CN116925065A

CN116925065A - Compounds for inhibiting KIF18A and application thereof

Info

Publication number: CN116925065A
Application number: CN202310435490.7A
Authority: CN
Inventors: 张学军; 臧杨; 李群; 赵心; 孙小川; 李金平; 李学强; 李莉娥; 杨俊�; 李禹琼
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: 2022-04-22
Filing date: 2023-04-21
Publication date: 2023-10-24

Abstract

The application 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

Compounds for inhibiting KIF18A and application thereof

the present application claims priority from a prior application filed 22 at 2022, 4, to the chinese national intellectual property agency, under patent application number 202210431370.5, entitled "compounds and uses that inhibit KIF 18A". The entirety of this prior application is incorporated by reference into the present application.

Technical Field

The application belongs to the field of medicines, and particularly relates to a compound for inhibiting KIF18A 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 a compound for inhibiting KIF 18A.

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 ¹ is N or-CR ⁵ ；

X ² is-CR ⁶ ；

X ³ Is N;

X ⁴ is N or-CR ⁸ ；

X ⁵ Is N or-CR ⁹ ；

X ⁶ Is N or-CR ¹⁰ ；

M is selected from quilt R ^c Substituted C _1-6 An alkylene group;

l is-NR ³ -C (=o) -or-C (=o) -NR ³ -；

R ¹ Selected from the group-ZR ¹² Wherein Z is independently selected from-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-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 Alternatively combined with the sulfur atoms to which they are each attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3N atoms and 0, 1, or 2 atoms selected from O and S;

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 Alternatively combined with the sulfur atoms to which they are each attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3N atoms and 0, 1, or 2 atoms selected from O and S;

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 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 ^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 ^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: 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 ^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 the same or different, independently of one another, 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 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;

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, certain substituents in the compounds of formula I may be defined as follows, and the substituents not mentioned are defined in any of the schemes above.

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 Identical or different, independently of one another, H, halogen, C _1-6 Alkyl or C _1-4 A haloalkyl group; and R is ^15a And R is ^15b Combined 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 Identical or different, independently of one another, H, methyl or ethyl; and R is ^15a And R is ^15b Combined with their respective attached carbon atoms to form a spiro union to R ^x A cyclopropane ring, a cyclobutane ring or a cyclopentane ring of the ring.

In a preferred embodiment of the application, the radicals mentionedSelected from the group consisting of 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 compound of formula I is selected from the following structures:

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

R ¹ 、R ² and R is ⁴ Is as defined in the first aspect of the application; 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 application; m and L are as defined in the first aspect of the applicationSaid method.

wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ Is as defined in the first aspect of the invention; r is R ¹ 、R ² And R is ⁴ 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 compound of formula I is selected from the following structures:

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

R ¹ 、R ² 、R ⁴ and M is as defined in the inventionThe first aspect is described.

R ¹ 、R ² 、R ⁴ and M is as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, the compound of formula I is selected from the following structures:wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ Is as defined in the first aspect of the invention; r is R ¹ 、R ⁴ 、R ^x And M is as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, the compound of formula I is selected from the following structures:wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ Is as defined in the first aspect of the invention; r is R ¹ 、R ⁴ And M is as defined in the first aspect of the invention.

wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ Is as defined in the first aspect of the invention; r is R ² 、R ⁴ And R is ^x Is as defined in the first aspect of the invention; preferably, said R ^x Selected from->

wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ Is as defined in the first aspect of the invention; r is R ² 、R ⁴ And R is ^x Is as defined in the first aspect of the invention; preferably, said R ^x Selected from the group consisting of

wherein the R is ² Is as defined in the first aspect of the invention.

wherein the saidR ² 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 R is ¹³ Is 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, which is selected from the following 0, 1,

2 or 3 groups: 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; r is R ¹³ Optionally substituted with 0, 1, 2 or 3 groups, which may be the same or different, selected from: F. cl, br, -C _1-3 Alkyl, -OH, CN, -C _1-3 alkyl-OH;

preferably, R ¹³ Optionally substituted with 0, 1, 2 or 3 groups, which may be the same or different, selected from: F. methyl, -OH, CN, -CH ₂ OH；

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

Preferably, 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 _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;

wherein X is ⁴ 、X ⁵ And X ⁶ Is as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, the X ⁴ 、X ⁵ And X ⁶ Each independently selecting N or C; preferably, the X ⁴ 、X ⁵ And X ⁶ 0 of (2) are N; preferably, the X ⁴ 、X ⁵ And X ⁶ 1 of (a) is N; preferably, the X ⁴ 、X ⁵ And X ⁶ And 2 of them are N.

wherein M is as defined in the first aspect of the invention.

