CN111808080A

CN111808080A - Substituted pyridine or pyrimidine compound, preparation method thereof and application thereof in medicine

Info

Publication number: CN111808080A
Application number: CN201910292859.7A
Authority: CN
Inventors: 王超磊; 吴勇勇; 李桂英; 吴政; 景连栋; 田强; 宋宏梅; 薛彤彤; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2019-04-12
Filing date: 2019-04-12
Publication date: 2020-10-23
Anticipated expiration: 2039-04-12
Also published as: CN111808080B

Abstract

The invention relates to substituted pyridine or pyrimidine compounds, a preparation method thereof and application thereof in medicines. In particular, the invention relates to compounds wherein R¹、R²、R³、R⁴、R⁵、R⁶X, Y, A, B and n, processes for their preparation, pharmaceutical compositions containing them and their use in medicine.

Description

Substituted pyridine or pyrimidine compound, preparation method thereof and application thereof in medicine

Technical Field

The invention relates to a substituted pyridine or pyrimidine compound, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in medicines.

Background

Spindle Assembly Checkpoint (SAC) is one of the major checkpoints in the Cell cycle, and monitors the alignment of chromosomes on the equatorial plate and their separation to the Spindle dipole, ensuring kinetochore-microtubule adhesion and mitotic integrity, allowing all chromosomes to settle on the equatorial plate and enter late after bipolar orientation, ensuring accurate chromosome assignment to daughter cells during mitosis (Nature Reviews Molecular Cell Biology, vol.8, No.5, pp.379-393,2007; Cell Proliferation, vol.44, No.5, pp.391-400,2011). When the spindle microtubules are incorrectly linked to chromosomes or the assembly of the spindle is incorrect, the spindle checkpoint is activated, inhibiting cell cycle progression. Over-expression or non-expression of SAC members has been reported in various Cancer types, and in most cases, expression status of SAC members correlates with hyperproliferative activity and poor prognosis of tumors (Nature Reviews Cancer, vol.10, No.2, pp.102-115,2010).

Threonine/Tyrosine Kinase (TTK), also known as Mps1 (Monocola screw 1), is a key Kinase for the activation and maintenance of SAC function (Novel TTK Kinase inhibitors with a potential enzyme anti-tumor activity. mol Cancer Ther.15(4): 583-592.2016). TTK was barely detectable in normal tissues except testis and placenta. But elevated levels of TTK mRNA in many human cancers, including papillary thyroid, breast, stomach, bronchial and lung cancers (Cancer Res.2007; 67(21): 10148-. Inhibition of TTK can cause a lack of SAC function, leading to premature mitotic withdrawal and to severe chromosome missegregation, ultimately leading to cancer cell death. Thus, TTK inhibitors have great potential for treating tumors.

The compounds were in clinical study with Serier S-81694 (phase I/II clinics), Bayer BAY-1217389 (phase I clinics), University Health Network CFI-402257 (phase I/II clinics) and Boston pharmaceuticals BOS-172722 (phase I clinics). Patent application WO 200915639/WO 2014131739/WO2015070349/WO2014037750 also discloses compounds as TTK inhibitors, but no TTK selective inhibitors are yet on the market. In order to better meet the clinical requirements, the development of a new TTK selective inhibitor with high efficiency and low toxicity is urgently needed.

Disclosure of Invention

The invention provides a safe and effective TTK inhibitor with a novel structure, which is a compound shown as a formula I or a stereoisomer, a tautomer, a stable isotope derivative, a metabolite or a prodrug thereof, or a pharmaceutically acceptable salt, a eutectic compound, a polymorphic substance or a solvate thereof,

wherein:

ring A is selected from 6-12 membered aryl, 9-12 membered arylheterocyclo, and 5-14 membered heteroaryl;

