CN117466899A

CN117466899A - KIF18A inhibitor and application thereof

Info

Publication number: CN117466899A
Application number: CN202310941716.0A
Authority: CN
Inventors: 张学军; 臧杨; 李群; 丁肖华; 孙小川; 付浩亮; 胡文兵; 杨洋; 朱海勇; 李莉娥; 杨俊�
Original assignee: Humanwell Healthcare Group Co ltd; Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Current assignee: Humanwell Healthcare Group Co ltd; Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Priority date: 2022-07-29
Filing date: 2023-07-28
Publication date: 2024-01-30
Also published as: WO2024022508A1

Abstract

The present invention provides heterocyclic compounds of formula I, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof; the compound has better KIF18A inhibition effect,

Description

KIF18A inhibitor and application thereof

the invention requires enjoying:

priority of prior application filed in the China national intellectual property office at the year 2022, 7 and 29, with patent application number 202210908137.1 and entitled "KIF18A inhibitor and use";

priority of prior application entitled "KIF18A inhibitor and use" filed by the national intellectual property office of china at 3, month 17 of 2023, patent application number 202310266738.1.

The entirety of the prior application is incorporated by reference into this application.

Technical Field

The invention belongs to the field of medicines, and particularly relates to a KIF18A inhibitor and application thereof.

Background

KIF18A is a mitotic kinesin that regulates chromosomal localization during cell division and is overexpressed in a portion of human cancers. TP53 mutant unstable aneuploid cancer cells characterized by Chromosomal Instability (CIN) rely on KIF18A motor activity to prevent lethal multipolar cell division. The KIF18A gene belongs to the kinesin-8 subfamily and is a positive-end directed motor. KIF18A is thought to influence the dynamics of the positive end of the centromere microtubules to control correct chromosomal location and spindle tension. Depletion of human KIF18A results in longer spindles in HeLa cervical cancer cells, increased chromosomal oscillations in metaphase and activation of mitotic spindle assembly checkpoints. KIF18A is overexpressed in various types of cancers, including, but not limited to, colon, breast, lung, pancreas, prostate, bladder, head, neck, cervical and ovarian cancers. Furthermore, in cancer cell lines, gene deletions or knockouts or KIF18A inhibition affect mitotic spindle devices. In particular, inhibition of KIF18A has been found to induce mitotic cell arrest, which can promote mitotic cell death by apoptosis, mitotic catastrophe or heterogeneously driven lethality or death following mitotic slippage in the interphase.

There is currently no drug on the market that treats many conditions including cancer by the KIF18A inhibition pathway. Thus, the development of novel compounds that inhibit KIF18A activity would be of positive interest for the treatment of diseases.

Disclosure of Invention

It is an object of the present invention to provide a novel class of compounds useful as KIF18A inhibitors.

In a first aspect of the invention, there is provided a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

wherein X is ¹ Is N or-CR ⁵ ；

X ² Is N or-CR ⁶ ；

X ³ Is N or-CR ⁷ ；

X ⁴ Is N or-CR ⁸ ；

X ⁵ Is N or-CR ⁹ ；

X ⁶ Is N or-CR ¹⁰ ；

X ⁷ Is N or-CR ⁴ ；

Ring a, ring B are absent or each independently selected from 5-6 membered heterocycles, and further wherein the 5-6 membered heterocycles are substituted with 0, 1, 2 or 3 groups selected from: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, cyano, -NR ^a R ^a The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

At least one of ring a or ring B is present;

l is-NR ³ -C (=o) -or-C (=o) -NR ³ -；

M is absent, or is selected from ^c Substituted C _1-6 An alkylene group;

R ¹ selected from cyano or a group-ZR ¹² Wherein Z is independently selected from-C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹¹ -C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹¹ SO ₂ -C _0-6 Alkyl-, -C _0-6 alkyl-SO ₂ NR ¹¹ -C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹¹ SO ₂ NR ¹¹ -C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹¹ SO ₂ NR ¹¹ -C(＝O)-O-C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹¹ -S(＝O)(＝NH)-C _0-6 Alkyl-, -C _0-6 alkyl-S (=o) (=nh) -C _0-6 Alkyl-, -C _0-6 alkyl-S-C _0-6 Alkyl-, -C _0-6 alkyl-S (=o) -C _0-6 Alkyl-, -C _0-6 alkyl-SO ₂ -C _0-6 Alkyl-, -C _0-6 alkyl-O-C _0-6 Alkyl-, -P-, -C _0-6 alkyl-P (=o) (R ¹¹ )-、-C _0-6 alkyl-P (=o) ₂ 、-C _0-6 Alkyl- (c=o) -C _0-6 Alkyl-, -C _0-6 Alkyl- (c=o) -O-C _0-6 Alkyl-, -C _0-6 Alkyl- (c=o) NR ¹¹ -C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹¹ (C＝O)-C _0-6 alkyl-or-C (=n-OH) -; or said group-ZR ¹² Is-n=s (=o) - (R ¹² ) ₂ Wherein two R ¹² Pairs of saturated or partially saturated 3-, 4-, 5-or 6-membered monocyclic rings containing 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, which may alternatively be combined with the sulfur atoms to which they are each attached;

R ² is halogenOr a group-Y-R ¹³ Wherein Y is-C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹³ -C _0-6 Alkyl-, -C _0-6 alkyl-O-C _0-6 Alkyl-, -C _0-6 alkyl-S-C _0-6 Alkyl-, -C _0-6 alkyl-S (=o) -C _0-6 Alkyl-, -C _0-6 alkyl-S (=o) ₂ -C _0-6 Alkyl-, -C _0-6 alkyl-SO ₂ NR ¹³ -C _0-6 Alkyl-, -C _0-6 alkyl-S (=o) (=nh) -, -C _0-6 alkyl-NR ¹³ -SO ₂ -C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹³ SO ₂ NR ¹³ -C _0-6 Alkyl-, -C _0-6 alkyl-C (=o) -C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹³ C(＝O)-C _0-6 Alkyl-, -C _0-6 Alkyl- (c=o) NR ¹³ -C _0-6 alkyl-or-C _0-6 alkyl-C (=O) -O-C _0-6 Alkyl-; or-Y-R ¹³ Is-n=s (=o) - (R ¹³ ) ₂ Wherein two R ¹³ Pairs of saturated or partially saturated 3-, 4-, 5-or 6-membered monocyclic rings containing 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, which may alternatively be combined with the sulfur atoms to which they are each attached;

R ³ selected from hydrogen, C _1-6 Alkyl, C _1-4 Haloalkyl, C _3-8 Cycloalkyl, halo C _3-8 Cycloalkyl;

R ⁴ 、R ⁶ and R is ⁷ Are independently selected from hydrogen, halogen, C _1-8 Alkyl, C _1-4 Haloalkyl, cyano;

R ⁵ selected from hydrogen, halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, C _3-8 Cycloalkyl, halo C _3-8 Cycloalkyl, -O-C _1-8 Alkyl or-O-R ^5a The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^5a A saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring containing 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S;

or alternatively, R ² And R is ⁵ Can be used forIn combination with the carbon atoms to which they are each attached, form a saturated or partially saturated 5-or 6-membered monocyclic ring fused to the heteroaromatic ring; wherein the 5-or 6-membered monocyclic ring contains 0, 1, 2 or 3N atoms and 0 or 1 atoms selected from O and S, and further wherein the 5-or 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, cyano, -NR ^a R ^a Or oxo;

R ⁸ and R is ⁹ Are independently selected from hydrogen, halogen, cyano, C _1-8 Alkyl, -O-C _1-8 Alkyl, C _3-8 Cycloalkyl, C _3-8 Halogenated cycloalkyl or C _1-4 A haloalkyl group;

R ¹⁰ is hydrogen, halogen, hydroxy, cyano, C _1-8 Alkyl, C _3-8 Cycloalkyl, C _3-8 Halogenated cycloalkyl, C _1-4 Haloalkyl, -O-R ^10a or-O-R ^10b ；

R ¹¹ Is hydrogen, R ^11a Or R is ^11b ；

R ¹² Is hydrogen, halogen, hydroxy, cyano, R ^12a Or R is ^12b ；

R ¹³ Is hydrogen, halogen, cyano, R ^13a Or R is ^13b ；

R ^10a 、R ^11a 、R ^12a And R is ^13a Each independently selected from the group consisting of: 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 3N atoms and 0, 1 or 2 atoms selected from O and S, substituted with 0, 1, 2 or 3 groups selected from: halogen, cyano, amino, C _1-6 Alkyl, C _1-6 Haloalkyl, -OR ^a 、-OC _1-6 Haloalkyl, -C (=o) R ^b 、-C(＝O)OR ^a 、-C(＝O)NR ^a R ^a 、-C(＝NR ^a )NR ^a R ^a 、-OC(＝O)R ^b 、-OC(＝O)NR ^a R ^a 、-OC _2-6 Alkyl NR ^a R ^a 、-OC _2-6 Alkyl OR ^a 、-SR ^a 、-S(＝O)R ^b 、-S(＝O) ₂ R ^b 、-S(＝O) ₂ NR ^a R ^a 、-NR ^a R ^a 、-N(R ^a )C(＝O)R ^b 、-N(R ^a )C(＝O)OR ^b 、-N(R ^a )C(＝O)NR ^a R ^a 、-N(R ^a )C(＝NR ^a )NR ^a R ^a 、-N(R ^a )S(＝O) ₂ R ^b 、-N(R ^a )S(＝O) ₂ NR ^a R ^a 、-NR ^a C _2-6 Alkyl NR ^a R ^a 、-NR ^a C _2-6 Alkyl OR ^a 、-C _1-6 Alkyl NR ^a R ^a 、-C _1-6 Alkyl OR ^a 、-C _1-6 Alkyl N (R) ^a )C(＝O)R ^b 、-C _1-6 Alkyl OC (=o) R ^b 、-C _1-6 Alkyl C (=O) NR ^a R ^a 、-C _1-6 Alkyl C (=O) OR ^a 、R ¹⁴ And oxo;