In a preferred embodiment of the invention, said M is selected from the group consisting of-CH ₂ -、In a preferred embodiment of the present invention, the compound of formula I is selected from the following structures:

wherein R is ¹ Is as defined in the first aspect of the invention.

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

In a preferred embodiment of the present invention, the R ⁴ Selected from hydrogen, methyl, halogen, cyano, methoxy, cyclopropyl.

wherein R is ¹⁰ Is as defined in the first aspect of the invention.

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

wherein M is as defined in the first aspect of the invention; preferably, said M is selected from the group consisting of-CH ₂ -、/>

wherein R is ¹² Is as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, the R ¹² Selected from hydrogen, methyl, ethyl, cyclopropyl,

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

/>

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

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

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 application provides a method for preparing a compound shown in a formula 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.

Definition and description of terms

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 invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

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

The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this 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 "means in branched or linear relationship or any combination of the threeAlkyl groups containing a minimum of alpha and a maximum of beta carbon atoms, where alpha and beta represent integers, may also be used as "C _α- C _β The form of "alkyl". The alkyl groups described in this section may also contain one or two double or triple bonds. C (C) ₀ The designation of alkyl represents a direct bond. Exemplary, C _0-6 Alkyl groups including direct bonds, C _1-6 Alkyl (e.g. C ₁ ，C ₂ ，C ₃ ，C ₄ ，C ₅ ，C ₆ An alkyl group); c (C) _1-6 Examples of alkyl groups include, but are not limited to, the following:

the term "alkylene" when used alone or as part of another substituent is understood to mean a straight or branched chain saturated, unsaturated or partially saturated divalent hydrocarbon radical. For example "C _1-6 Alkylene "or" C _1- C ₆ Alkylene "means a straight or branched chain divalent hydrocarbon radical having 1 to 6 carbon atoms including, but not limited to, methylene, ethylene, propylene, 1-methylpropylene, butylene.

"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 "means having 3 to 15,3 to 9,3 to 6 or 3 to 5 carbonsCyclic alkyl of 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 adamantyl, or a bicyclic hydrocarbon group 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.

Alone or as a wholeThe term "alkoxy" when used in connection with a portion of other substituents 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:

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

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

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 application can be obtained.

Detailed Description

The application 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 application and should not be taken as limiting the scope of the application. Upon a complete understanding of the present application, 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 application, and such changes should be considered as included in the scope of the present application.

The application has the following definitions:

symbol or unit:

IC ₅₀ : half of the numberInhibitory concentration, meaning the concentration at which half of the maximum inhibitory 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

NBS: n-bromosuccinimide

AIBN: azobisisobutyronitrile

DMF: n, N-dimethylformamide

THF: tetrahydrofuran intermediate A1: synthesis of (R) -6-methyl-2- (2-methylmorpholino) pyrimidin-4-amine

The synthetic route for intermediate A1 is shown below:

to a solution of 2-chloro-6-methylpyrimidin-4-amine (500 mg,3.48 mmol) in N, N-diisopropylethylamine (5 mL) in a closed-tube reactor was added (R) -2-methylmorpholine hydrochloride (704 mg,6.97 mmol), followed by stirring at 150℃for 18h. The reaction mixture was added to water (100 mL) and extracted with ethyl acetate (30 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 product (R) -6-methyl-2- (2-methylmorpholino) pyrimidin-4-amine (520 mg, 71.7% yield).

LC-MS,M/Z(ESI):209.1[M+H] ⁺ 。

Intermediate A2: synthesis of 2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-amine

The synthetic route for intermediate A2 is shown below:

to a solution of 4, 4-difluoropiperidine (4.39 g,36.2 mmol) and 2-chloro-6-methylpyrimidin-4-amine (4 g,27.9 mmol) in dimethyl sulfoxide (20 mL) was added N, N-diisopropylethylamine (9.87 mL,55.7 mmol), and the reaction was reacted under microwave conditions at 150℃for 1h. The reaction was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (30 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was subjected to column chromatography (petroleum ether/ethyl acetate (V/V) =1/0-0/1) to give the product 2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-amine (2.2 g, 34.6% yield).

