CN116903589A

CN116903589A - KIF18A inhibitor and application thereof

Info

Publication number: CN116903589A
Application number: CN202310400930.5A
Authority: CN
Inventors: 张学军; 臧杨; 李群; 付浩亮; 孙小川; 丁肖华; 刘礼飞; 钱丽娜; 李莉娥; 杨俊�
Original assignee: Hubei Bio-Pharmaceutical Industrial Technological Institute Inc; Humanwell Healthcare Group Co ltd; Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Current assignee: Hubei Bio-Pharmaceutical Industrial Technological Institute Inc; Humanwell Healthcare Group Co ltd; Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Priority date: 2022-04-15
Filing date: 2023-04-14
Publication date: 2023-10-20

Abstract

The invention provides a compound shown in a formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof; the compound has better KIF18A inhibition effect,

Description

KIF18A inhibitor and application thereof

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 resulted in longer spindles in HeLa cervical cancer cells, increased chromosomal oscillations in metaphase (chromosome oscillation), and activation of mitotic spindle assembly checkpoints (MI Mayr et al, current Biology [ contemporary Biology ]17,488-98,2007). 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 compound useful as KIF18A inhibitor.

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 ⁴ is N or-CR ⁸ ；

X ⁵ Is N or-CR ⁹ ；

X ⁶ Is N or-CR ¹⁰ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

X ⁵ When N is N, X ⁴ Must be CR ⁸ ；X ⁵ Is CR (CR) ⁹ When X is ⁴ And X ⁶ And simultaneously N;

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 CN or a group-ZR ¹² Wherein Z is independently selected from-C _0-6 Alkyl-, -c=n (OH) -, -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-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-O-C _0-6 Alkyl-, -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-, -C _0-6 alkyl-S (=o) (=nh) -C _0-6 Alkyl-, -C- ((C=O) -O-R ¹¹ ) ₂ -、-C _0-6 alkyl-NR ¹¹ -S(＝O)(＝NH)-C _0-6 Alkyl-, -C _0-6 alkyl-S (=o) (=n ⁺ (CH ₃ ) ₂ )-、-NR ¹¹ SO ₂ NR ¹¹ -C(＝O)-O-、-P-、-C _0-6 alkyl-P (=o) (R ¹¹ )-、-C _0-6 alkyl-P (=o) ₂ The method comprises the steps of carrying out a first treatment on the surface of the 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 halogen or a group-Y-R ¹³ Wherein Y is-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-NR ¹³ -C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹³ SO ₂ -C _0-6 Alkyl-, -C _0-6 alkyl-SO ₂ NR ¹³ -C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹³ SO ₂ NR ¹³ _- C _0-6 Alkyl-, -C _0-6 alkyl-O-C _0-6 Alkyl-, -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 ¹³ -C _0-6 Alkyl-, -C _0-6 alkyl-NR ¹³ (C＝O)-C _0-6 Alkyl-, -SO ₂ N(C _1-6 alkyl-O-C _1-6 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 selected from hydrogen, halogen, CN, C _1-8 Alkyl, -OC _1-8 Alkyl, C _1-4 Haloalkyl, C _0-6 Alkyl- (c=o) -NH-C _0-6 Alkyl, -C _0-6 alkyl-SO ₂ NH-C _0-6 Alkyl, -C _0-6 alkyl-SO ₂ N(CH ₃ )-C _0-6 Alkyl, R ^4a Or R is ^4b ；

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 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 benzene 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、CN、-NR ^a R ^a Or oxo;

R ⁶ 、R ⁸ 、R ⁹ are independently selected from hydrogen, halogen, CN, C _1-8 Alkyl, halogenated C _3-8 Cycloalkyl, C _1-4 Haloalkyl or C _3-8 Cycloalkyl;

R ⁷ is hydrogen, halogen, CN, C _1-8 Alkyl, C _1-4 Haloalkyl, C _3-8 Cycloalkyl, halo C _3-8 Cycloalkyl, -O-C _1-8 Alkyl or R ^7a The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively, R ² And R is ⁷ 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 benzene 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, CN, -NR ^a R ^a Or oxo;

R ¹⁰ is hydrogen, halogen, CN, hydroxy, C _1-8 Alkyl, C _3-8 Cycloalkyl, halo C _3-8 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, OH, CN, R ^12a Or R is ^12b ；

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

R ^4a 、R ^7a 、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-free foodElement, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, CN, -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 -C 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 ^4b 、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, CH ₂ F、CHF ₂ 、CF ₃ 、-C(＝O)OR ^a 、-OR ^a 、-OC _1-4 Haloalkyl, CN, -NH ₂ 、NH(CH ₃ )、N(CH ₃ ) ₂ And saturated, partially saturated or unsaturated 3-, 4-, 5-or 6-membered monocyclic rings;

R ¹⁴ independently selected from the group consisting of: containing 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from OAnd 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 of atoms of S, substituted with 0, 1, 2 or 3 groups selected from: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-O C _1-4 Haloalkyl, CN, -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 、-O C _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 And oxo;

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

Or R is ^x Is selected from the group consisting of 0. C substituted by 1, 2, 3, 4 or 5 groups _2-8 Alkyl: halogen, -CH ₂ F、CHF ₂ 、-CF ₃ 、-C(＝O)OR ^a 、-OR ^a 、-OC _1-4 Haloalkyl, CN, -NH ₂ 、NH(CH ₃ )、N(CH ₃ ) ₂ Or R is ¹⁵ⁿ ；

Or R is ^x Phenyl or an unsaturated 5 membered monocyclic ring substituted with 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of: halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, -C (=o) OR ^a 、-OR ^a 、-OC _1-4 Haloalkyl, CN, -NH ₂ 、NH(CH ₃ )、N(CH ₃ ) ₂ Or R is ¹⁵ⁿ The method comprises the steps of carrying out a first treatment on the surface of the Wherein 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 、R ^15l 、R ^15m 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, 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, CN, -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 、R ^15o each independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 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, 3, or 4 groups selected from: halogen, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, CN, -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 -C 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 ^15p 0, 1, selected from the group consisting of,2. 3, 4 or 5 groups substituted C _1-8 Alkyl: halogen, CH ₂ F、CHF ₂ 、-CF ₃ 、-C(＝O)OR ^a 、-OR ^a 、-OC _1-4 Haloalkyl, CN, -NH ₂ 、NH(CH ₃ )、N(CH ₃ ) ₂ ；

R ^a Independently selected from hydrogen 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 _1-3 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 ^15c 、R ^15d 、R ^15e 、R ^15f 、R ^15g 、R ^15h 、R ¹⁵ⁱ And R is ^15j Each of H, halogen, C _1-6 Alkyl or C _1-4 A haloalkyl group; and 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.

In a preferred embodiment of the present invention, the R ^15c 、R ^15d 、R ¹⁵ⁱ And R is ^15j Each of which is H, methyl or ethyl; and 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 Cyclopropyl, cyclobutyl or cyclopentyl ring of the ring.

In a preferred embodiment of the application, the radicals mentionedSelected from-> Preferably, said group +.>Selected from->

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

As will be appreciated by those skilled in the art, in accordance with the conventions used in the art, in the structural formulae of the present application,for depicting chemical bonds, which are points where a moiety or substituent is attached to a core structure or a backbone structure.

In a preferred embodiment of the present application, the R ³ Is hydrogen or methyl.

In a preferred embodiment of the present application, the heterocyclic compound of formula I is selected from the following structures:

wherein X is ⁴ And X ⁶ Is as defined in the first aspect of the application; r is R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ And R is ^x Is as defined in the first aspect of the application; the definition of M and L is as described in the first aspect of the application.

In a preferred embodiment of the present application, the heterocyclic compound of formula I is selected from the following structures:wherein X is ⁴ And X ⁵ Is as defined in the first aspect of the application; r is R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ And R is ^x Is as defined in the first aspect of the application; the definition of M and L is as described in the first aspect of the application.

In a preferred embodiment of the present application, the heterocyclic compound of formula I is selected from the following structures: Wherein X is ⁴ 、X ⁵ And X ⁶ Is as defined in the first aspect of the invention; r is R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Is as defined in the first aspect of the invention; r is R ^15a 、R ^15b 、R ^15c 、R ^15d 、R ¹⁵ⁱ And R is ^15j Is defined as the present inventionThe first aspect; the definition of M and L is as described in the first aspect of the invention.

