene , C0 6-alkylene S(=O) C0 6-alkylene , C0 6-alkylene SO2 C0 6-alkylene , C0 6-alkylene O C0 6-alkylene , P , C0 6-alkylene P(=O) (R 7 ) , C0 6-alkylene P(=O)2、 C0 6-alkylene (C=O) C0 6-alkylene , C0 6-alkylene (C=O) O C0 6-alkylene , C0 6-alkylene (C=O)NR 7 C0 6-alkylene , C0 6-alkylene NR 7 (C=O) C0 6-alkylene or C(=N OH) ; or the group ZR 6 for N = S (= O) (R 6 )2, where two R 6 Alternatively, they can be combined with the carbon atoms to which they are attached to form saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic rings containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S. Among them, R 6 Hydrogen, halogen, hydroxyl, cyano, R 6a Or R 6b ; R 7 For hydrogen, R 7a Or R 7b ; R 3 Selected from hydrogen, halogen, cyano, C1 8-alkyl, OC1 8-alkyl, C1 4-Halogenated Alkyl Groups OR 3a , OR 3b , C0 6-alkylene (C=O)N(C0 6-alkyl)2, C0 6-alkylene SO2N(C0 6-alkyl)2, R 3a Or R 3b ; and R 3 and R 4 They can combine with their respective attached carbon atoms to form saturated or partially saturated 5- or 6-membered monocyclic rings fused with benzene rings or heteroaromatic rings; wherein the 5- or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, and further, wherein the hydrogen on the 5- or 6-membered monocyclic ring is substituted by 0, 1, 2, or 3 groups selected from: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OR a , OC1 4-Hydroalkyl, -CN, NR a R b Or oxygenation; R 4 Selected from hydrogen, halogen, cyano, 5 6-membered heteroaryl, phenyl, SR a , SF5, nitro, hydroxyl, C1 8-alkyl, C3 8-cycloalkyl, C3 8-Halogenated cycloalkyl group, C3 with at least two deuterated hydrogen atoms on the carbon atom. 8-Halogenated cycloalkyl, C1 4. Haloalkyl group, C1 with at least two hydrogens on the carbon atom deuterated. 4-Halogenated Alkyl Groups OC1 8 alkyl groups, with at least two hydrogen atoms on the carbon atom being deuterated. OC1 8-alkyl, OC3 8-cycloalkyl group, with at least two hydrogen atoms on the carbon atom replaced by deuterium. OC3 8-cycloalkyl, OC1 8-Hydroalkyl, OC3 8-Halogenated cycloalkyl groups, NR a R b , NR a C(O)R b , C(O)NR a R b , OC(O)R a , C(O)R a , P(O)R a R b , C(O)OR a , S(O)R a , S(O)2R a and S(O)2NR a R b R 4a Or R 4b The hydrogen atoms on the 5-6 heteroaryl group and the phenyl group are substituted by 0, 1, 2, or 3 groups selected from the following: halogen, C1... 6-alkyl, C1 4-Halogenated Alkyl Groups OR a , OC1 4-Hydroalkyl, CN, NR a R b Or oxidized; or alternatively, and R 3 With R 4 They can combine with their respective attached carbon atoms to form saturated or partially saturated 5- or 6-membered monocyclic rings fused with benzene rings or heteroaromatic rings; wherein the 5- or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, and further, wherein the hydrogen on the 5- or 6-membered monocyclic ring is substituted by 0, 1, 2, or 3 groups selected from: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OR a , OC1 4-Hydroalkyl, -CN, NR a R b Or oxygenation; R 5 Halogen or group Y R 8 , where Y is C0 7-alkylene , C3 7-cycloalkylene , C0 6-alkylene NR 9 C0 6-alkylene , C0 6-alkylene NR 9 C3 7-cycloalkylene , C0 6-alkylene O C0 6-alkylene , C0 6-alkylene O C3 7-cycloalkylene , C0 6-alkylene S C0 6-alkylene , C0 6-alkylene S C3 7-cycloalkylene , C0 6-alkylene S(=O) C0 6-alkylene , C0 6-alkylene S(=O) C3 7-cycloalkylene , C0 6-alkylene S(=O)2 C0 6-alkylene , C0 6-alkylene S(=O)2 C3 7-cycloalkylene , C0 6-alkylene SO2NR 9 C0 6-alkylene , C0 6-alkylene SO2NR 9 C3 7-cycloalkylene , C0 6-alkylene S(=O)(=NH) , C0 6-alkylene NR 9 SO2 C0 6-alkylene , C0 6-alkylene NR 9 SO2 C3 7-cycloalkylene , C0 6-alkylene NR 9 SO2NR 9 C0 6-alkylene , C0 6-alkylene NR 9 SO2NR 9 C3 7-cycloalkylene , C0 6-alkylene C(=O) C0 6-alkylene , C0 6-alkylene C(=O) C3 7-cycloalkylene , C0 6-alkylene NR 9 C(=O) C0 6-alkylene , C0 6-alkylene NR 9 C(=O) C3 7-cycloalkylene , C0 6-alkylene (C=O)NR 9 C0 6-alkylene or C0 6-alkylene C(=O) O C0 6-alkylene ;or Y R 8 for N = S (= O) (R 8 )2, where two R 8 Alternatively, they can be combined with the carbon atoms to which they are attached to form saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic rings containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S. Among them, R 8 Hydrogen, halogen, cyano, R 8a Or R 8b ; R 9 For hydrogen, R 9a Or R 9b ; Ring A is a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms; R 3a R 4a R 6a R 7a R 8a R 9a Each of the following groups is independently selected: saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, wherein the hydrogen atom on the carbon atom is substituted by 0, 1, 2, or 3 groups selected from: halogen, cyano, amino, C1 6-alkyl, C3 6-cycloalkyl, C1 6-Hydroalkyl, C3 6-Halogenated cycloalkyl groups OR a , OC1 6-Hydroalkyl, C(=O)R b , C(=O)OR a , C(=O)NR a R b , C(=NR a )NR a R b , OC(=O)R b , OC(=O)NR a R b , OC2 6-alkylene NR a R b , OC2 6-alkylene OR a , SR a , S(=O)R b , S(=O)2R b , S(=O)2NR a R b , NR a R b , N(R a )C(=O)R b , N(R a )C(=O)OR b , N(R a )C(=O)NR a R b , N(R a )C(=NR a )NR a R b , N(R a )S(=O)2R b , N(R a )S(=O)2NR a R b , NR a C2 6-alkylene NR a R b , NR a C2 6-alkylene OR a , C1 6-alkylene NR a R b , C1 6-alkylene OR a , C1 6-alkylene N(R) a )C(=O)R b , C1 6-alkylene OC(=O)R b , C1 6-alkylene C(=O)NR a R b , C1 6-alkylene C(=O)OR a R 10 And oxygenation; R 3b R 4b R 6b R 7b R 8b R 9b C1 groups that are independently substituted by 0, 1, 2, 3, 4, or 5 groups selected from the following groups. 6-alkyl, C3 6-cycloalkyl groups: deuterium, halogen, cyano, C1 6-alkyl, C3 6-cycloalkyl, C1 6-Hydroalkyl, C1 6-Halogenated cycloalkyl groups C0 6NR a R b , OR a , C(=O)OR a And saturated, partially saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic rings; R 10 Independently selected from the group consisting of: saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, wherein the hydrogen atoms are substituted by 0, 1, 2, or 3 groups selected from: halogen, cyano, amino, C1 6-alkyl, C1 6-Hydroalkyl, OR a , OC1 6-Hydroalkyl, C(=O)R b , C(=O)OR a , C(=O)NR a R b , C(=NR a )NR a R b , OC(=O)R b , OC(=O)NR a R b , OC2 6-alkylene NR a R b , OC2 6-alkylene OR a , SR a , S(=O)R b , S(=O)2R b , S(=O)2NR a R b , NR a R b , N(R a )C(=O)R b , N(R a )C(=O)OR b , N(R a )C(=O)NR a R b , N(R a )C(=NR a )NR a R b , N(R a )S(=O)2R b , N(R a )S(=O)2NR a R b , NR a C2 6-alkylene NR a R b , NR a C2 6-alkylene OR b , C1 6-alkylene NR a R b , C1 6-alkylene OR a , C1 6-alkylene N(R) a )C(=O)R b , C1 6-alkylene OC(=O)R b , C1 6-alkylene C(=O)NR a R b , C1 6-alkylene C(=O)OR a And oxygenation; R 2 Choose from the following groups: hydrogen, Or R 2 C2 substituted with 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of the following.