LC-MS,M/Z(ESI):229.3[M+H] ⁺ 。

Example 1: preparation of (R) -N- (6-methyl-2- (2-methylmorpholino) pyrimidin-4-yl) -4- ((methylsulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (compound 1) the synthetic route for the preparation of the target compound 1 is as follows:

the first step: synthesis of methyl 4- (bromomethyl) -2-fluorobenzoate (1-2)

To a solution of methyl 2-fluoro-4-methylbenzoate (5.0 g,29.7 mmol) in carbon tetrachloride (100 mL) were added azobisisobutyronitrile (0.49 g,2.97 mmol) and N-bromosuccinimide (5.82 g,32.7 mmol), and the reaction solution was stirred at 70℃for 3 hours. To the mixture was added water (200 mL) and extracted with dichloromethane (50 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) =1/0-1/3) to give methyl 4- (bromomethyl) -2-fluorobenzoate as a product (3.5 g, yield 47.6%).

LC-MS,M/Z(ESI):247.0[M+H] ⁺ 。

And a second step of: synthesis of methyl 2-fluoro-4- ((methylsulfonyl) methyl) benzoate (1-3)

To a solution of methyl 4- (bromomethyl) -2-fluorobenzoate (3.5 g,14.17 mmol) in N, N-dimethylformamide (10 mL) was added sodium methylsulfinate (2.89 g,28.3 mmol) and stirred under microwave conditions at 120℃for 0.5h. To the reaction mixture was added water (100 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with saturated brine (30 ml x 3), 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 methyl 2-fluoro-4- ((methylsulfonyl) methyl) benzoate (2.5 g, 71.7% yield).

LC-MS,M/Z(ESI):247.2[M+H] ⁺ 。

And a third step of: synthesis of methyl 4- ((methylsulfonyl) methyl) -2- (6-azaspiro [2.5] octane-6-yl) benzoate (1-5)

To a solution of methyl 2-fluoro-4- ((methylsulfonyl) methyl) benzoate (1 g,4.06 mmol) in dimethyl sulfoxide (10 mL) was added 6-azaspiro [2.5] octane hydrochloride (0.68 g,6.09 mmol) and N, N-diisopropylethylamine (1.58 g,12.18 mmol) and reacted at 150℃under microwave conditions for 1h. To the reaction mixture was added water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was 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) =1/0-0/1) to give methyl 4- ((methylsulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzoate (600 mg, 43.8% yield).

LC-MS,M/Z(ESI):338.3[M+H] ⁺ 。

Fourth step: synthesis of 4- ((methylsulfonyl) methyl) -2- (6-azaspiro [2.5] octane-6-yl) benzoic acid (1-6)

To a solution of methyl 4- ((methylsulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzoate (600 mg,1.78 mmol) in tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide (213 mg,8.89 mmol), followed by reaction at 25℃for 18h. The reaction mixture was adjusted to ph=4-5 with 1N aqueous hydrochloric acid and lyophilized to give the crude product. Dichloromethane (20 mL) was added to the crude product and filtered. The filtrate was concentrated to give the product 4- ((methylsulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid (500 mg, 87% yield).

LC-MS,M/Z(ESI):324.3[M+H] ⁺ 。

Fifth step: synthesis of (R) -N- (6-methyl-2- (2-methylmorpholino) pyrimidin-4-yl) -4- ((methylsulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (Compound 1)

4- ((methylsulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid (500 mg,1.55 mmol) was dissolved in dichloromethane (5 mL) and N, N-dimethylformamide (0.1 mL), thionyl chloride (0.6 mL) was slowly added dropwise at 0deg.C, followed by stirring at 25deg.C 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 (1.35 mL,7.73 mmol), potassium phosphate (1.64 g,7.73 mmol) and (R) -6-methyl-2- (2-methylmorpholino) pyrimidin-4-amine (386 mg,1.86 mmol) were added to the reaction solution and stirred at 25℃for 3 hours. 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 product (R) -N- (6-methyl-2- (2-methylmorpholino) pyrimidin-4-yl) -4- ((methylsulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (compound 1) (61.4 mg, yield 7.42%).