In a preferred embodiment of the present invention, the heterocyclic compound of formula I is selected from the following structures:wherein X is ⁴ 、X ⁵ And X ⁶ Is as defined in the first aspect of the invention; r is R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Is as defined in the first aspect of the invention; r is R ^15a 、R ^15b 、R ^15c 、R ^15d 、R ¹⁵ⁱ And R is ^15j Is as defined in the first aspect of the invention; m is as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, the heterocyclic compound of formula I is selected from the following structures:wherein X is ⁴ 、X ⁵ And X ⁶ Is as defined in the first aspect of the invention; r is R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Is as defined in the first aspect of the invention; m is as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, the heterocyclic compound of formula I is selected from the following structures:wherein X is ⁴ And X ⁶ Is as defined in the first aspect of the invention; r is R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Is as defined in the first aspect of the invention; m is as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, the heterocyclic compound of formula I is selected from the following structures:wherein X is ⁴ Is as defined in the first aspect of the invention; r is R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Is as defined in the first aspect of the invention; m is as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, the heterocyclic compound of formula I is selected from the following structures:wherein X is ⁵ Is as defined in the first aspect of the invention; r is R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Is as defined in the first aspect of the invention; m is as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, the heterocyclic compound of formula I is selected from the following structures:

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

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

In a preferred embodiment of the present invention, the R ² Selected from the group consisting of; F. cl, br or a group-Y-R ¹³ Wherein Y is a bond, -NH- (CH) ₂ ) _0-4 -、-O-(CH ₂ ) _0-4 -、-S-、-S＝O-、-S(＝O) _2- -S (=o) (=nh) -, -C (=o) -; and is combined with

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, CN, 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 CN _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, cl, br, methyl, -OH, -OCH ₃ 、CN、-CH ₂ OH; or,

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

Or Y is a bond, -NH- (CH) ₂ ) _0-4 -、-O-(CH ₂ ) _0-4 -or-SO ₂ NH-；R ¹³ Is C substituted by 0, 1, 2, 3, 4 or 5 identical or different substituents selected from _1-6 Alkyl, the substituent is-OH, methyl, CF ₃ 。

In a preferred embodiment of the present invention, the R ² Selected from the group consisting of;

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

In a preferred embodiment of the invention, Z is selected from the group consisting of 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) -;

preferably, said Z is selected from the group consisting of-SO ₂ NH-、-S(＝O)(＝NH)-、-SO ₂ -。

In a preferred embodiment of the present invention, the R ¹² Selected from (a) hydrogen; (b) Is selected from F, cl, br, -OH, -OCH ₃ Or C substituted by 0, 1, 2 or 3 radicals of cyclopropyl _1-6 An alkyl group; or (c) a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic 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, -C _1-6 Alkyl OH, -OCH ₃ 、-NH ₂ Or oxo.

In a preferred embodiment of the present invention, the R ¹² Selected from (a) hydrogen; (b) is-OH

Substituted C _1-6 An alkyl group; or (C) cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, 1,3, 4-oxathiazinyl, C substituted by-OH _3-8 Cycloalkyl groups.

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

in a preferred embodiment of the present invention, said R ⁴ Selected from (a) hydrogen, F, cl, br, CN, -OC _1-6 An alkyl group; (b)

C substituted by 0, 1, 2 or 3 OH groups _1-6 An alkyl group; (c) Cyclopropyl or (d) C _1-3 A haloalkyl group.

In a preferred embodiment of the present invention, the R ⁴ Selected from hydrogen, methyl, F, cl, br, CN, cyclopropyl, methoxy, - (c=o) NH ₂ 、CF ₃ 、CHF ₂ Furyl, pyridyl, morpholinyl or azetidine.

In a preferred embodiment of the present invention, the R ⁵ Selected from hydrogen, F or methyl.

In a preferred embodiment of the present invention, the R ⁶ Selected from hydrogen.

In a preferred embodiment of the present invention, the R ⁷ Selected from hydrogen, F, cl, br, CN, methyl, methoxy, cyclopropyl; or R is ² And R is ⁷ Combined with the carbon atoms to which they are each attached to form In a preferred embodiment of the present invention, the R ⁸ Selected from hydrogen, F, cl, br, cyclopropyl, - (c=o) CH ₃ Or CF (CF) ₃ ；

Preferably, R ⁸ Selected from hydrogen.

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

In a preferred embodiment of the present invention, the R ¹⁰ Selected from hydrogen, F, methyl methoxy or cyclopropyl.

In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from any one of the following compounds:

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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 of the invention, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable carrier.

In a third aspect of the present invention there is provided 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 of the invention, or the use of a pharmaceutical composition according to the fifth aspect of the invention, the use comprising: 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.

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 cancer, 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, lyter'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.

In a fourth aspect of the application, 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 application, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

Additional aspects and advantages of the application 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 application.

Terminology and definitions

Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present 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 combinations of radical definitions and structures of compounds should fall within the scope of the present description.

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 the present 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 application. 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 disclosure, 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 the present application, the following terms have the meanings indicated below, unless otherwise specified.

Where a range of values recited in the specification and claims is understood to be an "integer," it is understood that both ends 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. When a numerical range is understood as a "number," it is understood that both endpoints of the range are noted, as well as each integer within the range, and each fraction within the range. For example, a "number of 1 to 10" should be understood to describe not only each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least the sum of each integer with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.

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 the present application, the term "halogen" means fluorine, chlorine, bromine, iodine, alone or as part of other substituents; fluorine or chlorine is preferred.

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 。

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 three, 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. C (C) _1-6 Examples of alkyl groups include, but are not limited to, the following:

"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 "cycloalkyl" alone or as part of another substituent means 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. "3-to 10-membered cycloalkyl" contains 3 to 10 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 adamantane A radical, or a bicyclic hydrocarbon radical 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 ring groups. The term "cycloalkyl" may be used interchangeably with the term "carbocyclyl".

The term "heterocycloalkyl" when used alone or as part of another substituent refers to cycloalkyl 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 "m-n membered heterocycloalkyl" or "C _m -C _n Heterocycloalkyl "is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms, wherein the heterocyclic atoms are selected from N, O, S, P, preferably from N, O or S. For example, the term "4-8 membered heterocycloalkyl" or "C ₄ -C ₈ Heterocycloalkyl "is understood to mean a saturated, unsaturated or partially saturated ring having from 4 to 8 atoms, wherein 1, 2, 3 or 4 ring atoms are selected from N, O, S, P, preferably from N, O or S. "4-10 membered heterocyclyl" is intended to mean a saturated, unsaturated or partially saturated ring having 4 to 10 atoms. In some embodiments, the heterocycloalkyl group can be a heterocycloalkyl group fused with an aromatic or heteroaromatic ring group. When a prefix such as 4-8 or 4-10 membered is used to represent a heterocycloalkyl group, the number of carbons is also meant to include heteroatoms. Including monocyclic, bicyclic, tricyclic, spiro, or bridged rings. Examples of heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepinyl, oxazepanyl, and the like. The term "heterocycloalkyl" may be used interchangeably with the term "heteroalkyl" ring.

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 "aryl" when used alone or as part of another substituent means a monocyclic or polycyclic carbocycle having 6 to 20 carbon atoms, wherein at least one ring is an aromatic ring. When one of the rings is a non-aromatic ring, the groups may be linked through an aromatic ring or through a non-aromatic ring. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthracyl and acenaphthylenyl.

The term "heteroaryl ring", alone or as part of another substituent, refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, the remaining ring atoms being C, wherein at least one ring is an aromatic ring. The group may be a carbon group or a heteroatom group (i.e., it may be C-linked or N-linked, as long as it is possible). When one of the rings is a non-aromatic ring, the groups may be linked through an aromatic ring or through a non-aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazole, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, N-methylpyrrolidinyl, and tetrahydroquinolinyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic", "heteroaryl" or "heteroaryl ring radical".

The term "bicyclic" refers to 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:

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NR, alone or as part of other substituents ^a R ^a The groups may beIn the form of, or can also includeWherein two 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:

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 the present 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 application. 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 application.

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

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 application 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 application 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.

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.

In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present application 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 the present 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 "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" refers to therapeutic therapy. When specific conditions are involved, treatment refers to: (1) alleviating a disease or one or more biological manifestations of a disorder, (2) interfering with (a) one or more points in a biological cascade that results in or causes a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of a disorder or one or more biological manifestations of a disorder.

The term "preventing" refers to a reduced risk of acquiring or developing a disease or disorder.

The term "patient" refers to any animal, preferably a mammal, that is about to or has received administration of the compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.

The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or disorder described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and severity thereof, and the age of the patient to be treated, and can be adjusted as desired by those skilled in the art.