R ^10b 、R ^11b 、R ^12b and R is ^13b Each independently selected from the group consisting of: c substituted with 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of _1-6 Alkyl: halogen, cyano, C _1-6 Alkyl, C _1-6 Haloalkyl, -C _0-6 NR ^a R ^a 、-OR ^a 、-C(＝O)OR ^a And a saturated, partially saturated or unsaturated 3-, 4-, 5-or 6-membered monocyclic ring;

R ¹⁴ independently selected from the group consisting of: 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 3N atoms and 0, 1 or 2 atoms selected from O and S, substituted with 0, 1, 2 or 3 groups selected from: halogen, cyano, amino, C _1-6 Alkyl, C _1-6 Haloalkyl, -OR ^a 、-OC _1-6 Haloalkyl, -C (=o) R ^b 、-C(＝O)OR ^a 、-C(＝O)NR ^a R ^a 、-C(＝NR ^a )NR ^a R ^a 、-OC(＝O)R ^b 、-OC(＝O)NR ^a R ^a 、-OC _2-6 Alkyl NR ^a R ^a 、-OC ₂ -C ₆ Alkyl OR ^a 、-SR ^a 、-S(＝O)R ^b 、-S(＝O) ₂ R ^b 、-S(＝O) ₂ NR ^a R ^a 、-NR ^a R ^a 、-N(R ^a )C(＝O)R ^b 、-N(R ^a )C(＝O)OR ^b 、-N(R ^a )C(＝O)NR ^a R ^a 、-N(R ^a )C(＝NR ^a )NR ^a R ^a 、-N(R ^a )S(＝O) ₂ R ^b 、-N(R ^a )S(＝O) ₂ NR ^a R ^a 、-NR ^a C _2-6 Alkyl NR ^a R ^a 、-NR ^a C _2-6 Alkyl OR ^a 、-C _1-6 Alkyl NR ^a R ^a 、-C _1-6 Alkyl OR ^a 、-C _1-6 Alkyl N (R) ^a )C(＝O)R ^b 、-C _1-6 Alkyl OC (=o) R ^b 、-C _1-6 Alkyl C (=O) NR ^a R ^a 、-C _1-6 Alkyl C (=O) OR ^a And oxo;

R ^x selected from the group consisting of: hydrogen, hydrogen,

Or R is ^x C being substituted by 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of _2-8 Alkyl: halogen, cyano, amino, C _1-6 Alkyl, C _1-6 Haloalkyl, -OR ^a 、-NR ^a R ^a 、-C(＝O)OR ^a 、-OC _1-4 Haloalkyl or R ¹⁵ⁿ ；

Or R is ^x Phenyl or an unsaturated 5 membered monocyclic ring which is phenyl or phenyl substituted with 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of: halogen (halogen)Cyano, amino, C _1-6 Alkyl, C _1-6 Haloalkyl, -OR ^a 、-NR ^a R ^a 、-C(＝O)OR ^a 、-OC _1-4 Haloalkyl or R ¹⁵ⁿ ；

The 5-membered monocyclic ring contains 0, 1, 2 or 3N atoms and 0 or 1 atom selected from O and S;

R ^15a 、R ^15b 、R ^15c 、R ^15d 、R ^15e 、R ^15f 、R ^15g 、R ^15h 、R ¹⁵ⁱ 、R ^15j 、R ^15k and R is ^15l Each of which is hydrogen, halogen, R ^15o Or R is ^15p ；

Or alternatively, R ^15a And R is ^15b To, R ^15c And R is ^15d To, R ^15e And R is ^15f To, R ^15g And R is ^15h To, R ¹⁵ⁱ And R is ^15j Pair and R ^15k And R is ^15l Each of the pairs may be independently combined with their respective attached carbon atoms to form a spiro union to R ^x A cyclic saturated or partially saturated 3-, 4-, 5-, 6-membered monocyclic ring; wherein the 3-, 4-, 5-, 6-, membered monocyclic ring contains 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, 6-, membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, cyano, -NR ^a R ^a Or oxo;

or, alternatively, R ^15a And R is ^15b To, R ^15c And R is ^15d To, R ^15e And R is ^15f To, R ^15g And R is ^15h To, R ¹⁵ⁱ And R is ^15j Pair, R ^15k And R is ^15l Each of the pairs may independently combine to form a double bond;

R ¹⁵ⁿ and R is ^15o May be independently selected from saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, 7-, or 8-, 9-, 10-, 11-, 12-membered bicyclic rings; wherein the single ringOr bicyclic ring containing 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, and further wherein the monocyclic or bicyclic ring is substituted with 0, 1, 2, 3 or 4 groups selected from: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, cyano, -C (=o) OR ^a 、-C(＝O)R ^b 、-C(＝O)NR ^a R ^a 、-C(＝NR ^a )NR ^a R ^a 、-OC(＝O)R ^b 、-OC(＝O)NR ^a R ^a 、-OC _2-6 Alkyl NR ^a R ^a 、-NR ^a R ^a 、-OC _2-6 OR ^a 、-SR ^a 、-S(＝O)R ^b 、-S(＝O) ₂ R ^b 、-S(＝O) ₂ NR ^a R ^a 、-NR ^a C(＝O)R ^b 、-NR ^a C(＝O)OR ^b 、-NR ^a C(＝O)NR ^a R ^a 、-NR ^a C(＝NR ^a )NR ^a R ^a 、-NR ^a S(＝O) ₂ NR ^b 、-NR ^a S(＝O) ₂ NR ^a R ^a 、-R ^a C _2-6 Alkyl NR ^a R ^a 、-NR ^a C _2-6 Alkyl OR ^a 、-C _1-6 Alkyl NR ^a R ^a 、-C _1-6 Alkyl OR ^a 、-C _1-6 Alkyl OC (=o) R ^b 、-C _1-6 Alkyl NR ^a C(＝O)R ^b 、-C _1-6 Alkyl NR ^a C(＝O)NR ^a R ^a 、-C _1-6 alkyl-C (=o) OR ^a Or oxo;

R ^15p can be independently selected from 0, 1, 2, 3, 4 or 5 groups selected from halogen and C _1-4 Haloalkyl, cyano, -C (=o) OR ^a 、-OR ^a 、-OC _1-4 Haloalkyl or-NR ^a R ^a Group-substituted C _1-8 An alkyl group;

R ^a independently selected from H or R ^b ；

R ^b Independently selected from C _1-6 Alkyl, phenyl or benzyl, wherein said C _1-6 Alkyl is selected from 0, 1, 2 or 3Substituent substitution: halogen, hydroxy, -OC _1-6 Alkyl, -NH ₂ 、-NHC _1-6 Alkyl, -OC (=o) C _1-6 Alkyl or-N (C) _1-6 Alkyl) C _1-6 An alkyl group; and the phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OH, -OC _1-6 Alkyl, -NH ₂ 、-NHC _1-6 Alkyl, -OC (=o) C _1-6 Alkyl or-N (C) _1-6 Alkyl) C _1-6 An alkyl group;

R ^c represents absence or independently selected from halogen, hydroxy, amino, cyano, carbonyl, oxo, carboxyl, C _2-6 Alkenyl, C _1-6 Alkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-4 Haloalkyl, hydroxy C _1-6 Alkyl, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, halo C _1-4 Alkoxy, -COO-C _1-6 Alkyl, -C (O) NR ^c1 R ^c2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^c1 And R is ^c2 Each independently is hydrogen, C _1-6 An alkyl group.

In the present invention, the definition of some substituents in the heterocyclic compounds shown in the formula I can be as follows, and the definitions of the substituents which are not mentioned are as described in any scheme.

In a preferred embodiment of the present invention, the R ^x Selected from the group consisting ofThe R is ^15a 、R ^15b 、R ^15c 、R ^15d 、R ^15e 、R ^15f 、R ^15g 、R ^15h 、R ¹⁵ⁱ And R is ^15j Each of which is independently hydrogen, halogen, C _1-6 Alkyl or C _1-4 A haloalkyl group;

the R is ^15a And R is ^15b Each of the pairs combines with their respective attached carbon atoms to form a spiro union to R ^x A saturated 3-, 4-, or 5-membered monocyclic ring; wherein the ring contains 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S；

The R is ^15c 、R ^15d 、R ¹⁵ⁱ And R is ^15j Each of which is hydrogen, methyl or ethyl;

preferably, the ring contains 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S.

Preferably, R ^15a And R is ^15b Each of the pairs combines with their respective attached carbon atoms to form a spiro union to R ^x Cyclopropyl, cyclobutyl or cyclopentyl of the ring.

In a preferred embodiment of the invention, the radicals mentionedIs->R ^15a 、R ^15b Each independently is methyl, ethyl, propyl, fluoro or chloro, or R ^15a 、R ^15b Combined with their respective attached carbon atoms to form a spiro union to R ^x Cyclopropyl, cyclobutyl or cyclopentyl of the ring;

R ^15c 、R ¹⁵ⁱ Each independently is methyl, ethyl, propyl, F, cl or hydroxy;

preferably, the groupSelected from->

Preferably, the groupSelected from->

In a preferred embodiment of the invention, the radicals mentionedSelected from the group consisting of

Preferably, the groupSelected from->

In a preferred embodiment of the invention, the radicals mentionedSelected from->

In a preferred embodiment of the invention, ring A, ring B are absent or are each independently selected from 5-6 membered heteroaromatic rings containing 1, 2, 3, 4 heteroatoms;

the 5-6 membered heteroaryl ring is substituted with 0, 1, 2 or 3 groups selected from: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, cyano, -NR ^a R ^a ；

At least one of the rings a or B is present;

in a preferred embodiment of the invention, ring a or ring B are not present at the same time;

the heteroatom is selected from N, O, S; when the number of heteroatoms is 2, 3 or 4, the heteroatoms may be the same or different;

preferably, the ring a or ring B contains at least one N;

the ring A or the ring B is selected from pyrrole, imidazole, pyrazole, triazole, furan, thiophene, oxazole, thiazole, pyridine, pyrimidine and pyrazine;

the ring a or ring B is substituted with 0, 1, 2 or 3 groups selected from: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, cyano, -NR ^a R ^a ；

Preferably, the ring a or ring B is selected from pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyrazine;

the ring a or ring B is substituted with 0, 1, 2 or 3 groups selected from: halogen, C _1-3 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, cyano;

more preferably, the ring a or ring B is selected from pyrrole, imidazole, pyrazole; the ring a or ring B is substituted with 0, 1, 2 or 3 groups selected from: halogen, methyl, ethyl.