¹ H NMR(400MHz,dmso)δ13.49(s,1H),8.12(d,J＝8.1Hz,1H),7.60(d,J＝1.1Hz,1H),7.42-7.32(m,2H),4.59(s,2H),4.51-4.35(m,2H),3.89(dd,J＝11.5,2.5Hz,1H),3.50(ddd,J＝14.0,10.7,4.7Hz,2H),3.03-2.90(m,8H),2.60(dd,J＝13.0,10.5Hz,1H),2.30(s,3H),1.72(s,4H),1.16(d,J＝6.2Hz,3H),0.38(s,4H)

LC-MS,M/Z(ESI):514.3[M+H] ⁺ 。

Example 2: the synthetic route for the preparation of the target compound 2 of N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- ((methylsulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (compound 2) is as follows:

4- ((methylsulfonyl) methyl) -2- (6-azaspiro [ 2.5)]Octane-6-yl) benzoic acid (300 mg,0.93 mmol) was dissolved in dichloromethane (5 mL) and N, N-dimethylformamide (0.1 mL), thionyl chloride (0.34 mL,4.64 mmol) was slowly added dropwise at 0deg.C, and then stirred at 25deg.C 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 (0.81 mL,4.64 mmol), potassium phosphate (985 mg,4.64 mmol) and 2- (4, 4-difluoropiperidin-1-yl) -6-methylpyridin-4-amine (275 mg,1.21 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 prepared in reverse phase (column: phenomenex Synergi C) ₁₈ 100 x 25mm x 4um; solvent: a=water+0.1 volume% formic acid (99%), b=acetonitrile; gradient: 5% -95%,7 min) to give the product N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- ((methylsulfonyl) methyl) -2- (6-azaspiro [ 2.5) ]Octane-6-yl) benzamide (13.3 mg, yield 2.68%).

¹ H NMR(400MHz,dmso)δ13.64(s,1H),8.12(d,J＝8.1Hz,1H),7.61(s,1H),7.45-7.33(m,2H),4.59(s,2H),4.01-3.82(m,4H),3.08-2.84(m,7H),2.32(s,3H),2.04-1.93(m,4H),1.73(s,4H),0.39(s,4H)

LC-MS,M/Z(ESI):534.20[M+H] ⁺ 。

Example 3: the synthetic route for the preparation of the target compound 35 of N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- (((2-hydroxyethyl) sulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (compound 35) is as follows:

the first step: synthesis of methyl 2-fluoro-4- (((2-hydroxyethyl) thio) methyl) benzoate (3-1)

To a solution of methyl 4- (bromomethyl) -2-fluorobenzoate (4 g,16.2 mmol) in N, N-dimethylformamide (16 mL) was added 2-mercaptoethanol (1.3 g,16.2 mmol), and the mixture was reacted at 120℃for 2 hours under microwave conditions. The reaction was slowly poured into water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 ml x 3), 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) =1/0-0/1) to give methyl 2-fluoro-4- (((2-hydroxyethyl) thio) methyl) benzoate (1.4 g, yield 35.4%).

LC-MS,M/Z(ESI):245.3[M+H] ⁺ 。

And a second step of: synthesis of methyl 2-fluoro-4- (((2-hydroxyethyl) sulfonyl) methyl) benzoate (3-2)

To a solution of methyl 2-fluoro-4- (((2-hydroxyethyl) thio) methyl) benzoate (1.4 g,5.7 mmol) in dichloromethane (14 mL) was slowly added m-chloroperoxybenzoic acid (3.9 g,22.8 mmol) at 0deg.C, and the temperature was naturally raised to room temperature and stirring was continued for 4h. The reaction solution was slowly dropped into ice water (100 mL) and extracted with dichloromethane (20 ml×3). The organic phase was washed with saturated aqueous sodium thiosulfate (20 ml x 2), saturated brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 2-fluoro-4- (((2-hydroxyethyl) sulfonyl) methyl) benzoate (1.3 g, 82% yield).

LC-MS,M/Z(ESI):277.4[M+H] ⁺ 。

And a third step of: synthesis of methyl 4- (((2-hydroxyethyl) sulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzoate (3-3)

To a solution of methyl 2-fluoro-4- (((2-hydroxyethyl) sulfonyl) methyl) benzoate (1.3 g,4.7 mmol) in dimethyl sulfoxide (13 mL) was added 6-azaspiro [2.5] octane hydrochloride (1.0 g,9.4 mmol) and N, N-diisopropylethylamine (2.4 g,18.8 mmol) and reacted at 120℃for 3h under microwave conditions. The reaction was poured into water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase 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 methyl 4- (((2-hydroxyethyl) sulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzoate (0.5 g, 26.9% yield).