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.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

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, a pharmaceutically acceptable salt or a prodrug thereof, wherein the compound shown in the formula I has an obvious inhibition effect on KIF18A 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, for example n-butyllithium (14.56 mL,29.1mmol,2.5M in n-hexane) means an n-hexane solution of n-butyllithium at a molar concentration of 2.5mol/L

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

Reagent:

DIPEA: n, N-diisopropylethylamine

Boc: boc-group

HATU:2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate intermediate A1: preparation of 3- (4, 4-difluoropiperidin-1-yl) aniline

The synthetic route for intermediate A1 is as follows:

the first step: synthesis of 4, 4-difluoro-1- (3-nitrophenyl) piperidine (A1-3)

To a solution of 1-bromo-3-nitrobenzene (A1-3) (8.0 g,39.6 mmol) and 4, 4-difluoropiperidine hydrochloride (8.74 g,55.4 mmol) in 1, 4-dioxane (80 mL) under nitrogen was added palladium acetate (1.07 g,4.75 mmol), 4, 5-bis (diphenylphosphorus) -9, 9-dimethylxanthene (2.75 g,4.75 mmol) and cesium carbonate (38.7 g,119 mmol), and the reaction was reacted at 80℃for 16h under nitrogen. After completion of the reaction, diluted with water (100 mL) at room temperature, then extracted with ethyl acetate (200 mL x 3), the organic layers were combined, dried over sodium sulfate, concentrated to give the crude product, which was then purified by column on silica gel (petroleum ether: ethyl acetate (V/V) =15:1 to 5:1) to give compound 4, 4-difluoro-1- (3-nitrophenyl) piperidine (A1-3) (yellow solid, 9.0g, yield 93.8%).

LC-MS,M/Z(ESI):243.0[M+H] ⁺ 。

And a second step of: synthesis of 3- (4, 4-difluoropiperidin-1-yl) aniline (A1)

To a solution of 4, 4-difluoro-1- (3-nitrophenyl) piperidine (A1-3) (8.0 g,33.0 mmol) in ethanol (80 mL) and water (20 mL) under nitrogen was added iron powder (18.4 g,330 mmol) and ammonium chloride (17.7 g,330 mmol), and the reaction was carried out at 75℃under nitrogen for 16h. After completion of the reaction, diluted with water (300 mL) and ethyl acetate (500 mL) at room temperature, followed by filtration, extraction of the filtrate with ethyl acetate (300 mL x 2), drying of the combined organic phases over sodium sulfate, concentration to give crude product, separation and purification by silica gel column (petroleum ether: ethyl acetate (V/V) =10:1 to 2:1) to give compound 3- (4, 4-difluoropiperidin-1-yl) aniline (intermediate A1) (brown solid, 5.7g, yield 81.3%).

¹ H NMR(400MHz,CDCl ₃ )δ7.08(t,1H),6.38-6.40(m,1H),6.25-6.29(m,2H),3.65(s,2H),3.35(t,4H),2.06-2.15(m,4H).

LC-MS,M/Z(ESI):213.2[M+H] ⁺ 。

Intermediate A2: preparation of 5-bromo-3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxylic acid

The synthetic route for intermediate A2 is as follows:

5-bromo-3-fluoropyridine-2-carboxylic acid (10 g,35.47 mmol) was added to N-methylpyrrolidone (100 mL), then 6-azaspiro [2.5] octane hydrochloride (7.83 g,53.2 mmol), DIPEA (22.88 g,177.35 mmol) was heated to 140℃for 3h, ethyl acetate (100 mL. Times.2) was extracted, the aqueous pH was adjusted to 1 with 1M dilute hydrochloric acid, then dichloromethane (100 mL. Times.2) was used, and the organic phase was concentrated by drying to give the compound 5-bromo-3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxylic acid (intermediate A2) (pale yellow solid, 10g, 91.8% yield).

LC-MS,M/Z(ESI):311.0[M+H] ⁺ 。

Intermediate A3: preparation of 3- (4, 4-difluoropiperidin-1-yl) -5-methylaniline

The synthetic route for intermediate A3 is as follows:

the first step: synthesis of 4, 4-difluoro-1- (3-methyl-5-nitrophenyl) piperidine (A3-2)

1-bromo-3-methyl-5-nitrobenzene (A3-1) (1 g,4.63 mmol) was dissolved in dry 1, 4-dioxane (10 mL), 4-difluoropiperidine hydrochloride (1.1 g,6.98 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (535 mg,0.93 mmol), tris-dibenzylideneacetone dipalladium (284 mg,0.46 mmol) and cesium carbonate (4.53 g,13.9 mmol) were added sequentially, argon was replaced three times, and the temperature was raised to 100℃for reaction 18h. Cooled to room temperature, the solvent was concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =20:1) to give 4, 4-difluoro-1- (3-methyl-5-nitrophenyl) piperidine (A3-2) (850 mg, yield 71.7%).

And a second step of: synthesis of 3- (4, 4-difluoropiperidin-1-yl) -5-methylaniline (A3)

4, 4-difluoro-1- (3-methyl-5-nitrophenyl) piperidine (A3-2) (850 mg,3.32 mmol) was dissolved in ethanol (20 mL) and water (5 mL), iron powder (1.12 g,20 mmol) was added, the reaction was warmed to 50℃for 2h, celite was filtered, the cake was rinsed with dichloromethane, the filtrate was concentrated, and the residue was purified on a silica gel column (petroleum ether: ethyl acetate (V/V) =3:1) to give 3- (4, 4-difluoropiperidin-1-yl) -5-methylaniline (A3) (720 mg, yield 96.0%)

LC-MS,M/Z(ESI)：227.2[M+H] ⁺ 。

Intermediate A4: preparation of 3- (4, 4-difluoropiperidin-1-yl) -5-fluoroaniline

The synthetic route for intermediate A4 is as follows:

the first step: synthesis of 4, 4-difluoro-1- (3-fluoro-5-nitrophenyl) piperidine (A4-2)

1-bromo-3-fluoro-5-nitrobenzene (A4-1) (1 g,4.5 mmol) was dissolved in dry 1, 4-dioxane (10 mL), 4-difluoropiperidine hydrochloride (1.06 g,6.7 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (521 mg,0.9 mmol), tris-dibenzylideneacetone dipalladium (365 mg,0.4 mmol) and cesium carbonate (4.40 g,13.5 mmol) were added sequentially, argon was replaced three times, and the temperature was raised to 100℃for reaction 18h. Cooled to room temperature, the solvent was concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =20:1) to give 4, 4-difluoro-1- (3-fluoro-5-nitrophenyl) piperidine (A4-2) (750 mg, yield 63.4%).

And a second step of: synthesis of 3- (4, 4-difluoropiperidin-1-yl) -5-fluoroaniline (A4)

4, 4-difluoro-1- (3-fluoro-5-nitrophenyl) piperidine (A4-2) (750 mg,2.9 mmol) was dissolved in ethanol (20 mL) and water (5 mL), iron powder (972 mg,17.4 mmol) was added, the reaction was carried out at 50℃for 2h, celite was filtered, the cake was rinsed with dichloromethane, the filtrate was concentrated, and the residue was purified by silica gel column (petroleum ether: ethyl acetate (V/V) =3:1) to give 3- (4, 4-difluoropiperidin-1-yl) -5-fluoroaniline (A4) (560 mg, yield 84.4%)

LC-MS,M/Z(ESI)：231.2[M+H] ⁺ 。

Intermediate A5: preparation of 3-amino-5- (4, 4-difluoropiperidin-1-yl) benzonitrile

The synthetic route for intermediate A5 is as follows:

the first step: synthesis of 3- (4, 4-difluoropiperidin-1-yl) -5-nitrobenzonitrile (A5-2)

3-fluoro-5-nitrobenzonitrile (2 g,0.01 mol), 4-difluoropiperidine hydrochloride (2.2 g,0.02 mol) and potassium carbonate (3.3 g,0.03 mol) were added to N, N-dimethylformamide (15 mL), stirred at 80℃for 2h, diluted with water (100 mL), extracted with ethyl acetate (30 mL. Times.2), the organic phase concentrated to dryness and the residue was isolated and purified using a silica gel column (petroleum ether: ethyl acetate (V/V) =50:1) to give 3- (4, 4-difluoropiperidin-1-yl) -5-nitrobenzonitrile (A5-2) (1.8 g, yield 50%).

And a second step of: synthesis of 3-amino-5- (4, 4-difluoropiperidin-1-yl) benzonitrile (A5)

3- (4, 4-Dihalopiperidin-1-yl) -5-nitrobenzonitrile (A5-2) (1.5 g,5.62 mmol), iron powder (1 g,16.2 mmol), saturated ammonium chloride solution (5 mL) was added to ethanol (15 mL) and reacted at 80℃for 2h. Water (60 mL) was added to dilute, extracted with ethyl acetate (30 mL. Times.2), the organic phase was concentrated to dryness, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =10:1) to give 3-amino-5- (4, 4-difluoropiperidin-1-yl) benzonitrile (800 mg, yield 50%).