R¹selected from the group consisting of H, -CN, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, 5-6 membered heteroarylo 5-7 membered heterocyclyl, -C (O) N (R)^f)R^eand-S (O)₂N(R^f)R^e(ii) a The 5-6 membered heteroaryl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl may be optionally substituted with one or more of the following groups: halogen, cyano, nitro, OH, halogeno C_1-3Alkyl, halo C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl radical, C_3-6Cycloalkyloxy, 4-7 membered heterocyclyl, -NR^aR^b、-C(O)R^a、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^aor-N (R)^b)SO₂R^aSaid halo C_1-3Alkyl, halo C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl radical, C_3-6Cycloalkyloxy, 4-7 membered heterocyclyl may be optionally substituted with one or more of the following: -OH, halogen, -CN, C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-3Haloalkyl, C_1-3A haloalkoxy group;

wherein R is^aAnd R^bEach independently selected from H, C_1-4Alkyl and C_3-6Cycloalkyl radical, said C_1-4Alkyl radical, C_3-6Cycloalkyl groups may be optionally substituted with one or more of the following groups: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-7 membered heterocyclyl, -NR^cR^d、-C(O)R^c、-C(O)OR^c、-OC(O)R^c、-N(R^d)OR^c、-C(O)N(R^d)R^c、-N(R^d)C(O)R^c、-S(O)_pR^c、-SO₂N(R^d)R^cor-N (R)^d)SO₂R^c；

R^eAnd R^fEach independently selected from H and C_1-4Alkyl radical, said C_1-4Alkyl optionally substituted by halogen or C_1-3Alkoxy substitution; or, R^eAnd R^fLinked to each other to form, together with the nitrogen atom to which they are attached, a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring being optionally substituted with one or more of the following substituents: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-7 membered heterocyclyl, -NR^cR^d、-C(O)R^c、-C(O)OR^c、-OC(O)R^c、-N(R^d)OR^c、-C(O)N(R^d)R^c、-N(R^d)C(O)R^c、-S(O)_pR^c、-SO₂N(R^d)R^cor-N (R)^d)SO₂R^c；

R^cAnd R^dEach independently selected from H and C_1-4An alkyl group;

p is selected from 0, 1 and 2;

R²each independently selected from hydrogen, halogen, cyano, OH, C_1-6Alkoxy radical, C_1-6Alkyl radical, C_1-3Haloalkyl and C_1-3A haloalkoxy group;

R³and R⁴Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl, -C_1-2alkyl-C_3-8Cycloalkyl, phenyl, 4-7 membered heterocyclyl, -C_1-2Alkyl- (4-7 membered heterocyclyl) and 5-6 membered heteroaryl, said C_1-6Alkyl radical, C_3-8Cycloalkyl, -C_1-2alkyl-C_3-8Cycloalkyl, phenyl, 4-7 membered heterocyclyl, -C_1-2Alkyl- (4-7 membered heterocyclyl), 5-6 membered heteroaryl may be optionally substituted with one or more of the following: hydroxy, halogen, cyano, C_1-3Haloalkyl, C_1-3Haloalkoxy, C_1-4Alkyl radical, C_1-4Alkoxy, -NR^aR^b、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^aor-N (R)^b)SO₂R^a4-7 membered heterocyclyl; or

R³And R⁴Are linked to each other to form, together with the nitrogen atom to which they are attached, a 4-12 membered heterocyclic ring; the 4-12 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-7 membered heterocyclyl, -NR^aR^b、-C(O)R^a、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^a)R^bor-N (R)^b)SO₂R^a；

X is selected from N and CH;

y is selected from N and CH;

ring B is selected from 6-12 membered aryl, 9-12 membered arylheterocyclo, and 5-14 membered heteroaryl;

R⁵selected from H, cyano, C_1-6Alkyl radical, C_3-8Cycloalkyl, -O-C_1-6Alkyl, -O-C_1-6Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, -NR^gR^h、-C(＝O)OR^h、-C(＝O)NR^gR^h、-NR^gC(＝O)NR^gR^hand-NR^gC(＝O)R^hSaid C is_1-6Alkyl radical, C_3-8Cycloalkyl, -O-C_1-6Alkyl, -O-C_1-6Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-10 membered heterocycleRadical, -NR^aR^b、-C(O)R^a、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^aor-N (R)^b)SO₂R^a(ii) a The 4-10 membered heterocyclyl may be optionally substituted with one or more of the following: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, C_3-8A cycloalkyl group;

wherein R is^gAnd R^hEach independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, said C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂、-O-(C_1-3Alkyl group), C_3-6Cycloalkyl, 4-10 membered heterocyclyl; and R is^gAnd R^hMay form, together with the nitrogen atom to which it is attached, a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring being optionally substituted by one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂、-O-(C_1-3Alkyl group), C_3-6Cycloalkyl, 4-10 membered heterocyclyl;