LC-MS,M/Z(ESI):368.2[M+H] ⁺ 。

Fourth step: synthesis of 4- (((2-hydroxyethyl) sulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid (3-4)

To a solution of methyl 4- (((2-hydroxyethyl) sulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzoate (0.5 g,1.4 mmol) in tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide (168 mg,7 mmol), and the mixture was stirred at 25℃for 2h. To the reaction solution was added water (50 mL), ph=5 to 6 was adjusted with 1N aqueous hydrochloric acid, and extraction was performed with ethyl acetate (20 ml×3). The organic phase was washed with saturated brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give 4- (((2-hydroxyethyl) sulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid (0.2 g, 41.6% yield).

LC-MS,M/Z(ESI):354.3[M+H] ⁺ 。

Fifth step: synthesis of N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- (((2-hydroxyethyl) sulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (compound 35)

To a solution of 4- (((2-hydroxyethyl) sulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid (0.2 g,0.6 mmol) in dichloromethane (2 mL) was added O- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (684 mg,1.8 mmol) and diisopropylethylamine (233 mg,1.8 mmol), and the mixture was stirred at room temperature for 0.5h. To the reaction solution was added 2- (4, 4-difluoropiperidin-1-yl) -6-methylpyridin-4-amine (205 mg,0.9 mmol), and stirring was continued at room temperature for 2 hours. To the reaction solution was added water (20 mL), and extracted with dichloromethane (5 ml×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, 100 x 25mm x 4um; solvent: a = water + 0.1% formic acid (99%), B = acetonitrile; gradient: 5% -95%,7 min) to give N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyridin-4-yl) -4- (((2-hydroxyethyl) sulfonyl) methyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (compound 35) (31.9 mg, 10% yield).

¹ H NMR(400MHz,dmso)δ13.79(s,1H),8.12(d,1H),7.59(d,1H),7.46(s,1H),7.40(dd,1H),4.59(s,2H),3.99-3.87(m,4H),3.83(t,2H),3.21(t,2H),3.03(t,4H),2.36(s,3H),2.03(td,4H),1.72(s,3H),1.48(s,1H),0.48-0.26(m,5H).

LC-MS,M/Z(ESI):564.2[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) Group)) x 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 (μM)
		Compound 2	0.398
Compound 35	0.443

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) to Aqueous 2% dmso. To the prepared assay buffer (50 μl), KIF18A protein (final concentration 80 nM) and different concentrations of compound (1 μl) were added and incubated for 15min at room temperature; ATP (final concentration 80. Mu.M) was then added to the reaction mixture and incubated at room temperature for 3hr. After the reaction was completed, 5. Mu.L of ADP-GloTM reagent and 2.5. Mu.L of the reaction mixture were added to 384 well plates (Grenier Inc), and after mixing well, they were sealed with an aluminum foil sealing film and incubated at room temperature for 40min in the absence of light; 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 follows = (1- (compound group-blank)/(negative control group-blank)) ×100%, and IC of test compound was calculated in GraphPad Prism8 software according to inhibition ratio of different concentration of compound ₅₀ Values.

TABLE 2 inhibition of KIF18A enzymatic Activity by Compounds

Test compounds	IC ₅₀ (μM)
		Compound 35	0.007

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

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

Claims

1. A compound shown in formula I, its tautomer, stereoisomer, hydrate, solvate, and pharmaceutically acceptable salt

The salt or prodrug:

wherein,,

X ¹ is N or-CR ⁵ ；

X ² is-CR ⁶ ；

X ³ Is N;

X ⁴ is N or-CR ⁸ ；

X ⁵ Is N or-CR ⁹ ；

X ⁶ Is N or-CR ¹⁰ ；

M is selected from quilt R ^c Substituted C _1-6 An alkylene group;

l is-NR ³ -C (=o) -or-C (=o) -NR ³ -；

R ¹ Selected from the group-ZR ¹² Wherein Z is independently selected from-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-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 group-、-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 Alternatively combined with the sulfur atoms to which they are each attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3N atoms and 0, 1, or 2 atoms selected from O and S;