LC-MS,M/Z(ESI):238.1[M+H] ⁺ 。

Intermediate A6: preparation of 3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylaniline

The synthetic route for intermediate A6 is as follows:

the first step: synthesis of 1-bromo-2-fluoro-3-methyl-5-nitrobenzene (A6-2)

1-fluoro-2-methyl-4-nitrobenzene (A6-1) (2 g,12.9 mmol) was dissolved in dilute sulfuric acid (2N, 20 mL), cooled to about 0 ℃, N-bromosuccinimide (2.76 g,15.5 mmol) was added in portions, the reaction was completed after the addition was restored to room temperature for 20h, water (30 mL) was added for dilution, dichloromethane extraction (30 ml×3), solvent concentration, and purification by column separation of the residue on silica gel (petroleum ether: ethyl acetate (V/V) =50:1) afforded 1-bromo-2-fluoro-3-methyl-5-nitrobenzene (A6-2) (2.0 g, yield 66.4%).

And a second step of: synthesis of 4, 4-difluoro-1- (2-fluoro-3-methyl-5-nitrophenyl) piperidine (A6-3)

1-bromo-2-fluoro-3-methyl-5-nitrobenzene (A6-2) (2 g,8.5 mmol) was dissolved in dry 1, 4-dioxane (30 mL), 4-difluoropiperidine hydrochloride (2.02 g,12.8 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (983 mg,1.7 mmol), tris dibenzylideneacetone dipalladium (284 mg,0.9 mmol) and cesium carbonate (8.31 g,25.5 mmol) were added sequentially, argon was replaced three times, and the reaction was warmed to 100℃for 18h. Cooled to room temperature, the solvent was concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =20:1) to give 4, 4-difluoro-1- (2-fluoro-3-methyl-5-nitrophenyl) piperidine (A6-3) (1.8 g, yield 85.3%).

And a third step of: synthesis of 3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylaniline (A6)

4, 4-difluoro-1- (2-fluoro-3-methyl-5-nitrophenyl) piperidine (A6-3) (1.8 g,6.6 mmol) was dissolved in ethanol (60 mL) and water (15 mL), iron powder (2.21 g,39.6 mmol) was added, the temperature was raised to 50℃for 2h, celite was filtered, the filter cake was rinsed with methanol, the filtrate was concentrated, and the residue was purified on a silica gel column (petroleum ether: ethyl acetate (V/V) =3:1) to give 3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylaniline (A6) (500 mg, yield 31.2%)

LC-MS,M/Z(ESI)：245.2[M+H] ⁺ 。

Intermediate A7: preparation of 3- (4, 4-difluoropiperidin-1-yl) -2-fluoro-5-methylaniline

The synthetic route for intermediate A7 is as follows:

the first step: synthesis of 3-bromo-2-fluoro-5-methylbenzamide (A7-2)

3-bromo-2-fluoro-5-methylbenzoic acid (A7-1) (1 g,4.3 mmol) was dissolved in dry N, N-dimethylformamide (10 mL), ammonium chloride (460 mg,12.9 mmol), N, N-diisopropylethylamine (1.67 g,12.9 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (2.47 g,6.5 mmol) were added in this order, and the mixture was stirred at room temperature for 20 hours, diluted with water (30 mL), extracted with ethyl acetate (30 mL. Times.3), the solvent was concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =10:1) to give 3-bromo-2-fluoro-5-methylbenzamide (A7-2) (930 mg, yield 93.4%).

And a second step of: synthesis of 3-bromo-2-fluoro-5-methylaniline (A7-3)

Sodium hydroxide (1.6 g,40 mmol) was dissolved in water (20 mL), cooled to 0-5 ℃, bromine (1.09 g,6.8 mmol) was added dropwise as a yellow clear solution, 3-bromo-2-fluoro-5-methylbenzamide (A7-2) (930 mg,4.0 mmol) was added, the reaction was completed at 85 ℃ for 2h, cooled to room temperature, dichloromethane extraction (20 mL x 3), the organic phases were combined, the solvent was concentrated, and silica gel column separation purification (petroleum ether: ethyl acetate (V/V) =20:1) gave 3-bromo-2-fluoro-5-methylaniline (A7-3) (600 mg, yield 73.4%).

And a third step of: synthesis of tert-butyl (3-bromo-2-fluoro-5-methylphenyl) carbamate (A7-4)

3-bromo-2-fluoro-5-methylaniline (A7-3) (600 mg,2.94 mmol) was dissolved in aqueous sodium hydroxide (2N, 10mL,20 mmol), di-tert-butyl dicarbonate (1.02 g,4.7 mmol) was added, the reaction was continued at 100℃for 20h, cooled to room temperature, ethyl acetate was added for extraction (10 mL. Times.3), the organic phases were combined, concentrated, and the residue was purified on a silica gel column (petroleum ether: ethyl acetate (V/V) =20:1) to give tert-butyl (3-bromo-2-fluoro-5-methylphenyl) carbamate (A7-4) (440 mg, yield 49.2%)

Fourth step: synthesis of tert-butyl (3- (4, 4-difluoropiperidin-1-yl) -2-fluoro-5-methylphenyl) carbamate (A7-5)

Tert-butyl (3-bromo-2-fluoro-5-methylphenyl) carbamate (A7-4) (300 mg,0.99 mmol) was dissolved in dry 1, 4-dioxane (5 mL), 4-difluoropiperidine hydrochloride (233 mg,1.48 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (82.6 mg,0.1 mmol), 2-dicyclohexylphosphine-2 ',6' -diisopropyloxybiphenyl (88.6 mg,0.19 mmol) and cesium carbonate (965 mg,2.96 mmol) were sequentially added, and the mixture was reacted under argon atmosphere at elevated temperature to 100℃for 18h. The reaction mixture was quenched with water (50 mL), separated, the aqueous phase extracted with ethyl acetate (30 mL x 3), the organic phases combined, concentrated, and the residue purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =20:1) to give tert-butyl (3- (4, 4-difluoropiperidin-1-yl) -2-fluoro-5-methylphenyl) carbamate (A7-5) (180 mg, yield 53.1%).

Fifth step: synthesis of 3- (4, 4-difluoropiperidin-1-yl) -2-fluoro-5-methylaniline (A7)

To tert-butyl (3- (4, 4-difluoropiperidin-1-yl) -2-fluoro-5-methylphenyl) carbamate (A7-5) (180 mg,0.52 mmol) was added a solution of 1, 4-dioxane hydrochloride (4N, 2mL,8 mmol), the reaction was stirred at room temperature for 1h, and the solvent was concentrated to give 3- (4, 4-difluoropiperidin-1-yl) -2-fluoro-5-methylaniline (A7) (130 mg, yield 100%).

Intermediate A8: preparation of 3-chloro-5- (4, 4-difluoropiperidin-1-yl) aniline

The synthetic route for intermediate A8 is as follows:

the first step: synthesis of 1- (3-chloro-5-nitrophenyl) -4, 4-difluoropiperidine (A8-2)

1-chloro-3-fluoro-5-nitrobenzene (A8-1) (1 g,5.7 mmol) was dissolved in N, N-dimethylformamide (10 mL), followed by the addition of 4, 4-difluoropiperidine hydrochloride (1.38 g,11.4 mmol) and potassium carbonate (3.15 g,22.8 mmol) and reacted under microwave conditions at 120℃for 2h. The reaction solution was poured into water (100 mL), extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/0-1/1) to give 1- (3-chloro-5-nitrophenyl) -4, 4-difluoropiperidine (A8-2) (0.5 g, yield 31.7%).

And a second step of: synthesis of 3-chloro-5- (4, 4-difluoropiperidin-1-yl) aniline (A8)

To a solution of 1- (3-chloro-5-nitrophenyl) -4, 4-difluoropiperidine (A8-2) (0.5 g,1.8 mmol) in ethanol (4 mL) and water (1 mL) was added iron powder (0.5 g,9 mmol) and ammonium chloride (0.96 g,18 mmol), and the mixture was reacted at 85℃for 2h. The reaction was poured into water (50 mL) and filtered, and the filtrate was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give 3-chloro-5- (4, 4-difluoropiperidin-1-yl) aniline (A8) (0.42 g, 94.2% yield).

LC-MS,M/Z(ESI):247.4[M+H] ⁺

Example 1: preparation of N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -5- (2-hydroxyethyl sulfanilamide) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 1) the synthetic route for the preparation of the target compound 1 is as follows:

the first step: synthesis of 5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) phenyl-3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B1-2)

5-bromo 3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxylic acid (400 mg, 1.284 mmol) was dissolved in dichloromethane (5 mL) and N, N-dimethylformamide (0.1 mL), thionyl chloride (0.469 mL,6.43 mmol) was slowly added dropwise at 0℃and then stirred at 25℃for 0.5h. The reaction solution was dried by spinning, methylene chloride (5 mL) was added to dissolve the residue, and then N, N-diisopropylethylamine (1.123 mL,6.43 mmol), potassium phosphate (1364 mg,6.43 mmol) and 3- (4, 4-difluoropiperidin-1-yl) aniline (2793 mg, 1.284 mmol) were added to the reaction solution and stirred at 25℃for 3h. The reaction was poured into water (30 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered and spun-dried to give the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/0-0/1) to give the compound 5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) phenyl-3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B1-2) (yellow solid, 450mg, 69.3% yield).