R⁶each independently selected from H, halogen, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-6Alkyl radical, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, -NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-6Alkyl can beOptionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-3An alkyl group;

when R is⁵And R⁶Adjacent to the B ring, may be joined to form, together with two atoms of the B ring, a 5-8 membered carbocyclic or heterocyclic ring which may be optionally substituted by one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-(C_1-3Alkyl), -N (C)_1-3Alkyl radical)₂、-O-(C_1-3Alkyl group), C_3-6Cycloalkyl, 4-10 membered heterocyclyl;

n is selected from 0, 1,2 and 3;

when more than one R is present^a、R^b、R^c、R^d、R^eOr R^fAnd when occurring at the same time, may be the same or different.

In some embodiments of the invention, ring a is selected from 6-12 membered aryl, 9-12 membered benzoheterocyclyl and 5-14 membered heteroaryl; preferably, ring A is selected from 6-12 membered aryl and 5-14 membered heteroaryl; preferably, ring a is phenyl.

In some embodiments of the invention, R¹Selected from the group consisting of H, -CN, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, 5-6 membered heteroarylo 5-7 membered heterocyclyl, -C (O) N (R)^f)R^eand-S (O)₂N(R^f)R^e(ii) a The 5-6 membered heteroaryl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl may be optionally substituted with one or more of the following groups: halogen, cyano, nitro, OH, halogeno C_1-3Alkyl, halo C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl, 4-7 membered heterocyclyl, -NR^aR^b、-C(O)R^a、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^aOr N (R)^b)SO₂R^aSaid C is_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl, 4-7 membered heterocyclyl may be optionally substituted with one or more of the following: -OH, halogen, -CN, C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-3Haloalkyl, C_1-3A haloalkoxy group;

wherein R is^aAnd R^bEach independently selected from H, C_1-4Alkyl and C_3-6Cycloalkyl radical, said C_1-4Alkyl or C_3-6Cycloalkyl groups may be optionally substituted with one or more of the following groups: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkyl, halo C_1-3Alkoxy, 4-7 membered heterocyclyl, -NR^cR^d、-C(O)R^c、-C(O)OR^c、-OC(O)R^c、-N(R^d)OR^c、-C(O)N(R^d)R^c、-N(R^d)C(O)R^c、-S(O)_pR^c、-SO₂N(R^d)R^cor-N (R)^d)SO₂R^c；

R^eAnd R^fEach independently selected from H and C_1-4Alkyl radical, said C_1-4Alkyl optionally substituted by halogen or C_1-3Alkoxy substitution; or R^eAnd R^fLinked to each other to form, together with the nitrogen atom to which they are attached, a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring being optionally substituted with one or more of the following substituents: halogen, -OH, cyano, nitro, C_1-4Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-7 membered heterocyclyl, -NR^cR^d、-C(O)R^c、-C(O)OR^c、-OC(O)R^c、-N(R^d)OR^c、-C(O)N(R^d)R^c、-N(R^d)C(O)R^c、-S(O)_pR^c、-SO₂N(R^d)R^cor-N (R)^d)SO₂R^c；

R^cAnd R^dEach independently selected from H and C_1-4An alkyl group;

p is selected from 0, 1 and 2.

In some embodiments of the invention, R¹Selected from the group consisting of H, -CN, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, -C (O) N (R)^f)R^eand-S (O)₂N(R^f)R^e(ii) a The 5-6 membered heteroaryl and 5-6 membered heterocyclyl may be optionally substituted with one or more of the following: halogen, cyano, nitro, -OH, halogeno-C_1-3Alkyl, halo C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl, 4-7 membered heterocyclyl, -C (O) R^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^aor-N (R)^b)SO₂R^aSaid C is_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl, 4-7 membered heterocyclyl may be optionally substituted with one or more of the following: -OH, halogen, -CN, C_1-3Alkoxy radical, C_1-4Alkyl, halo C_1-3Alkyl, halo C_1-3An alkoxy group;

wherein R is^aAnd R^bEach independently selected from H and C_1-4Alkyl radical, said C_1-4Alkyl groups may be optionally substituted with one or more of the following groups: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-7 membered heterocyclyl, -NR^cR^d、-N(R^d)OR^c、-C(O)N(R^d)R^c、-N(R^d)C(O)R^c、-S(O)_pR^c、-SO₂N(R^d)R^cor-N (R)^d)SO₂R^c；