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 Alternatively combined with sulfur atoms to which they are each attached to form a saturated or partially saturated 3-, 4-, 5-, or 5-membered ring containing 0, 1, 2, or 3N atoms and 0, 1, or 2 atoms selected from O and SA 6 membered single ring;

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 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 、-OC _2-6 Alkyl OR ^a 、-SR ^a 、-S(＝O)R ^b 、-S(＝O) ₂ R ^b 、-S(＝O) ₂ NR ^a R ^a 、-NR ^a R ^a 、-N(R ^a )C(＝O)R ^b 、-N(R ^a )C(＝O)OR ^b 、-N(R ^a )C(＝O)NR ^a R ^a 、-N(R ^a )C(＝NR ^a )NR ^a R ^a 、-N(R ^a )S(＝O) ₂ R ^b 、-N(R ^a )S(＝O) ₂ NR ^a R ^a 、-NR ^a C _2-6 Alkyl NR ^a R ^a 、-NR ^a C _2-6 Alkyl OR ^a 、-C _1-6 Alkyl NR ^a R ^a 、-C _1-6 Alkyl OR ^a 、-C _1-6 Alkyl N (R) ^a )C(＝O)R ^b 、-C _1-6 Alkyl OC (=o) R ^b 、-C _1-6 Alkyl C (=O) NR ^a R ^a 、-C _1-6 Alkyl C (=O) OR ^a And oxo;

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

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 the same or different are independently of each other hydrogen, halogen, R ^15o Or R is ^15p ；

R ¹⁵ⁿ 、R ¹⁵ o are 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 ^a Independently selected from hydrogen or R ^b ；

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 group,-COO-C _1-6 Alkyl, -C (O) NR ^c1 R ^c2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^c1 And R is ^c2 Each independently is hydrogen, C _1-6 An alkyl group.

2. 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 Identical or different, independently of one another, H, halogen, C _1-6 Alkyl or C _1-4 A haloalkyl group; and R is ^15a And R is ^15b Combined 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.

3. 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 ¹⁵ⁱ And R is ^15j Identical or different, independently of one another, H, methyl or ethyl; and R is ^15a And R is ^15b Combined 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 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 claim 1, wherein the groupSelected from->

6. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to 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 ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ Having the definition of claim 1;

R ¹ 、R ² And R is ⁴ 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.

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:

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

m has the definition of 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:

R ¹ 、R ² 、R ⁴ and M has the definition as defined 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:

R ¹ 、R ⁴ 、R ^x and M has the definition as defined in 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:

R ¹ 、R ⁴ and M has the definition as defined in 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:

R ² 、R ⁴ and R is ^x Having the definition of claim 1.

13. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof as claimed in claim 12 wherein R is ^x Selected from the group consisting of

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 the R is ² Having the definition of claim 1.

15. The compound of formula I, as defined in claim 1, a tautomer thereof,Stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, wherein R is 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;

16. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claims 1, 7 to 9, 12 or 14, wherein R is 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 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.

18. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, any one of claims 7 to 12, or claim 17, wherein X is ⁴ 、X ⁵ And X ⁶ Each independently selecting N or C;

preferably, the X ⁴ 、X ⁵ And X ⁶ 0 of (2) are N;

preferably, the X ⁴ 、X ⁵ And X ⁶ 1 of (a) is N;

preferably, the X ⁴ 、X ⁵ And X ⁶ And 2 of them are N.

19. 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 M has the definition as defined in claim 1.

20. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, any one of claims 7 to 11, or claim 19, wherein M is selected from the group consisting of-CH ₂ -、

21. 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 R is ¹ Having the definition of claim 1.

22. The method according to claim 1, any one of claims 7 to 11,Or a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 21, wherein R is ¹ Selected from the group consisting of

23. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claims 1 to 7 to 12, wherein R ⁴ Selected from hydrogen, methyl, halogen, cyano, methoxy, cyclopropyl.

24. The heterocyclic 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 R is ¹⁰ Having the definition of claim 1.

25. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or claim 24, wherein R ¹⁰ Selected from hydrogen, methyl, halogen, cyano, methoxy, cyclopropyl.

26. 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 M has the definition as defined in claim 1.

27. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 26, wherein M is selected from the group consisting of-CH ₂ -、

28. 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 R is ¹² Having the definition of claim 1.

29. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or claim 22, wherein R ¹² Selected from hydrogen, methyl, ethyl, 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.