LC-MS,M/Z(ESI):505.1[M+H] ⁺ 。

And a second step of: synthesis of N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -5- (2-hydroxyethyl sulfanilamide) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 1)

To 5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) phenyl-3 (6-azaspiro [ 2.5)]To a solution of oct-6-yl) pyridine-2-carboxamide (350 mg,0.693 mmol) in N, N-dimethylformamide (5 mL) was added 2-hydroxyethanesulfonamide (130 mg,1.039 mmol), N, N-dimethylglycine (14.28 mg,0.139 mmol), cuprous iodide (13.19 mg,0.069 mmol) and potassium carbonate (191 mg,1.385 mmol). The reaction mixture was reacted at 130℃for 18 hours. The reaction was added to water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was prepared in reverse phase (column: phenomenex Synergi C) ₁₈ 100 x 25mm x 4 μm; solvent: a=water+0.1 volume% formic acid (99%), b=acetonitrile; gradient: 5% -95% and 7 min) to obtain the compound N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -5- (2-hydroxyethyl sulfanilamide) -3- (6-azaspiro [2.5]]Oct-6-yl) pyridine-2-carboxamide (compound 1) (174.8 mg, 44.4% yield).

1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),7.91(s,1H),7.40(s,1H),7.31-7.22(m,2H),7.18(t,J＝8.1Hz,1H),6.75-6.67(m,1H),3.75(t,J＝6.5Hz,2H),3.32(s,4H),3.19(t,J＝6.5Hz,2H),3.03-2.95(m,4H),2.13-1.97(m,4H),1.46(s,4H),0.31(s,4H).

LC-MS,M/Z(ESI):550.3[M+H] ⁺ 。

Example 2: preparation of N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -6- (2-hydroxyethylsulfonamide) -4- (6-azaspiro [2.5] oct-6-yl) pyridazine-3-carboxamide (compound 2) the synthetic route for the target compound 2 is as follows:

The first step: synthesis of ethyl 6-chloro-4- (6-azaspiro [2.5] oct-6-yl) pyridazine-3-carboxylate (B2-2)

To a solution of ethyl 4, 6-dichloropyridazine-3-carboxylate (500 mg,2.262 mmol) in acetonitrile (5 mL) was added 6-azaspiro [2.5] octane hydrochloride (302 mg,2.71 mmol) and N, N-diisopropylethylamine (585 mg,4.52 mmol), and stirred at 25℃for 18h. To the mixture was added water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with saturated brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/0-1/1) to give the compound 6-chloro-4- (6-azaspiro [2.5] oct-6-yl) pyridazine-3-carboxylic acid ethyl ester (B2-2) (colorless oil, 430mg, yield 64.3%).

LC-MS,M/Z(ESI):296.2[M+H] ⁺ 。

And a second step of: synthesis of 6-chloro-4- (6-azaspiro [2.5] oct-6-yl) pyridazine-3-carboxylic acid (B2-3)

Ethyl 6-chloro-4- (6-azaspiro [2.5] oct-6-yl) pyridazine-3-carboxylate (430 mg,1.454 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL), followed by addition of lithium hydroxide (174 mg,7.27 mmol). The reaction solution was stirred at 25℃for 18h. Water (50 mL) was added to the reaction solution, the pH was adjusted to 4 to 5 with 1N aqueous hydrochloric acid, and the mixture was lyophilized. The solid was dissolved with ethyl acetate (50 mL), filtered, and the filtrate was dried by spin to give the compound 6-chloro-4- (6-azaspiro [2.5] oct-6-yl) pyridazine-3-carboxylic acid (B2-3) (white solid, 380mg, yield 98%).

LC-MS,M/Z(ESI):268.2[M+H] ⁺ 。

And a third step of: synthesis of 6-chloro-N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -4- (6-azaspiro [2.5] oct-6-yl) pyridazine-3-carboxamide (B2-4)

To a solution of 6-chloro-4- (6-azaspiro [2.5] oct-6-yl) pyridazine-3-carboxylic acid (370 mg,1.382 mmol) in dichloromethane (5 mL) were added O- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1577 mg,4.15 mmol) and N, N-diisopropylethylamine (534 mg,4.15 mmol). The reaction was stirred at 25℃for 0.5h and 3- (4, 4-difluoropiperidin-1-yl) aniline (352 mg,1.659 mmol) was added. The reaction solution was then stirred for a further 18h at 25 ℃. To the reaction was added water (50 mL) and extracted with dichloromethane (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/0-1/1) to give the compound 6-chloro-N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -4- (6-azaspiro [2.5] oct-6-yl) pyridazine-3-carboxamide (B2-4) (white solid, 400mg, yield 62.7%).

LC-MS,M/Z(ESI):462.2[M+H] ⁺ 。

Fourth step: synthesis of N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -6- (2-hydroxyethylsulfonamide) -4- (6-azaspiro [2.5] oct-6-yl) pyridazine-3-carboxamide (Compound 2)

To 6-chloro-N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -4- (6-azaspiro [2.5] ]To a solution of oct-6-yl) pyridazine-3-carboxamide (350 mg,0.758 mmol) in 1, 4-dioxane (3 mL) was added 2-hydroxyethanesulfonamide (171 mg, 1.264 mmol), 4, 5-bisdibenzoylAlkylphosphine-9, 9-dimethylxanthene (88 mg,0.152 mmol), potassium carbonate (262 mg,1.894 mmol) and bis (dibenzylideneacetone) palladium (43.6 mg,0.076 mmol), the reaction solution was replaced three times with N ₂ The reaction was carried out at 90℃for 18h under nitrogen atmosphere. The reaction solution is concentrated to obtain crude products. The crude product was prepared in reverse phase (column: phenomenex Synergi C) ₁₈ 100 x 25mm x 4 μm; solvent: a=water+0.1 volume% formic acid (99%), b=acetonitrile; gradient: 5% -95% and 7 min) to obtain the compound N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -6- (2-hydroxyethyl sulfonamide) -4- (6-azaspiro [2.5]]Oct-6-yl) pyridazine-3-carboxamide (compound 2) (28.1 mg, yield 6.7%).

1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),7.40(s,1H),7.25(d,J＝8.0Hz,1H),7.18(t,J＝8.1Hz,1H),6.75(d,J＝8.2Hz,1H),6.49(s,1H),3.72(t,J＝6.8Hz,2H),3.30(s,5H),3.20(dd,J＝16.4,9.2Hz,5H),2.05(dt,J＝19.8,7.2Hz,4H),1.42(d,J＝4.6Hz,4H),0.31(s,4H).

LC-MS,M/Z(ESI):551.2[M+H] ⁺ 。

Example 3: preparation of N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -2- (2-hydroxyethylsulfonamide) -4- (6-azaspiro [2.5] oct-6-yl) pyrimidine-5-carboxamide (compound 3) the synthetic route for the preparation of the target compound 3 is as follows:

the first step: synthesis of methyl 2-chloro-4- (6-azaspiro [2.5] oct-6-yl) pyrimidine-5-carboxylate (B3-2)

To a solution of methyl 2, 4-dichloropyrimidine-5-carboxylate (500 mg, 2.418 mmol) in acetonitrile (5 mL) were added 6-azaspiro [2.5] octane hydrochloride (322 mg,2.90 mmol) and N, N-diisopropylethylamine (624 mg,4.83 mmol) and stirred at 25℃for 18h. To the mixture was added water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with saturated brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/0-1/1) to give the compound methyl 2-chloro-4- (6-azaspiro [2.5] oct-6-yl) pyrimidine-3-carboxylate (colorless oil, 450mg, 66.1% yield).

LC-MS,M/Z(ESI):282.0[M+H] ⁺ 。

And a second step of: synthesis of 2-chloro-4- (6-azaspiro [2.5] oct-6-yl) pyrimidine-5-carboxylic acid (B3-3)

Methyl 2-chloro-4- (6-azaspiro [2.5] oct-6-yl) pyrimidine-3-carboxylate (420 mg,1.491 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL), followed by addition of lithium hydroxide (178 mg,7.45 mmol). The reaction solution was stirred at 25℃for 18h. Water (10 mL) was added to the reaction solution, the pH was adjusted to 4 to 5 with 1N aqueous hydrochloric acid, and the mixture was lyophilized. The solid was dissolved with ethyl acetate (50 mL), filtered, and the filtrate was dried by spin to give the compound 2-chloro-4- (6-azaspiro [2.5] oct-6-yl) pyrimidine-5-carboxylic acid (white solid, 390mg, 98% yield).