8. Alkyl groups: Halogen, Cyano, Amino, C1 6-alkyl, C1 6-Hydroalkyl, C3 6-Halogenated cycloalkyl groups OR a , NR a R b , C(=O)OR a , OC1 4-Halogenated alkyl or R 11n ; or R 2 A phenyl or an unsaturated 5-membered monocyclic phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups selected from the group consisting of: halogen, cyano, amino, C1 6-alkyl, C1 6-Hydroalkyl, OR a , NR a R b , C(=O)OR a , OC1 4-Halogenated alkyl or R 11n The 5-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S. R 11a R 11b R 11c R 11d R 11e R 11f R 11g R 11h R 11i R 11j R 11k R 11l R 11m Each of these elements is independently hydrogen, halogen, hydroxyl, or R. 11o or R 11p ; Alternatively, R 11a and R 11b Yes, R 11c and R 11d Yes, R 11e and R 11f Yes, R 11g and R 11h Yes, R 11i and R 11j and R 11k and R 11l Each pair can independently combine with its respective attached carbon atom to form a screw-in connection to R. 2 A saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring; wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further, wherein the 3-, 4-, 5-, or 6-membered monocyclic ring is substituted by 0, 1, 2, or 3 groups selected from: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OR a , OC1 4-Hydroalkyl, CN, NR a R b Or oxidized; or alternatively, R 11a and R 11b Yes, R 11c and R 11d Yes, R 11e and R 11f Yes, R 11g and R 11h Yes, R 11i and R 11j Yes, and R 11k and R 11l Each pair in the pair can independently combine to form a double bond; The R 11n and R 11o The carbon atoms that can be connected to them and the saturated monocyclic rings they belong to form 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered saturated bicyclic rings; or alternative R... 11n and R 11o It can be independently selected from saturated, partially saturated, or unsaturated 3-membered, 4-membered, 5-membered, 6-membered, and 7-membered monocyclic rings or 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered bicyclic rings; wherein the monocyclic or bicyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further, wherein the monocyclic or bicyclic ring is substituted by 0, 1, 2, 3, or 4 groups selected from: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OR a , OC1 4-Hydroalkyl, CN, C(=O)OR a , C(=O)R b , C(=O)NR a R b , C(=NR a )NR a R b , OC(=O)R b , OC(=O)NR a R b , OC2 6-alkylene NR a R b , NR a R b , OC2 6OR a , SR a , S(=O)R b , S(=O)2R b , S(=O)2NR a R b , NR a C(=O)R b , NR a C (=O)OR b , NR a C (=O)NR a R b , NR a C(=NR a )NR a R b , NR a S(=O)2NR b , NR a S(=O)2NR a R b , R a C2 6-alkylene NR a R b , NR a C2 6-alkylene OR a , C1 6-alkylene NR a R b , C1 6-alkylene OR a , C1 6-alkylene OC(=O)R b , C1 6-alkylene NR a C(=O)R b , C1 6-alkylene NR a C(=O)NR a R b , C1 6-alkylene C(=O)OR a Or oxygenation; R 11p It can be independently selected from 0, 1, 2, 3, 4 or 5 elements selected from halogens, C1 4-Hydroalkyl, CN, C(=O)OR a , OR a , OC1 4-Halogenated alkyl or NR a R b C1 with substituent group 8-alkyl; R a It can be independently selected from H and R. b -C(O)R b -P(O)(OR) b )2, -P(O)(ONa)2, -CH2P(O)(OR b )2、 -CH2P(O)(ONa)2; R b Independently selected from C1 6-alkyl, C3 7. Cycloalkyl, phenyl, or benzyl, wherein the C1 6-alkyl, C3 The hydrogen atom on the 7-cycloalkyl group is substituted by not less than two deuterium groups or by 0, 1, 2, or 3 substituents selected from the following: halogen, hydroxyl, ... OC1 6-alkyl, NH2, NHC1 6-alkyl, OC(=O)C1 6-alkyl or N(C1 6-alkyl)C1 6-alkyl, 5-6-membered heteroaryl; and the phenyl or benzyl group is substituted by 0, 1, 2 or 3 substituents selected from the following: halogen, C1 6-alkyl, C1 4-Halogenated Alkyl Groups OH、 OC1 6-alkyl, NH2, NHC1 6-alkyl, OC(=O)C1 6-alkyl or N(C1 6-alkyl)C1 6-alkyl, 5-6-membered heteroaryl.