In a preferred embodiment of the invention, the radicalsSelected from the following (1) or (2):

(1)wherein X is ¹ 、X ³ Each independently is N or CH, X ² 、X ⁷ Each independently represents N or C, X ⁸ 、X ⁹ 、X ¹⁰ Each independently is N or CRm; wherein Rm is hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ A haloalkyl group; preferably, rm is hydrogen or methyl;

(2)wherein X is ¹ 、X ² Each independently is N or CH, X ³ 、X ⁷ Each independently represents N or C, X ¹¹ 、X ¹² 、X ¹³ Each independently is N or CRm; wherein Rm is hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ A haloalkyl group; preferably, rm is hydrogen or methyl;

preferably, the method comprises the steps of,selected from: />

Preferably, the method comprises the steps of,selected from: />

At least one of the rings a or B is present;

preferably, the ring a or ring B contains at least one N;

more preferably, the ring a or ring B is selected from pyrrole, imidazole, pyrazole.

In a preferred embodiment of the present invention, the L is-NR ³ -C (=o) -or-C (=o) -NR ³ -；

Preferably, R ³ Is hydrogen or methyl.

In a preferred embodiment of the invention, the compound is selected from the following structures:

wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ Is as defined in the first aspect of the invention;

the definition of ring a and ring B is as described in the first aspect of the invention;

R ¹ 、R ² and R is ^x Is as defined in the first aspect of the invention;

l and M are as defined in the first aspect of the invention;

Preferably, the method comprises the steps of,selected from: />

Preferably, the method comprises the steps of,selected from->

R ¹ 、R ² and R is ^x Is as defined in the first aspect of the invention;

l and M are as defined in the first aspect of the invention.

R ¹ and R is ² Is as defined in the first aspect of the invention;

m is as defined in the first aspect of the invention;

preferably, the method comprises the steps of,selected from: />

Preferably, the method comprises the steps of,selected from: />

Preferably, the method comprises the steps of,selected from->

R ¹ and R is ² Is as defined in the first aspect of the invention;

m is as defined in the first aspect of the invention.

Wherein X is ¹ Is as defined in the first aspect of the invention;

R ¹ 、R ² 、R ⁸ 、R ⁹ and R is ¹⁰ Is as defined in the first aspect of the invention;

m is as defined in the first aspect of the invention.

wherein Rm is hydrogen, C ₁ -C ₃ Alkyl or C ₁ -C ₃ A haloalkyl group;

R ¹ 、R ² and M is as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, the R ² Selected from F, cl, br or a group-Y-R ¹³ Wherein Y is a bond, -NH- (CH) ₂ ) _0-4 -or-O- (CH) ₂ ) _0-4 The method comprises the steps of carrying out a first treatment on the surface of the And R is ¹³ 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 3N atoms and 0 or 1 atom selected from O and S, substituted with 0, 1, 2, or 3 groups selected from: F. cl, br, C _1-6 Alkyl, C _1-4 Haloalkyl, -OH, -OC _1-4 Haloalkyl, cyano, R ¹⁴ And oxo; or R is ¹³ Is selected from F, cl, br, -OH, -OC _1-4 C substituted by 0, 1, 2, 3, 4 or 5 groups of haloalkyl or cyano _1-6 An alkyl group; wherein the R is ¹⁴ Is as defined in the first aspect of the invention;

preferably, Y is a bond, R ¹³ A saturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0 or 1N atom and 0 or 1O atom; which is substituted with 0, 1, 2 or 3 identical or different groups selected from: F. cl, br, -C _1-3 Alkyl, -OH, CN, -C _1-3 alkyl-OH;

preferably F, methyl, -OH, CN, -CH ₂ OH; or,

y is-NH-, -NH- (CH) ₂ ) _0-4 -、-O-(CH ₂ ) _0-4 -or-SO ₂ NH-；R ¹³ A saturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring containing 0 or 1N atom and 0 or 1O atom; which is substituted with 0, 1, 2 or 3 identical or different groups selected from: F. methyl, trifluoromethyl, -CN, -OH, CH ₂ OH；

Or Y is a bond, R ¹³ Is tert-butyl or isopropyl which is unsubstituted or substituted by hydroxy.

In a preferred embodiment of the present invention, the R ² Selected from F, cl, br or a group-Y-R ¹³ Wherein Y is a bond, -NH- (CH) ₂ ) _0-4 -or-O- (CH) ₂ ) _0-4 The method comprises the steps of carrying out a first treatment on the surface of the And R is ¹³ 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 3N atoms and 0 or 1 atom selected from O and S, substituted with 0, 1, 2, or 3 groups selected from: F. cl, br, C _1-6 Alkyl, C _1-4 Haloalkyl, -OH, -OC _1-4 Haloalkyl, cyano, R ¹⁴ And oxo; or R is ¹³ Is selected from F, cl, br, -OH, -OC _1-4 C substituted by 0, 1, 2, 3, 4 or 5 groups of haloalkyl or cyano _1-6 An alkyl group; wherein the R is ¹⁴ Is as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, the R ² Selected from the following structures:

in a preferred embodiment of the invention, said M is absent or selected from the group consisting of-NH-, -CH ₂ -、Preferably, M is absent or selected from-CH ₂ -。

In a preferred embodiment of the present invention, Z is a bond, -NH-, -NHSO ₂ -、-SO ₂ NH-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO ₂ -、-O-、-P-、-P(＝O)CH ₃ -、-P(＝O) ₂ - (c=o) -, - (c=o) NH-or-NH (c=o) -.

In a preferred embodiment of the present invention, the R ¹² Selected from R ^12a Or R is ^12b ；

R ^12a Selected from: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring containing 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, substituted with 0, 1, 2 or 3 groups selected from: halogen, hydroxy, C _1-6 Alkyl, C _1-6 A haloalkyl group;

R ^12b is C substituted with 0, 1, 2, 3, 4 or 5 groups selected from _1-6 Alkyl: halogen, hydroxy, C _1-6 Alkyl, and saturated, partially saturated or unsaturated 3-, 4-, 5-, or 6-membered monocyclic rings; preferably, the 3-, 4-, 5-, or 6-membered monocyclic ring is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

Preferably, R ¹² Selected from: c (C) _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 alkyl-C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl or C _1-6 Alkyl-4-6 membered heterocycloalkyl;

the C is _1-6 Alkyl, C _3-6 Cycloalkyl or 4-6 membered heterocycloalkyl is substituted with 0, 1, 2 or 3 substituents selected from: F. cl, hydroxy, methyl, ethyl, propyl, butyl;

more preferably, said R ¹² Selected from-CH ₂ CH ₂ OH, tert-butyl group,Methyl, -CH ₂ F、Cyclopropyl, cyclopropyl-CH ₃ 、-CH ₂ -cyclopropyl,/->Tetrahydrofuranyl, < - > and->Cyclopentyl, oxetanyl, azetidinyl or 1,3, 4-oxathiazinyl alkyl.

R ^12b is C substituted with 0, 1, 2, 3,4 or 5 groups selected from _1-6 Alkyl: halogen, hydroxy, C _1-6 Alkyl, and saturated, partially saturated or unsaturated 3-, 4-, 5-, or 6-membered monocyclic rings; preferably, the 3-, 4-, 5-, or 6-membered monocyclic ring is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

the C is _1-6 Alkyl, C _3-6 Cycloalkyl or 4-6 membered heterocycloalkyl optionally substituted with a substituent selected from the group consisting of: F. cl, hydroxy, methyl, ethyl, propyl, butyl;

In a preferred embodiment of the present invention, the R ¹ Selected from Z-R ^12a Or Z-R ^12b ；

The Z is selected from-NH-, -NHSO ₂ -、-SO ₂ NH-、-S(＝O)(＝NH)-、-SO ₂ -；

The R is ^12a Selected from C _3-6 Cycloalkyl or 4-6 membered heterocycloalkyl; the C is _3-6 Cycloalkyl or 4-6 membered heterocycloalkyl is substituted with 0, 1, 2 or 3 substituents selected from: F. cl, hydroxy, methyl, ethyl, propyl, butyl;

the R is ^12b Selected from C _1-6 An alkyl group; the C is _1-6 Alkyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: F. cl, hydroxy, methyl, ethyl, propyl, butyl;

preferably, said R ^12a Selected from cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydrofuranyl; the cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydrofuranyl are substituted with 0, 1, 2 or 3 substituents selected from: F. hydroxy, methyl;

Preferably, said R ^12b Selected from methyl, ethyl, t-butyl, isopropyl; the methyl, ethyl, tert-butyl, isopropyl are substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: F. hydroxy, methyl.

In a preferred embodiment of the present invention, the R ¹ Selected from:

in a preferred embodiment of the present invention, the R ⁴ Selected from hydrogen, halogen, C _1-3 Alkyl or C _1-4 A haloalkyl group; preferably, R ⁴ Selected from hydrogen.

In a preferred embodiment of the present invention, the R ⁵ Selected from hydrogen, halogen, methyl, halomethyl, methoxy, cyclopropyl, oxetanyl, N-cyclopropyl; preferably, R ⁵ Selected from hydrogen.

In a preferred embodiment of the present invention, the R ⁶ Selected from hydrogen, halogen, C _1-3 Alkyl or C _1-4 A haloalkyl group; preferably, R ⁶ Selected from hydrogen.