LC-MS,M/Z(ESI):268.2[M+H] ⁺ 。

And a third step of: synthesis of 2-chloro-N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -4- (6-azaspiro [2.5] oct-6-yl) pyrimidine-5-carboxamide (B3-4)

To a solution of 2-chloro-4- (6-azaspiro [2.5] oct-6-yl) pyrimidine-5-carboxylic acid (390 mg,1.457 mmol) in dichloromethane (5 mL) was added O- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1662 mg,4.37 mmol) and N, N-diisopropylethylamine (560 mg,4.37 mmol). The reaction was stirred at 25℃for 0.5h and 3- (4, 4-difluoropiperidin-1-yl) aniline (460 mg,2.185 mmol) was added. The reaction solution was then stirred for a further 18h at 25 ℃. To the reaction was added water (50 mL) and extracted with dichloromethane (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/0-1/1) to give the compound 2-chloro-N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -4- (6-azaspiro [2.5] oct-6-yl) pyrimidine-5-carboxamide (white solid, 350mg, 52% yield).

LC-MS,M/Z(ESI):462.2[M+H] ⁺ 。

Fourth step: synthesis of N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -2- (2-hydroxyethylsulfonamide) -4- (6-azaspiro [2.5] oct-6-yl) pyrimidine-5-carboxamide (compound 3)

To 2-chloro-N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -4- (6-azaspiro [2.5]]To a solution of oct-6-yl) pyrimidine-5-carboxamide (350 mg,0.758 mmol) in 1, 4-dioxane (3 mL) was added 2-hydroxyethanesulfonamide (171 mg, 1.264 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (88 mg,0.152 mmol), potassium carbonate (262 mg,1.894 mmol) and bis (dibenzylideneacetone) palladium (43.6 mg,0.076 mmol), and the reaction was replaced three times with N ₂ Then reacted at 90℃for 18 hours. The reaction solution is concentrated to obtain crude products. The crude product was prepared in reverse phase (column: phenomenex Synergi C) ₁₈ 100 x 25mm x 4 μm; solvent: a=water+0.1 volume% formic acid (99%), b=acetonitrile; gradient: 5% -95% and 7 min) to obtain the compound N- (3- (4, 4-difluoropiperidin-1-yl) phenyl) -2- (2-hydroxyethyl sulfonamide) -4- (6-azaspiro [2.5]]Oct-6-yl) pyrimidine-5-carboxamide (compound 3) (165.7 mg, 38.7% yield).

¹ H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.07(s,1H),7.38(s,1H),7.19-7.07(m,2H),6.72(d,J＝7.0Hz,1H),3.71(t,J＝7.0Hz,2H),3.62-3.47(m,4H),3.42(t,J＝7.0Hz,2H),3.36-3.23(m,4H),2.05(ddd,J＝19.7,13.9,5.6Hz,4H),1.44-1.27(m,4H),0.31(s,4H).

LC-MS,M/Z(ESI):551.4[M+H] ⁺ 。

Example 4: preparation of N- (3- (4, 4-difluoropiperidin-1-yl) -5-methylphenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] -6-yl) pyridine-2-carboxamide (compound 4)

The synthetic route for target compound 4 is as follows:

the first step: 5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) -5-methylphenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-methyl

Synthesis of amide (B4-1)

5-bromo-3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxylic acid (500 mg,1.61 mmol) was dissolved in thionyl chloride (5 mL), heated to 70℃and reacted for 2h, the solvent was concentrated, dried dichloromethane (10 mL) was added to the residue, 3- (4, 4-difluoropiperidin-1-yl) -5-methylaniline (A3) (545 mg,2.41 mmol) and N, N-diisopropylethylamine (1.03 g,7.98 mmol) were sequentially added, and the reaction was stirred at room temperature for 3h. The reaction was quenched with water (50 mL), separated, the aqueous phase extracted with dichloromethane (30 mL x 2), the organic phases combined, concentrated, and the residue purified by silica gel plate separation (petroleum ether: ethyl acetate (V/V) =3:1) to give 5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) -5-methylphenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B4-1) (430 mg, yield 51.5%).

LC-MS,M/Z(ESI)：519.2[M+H] ⁺ 。

And a second step of: synthesis of N- (3- (4, 4-difluoropiperidin-1-yl) -5-methylphenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 4)

5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) -5-methylphenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B4-1) (130 mg,0.25 mmol) was dissolved in dry N, N-dimethylformamide (5 mL), 2-hydroxyethane-1-sulfonamide (63 mg,0.50 mmol), cuprous iodide (24 mg,0.13 mmol), sarcosine (22 mg,0.25 mmol) and potassium carbonate (104 mg,0.75 mmol) were added sequentially, argon was replaced three times, and the temperature was raised to 130℃under argon to react for 3h. The reaction solution was concentrated and the residue was chromatographed at high pressure to give N- (3- (4, 4-difluoropiperidin-1-yl) -5-methylphenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 4) (40.2 mg, yield 28.5%).

¹ H NMR(400MHz,DMSO-d6)：δ10.18(s,1H),10.14(s,1H),8.03(brs,1H),7.34(s,1H),7.20-7.07(m,2H),6.57(s,1H),3.77(t,2H),3.34-3.16(m,10H),2.24(s,3H),2.07-1.98(m,4H),1.44-1.42(m,4H),0.30(s,4H)。

LC-MS,M/Z(ESI)：564.4[M+H] ⁺ 。

Example 5: preparation of N- (3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylphenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 40)

The synthetic route for target compound 40 is as follows:

the first step: synthesis of 5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) -5-fluorophenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B40-1)

5-bromo-3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxylic acid (349mg, 1.1 mmol) was dissolved in thionyl chloride (3 mL), heated to 70℃for 2h, the solvent was concentrated, dried dichloromethane (10 mL) was added to the residue, 3- (4, 4-difluoropiperidin-1-yl) -5-fluoroaniline (A4) (385 mg,1.7 mmol) and N, N-diisopropylethylamine (737 mg,5.7 mmol) were added in this order, and the reaction was stirred at room temperature for 18h. The reaction was quenched with water (50 mL), separated, the aqueous phase extracted with dichloromethane (30 mL x 2), the organic phases combined, concentrated, and the residue purified by silica gel plate separation (petroleum ether: ethyl acetate (V/V) =5:1) to give 5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) -5-fluorophenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B40-1) (280 mg, yield 32.0%).

LC-MS,M/Z(ESI)：523.2[M+H] ⁺ 。

And a second step of: synthesis of N- (3- (4, 4-difluoropiperidin-1-yl) -5-fluorophenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 40)

5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) -5-fluorophenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B40-1) (280 mg,0.5 mmol) was dissolved in dry N, N-dimethylformamide (10 mL), 2-hydroxyethane-1-sulfonamide (188 mg,1.5 mmol), cuprous iodide (57.1 mg,0.3 mmol), N, N-dimethylglycine (51.6 mg,0.5 mmol) and potassium carbonate (207 mg,1.5 mmol) were added sequentially, argon was replaced three times, and the temperature was raised to 130℃under argon protection for reaction for 3h. The reaction solution was concentrated, and the residue was subjected to high pressure chromatography and freeze-dried to give N- (3- (4, 4-difluoropiperidin-1-yl) -5-fluorophenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 40) (136 mg, yield 45.9%).

¹ H NMR(400MHz,DMSO-d6)δ10.39(s,1H),10.16(s,1H),8.03(s,1H),7.33(s,1H),7.21(d,1H),7.12(s,1H),6.58(d,1H),4.97(s,1H),3.77(t,2H),3.34(d,6H),3.05(s,4H),2.12-1.93(m,4H),1.43(s,4H),0.30(s,4H).

LC-MS,M/Z(ESI)：568.4[M+H] ⁺ 。

Example 6: the synthetic route for the preparation of the target compound 41, N- (3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylphenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 41), is as follows:

the first step: synthesis of 5-bromo-N- (3-cyano-5- (4, 4-difluoropiperidin-1-yl) phenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B41-1)

5-bromo-3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxylic acid (A2) (284 mg,0.8 mmol) was added to dichloromethane (10 mL), thionyl chloride (2.85 mL) and two drops of N, N-dimethylformamide were added dropwise thereto, stirred at room temperature for 2 hours, then concentrated to dryness to give a crude product, which was dissolved with dichloromethane (10 mL), and 3-amino-5- (4, 4-difluoropiperidin-1-yl) benzonitrile (200 mg,0.8 mmol) and N, N-diisopropylethylamine (2 mL) were added and reacted at room temperature for 14 hours. Water (30 mL) was added to dilute, dichloromethane (10 mL. Times.2) was used to extract, the organic phase was concentrated to dryness, and the residue was separated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1) to give 5-bromo-N- (3-cyano-5- (4, 4-difluoropiperidin-1-yl) phenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B41-1) (150 mg, yield 51%).