R^eAnd R^fEach independently selected from H and C_1-4Alkyl radical, said C_1-4Alkyl optionally substituted by halogen or C_1-3Alkoxy substitution; or R^eAnd R^fLinked to each other to form, together with the nitrogen atom to which they are attached, a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring being optionally substituted with one or more of the following substituents: halogen, -OH, halogen,Cyano, nitro, C_1-4Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkyl, halo C_1-3Alkoxy, 4-7 membered heterocyclyl, -NR^cR^d、-N(R^d)OR^c、-C(O)N(R^d)R^c、-N(R^d)C(O)R^c、-S(O)_pR^c、-SO₂N(R^d)R^cor-N (R)^d)SO₂R^c；

R^cAnd R^dEach independently selected from H and C_1-4An alkyl group;

p is selected from 0, 1 and 2.

In some embodiments of the invention, R¹Selected from the group consisting of H, -CN, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and-C (O) N (R)^f)R^e(ii) a The 5-6 membered heteroaryl and 5-6 membered heterocyclyl may be optionally substituted with one or more of the following: halogen, cyano, halogeno C_1-3Alkyl, halo C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl, 4-7 membered heterocyclyl, -C (O) R^a、-C(O)N(R^b)R^aOr N (R)^b)SO₂R^aSaid C is_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl, 4-7 membered heterocyclyl may be optionally substituted with one or more of the following: -OH, halogen, -CN, C_1-3Alkoxy radical, C_1-4Alkyl, halo C_1-3Alkyl, halo C_1-3An alkoxy group;

wherein R is^aAnd R^bEach independently selected from H and C_1-4Alkyl radical, said C_1-4Alkyl groups may be optionally substituted with one or more of the following groups: halogen, OH, cyano, C_1-4Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-7 membered heterocyclyl;

R^eand R^fEach independently selected from H and C_1-4Alkyl radical, said C_1-4Alkyl optionally substituted by halogen or C_1-3Alkoxy substitution; or R^eAnd R^fAre attached to each other together with the nitrogen atom to which they are attachedForming a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring optionally substituted with one or more of the following substituents: halogen, OH, cyano, C_1-4Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkyl, halo C_1-3Alkoxy, 4-7 membered heterocyclyl;

R^cand R^dEach independently selected from H and C_1-4An alkyl group;

p is selected from 0, 1 and 2, preferably p is 2.

In some embodiments of the invention, R¹Selected from the group consisting of H, -CN, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and-C (O) N (R^f)R^e(ii) a Said heteroaryl and heterocyclyl groups may be optionally substituted with one or more of the following groups: halogen, cyano, halogeno C_1-3Alkyl, halo C_1-3Alkoxy radical, C_1-4Alkyl or C_1-4An alkoxy group;

R^eand R^fEach independently selected from H and C_1-4Alkyl radical, said C_1-4Alkyl optionally substituted by halogen or C_1-3Alkoxy substitution; or R^eAnd R^fLinked to each other to form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring, said 4-6 membered heterocyclic ring being optionally substituted with one or more of the following substituents: halogen, -OH, cyano, C_1-4Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkyl or halo C_1-3An alkoxy group.

In some embodiments of the invention, R¹Selected from hydrogen,

Preferably, R is relative to the amino group attached to the A ring¹Is located at 4 bits.

In some embodiments of the invention, R²Each independently selected from hydrogen, halogen, cyano, C_1-3Alkoxy radical, C_1-3Alkyl and C_1-3A haloalkoxy group; preferably, R²Each independently selected from chlorine, fluorine, bromine, iodine, cyano, C_1-3Alkoxy radical, C_1-3Alkyl and C_1-3A haloalkoxy group; preferably, R²Each independently selected from chlorine, fluorine, C_1-3Alkoxy and C_1-3An alkyl group; preferably, R²Selected from the group consisting of chloro, fluoro, methoxy, ethoxy and methyl;

preferably, R is relative to the amino group attached to the A ring²In ortho-and/or meta-position.