In a preferred embodiment of the present invention, the R ⁷ Selected from hydrogen, halogen, C _1-3 Alkyl or C _1-4 A haloalkyl group; preferably, R ⁷ Selected from hydrogen.

In a preferred embodiment of the present invention, the R ⁸ Selected from hydrogen, halogen, cyano, C _1-3 Alkyl, -O-C _1-3 Alkyl, C _3-6 Cycloalkyl, C _3-6 Halogenated cycloalkyl or C _1-4 A haloalkyl group.

In a preferred embodiment of the present invention, the R ⁸ Selected from hydrogen, F, cl, br, methyl, cyclopropyl or CF ₃ The method comprises the steps of carrying out a first treatment on the surface of the Preferably, said R ⁸ Selected from hydrogen.

In a preferred embodiment of the present invention, the R ⁹ Selected from hydrogen, halogen, hydroxy, cyano, C _1-3 Alkyl, -O-C _1-3 Alkyl, C _3-6 Cycloalkyl, C _3-6 Halogenated cycloalkyl or C _1-4 A haloalkyl group;

preferably, R ⁹ Selected from hydrogen, halogen, C _1-3 An alkyl group.

In a preferred embodiment of the present invention, the R ⁹ Selected from hydrogen, methyl or F; preferably, said R ⁹ Selected from hydrogen.

In a preferred embodiment of the present invention, the R ¹⁰ Selected from hydrogen, halogen, hydroxy, cyano, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _3-6 Halogenated cycloalkyl, C _1-4 Haloalkyl, -O-R ^10a or-O-R ^10b ；

Preferably, R ¹⁰ Selected from hydrogen, halogen, C _1-3 An alkyl group.

In a preferred embodiment of the present invention, the R ¹⁰ Selected from hydrogen, methyl or F; preferably, said R ¹⁰ Selected from hydrogen.

In a preferred embodiment of the present invention,selected from benzene rings or F-substituted benzene rings.

In a preferred embodiment of the invention, the compound comprises:

/>

in a second aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula I as described in the first aspect, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable carrier.

In a third aspect of the present invention, the use of a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, as described in the first aspect, or the use of a pharmaceutical composition according to the second aspect, comprises:

inhibition of KIF18A;

and/or preventing and/or treating KIF 18A-related diseases;

and/or preparing a medicament, a pharmaceutical composition or a preparation for inhibiting the KIF18A and/or preventing and/or treating the diseases related to the KIF 18A.

Preferably, the KIF 18A-related disease comprises: proliferative disorders of cancer, psoriasis, atopic dermatitis, autoimmune diseases or inflammatory bowel disease.

Cancers that should be mentioned include mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, hepatocellular carcinoma, gall bladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choriocarcinoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, ewing sarcoma, and plasmacytoma.

Autoimmune diseases which should be mentioned include rheumatoid arthritis, systemic lupus erythematosus, sjogren's syndrome, scleroderma, mixed connective tissue disease, dermatomyositis, polymyositis, lyter's syndrome, autoimmune lymphoproliferative syndrome, multiple sclerosis, myasthenia gravis and encephalomyelitis.

Inflammatory bowel disease that should be mentioned includes ulcerative colitis or Crohn's disease.

In a fourth aspect of the invention, there is provided a method of inhibiting KIF18A, or preventing and/or treating a KIF 18A-related disease, comprising the steps of: administering to a subject in need thereof a compound of formula I according to the first aspect of the invention, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the second aspect. The KIF 18A-associated disease is as described in the third aspect.

Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

Terminology and definitions

Unless otherwise indicated, the radical and term definitions recited in the specification and claims of this application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combined group definitions and structures of compounds should fall within the scope of the description herein.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definitions of this chapter shall control.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In this application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.

The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 speed." vols. A (2000) and B (2001), plenum Press, new York). Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, CH ₂ O is equal to OCH ₂ . As used herein, representing the attachment site of the group. As used herein, "R ₁ "," R1 "and" R ¹ "has the same meaning and can be replaced with each other. For R ₂ And the like, and the meanings of like definitions are the same.

The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.

In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below, unless specifically indicated otherwise.

Where a range of values recited in the specification and claims is understood to be an "integer," it is understood that both endpoints of the range and each integer within the range are recited. For example, an "integer of 1 to 6" should be understood to describe each integer of 0, 1, 2, 3, 4, 5, and 6.

In the present application, "saturated, partially saturated or unsaturated" includes substituents saturated with hydrogen, substituents fully unsaturated with hydrogen, and substituents partially saturated with hydrogen.

In this application, the term "halogen" means fluorine, chlorine, bromine, iodine, alone or as part of other substituents.

As used herein, the term "cyano" means —cn, alone or as part of another substituent.

As used herein, the term "amino" means-NH, alone or as part of another substituent ₂ 。

As used herein, the term "alkyl" when used alone or as part of another substituent means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, having, for example, 1 to 6 carbon atoms, and being attached to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl and hexyl. The alkyl group may be unsubstituted or substituted with one or more suitable substituents. The alkyl group can also be an isotopic isomer of a naturally abundant alkyl group that is enriched in isotopes of carbon and/or hydrogen (i.e., deuterium or tritium).

The term "C _α-β Alkyl "refers to an alkyl group containing a minimum of alpha and a maximum of beta carbon atoms in a branched or linear relationship or any combination of the two, where alpha and beta represent integers, and" C "may also be used _α- C _β The form of "alkyl". The alkyl groups described in this section may also contain one or two double or triple bonds. C (C) ₀ The designation of alkyl represents a direct bond. Exemplary, C _0-6 Alkyl groups including direct bonds, C _1-6 Alkyl (e.g., C1, C2, C3, C4, C5, C6 alkyl). Those skilled in the art will recognize that the term "alkyl" may include "alkylene" groups. C (C) _1-6 Examples of alkyl groups include, but are not limited to, the following:

the term "alkylene" is understood to mean a straight-chain divalent hydrocarbon radical having 1 to 6 carbon atoms or a branched-chain divalent hydrocarbon radical having 3 to 6 carbon atoms, unless otherwise indicated, such as methylene, ethylene, propylene, 1-methylpropylene, butylene, and the like.

"benzo group", alone or in combination, means a divalent group C ₄ H ₄ =, wherein one representation is-ch=ch-, forming a benzene-like ring when ortho-attached to another ring, e.g. tetrahydronaphthalene, indole, etc.

The term "C", alone or as part of another substituent _α-β Haloalkyl "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 with fluorine, chlorine, bromine or iodine.

The term "alkoxy" when used alone or as part of another substituent means a group-O-R ^Q Wherein R is ^Q Is an "alkyl" group as defined above.

The term "oxo" when used alone or as part of another substituent means that the two hydrogens on the methylene group are replaced with oxygen, i.e., the methylene group is replaced with a carbonyl group, representing =o.

The term "thio" when used alone or as part of another substituent means that two hydrogens on the methylene group are replaced with sulfur, representing =s.

The term "cycloalkyl" or "carbocyclyl" alone or as part of another substituent refers to a cyclic alkyl group. The term "m-n membered cycloalkyl" or "C _m -C _n Cycloalkyl "is understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms. For example, "3-15 membered cycloalkyl" or "C ₃ -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, which may contain 1 to 4 rings. "5-8 membered cycloalkyl" contains 5-8 carbon atoms. Including monocyclic, bicyclic, tricyclic, spiro, or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cycloHexyl and adamantyl, or a bicycloalkyl such as a decalin ring. Cycloalkyl groups may be substituted with one or more substituents. In some embodiments, cycloalkyl groups may be cycloalkyl groups fused to aryl or heteroaryl groups. The term "C ₃ -C ₆ Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

In this application, the term "monocyclic" means a group of only one ring, which may be saturated, unsaturated or partially saturated, either carbocyclic (all ring atoms being carbon atoms) or heterocyclic (ring atoms other than carbon atoms including, for example, 1, 2 or 3 heteroatoms, such as N, O or S), alone or as part of another substituent.

In this application, the term "bicyclic" means a group having two connecting rings, alone or as part of another substituent. A bicyclic ring may be a carbocycle (all ring atoms being carbon atoms) or a heterocycle (ring atoms include, in addition to carbon atoms, for example, 1, 2 or 3 heteroatoms, such as N, O or S). Both rings may be aliphatic (e.g., decalin and norbornane), or may be aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetrahydronaphthalene). Bicyclic rings include (a) spiro compounds in which two rings share only one single atom (the spiro atom, which is typically a quaternary carbon). Examples of spiro compounds include, but are not limited to:

Spirocycloalkyl groups also containing a spiro atom common to both the monocyclocycloalkyl and heterocycloalkyl groups, non-limiting examples include:

(b) Fused bicyclic compounds in which two rings share two adjacent atoms. In other words, the rings share a covalent bond, i.e. the bridgehead atoms are directly linked (e.g. α -thurene and decalin). Examples of fused bicyclic rings include, but are not limited to:

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

the term "heterocycle", alone or as part of another substituent, includes "heterocycloalkyl" and "heteroaryl" and refers to cycloalkyl or aromatic ring groups in which one or more (in some embodiments 1 to 3) carbon atoms are replaced with heteroatoms such as, but not limited to N, O, S and P.

The term "3-8 membered heterocycloalkyl" is understood to mean a single, bi-or tri-ring having 3 to 8 atoms, wherein the heteroatoms are preferably selected from N, O and S, it being understood that when the total number of S and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other. Examples of heterocycloalkyl groups include, but are not limited to: tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl.

The term "5-or 6-membered heteroaryl" is understood to mean an aromatic ring radical having 5 or 6 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, preferably 1 to 3 heteroatoms independently selected from N, O and S. Examples of heteroaryl groups include, but are not limited to: thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like.

NR, alone or as part of other substituents ^a R ^a The groups may beIn the form of (C) or may also include two of R ^a The groups together form a ring, which optionally contains N, O or S atoms, and may also include groups such as: />

The radicals N (C _α-β Alkyl) C _α-β Alkyl (wherein alpha and beta are as defined above) includes two of these C' s _α-β The alkyl groups together form a substituent of a ring (optionally containing N, O or S atoms) and include, for example:/>

the term "inert solvent" includes, but is not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.