LC-MS,M/Z(ESI):578.4[M+H] ⁺ 。

And a second step of: synthesis of N- (3-cyano-5- (4, 4-difluoropiperidin-1-yl) phenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 41)

5-bromo-N- (3-cyano-5- (4, 4-difluoropiperidin-1-yl) phenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B41-1) (150 mg,0.26 mmol) was added to 2mL of N, N-dimethylformamide, 2-hydroxyethane-1-sulfonamide (72 mg,0.58 mmol), N-methylglycine (10 mg,0.10 mmol), cuprous iodide (11 mg,0.05 mmol), potassium carbonate (160 mg,1.16 mmol) was added and the mixture was heated to 120℃for reaction for 1h. Water (10 mL) was added to dilute, extracted with ethyl acetate (10 mL. Times.2), and the organic phase was concentrated to dryness, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give N- (3-cyano-5- (4, 4-difluoropiperidin-1-yl) phenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridinecarboxamide (compound 41) (50 mg, 30% yield).

¹ H NMR(400MHz,DMSO-d6)δ10.55(s,1H),10.21(s,1H),8.05(s,1H),7.74(s,1H),7.61(s,1H),7.36(s,1H),7.20(s,1H),3.88(m,2H),3.44(m,7H),3.07(m,4H),2.06(m,4H),1.49(m,4H),0.31(s,4H)。

LC-MS,M/Z(ESI):575.2[M+H] ⁺ 。

Example 7: the synthetic route for the preparation of the target compound 50 of N- (3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylphenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 50) is as follows:

the first step: synthesis of 5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylphenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B50-1)

5-bromo-3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxylic acid (300 mg,1.0 mmol) was dissolved in thionyl chloride (3 mL), heated to 70℃and reacted for 2h, the solvent was concentrated, dried dichloromethane (10 mL) was added to the residue, 3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylaniline (A6) (365 mg,1.5 mmol) and N, N-diisopropylethylamine (646 mg,5 mmol) were sequentially added, and the reaction was stirred at room temperature for 18h. The reaction was quenched with water (50 mL), separated, the aqueous phase extracted with dichloromethane (30 mL x 2), the organic phases combined, concentrated, and the residue purified by silica gel plate separation (petroleum ether: ethyl acetate (V/V) =3:1) to give 5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylphenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B50-1) (230 mg, yield 44.4%).

LC-MS,M/Z(ESI)：537.2[M+H] ⁺ 。

And a second step of: synthesis of N- (3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylphenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 50)

5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylphenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B50-1) (230 mg,0.4 mmol) was dissolved in dry N, N-dimethylformamide (6 mL), 2-hydroxyethane-1-sulfonamide (150 mg,1.2 mmol), cuprous iodide (38.1 mg,0.2 mmol), N, N-dimethylglycine (41.2 mg,0.4 mmol) and potassium carbonate (166 mg,1.2 mmol) were added sequentially, argon was replaced three times, and the temperature was raised to 130℃under argon to react for 3h. The reaction solution was concentrated, and the residue was subjected to high pressure chromatography and freeze-dried to give N- (3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylphenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 50) (26.6 mg, yield: 10.7%).

¹ H NMR(400MHz,DMSO-d6)δ10.29(s,1H),7.99(s,1H),7.37(d,1H),7.29(d,2H),3.76(t,2H),3.29-3.20(m,2H),3.11(s,4H),3.04(s,4H),2.20(s,3H),2.11(t,4H),1.43(s,4H),0.30(s,4H).

LC-MS,M/Z(ESI)：582.4[M+H] ⁺ 。

Example 8: the synthetic route for the preparation of the target compound 51 of N- (3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylphenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 51) is as follows:

the first step: synthesis of 5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) -2-fluoro-5-methylphenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B51-1)

5-bromo-3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxylic acid (110 mg,0.353 mmol) was dissolved in thionyl chloride (2 mL), the reaction was carried out at 70℃for 2h, the solvent was concentrated, dried dichloromethane (10 mL) was added to the residue, 3- (4, 4-difluoropiperidin-1-yl) -2-fluoro-5-methylaniline (A5) (130 mg,0.53 mmol) and N, N-diisopropylethylamine (29 mg,2.26 mmol) were sequentially added, and the reaction was stirred at room temperature for 18h. The reaction was quenched with water (50 mL), separated, the aqueous phase extracted with dichloromethane (30 mL x 2), the organic phases combined, concentrated, and the residue was purified by silica gel plate separation (petroleum ether: ethyl acetate (V/V) =5:1) to give 5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) -2-fluoro-5-methylphenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B51-1) (90 mg, yield 47.4%).

LC-MS,M/Z(ESI)：537.2[M+H] ⁺ 。

And a second step of: synthesis of N- (3- (4, 4-difluoropiperidin-1-yl) -2-fluoro-5-methylphenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 51)

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5-bromo-N- (3- (4, 4-difluoropiperidin-1-yl) -2-fluoro-5-methylphenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B51-1) (90 mg,0.17 mmol) was dissolved in dry N, N-dimethylformamide (3 mL), 2-hydroxyethane-1-sulfonamide (63 mg,0.5 mmol), cuprous iodide (15.9 mg,0.08 mmol), N, N-dimethylglycine (17.3 mg,0.17 mmol) and potassium carbonate (69.3 mg,0.5 mmol) were added sequentially, argon was replaced three times, and the temperature was raised to 130℃under argon to react for 3h. The reaction solution was concentrated to dryness, and the residue was subjected to high pressure chromatography and freeze-dried to give N- (3- (4, 4-difluoropiperidin-1-yl) -2-fluoro-5-methylphenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 51) (13 mg, yield 13.3%).

¹ H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.04(s,1H),7.58(s,1H),7.37(s,1H),6.70(d,1H),3.76(t,2H),3.35(t,2H),3.12(s,4H),3.04(s,4H),2.26(s,3H),2.10(m,4H),1.47(s,4H),0.32(s,4H).

LC-MS,M/Z(ESI)：582.4[M+H] ⁺ 。

Example 9: the synthetic route for the preparation of the target compound 52 of N- (3- (4, 4-difluoropiperidin-1-yl) -4-fluoro-5-methylphenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 52) is as follows:

the first step: synthesis of 5-bromo-N- (3-chloro-5- (4, 4-difluoropiperidin-1-yl) phenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B52-1)

5-bromo-3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxylic acid (A3) (247 mg,0.8 mmol) was added to thionyl chloride (1 mL), and stirred at 70℃for 2h. The reaction solution was concentrated and dissolved in methylene chloride (4 mL), followed by addition of N, N-diisopropylethylamine (620 mg,4.8 mmol) and 3-chloro-5- (4, 4-difluoropiperidin-1-yl) aniline (A8) (400 mg,1.6 mmol) and stirring at room temperature for 18h. The reaction solution was concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/0-1/1) to give 5-bromo-N- (3-chloro-5- (4, 4-difluoropiperidin-1-yl) phenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B52-1) (260 mg, 29.7% yield).

LC-MS,M/Z(ESI):539.3[M+H] ⁺ 。

And a second step of: synthesis of N- (3-chloro-5- (4, 4-difluoropiperidin-1-yl) phenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 52)

To a solution of 5-bromo-N- (3-chloro-5- (4, 4-difluoropiperidin-1-yl) phenyl) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (B52-1) (260 mg,0.5 mmol) and 2-hydroxyethanesulfonamide (100 mg,0.8 mmol) in N, N-dimethylformamide (1 mL) was added 2- (dimethylamino) acetic acid (10 mg,0.1 mmol), cuprous iodide (10 mg,0.05 mmol) and potassium carbonate (138 mg,1 mmol), and the mixture was reacted at 90℃for 3h. The reaction was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was prepared in reverse phase (column: phenomenex Synergi C, 100 x 25mm x 4 μm; solvent: a=water+0.1 vol% formic acid (99%), b=acetonitrile; gradient: 5% -95%,7 min) to give N- (3-chloro-5- (4, 4-difluoropiperidin-1-yl) phenyl) -5- ((2-hydroxyethyl) sulfonylamino) -3- (6-azaspiro [2.5] oct-6-yl) pyridine-2-carboxamide (compound 52) (55.4 mg, 19.7%).

¹ H NMR(400MHz,DMSO-d6)δ10.39(s,1H),10.18(s,1H),8.04(s,1H),7.46(s,1H),7.34(s,1H),7.26(s,1H),6.79(s,1H),3.78(t,2H),3.36(dd,7H),3.15-2.95(m,4H),2.11-1.96(m,4H),1.56-1.35(m,4H),0.31(s,4H).