2. The compound of formula 1 according to claim 1, characterized in that... Selected from the following compounds: 。 3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a diluent and / or an excipient, and a compound of formula I according to any one of claims 1-2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt, hydrate and solvate, prodrug or deuterated derivative thereof as an active ingredient.

4. The use of the compound of Formula I according to any one of claims 1-2, or its stereoisomers, tautomers, and pharmaceutically acceptable salts, hydrates and solvates, prodrugs or deuterated derivatives, or the pharmaceutical composition according to claim 3, as an inhibitor of the kinin subfamily member 18A subprotein, or in the preparation of a medicament for the treatment and / or prevention of diseases associated with this subprotein.

5. The application according to claim 4, characterized in that, The diseases associated with the kinin subfamily member 18A subprotein include cancer, psoriasis, atopic dermatitis, other autoimmune diseases, or proliferative disorders of inflammatory bowel disease.

6. The application according to claim 5, characterized in that, The cancers mentioned include mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, nasal cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary tract cancer, and melanoma. Pigmentoma, brain tumor, lymphoma, head and neck cancer, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma.

7. A method for treating, modulating, or preventing diseases mediated by the subprotein, comprising administering to a subject a therapeutically effective amount of the compound of formula I as described in any one of claims 1-2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt, hydrate, or solvate thereof, a prodrug, a deuterated derivative thereof, or the pharmaceutical composition of claim 3.

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