Compounds provided herein, including intermediates useful in the preparation of compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof. "protected derivatives" are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as protecting groups). Suitable protecting groups for the carboxyl moiety include benzyl, t-butyl, and the like, as well as isotopes and the like. Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable hydroxyl protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art.

In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

In the present application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the invention.

The term "amine salt" refers to the product of neutralizing an alkyl primary, secondary or tertiary amine with an acid. The acid includes inorganic or organic acids as described herein.

The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers.

Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes D and L or (+) and (-) are symbols for designating the rotation of plane polarized light by a compound, where (-) or L represents that the compound is left-handed. The compound prefixed with (+) or D is dextrorotatory.

When the bonds to chiral carbons in the formulae of the present invention are depicted in straight lines, it is understood that both the (R) and (S) configurations of the chiral carbons and the enantiomerically pure compounds and mixtures thereof resulting therefrom are included within the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120. The absolute configuration of a solid center is represented by wedge-shaped keys and dashed keys.

The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-mobile tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.

In this application, "pharmaceutical composition" refers to a formulation of a compound of the invention with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.

In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.

The term "solvate" refers to a compound of the invention or a salt thereof that includes a stoichiometric or non-stoichiometric solvent that binds with non-covalent intermolecular forces, and when the solvent is water, is a hydrate.

The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be removed by conventional procedures or in vivo to give the parent compound. Prodrugs include compounds wherein a hydroxyl group or amino group of a compound of the invention is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group, free amino group, respectively.

The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with radioisotopes, such as deuterium ² H) Tritium% ³ H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the category of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical formulation, i.e., by increasing flowability and/or tackiness, making the formulation more suitable for direct compression.

The term "treatment" and other similar synonyms as used herein include the following meanings:

(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;

(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;

(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively

(iv) Alleviating symptoms caused by the disease or condition.

The reaction temperature of each step may be appropriately selected depending on the solvent, starting material, reagent, etc., and the reaction time may be appropriately selected depending on the reaction temperature, solvent, starting material, reagent, etc. After the reaction of each step is finished, the target compound can be separated and purified from the reaction system according to a common method, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and the like. Under the condition of not influencing the next reaction, the target compound can also directly enter the next reaction without separation and purification.

Advantageous effects

The present inventors have studied extensively and intensively, and have unexpectedly developed a compound or a pharmaceutically acceptable salt thereof, and a preparation method and use thereof.

The invention provides a compound shown in a formula I, a tautomer, a stereoisomer, a hydrate, a solvate and pharmaceutically acceptable salt or prodrug thereof, wherein the compound shown in the formula I has a remarkable inhibiting effect on KIF18A, can treat diseases or symptoms mediated by KIF18A, shows excellent pharmacokinetic properties, and has higher safety and pharmaceutical properties.

The invention provides a method for preparing a compound shown in I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof and an intermediate thereof, wherein the method is simple in operation, high in yield and high in purity, and can be used for medical industrial production.

Detailed Description

The invention will be further illustrated with reference to specific examples. It is to be understood that the following description is only of the most preferred embodiments of the present invention and should not be taken as limiting the scope of the invention. Upon a complete understanding of the present invention, experimental methods without specific references in the following examples, generally according to conventional conditions or according to conditions suggested by the manufacturer, may make insubstantial changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of the present invention.

The application has the following definitions:

symbol or unit:

IC ₅₀ : half inhibition concentration, meaning the concentration at which half of the maximum inhibition effect is achieved

M: mol/L, e.g., n-butyllithium (14.56 mL,29.1 mmol,2.5M in n-hexane) means an n-hexane solution of n-butyllithium having a molar concentration of 2.5mol/L

N: equivalent concentration, e.g. 2N hydrochloric acid means 2mol/L hydrochloric acid solution

RT: retention time

Reagent:

DMF: n, N-dimethylformamide

DIPEA: n, N-diisopropylethylamine

XPhos Pd G3: methane sulphonic acid (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II)

PE: petroleum ether

EA: acetic acid ethyl ester

The test method comprises the following steps:

LCMS: liquid chromatography-mass spectrometry

Intermediate A1: synthesis of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid (A1)

The synthetic route for intermediate A1 is shown below:

to a solution of 2-fluoro-4-iodobenzoic acid (8.00 g,30.1 mmol) in dimethyl sulfoxide (160 mL) was added 6-azaspiro [2.5] octane hydrochloride (5.77 g,39.1 mmol) and potassium carbonate (12.5 g,90.2 mmol) at room temperature, and the reaction was reacted under nitrogen at 140℃for 18h. After completion of the reaction, water (800 mL) was added to the reaction solution at room temperature for dilution, followed by extraction with ethyl acetate (200 ml×3), the aqueous phase was adjusted to ph=6 with dilute hydrochloric acid (2.00M), solids were precipitated, and the filter cake was filtered and dried to give the compound 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid (dark brown solid, 9.00g,83.8% yield).

¹ H NMR(400MHz,DMSO_d ₆ )δ8.06(s,1H),7.76-7.69(m,2H),3.11-3.08(t,4H),1.54(s,4H),0.41(s,4H)

LC-MS,M/Z(ESI):358.0[M+H] ⁺

Example 1: preparation of target Compound I-1

N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

The synthetic route for the target compound I-1 is shown below:

the first step: synthesis of 6-bromo-8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazines

Cesium carbonate (23.5 g,72.2 mmol) and 4, 4-difluoropiperidine hydrochloride (3.41 g,21.7 mmol) were added to a solution of 6, 8-dibromoimidazo [1,2-a ] pyrazine (5.00 g,18.1 mmol) in N-methylpyrrolidone (125 mL). Stirred at 80℃for 10 hours. The reaction solution was quenched with water (200 mL), extracted three times with ethyl acetate (450 mL), and the organic phase was washed with saturated brine (540 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =15:1-3:1) to give 6-bromo-8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazine (4.87 g, 85.1% yield).

LC-MS,M/Z(ESI):317.0[M+H] ⁺

And a second step of: synthesis of tert-butyl (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) carbamate

Tert-butyl carbamate (1.88 g,16.1 mmol), cesium carbonate (4.37 g,13.4 mmol), 2-di-tert-butylphosphine-2 ',4',6' -triisopropylbiphenyl (511 mg,1.07 mmol) and palladium acetate (120 mg, 536. Mu. Mol) were added to a solution of 6-bromo-8- (4, 4-difluoro-1-piperidinyl) imidazo [1,2-a ] pyrazine (1.70 g,5.36 mmol) in anhydrous 1, 4-dioxane (10 mL). Three times with nitrogen and stirring for 10 hours at 110℃under nitrogen atmosphere. The reaction solution was concentrated, and the resulting mixture was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =10:1-5:1) to give tert-butyl (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) carbamate (1.80 g, yield 95.0%).

LC-MS,M/Z(ESI):354.1[M+H] ⁺

And a third step of: synthesis of 8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-amine

To a solution of tert-butyl (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) carbamate (1.80 g,5.09 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (5.81 g,50.9mmol,3.77 mL). Stirred at 25℃for 2 hours. The reaction solution was concentrated, and the crude product was purified by reverse phase Flash (0.1% aqueous ammonia) to give 8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-amine (152 mg, yield 8.12%).

LC-MS,M/Z(ESI):254.1[M+H] ⁺

Fourth step: synthesis of N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid was dissolved in (420 mg,1.18 mmol) in dichloromethane, then a catalytic amount of N, N dimethylformamide (8.6 mg, 280. Mu. Mol) was added, finally oxalyl chloride (224 mg,1.77 mmol) was added, stirred at 25℃for 2 hours, and concentrated to give 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoyl chloride. Then 8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-amine (300 mg,1.18 mmol) was dissolved in dichloromethane (6 mL), triethylamine (599 mg,5.92 mmol) was added, and a solution of 2- (6-azaspiro [2.5] oct-6-yl) -4-iodo-benzoyl chloride (445 mg,1.18 mmol) in dichloromethane (3 mL) was added dropwise and the reaction was carried out at 25℃for 2 hours under nitrogen protection. After completion of the reaction, water (20 mL) was added at room temperature, extracted three times with methylene chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (44.0 mg, yield 6.3%).

LC-MS,M/Z(ESI):593.2[M+H] ⁺

Fifth step: synthesis of N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (I-1)

N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (30 mg, 50.6. Mu. Mol), 2-hydroxyethanesulfonamide (8.64 mg, 65.8. Mu. Mol), cuprous iodide (4.82 mg, 25.3. Mu. Mol), potassium carbonate (21 mg, 152. Mu. Mol) and sarcosine (2.26 mg, 25.3. Mu. Mol) were added to N, N-dimethylformamide (5 mL), and the reaction was carried out under nitrogen for 10 hours at 140 ℃. After completion of the reaction, water (10 mL) was added at room temperature, extraction was performed three times with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Then isolated by reverse phase high performance liquid chromatography (column: phenomenex luna C: 150 x 25mm x 10um; solvent: a = water +0.05% formic acid (99.0%) by volume, B = acetonitrile; gradient: 54% -84%,10 min), then freeze-dried to give N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (I-1) (7.00 mg, 23.2% yield).

¹ H NMR(400MHz,MeOD)δ8.83(s,1H),8.15(br d,J＝8.4Hz,1H),7.86(s,1H),7.56(s,1H),7.35(br s,1H),7.11-7.24(m,1H),4.41(br s,4H),3.97(br t,J＝6.0Hz,2H),3.40(br t,J＝6.0Hz,2H),3.02-3.16(m,4H),2.08-2.23(m,4H),1.26-1.43(m,4H),0.45(s,4H).