LC-MS,M/Z(ESI):584.1[M+H] ⁺ 。

The following target compounds were prepared analogously to the synthetic method of reference compound 1.

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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)
		Compound 41	650
Compound 50	256
		Compound 51	150
Compound 52	230

The experimental results show that: 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 was then added to the reaction mixture (final concentration 80. Mu.) M) 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 Mixing the reagent and 2.5 mu L of the reaction mixture uniformly, sealing with an aluminum foil sealing film, 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)
		Compound 41	0.002
Compound 50	0.012
		Compound 51	0.018
Compound 52	0.003

The experimental results show that: the KIF18A enzyme activity inhibition experiment shows that the compound has good inhibition activity on KIF18A enzyme.

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims

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

wherein,,

X ⁴ is N or-CR ⁸ ；

X ⁵ Is N or-CR ⁹ ；

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 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 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 benzene 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, CN, -NR ^a R ^a Or oxo;

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

R ¹² Is hydrogen, halogen, OH, CN, R ^12a Or R is ^12b ；

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

R ^4a 、R ^7a 、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, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-OC _1-4 Haloalkyl, CN, -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 -C 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 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, C _1-6 Alkyl, C _1-4 Haloalkyl, -OR ^a 、-O C _1-4 Haloalkyl, CN, -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 、-O C _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 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, CH ₂ F、CHF ₂ 、CF ₃ 、-C(＝O)OR ^a 、-OR ^a 、-OC _1-4 Haloalkyl, CN, NH ₂ 、NH(CH ₃ )、N(CH ₃ ) ₂ Or R is ¹⁵ⁿ ；

Or R is ^x Phenyl or an unsaturated 5 membered monocyclic ring substituted with 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of: halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, -C (=o) OR ^a 、-OR ^a 、-OC _1-4 Haloalkyl, CN, NH ₂ 、NH(CH ₃ )、N(CH ₃ ) ₂ Or R is ¹⁵ⁿ The method comprises the steps of carrying out a first treatment on the surface of the Wherein the 5-membered monocyclic ring contains 0, 1, 2 or 3N atoms and 0 or 1 atom selected from O and S;

R ^15p c being substituted by 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of _1-8 Alkyl: halogen, CH ₂ F、CHF ₂ 、CF ₃ 、-C(＝O)OR ^a 、-OR ^a 、-OC _1-4 Haloalkyl, CN, NH ₂ 、NH(CH ₃ )、N(CH ₃ ) ₂ ；

R ^a Independently selected from hydrogen 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 _1-3 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;

2. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R ^15c 、R ^15d 、R ^15e 、R ^15f 、R ^15g 、R ^15h 、R ¹⁵ⁱ And R is ^15j Each of H, halogen, C _1-6 Alkyl or C _1-4 A haloalkyl group; and R is ^15a And R is ^15b Each of the pairs and each of themFrom the combination of 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.

3. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claim 1, wherein R ^15c 、R ^15d 、R ¹⁵ⁱ And R is ^15j Each of which is H, methyl or ethyl; and 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 Cyclopropyl, cyclobutyl or cyclopentyl ring of the ring.

4. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claim 1, wherein the groupSelected from the group consisting of

Preferably, the groupSelected from->

5. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claim 1, wherein the groupSelected from->

6. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claim 1, wherein R ³ Is hydrogen or methyl.

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 ⁴ And X ⁶ Having the definition of claim 1;

R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ and R is ^x Having the definition of claim 1;

m and L have the meanings given in claim 1.

8. 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 ⁴ And X ⁵ Having the definition as defined in claim 1；

m and L have the meanings given in claim 1.

9. 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 ⁴ 、X ⁵ And X ⁶ Having the definition of claim 1;

R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ and R is ⁷ Having the definition of claim 1;

R ^15a 、R ^15b 、R ^15c 、R ^15d 、R ¹⁵ⁱ and R is ^15j Having the definition of claim 1;

m and L have the meanings given in claim 1.

10. 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 ⁴ 、X ⁵ And X ⁶ Having the definition of claim 1;

m has the definition of claim 1.

11. 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 ⁴ 、X ⁵ And X ⁶ Having the definition of claim 1;

m has the definition of claim 1.

12. 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 ⁴ And X ⁶ Having the definition of claim 1;

m has the definition of claim 1.

13. 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 ⁴ Having the definition of claim 1;

m has the definition of claim 1.

14. 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 ⁵ Having the definition of claim 1;

m has the definition of claim 1.

15. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R ² Selected from the group consisting of; F. cl, br or a group-Y-R ¹³ Wherein Y is a bond, -NH- (CH) ₂ ) _0-4 -、-O-(CH ₂ ) _0-4 -、-S-、-S＝O-、-S(＝O) _2- -S (=o) (=nh) -, -C (=o) -; 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, CN, 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 CN _1-6 An alkyl group; wherein the R is ¹⁴ Having the definition of claim 1;

preferably F, cl, br, methyl, -OH, -OCH ₃ 、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: fluorine, methyl, trifluoromethyl, -CN, -OH, CH ₂ OH；

Or Y is a bond, -NH- (CH) ₂ ) _0-4 -、-O-(CH ₂ ) _0-4 -or-SO ₂ NH-；R ¹³ Is selected from the following 0, 1,

2. C substituted by 3, 4 or 5 identical or different substituents _1-6 Alkyl, the substituent is-OH, methyl, CF ₃ 。

16. 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 7 to 15, wherein R ² Selected from the group consisting of;

17. a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claims 7 to 14, wherein M is absent or selected from the group consisting of-NH-

18. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein Z is selected from the group consisting of 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) -;

19. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R ¹² Selected from (a) hydrogen; (b) Is selected from F, cl, br, -OH, -OCH ₃ Or C substituted by 0, 1, 2 or 3 radicals of cyclopropyl _1-6 An alkyl group; or (c) a source containing 0, 1, 2 or 3N atoms and 0 or 1 selected from O and SA saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring of a child, substituted with 0, 1, 2 or 3 groups selected from: F. cl, br, C _1-6 Alkyl, C _1-4 Haloalkyl, -C _1-6 Alkyl OH, -OCH ₃ 、-NH ₂ Or oxo.

20. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 19, wherein R ¹² Selected from (a) hydrogen; (b) C substituted by-OH _1-6 An alkyl group; or (C) cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, 1,3, 4-oxathiazinyl, C substituted by-OH _3-8 Cycloalkyl groups.

21. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claims 7 to 14, wherein R ¹ Selected from:

22. 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 7 to 14, wherein R ⁴ Selected from (a) hydrogen, F, cl, br, CN, -OC _1-6 An alkyl group; (b) C substituted by 0, 1, 2 or 3 OH groups _1-6 An alkyl group; (c) Cyclopropyl or (d) C _1-3 A haloalkyl group.

23. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 22, The R is ⁴ Selected from hydrogen, methyl, F, cl, br, CN, cyclopropyl, methoxy, - (c=o) NH ₂ 、CF ₃ 、CHF ₂ Furyl, pyridyl, morpholinyl or

Azetidines.

24. 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 7 to 14, wherein R ⁵ Selected from hydrogen, F or methyl.

25. 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 7 to 14, wherein R ⁶ Selected from hydrogen.

26. 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 7 to 14, wherein R ⁷ Selected from hydrogen, F, cl, br, CN, methyl, methoxy, cyclopropyl; or R is ² And R is ⁷ Combined with the carbon atoms to which they are each attached to form

27. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R ⁸ Selected from hydrogen, F, cl, br, cyclopropyl, - (c=o) CH ₃ Or CF (CF) ₃ ；

Preferably, R ⁸ Selected from hydrogen.

28. The chemical formula I of claim 1A compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, characterized in that the R ⁹ Selected from hydrogen or F.

29. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R ¹⁰ Selected from hydrogen, F, methyl, methoxy or cyclopropyl.

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

/>

31. a pharmaceutical composition, the pharmaceutical composition comprising: a compound of formula I as defined in any one of claims 1 to 30, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable carrier.

32. Use of a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, according to any one of claims 1 to 30, or a pharmaceutical composition according to claim 31, the use comprising:

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.

33. The use of claim 32, wherein the KIF 18A-related disorder comprises: proliferative disorders of cancer, psoriasis, atopic dermatitis, autoimmune diseases or inflammatory bowel disease.

34. The use of claim 33, wherein the cancer is selected from mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary non-polyposis, 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 lympholeukemia, chronic lympholeukemia, acute myeloid leukemia, chronic myelogenous leukemia, hepatocellular carcinoma, gallbladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratocarcinoma, retinoblastoma, choriocarcinoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, ewing sarcoma, and ewing's sarcoma.

35. The use according to claim 33, wherein 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.

36. The use according to claim 33, wherein the inflammatory bowel disease is selected from ulcerative colitis or crohn's disease.