In some embodiments of the invention, R³And R⁴Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl, -C_1-2alkyl-C_3-8Cycloalkyl, phenyl, 4-7 membered heterocyclyl, -C_1-2Alkyl- (4-7 membered heterocyclyl) and 5-6 membered heteroaryl, said C_1-6Alkyl radical, C_3-8Cycloalkyl, -C_1-2alkyl-C_3-8Cycloalkyl, phenyl, 4-7 membered heterocyclyl, -C_1-2Alkyl- (4-7 membered heterocyclyl), 5-6 membered heteroaryl may be optionally substituted with one or more of the following: hydroxy, fluoro, chloro, cyano, C_1-3Haloalkyl, C_1-3Haloalkoxy, C_1-4Alkyl radical, C_1-4Alkoxy, -NR^aR^b、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^a4-7 membered heterocyclyl or-N (R)^b)SO₂R^a(ii) a Alternatively, the first and second electrodes may be,

R³and R⁴Are linked to each other to form, together with the nitrogen atom to which they are attached, a 4-7 membered heterocyclic ring; the 4-7 membered heterocyclic ring may be optionally substituted with one or more of the following substituents:halogen, hydroxy, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-7 membered heterocyclyl, -NR^aR^b、-C(O)R^a、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^a)R^bor-N (R)^b)SO₂R^a；

Preferably, R³And R⁴Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl, -C_1-2alkyl-C_3-8Cycloalkyl, 4-7 membered heterocyclyl, -C_1-2Alkyl- (4-7 membered heterocyclyl) and 5-6 membered heteroaryl, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following groups: hydroxy, fluoro, chloro, cyano, halogeno C_1-3Alkyl, halo C_1-3Alkoxy radical, C_1-4Alkyl, -NR^aR^b、-N(R^b)OR^a、-C(O)N(R^b)R^a、-S(O)_pR^a、-SO₂N(R^b)R^a4-7 membered heterocyclyl, -N (R)^b)SO₂R^a(ii) a Or

R³And R⁴Are linked to each other to form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring; the 4-6 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-7 membered heterocyclyl, -NR^aR^b、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^a)R^bor-N (R)^b)SO₂R^a；

Preferably, R³And R⁴Each independently selected fromHydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following groups: hydroxy, fluoro, chloro, cyano, halogeno C_1-3Alkyl, halo C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-4Alkoxy, -NR^aR^b4-6 membered heterocyclyl; alternatively, the first and second electrodes may be,

R³and R⁴Are linked to each other to form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring; the 4-6 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-7 membered heterocyclyl, -NR^aR^b；

Preferably, R³And R⁴Each independently selected from hydrogen and C_1-6Alkyl, -C_1-2alkyl-C_3-8Cycloalkyl radical, C_3-6Cycloalkyl, -C_1-2Alkyl- (4-6 membered heterocyclic group), said C_1-6Alkyl groups may be optionally substituted with one or more hydroxyl groups; or, R³And R⁴Are linked to each other to form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring; the 4-6 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: OH, C_1-4Alkoxy (e.g., methoxy);

preferably, -NR³R⁴Selected from:

in some embodiments of the invention, X is selected from N and CH, preferably, X is N; y is selected from N and CH, preferably Y is N.

In some embodiments of the invention, ring B is selected from 6-12 membered aryl, 9-12 membered arylheterocyclo, and 5-14 membered heteroaryl;

preferably, ring B is selected from phenyl and 5-6 membered heteroaryl;

preferably, ring B is selected from phenyl and furanyl.