LC-MS,M/Z(ESI):590.2[M+H] ⁺

Example 2: preparation of target Compound I-38

N- (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

The synthetic route for the target compound I-38 is shown below:

the first step: synthesis of 7-chloro-5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidine

N, N diisopropylethylamine (2.75 g,21.3 mmol) and 4, 4-difluoropiperidine (1.29 g,10.6 mmol) were added to a solution of 5, 7-dichloroimidazo [1,2-c ] pyrimidine (2.00 g,10.6 mmol) in dimethylsulfoxide (15 mL). Stirred at 20℃for 6h. The reaction solution was poured into water (50 mL), and solids were precipitated, filtered, and the cake was washed with water (50 mL), and the solids were collected and dried to give 7-chloro-5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidine (2.00 g, yield 68.9%).

LC-MS,M/Z(ESI):273.1[M+H] ⁺

And a second step of: synthesis of tert-butyl (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) carbamate

Tert-butyl carbamate (1.55 g,13.2 mmol), cesium carbonate (3.58 g,11.0 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (699 mg, 880. Mu. Mol) was added to a solution of 7-chloro-5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidine (1.20 g,4.40 mmol) in anhydrous 1, 4-dioxane (20 mL). Stirred at 110℃for 6 hours. The reaction solution was concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =3:1-0:1) to give tert-butyl (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) carbamate (1.00 g, yield 64.3%).

LC-MS,M/Z(ESI):354.2[M+H] ⁺

And a third step of: synthesis of 5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-amine

Tert-butyl (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) carbamate (1.00 g,2.83 mmol) is dissolved in ethyl acetate hydrochloride solution (4M, 20 mL) and stirred at 25℃for 2h. The reaction solution was concentrated to give 5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-amine (700 mg, 92.4% purity, 97.7% yield).

LC-MS,M/Z(ESI):254.2[M+H] ⁺

Fourth step: synthesis of N- (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

5- (4, 4-Dihalopiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-amine (0.15 g,0.42 mmol) was added to 3mL of N, N-dimethylformamide, followed by addition of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid (0.16 g,0.63 mmol), N, N-diisopropylethylamine (0.22 g,1.68 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.32 g,0.84 mmol) and heating to 60℃for 16h. LCMS showed complete reaction of the starting material, dilution with 20mL of water, extraction with ethyl acetate (100 mL x 2), concentration of the organic phase to dryness, and isolation and purification of the residue on a silica gel column (PE: EA (V/V) =3:1) gave N- (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (0.2 g, 80% yield).

LC-MS,M/Z(ESI):593.1[M+H] ⁺

Fifth step: synthesis of N- (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (0.2 g,0.338 mmol) was added to 4mL of N, N-dimethylformamide, 2-hydroxyethane-1-sulfonamide (84 mg,0.675 mmol), N, N-dimethylglycine (70 mg,0.675 mmol), cuprous iodide (64 mg,0.338 mmol), potassium carbonate (187 mg,1.35 mmol) was added and the mixture was heated to 130℃to react for 1h. LCMS showed complete reaction of the starting material, dilution with 5mL of water, extraction with ethyl acetate (10 mL x 2), concentration of the organic phase to dryness, and isolation and purification of the residue on a silica gel column (PE: EA (V/V) =1:1) afforded N- (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) -4- ((2-hydroxyethyl) sulfonamide) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (125 mg, 62.8% yield).

¹ H NMR(400MHz,DMSO-d6)δ13.28(s,1H),8.06(d,1H),7.91(s,1H),7.78(s,1H),7.52(d,1H),7.24(d,1H),7.13-7.11(dd,1H),3.74(t,2H),3.57(t,4H),3.31(t,2H),2.96(t,4H),2.28-2.21(m,4H),1.89-1.74(m,4H),0.38(s,4H)。

LC-MS,M/Z(ESI):590.2[M+H] ⁺

Example 3: preparation of target Compound I-44

N- (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

The synthetic route for the target compound I-44 is shown below:

The first step: synthesis of 6-bromo-8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazine

Cesium carbonate (19.0 g,58.4 mmol) and 4, 4-difluoropiperidine (4.25 g,35.1 mmol) are added to a solution of 6, 8-dibromo-2-methylimidazo [1,2-a ] pyrazine (8.50 g,29.2 mmol) in N-methylpyrrolidone (100 mL). Stirred at 80℃for 8h. The reaction solution was quenched in water (200 mL), and a solid was precipitated, filtered, and the cake was washed with water (100 mL), collected and dried to give 6-bromo-8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazine (8.00 g, 82.7% yield).

LC-MS,M/Z(ESI):331.0[M+H] ⁺

And a second step of: synthesis of tert-butyl (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) carbamate

Tert-butyl carbamate (7.96G, 67.9 mmol), cesium carbonate (18.5G, 56.6 mmol), XPhos Pd G3 (383 mg, 453. Mu. Mol) was added to a solution of 6-bromo-8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazine (7.50G, 22.7 mmol) in anhydrous dioxane (100 mL). Stirred at 110℃for 8 hours. The reaction solution was quenched with water (200 mL), extracted with ethyl acetate (200 ml×2), and the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =10:1-5:1) to give tert-butyl (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) carbamate (8.00 g, yield 96.2%).

LC-MS,M/Z(ESI):368.2[M+H] ⁺

And a third step of: synthesis of 8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-amine

Tert-butyl (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) carbamate (7.00 g,19.1 mmol) was dissolved in dichloromethane (35 mL), trifluoroacetic acid (35 mL) was added, and stirred at 25℃for 4h. The reaction solution was concentrated to give 8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-amine trifluoroacetate salt (4.80 g, yield 94.3%).

LC-MS,M/Z(ESI):268.1[M+H] ⁺

Fourth step: synthesis of N- (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

8- (4, 4-Dihalopiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-amine trifluoroacetate (2.50 g,6.6 mmol) was dissolved in acetonitrile (30 mL), N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (2.36 g,8.40 mmol) and N-methylimidazole (2.01 g,24.5 mmol) were added, and then 2- (6-azaspiro [2.5] oct-6-yl) -4-iodo-benzoic acid (2.24 g,8.40 mmol) was added and the reaction was reacted at 90℃for 1h under nitrogen. After the completion of the reaction, water (100 mL) and methylene chloride (50 mL. Times.2) were added at room temperature to extract, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Then separated by normal phase high performance liquid chromatography (column: welch Ultimate XB-CN 250 x 70mm x 10um; solvent: A=ethanol+0.1% volume ammonia (30.0%), B=n-hexane; gradient: 1% -25%,25 minutes), concentrated to give N- (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] octane-6-yl) benzamide (3.80 g, purity 62.1%).

LC-MS,M/Z(ESI):607.2[M+H] ⁺

Fifth step: synthesis of N- (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (1.30 g,2.14 mmol), 2-hydroxyethanesulfonamide (348 mg,2.79 mmol), cuprous iodide (204 mg,1.07 mmol), potassium carbonate (652 mg,4.72 mmol) and sarcosine (95.5 mg,1.07 mmol) were added to N, N-dimethylformamide (20 mL), and the reaction was reacted under nitrogen at 110℃for 10h. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Then isolated by reverse phase high performance liquid chromatography (column: phenomenex luna C: 150 x 25mm x 10um; solvent: a = water +0.05% v formic acid (99.0%), B = acetonitrile; gradient: 45% -75%,15 min), then freeze-dried to give N- (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (150 mg, 11.2% yield).

¹ H NMR(400MHz,DMSO_d ₆ )δ12.89(s,1H),10.19(s,1H),8.78(s,1H),8.07(d,1H),7.85(s,1H),7.29(s,1H),7.13-7.16(m,1H),4.38-4.41(m,4H),3.74-3.78(m,2H),3.35(t,2H),2.97-2.99(m,4H),2.34(s,3H),2.07-2.11(m,4H),1.74-1.76(m,4H),0.41(s,4H).

LC-MS,M/Z(ESI):604.2[M+H] ⁺

Example 4: preparation of target Compound I-45

N- (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) -5-fluoro-4- (2-hydroxyethylsulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

The synthetic route for the target compound I-45 is shown below:

the first step: synthesis of 2, 5-difluoro-4-iodobenzonitrile

To a solution of 4-amino-2, 5-difluorobenzonitrile (10.0 g,64.9 mmol) in hydrochloric acid (100 mL) at 0deg.C was slowly added sodium nitrite (5.37 g,77.9 mmol), the reaction was allowed to react at 0deg.C for half an hour, then potassium iodide (16.2 g,97.3 mmol) was slowly added, and the reaction was allowed to react at 0deg.C for 3 hours. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL. Times.2), and the organic phase was collected, washed with brine (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =10:1) to give 2, 5-difluoro-4-iodobenzonitrile (8.90 g, 51.7% yield). And a second step of: synthesis of 5-fluoro-4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzonitrile

To a solution of 2, 5-difluoro-4-iodobenzonitrile (5.00 g,18.9 mmol) in N, N-dimethylformamide (50 mL) was added potassium carbonate (754 mg,5.46 mmol) and 6-azaspiro [2.5] octane hydrochloride (2.93 g,19.8 mmol), and the reaction was carried out at 100℃for 6 hours. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL. Times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-fluoro-4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzonitrile (5.40 g, yield 80.3%).

LC-MS,M/Z(ESI):357.0[M+H] ⁺

And a third step of: synthesis of 5-fluoro-4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid

To a solution of 5-fluoro-4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzonitrile (1.40 g,3.93 mmol) in ethylene glycol (10 mL) was added a solution of sodium hydroxide (2.80 g,70.0 mmol) in water (10 mL), and the reaction was carried out at 130℃for 10 hours. The reaction solution was poured into water (50 mL), extracted three times with methyl tert-butyl ether (20 mL), the aqueous phase was adjusted to ph=2 with 1M hydrochloric acid, then extracted with dichloromethane (30 ml×3), the organic phase was collected, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =50:1-10:1) to give 5-fluoro-4-iodo-2- (6-azaspiro [2.5] octane-6-yl) benzoic acid (1.00 g, yield 67.8%).

¹ H NMR(400MHz,DMSO_d ₆ )δ7.93(d,1H),7.84(d,1H),3.04-3.10(m,4H),2.33(br d,2H),1.06(s,2H),0.40-0.58(m,4H).

LC-MS,M/Z(ESI):376.0[M+H] ⁺

Fourth step: synthesis of N- (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) -5-fluoro-4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

To 5-fluoro-4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid (200 mg, 533. Mu. Mol) and 8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-amine trifluoroacetate (1.12 g,3 mmol) in dichloromethane (20 mL) were added diisopropylethylamine (689 mg,5.33 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphine salt (304 mg, 800. Mu. Mol), followed by stirring at 25℃for 10 hours. The reaction solution was poured into water (20.0 mL), extracted with dichloromethane (20.0 ml×3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =20:1-5:1) to give crude product, which was then slurried with methanol (10 mL) for 12 hours, filtered, and the cake dried to give N- (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) -5-fluoro-4-iodo-2- (6-azaspiro [2.5] octane-6-yl) benzamide (100 mg, yield 30.0%).

LC-MS,M/Z(ESI):625.2[M+H] ⁺

Fifth step: synthesis of N- (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) -5-fluoro-4- (2-hydroxyethylsulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

To N- (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) -5-fluoro-4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (80.0 mg, 128. Mu. Mol) and 2-hydroxyethanesulfonamide (19.2 mg, 154. Mu. Mol) in N, N-dimethylformamide (2.00 mL) were added cuprous iodide (12.2 mg, 64.1. Mu. Mol), sarcosine (5.71 mg, 64.1. Mu. Mol) and potassium carbonate (70.8 mg, 512. Mu. Mol), and the reaction was stirred at 80℃under nitrogen for 10 hours. The reaction solution was poured into water (10 mL), then extracted with ethyl acetate (10 ml×3), the organic phase was collected, washed with water (10 ml×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by high performance liquid chromatography (column: phenomenex luna C, 150×25mm×10um; solvent: a=water+0.05 volume of formic acid (99%), b=acetonitrile; gradient: 62% -92%,7 minutes), and freeze-dried to give N- (8- (4, 4-difluoropiperidin-1-yl) -2-methylimidazo [1,2-a ] pyrazin-6-yl) -5-fluoro-4- (2-hydroxyethylsulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (38.5 mg, yield 48.3%).

¹ H NMR(400MHz,DMSO_d ₆ )δ13.11(s,1H),8.73(s,1H),8.09(d,1H),7.63-7.73(m,1H),7.30(s,1H),6.82-7.06(m,1H),4.44(t,4H),4.15(brs,2H),3.39(t,2H),3.06(br s,4H),2.43(s,3H),2.07-2.18(m,4H),1.56(s,4H),0.45(s,4H).

LC-MS,M/Z(ESI):622.2[M+H] ⁺

Example 5: the following target compounds were prepared similarly with reference to the synthetic methods of the above compounds.

/>

Test example 1 Compounds inhibit tumor cell OVCAR3 cell proliferation assay

NIH OVCAR-3 (ATCC, cat No. HTB-161, purchased from Co-Bier) cells were inoculated into T75 flasks and cultured in RPMI 1640 medium containing 20% FBS for 3 days for subsequent culture and inoculation into 96-well plates for cell proliferation assay.

OVCAR3 cells were seeded at a density of 3000cells/100 μl/well into 96-well cell plates and the cell plates were placed in an incubator for 18 hours (37 ℃,5% co) ₂ ). The next day of drug treatment was started, 100. Mu.L/well of gradient diluted test compound solution (initial concentration of each drug was 10. Mu.M, dilution was DMSO, dilution ratio was 1:3, nine gradient points for each drug) or DMSO (negative control) was added to the culture plate medium, a blank group was additionally provided without inoculating cell lines to which only the medium was added, and after the addition of the drugs, the culture plate was placed in an incubator for further incubation for 3 days (37 ℃ C., 5% CO) ₂ ). The fourth day plate was examined, 100. Mu.L CellTiter-Glo (Promega G9243) reagent was added to each well, and after shaking for 5 minutes, the mixture was allowed to stand at room temperature for 5 minutes, using an enzyme-labeled instrument (Perkinelmer)2104 Chemiluminescent signal values were determined for each well. Cell proliferation inhibition = (1- (compound group-blank)/(DMSO group-blank)) ×100%, IC of each compound was calculated using GraphPad Prism8 software ₅₀ Values.

TABLE 1 inhibition of tumor cell proliferation by Compounds

Numbering of compounds	IC ₅₀ (nM)
		I-1	6
I-38	133
		I-44	20
I-45	40

The results of OVCAR3 cell proliferation experiments show that the compound can obviously inhibit the proliferation of the OVCAR3 cells.

Test example 2 Compounds are tested for inhibition of KIF18A enzymatic Activity

The recombinant protein KIF18A (kinesin domain: aa 1-467) used in this test was expressed by the Bac-to-Bac baculovirus expression system of Invitrogen, and the resulting protein was purified and used in this test (Seki, M.et al.2003nucleic Acids Res.). Quantitative detection of KIF18A enzyme Activity Using ADP-Glo ^TM The kinase assay kit (Promega Inc) was completed and related procedures strictly follow the product instructions, now briefly described as follows:

the reaction system consists of a compound to be detected, recombinant protein KIF18A (aa 1-467), ATP (Promega Inc) and an experiment buffer solution. Test compounds were formulated as 0.5mM stock solutions with DMSO (Sigma Inc) and were diluted in gradient using DMSO. Experiment buffer is composed of 15mM Tris,10mM MgCl ₂ (Sigma Inc), 0.01% Pluronic F-68 (Life Technologies Inc), 1. Mu.M paclitaxel (Cytoskeleton Inc), 30. Mu.g/mL porcine tubulin (Cytoskeleton Inc), and 2% DMSO. To the prepared assay buffer (50 μl), KIF18A protein (final concentration 80 nM) and different concentrations of compound (1 μl) were added and incubated for 15min at room temperature; ATP (final concentration 80. Mu.M) was then added to the reaction mixture and incubated at room temperature for 3hr. After completion of the reaction, 5. Mu.L of ADP-Glo was added to 384 well plates (Grenier Inc) ^TM Reagent(s)And 2.5 mu L of the reaction mixture, sealing with an aluminum foil sealing film after uniform mixing, and incubating for 40min at room temperature in a dark place; finally, 10. Mu.L of ADP-Glo was added to each reaction well ^TM The detection reagent is incubated for 40min at room temperature in a dark place. After all reactions were completed, the luminescence values of each well were read using a microplate reader (Molecular device_spectromax Id 5), and the inhibition ratios were calculated. The inhibition ratio was calculated as = (1- (compound group-blank)/(negative control group-blank)) ×100%, and IC50 values of test compounds were calculated in GraphPad Prism8 software according to the inhibition ratio of compounds at different concentrations.

TABLE 2 inhibition of KIF18A enzymatic Activity by Compounds

Test compounds	IC ₅₀ (μM)
		I-1	0.001
I-38	0.001
		I-44	0.004
I-45	0.001

The KIF18A enzyme activity inhibition experiment shows that the compound has good inhibition activity on KIF18A enzyme.

The embodiments of the technical solutions of the present disclosure have been described above by way of example. It should be understood that the protection scope of the present disclosure is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principles of the present disclosure should be included in the scope of the claims of the present application.

Claims

1. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

Wherein X is ¹ Is N or-CR ⁵ ；

X ² Is N or-CR ⁶ ；

X ³ Is N or-CR ⁷ ；

X ⁴ Is N or-CR ⁸ ；

X ⁵ Is N or-CR ⁹ ；

X ⁶ Is N or-CR ¹⁰ ；

X ⁷ Is N or-CR ⁴ ；

At least one of ring a or ring B is present;

l is-NR ³ -C (=o) -or-C (=o) -NR ³ -；

M is absent, or is selected from ^c Substituted C _1-6 An alkylene group;

R ² Is halogen or a group-Y-R ¹³ Wherein Y is-C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹³ -C _0-6 Alkyl-, -C _0-6 alkyl-O-C _0-6 Alkyl-, -C _0-6 alkyl-S-C _0-6 Alkyl-, -C _0-6 alkyl-S (=o) -C _0-6 Alkyl-, -C _0-6 alkyl-S (=o) ₂ -C _0-6 Alkyl-, -C _0-6 alkyl-SO ₂ NR ¹³ -C _0-6 Alkyl-, -C _0-6 alkyl-S (=o) (=nh) -, -C _0-6 alkyl-NR ¹³ -SO ₂ -C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹³ SO ₂ NR ¹³ -C _0-6 Alkyl-, -C _0-6 alkyl-C (=o)-C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹³ C(＝O)-C _0-6 Alkyl-, -C _0-6 Alkyl- (c=o) NR ¹³ -C _0-6 alkyl-or-C _0-6 alkyl-C (=O) -O-C _0-6 Alkyl-; or-Y-R ¹³ Is-n=s (=o) - (R ¹³ ) ₂ Wherein two R ¹³ Pairs of saturated or partially saturated 3-, 4-, 5-or 6-membered monocyclic rings containing 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, which may alternatively be combined with the sulfur atoms to which they are each attached;

Or alternatively, R ² And R is ⁵ Can be combined with the carbon atoms to which they are each attached to form a saturated or partially saturated 5-or 6-membered monocyclic ring fused to a heteroaromatic ring; wherein the 5-or 6-membered monocyclic ring contains 0, 1, 2 or 3N atoms and 0 or 1 atoms selected from O and S, and further wherein the 5-or 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, cyano, -NR ^a R ^a Or oxo;

R ⁸ and R is ⁹ Are independently selected from hydrogen, halogen, cyano, C _1-8 Alkyl, -O-C _1-8 Alkyl, C _3-8 Cycloalkyl, C _3-8 Halogenated ringAlkyl or C _1-4 A haloalkyl group;

R ¹¹ Is hydrogen, R ^11a Or R is ^11b ；

R ¹² Is hydrogen, halogen, hydroxy, cyano, R ^12a Or R is ^12b ；

R ¹³ Is hydrogen, halogen, cyano, R ^13a Or R is ^13b ；

R ^x selected from the group consisting of: hydrogen, hydrogen,

Or R is ^x Phenyl or an unsaturated 5 membered monocyclic ring which is phenyl or phenyl substituted with 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of: halogen, cyano, amino, C _1-6 Alkyl, C _1-6 Haloalkyl, -OR ^a 、-NR ^a R ^a 、-C(＝O)OR ^a 、-OC _1-4 Haloalkyl or R ¹⁵ⁿ ；

Or alternativelyGround, R ^15a And R is ^15b To, R ^15c And R is ^15d To, R ^15e And R is ^15f To, R ^15g And R is ^15h To, R ¹⁵ⁱ And R is ^15j Pair and R ^15k And R is ^15l Each of the pairs may be independently combined with their respective attached carbon atoms to form a spiro union to R ^x A cyclic saturated or partially saturated 3-, 4-, 5-, 6-membered monocyclic ring; wherein the 3-, 4-, 5-, 6-, membered monocyclic ring contains 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, 6-, membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, cyano, -NR ^a R ^a Or oxo;

R ¹⁵ⁿ and R is ^15o May be independently selected from saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, 7-, or 8-, 9-, 10-, 11-, 12-membered bicyclic rings; wherein the monocyclic or bicyclic ring contains 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, and further wherein the monocyclic or bicyclic ring is substituted with 0, 1, 2, 3 or 4 groups selected from: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, cyano, -C (=o) OR ^a 、-C(＝O)R ^b 、-C(＝O)NR ^a R ^a 、-C(＝NR ^a )NR ^a R ^a 、-OC(＝O)R ^b 、-OC(＝O)NR ^a R ^a 、-OC _2-6 Alkyl NR ^a R ^a 、-NR ^a R ^a 、-OC _2-6 OR ^a 、-SR ^a 、-S(＝O)R ^b 、-S(＝O) ₂ R ^b 、-S(＝O) ₂ NR ^a R ^a 、-NR ^a C(＝O)R ^b 、-NR ^a C(＝O)OR ^b 、-NR ^a C(＝O)NR ^a R ^a 、-NR ^a C(＝NR ^a )NR ^a R ^a 、-NR ^a S(＝O) ₂ NR ^b 、-NR ^a S(＝O) ₂ NR ^a R ^a 、-R ^a C _2-6 Alkyl NR ^a R ^a 、-NR ^a C _2-6 Alkyl OR ^a 、-C _1-6 Alkyl NR ^a R ^a 、-C _1-6 Alkyl OR ^a 、-C _1-6 Alkyl OC (=o) R ^b 、-C _1-6 Alkyl NR ^a C(＝O)R ^b 、-C _1-6 Alkyl NR ^a C(＝O)NR ^a R ^a 、-C _1-6 alkyl-C (=o) OR ^a Or oxo;

R ^a independently selected from H or R ^b ；

R ^b Independently selected from C _1-6 Alkyl, phenyl or benzyl, wherein said C _1-6 Alkyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: halogen, hydroxy, -OC _1-6 Alkyl, -NH ₂ 、-NHC _1-6 Alkyl, -OC (=o) C _1-6 Alkyl or-N (C) _1-6 Alkyl) C _1-6 An alkyl group; and the phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OH, -OC _1-6 Alkyl, -NH ₂ 、-NHC _1-6 Alkyl, -OC (=o) C _1-6 Alkyl or-N (C) _1-6 Alkyl) C _1-6 An alkyl group;

R ^c represents absence or independently selected from halogen, hydroxy, amino, cyano, carbonyl, oxo, carboxyl, C _2-6 Alkenyl, C _1-6 Alkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-4 Haloalkyl, C _1-6 alkyl-OH, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, halo C _1-4 Alkoxy, -COO-C _1-6 Alkyl, -C (O) NR ^c1 R ^c2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^c1 And R is ^c2 Each independently is hydrogen, C _1-6 An alkyl group.

2. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein the groupIs->R ^15a 、R ^15b Each independently is methyl, ethyl, propyl, fluoro or chloro, or R ^15a 、R ^15b Combined with their respective attached carbon atoms to form a spiro union to R ^x Cyclopropyl, cyclobutyl or cyclopentyl of the ring;

R ^15c 、R ¹⁵ⁱ each independently is methyl, ethyl, propyl, fluoro, chloro, or hydroxy;

preferably, the groupSelected from->

Preferably, the groupSelected from->

3. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, Selected from the following (1) or (2):

preferably, the method comprises the steps of,selected from: />

Preferably, the method comprises the steps of,selected from: />

4. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein L is-NR ³ -C (=o) -or-C (=o) -NR ³ -；

Preferably, R ³ Is hydrogen or methyl;

preferably, L is-NH-C (=o) -.

5. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein the compound is selected from the group consisting of the following structures:

wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ Having the definition of claim 1;

ring a and ring B have the definition of claim 1;

R ¹ 、R ² and R is ^x Having the definition of claim 1;

L and M have the definition of claim 1;

preferably, the method comprises the steps of,selected from: />

Preferably, the method comprises the steps of,selected from: />

Preferably, the method comprises the steps of,selected from->

6. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein the compound is selected from the group consisting of the following structures:

ring a and ring B have the definition of claim 1;

R ¹ and R is ² Having the definition of claim 1;

m has the definition of claim 1;

preferably, the method comprises the steps of,selected from:

preferably, the method comprises the steps of,selected from: />

Preferably, the method comprises the steps of,selected from->

7. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein the compound is selected from the group consisting of the following structures:

wherein X is ¹ Having the definition of claim 1;

R ¹ 、R ² 、R ⁸ 、R ⁹ and R is ¹⁰ Having the definition of claim 1;

m has the definition of claim 1.

8. A compound of formula I according to claim 1The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof is characterized in that R ² Selected from F, cl, br or a group-Y-R ¹³ Wherein Y is a bond, -NH- (CH) ₂ ) _0-4 -or-O- (CH) ₂ ) _0-4 The method comprises the steps of carrying out a first treatment on the surface of the And R is ¹³ 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 3N atoms and 0 or 1 atom selected from O and S, substituted with 0, 1, 2, or 3 groups selected from: F. cl, br, C _1-6 Alkyl, C _1-4 Haloalkyl, -OH, -OC _1-4 Haloalkyl, cyano, R ¹⁴ And oxo; or R is ¹³ Is selected from F, cl, br, -OH, -OC _1-4 C substituted by 0, 1, 2, 3, 4 or 5 groups of haloalkyl or cyano _1-6 An alkyl group; wherein the R is ¹⁴ Having the definition of claim 1;

preferably F, methyl, -OH, CN, -CH ₂ OH; or,

9. As claimed in claim 1 orA compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, according to any one of claims 5 to 7, wherein R ² Selected from the following structures:

10. a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or any one of claims 5 to 7, wherein M is absent or is selected from-NH-, -CH ₂ -、Preferably, M is absent or selected from-CH ₂ -。

11. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein Z is a bond, -NH-, -NHSO ₂ -、-SO ₂ NH-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO ₂ -、-O-、-P-、-P(＝O)CH ₃ -、-P(＝O) ₂ - (c=o) -, - (c=o) NH-or-NH (c=o) -.

12. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R ¹² Selected from R ^12a Or R is ^12b ；

R ^12a Selected from: contains 0, 1,A saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring of 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, substituted with 0, 1, 2 or 3 groups selected from: halogen, hydroxy, C _1-6 Alkyl, C _1-6 A haloalkyl group;

more preferably, said R ¹² Selected from-CH ₂ CH ₂ OH, tert-butyl group,Methyl, -CH ₂ F、/> Cyclopropyl, cyclopropyl-CH ₃ 、-CH ₂ -cyclopropyl,/->Tetrahydrofuranyl, < - > and->CyclopentaneA radical, an oxetanyl radical, an azetidinyl radical or a 1,3, 4-oxathiazinyl alkyl radical.

13. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or any one of claims 5 to 7, wherein R ¹ Selected from Z-R ^12a Or Z-R ^12b ；

The R is ^12a Selected from C _3-6 Cycloalkyl, C _1-6 alkyl-C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl or C _1-6 Alkyl-4-6 membered heterocycloalkyl; the C is _1-6 Alkyl, C _3-6 Cycloalkyl or 4-6 membered heterocycloalkyl is substituted with 0, 1, 2 or 3 substituents selected from: F. cl, hydroxy, methyl, ethyl, propyl, butyl;

preferably, said R ^12b Selected from methyl, ethyl, t-butyl, isopropyl; the methyl, ethyl, tert-butyl, isopropyl are substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: F. hydroxy, methyl;

preferably, said R ¹ Selected from:

14. such as weightA compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or any one of claims 5 to 6, Selected from benzene rings or F-substituted benzene rings.

15. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein the compound comprises:

/>

16. a pharmaceutical composition, the pharmaceutical composition comprising: a compound of formula I as described in claims 1-15, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable carrier.

17. Use of a compound of formula I as described in claims 1-15, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or of a pharmaceutical composition as described in claim 16, said use comprising:

inhibition of KIF18A;

and/or preventing and/or treating KIF 18A-related diseases;

and/or preparing a medicament, pharmaceutical composition or preparation for inhibiting KIF18A, and/or preventing and/or treating KIF 18A-related diseases;

preferably, the KIF 18A-related disease comprises: proliferative disorders of cancer, psoriasis, atopic dermatitis, autoimmune diseases or inflammatory bowel disease;

Preferably, the cancer is selected from mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary carcinoma, melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic granulocytic leukemia, hepatocellular carcinoma, gall bladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choriocarcinoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, ewing sarcoma, and plasmacytoma;

preferably, the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, sjogren's syndrome, scleroderma, mixed connective tissue disease, dermatomyositis, polymyositis, lepterter's syndrome, autoimmune lymphoproliferative syndrome, multiple sclerosis, myasthenia gravis, and encephalomyelitis;

Preferably, the inflammatory bowel disease is selected from ulcerative colitis or crohn's disease.