In some embodiments of the invention, R⁵Selected from H, cyano, C_1-6Alkyl radical, C_3-8Cycloalkyl, -O-C_1-6Alkyl, -O-C_1-6Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, -NR^gR^h、-C(＝O)OR^h、-C(＝O)NR^gR^h、-NR^gC(＝O)NR^gR^hand-NR^gC(＝O)R^hSaid C is_1-6Alkyl radical, C_3-8Cycloalkyl, -O-C_1-6Alkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-10 membered heterocyclyl, -NR^aR^b、-C(O)R^a、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^aor-N (R)^b)SO₂R^a(ii) a The 4-10 membered heterocyclyl may be optionally substituted with one or more of the following: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, C_3-8A cycloalkyl group;

wherein R is^gAnd R^hEach independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, said C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂、-O-(C_1-3Alkyl group), C_3-6Cycloalkyl, 4-10 membered heterocyclyl; and R is^gAnd R^hMay form a 4-7 membered heterocyclic ring together with the nitrogen atom to which they are attached, said 4-The 7-membered heterocyclic ring may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂、-O-(C_1-3Alkyl group), C_3-6Cycloalkyl, 4-10 membered heterocyclyl;

preferably, R⁵Selected from H, cyano, C_1-6Alkyl, -C (═ O) OR^h、-C(＝O)NR^gR^h、-NR^gC(＝O)NR^gR^hand-NR^gC(＝O)R^h；

Wherein R is^gAnd R^hEach independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, said C_1-6Alkyl radical, C_3-6Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂、-O-(C_1-3Alkyl group), C_3-6Cycloalkyl, 4-10 membered heterocyclyl;

preferably, R⁵Selected from hydrogen, cyano, C_1-6Alkyl, -C (═ O) OR^h、-C(＝O)NR^gR^hand-NR^gC(＝O)R^hWherein R is^gAnd R^hEach independently selected from H, C_1-3Alkyl and C_3-6Cycloalkyl radical, said C_1-3Alkyl and C_3-6Cycloalkyl groups may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂、-O-C_1-3Alkyl radical, C_3-6Cycloalkyl, 4-7 membered heterocyclyl;

preferably, R^gAnd R^hEach independently selected from H, C_1-3Alkyl and C_3-6Cycloalkyl radical, said C_1-3Alkyl and C_3-6Cycloalkyl groups may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂；

Preferably, R^gAnd R^hEach independently selected from the group consisting of H, halo-cyclopropyl, methyl, ethyl, cyclopropyl and cyclobutyl;

preferably, R⁵Selected from optionally substituted 5-6 membered heteroaryl, halo-cyclopropylcarbamoyl and cyclopropylcarbamoyl; or, R⁵Selected from hydrogen, cyano, -CH₂OH、-COOH、CH₃CONH-、

Preferably, R is relative to the position of attachment of the ring containing X and Y⁵Is located at 4 bits.

In some embodiments of the invention, R⁶Each independently selected from H, halogen, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-6Alkyl radical, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, -NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-6Alkyl groups may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-3An alkyl group; n is selected from 1,2 and 3;

preferably, R⁶Each independently selected from H, halogen, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3Haloalkyl and C_1-3Haloalkoxy, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy groups may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-3An alkyl group; n is selected from 1,2 and 3;

preferably, R⁶Each independently selected from H, halogen, hydroxy, cyano, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl and C_1-3Haloalkoxy, said C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy groups may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-3An alkyl group; n is selected from 1,2 and 3;

preferably, R⁶Each independently selected from H, halogen, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl and C_1-3Haloalkoxy, said C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy groups may be optionally substituted with one or more of the following groups: halogen, cyano, C_1-3An alkyl group; n is selected from 1,2 and 3, preferably n is 1;

preferably, R is relative to the position of attachment of the ring containing X and Y⁶In ortho or meta position.

In some embodiments of the invention, the compound has the structure of formula II:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶A, B and n are as defined above for formula (I).

In some embodiments of the invention, in formula II, ring a is selected from 6-12 membered aryl (e.g., phenyl) and 5-14 membered heteroaryl, ring B is selected from phenyl and furanyl, and n is selected from 0 and 1.

In some embodiments of the invention, the compound has the structure of formula III:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶Ring A and n are as defined above for formula (I), X¹、X²、X³And X⁴Are all CH; or, X¹、X²、X³And X⁴One of them is N, and the others are CH.

In some embodiments of the invention, the compound has the structure of formula IV:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶As defined above for formula (I), X⁵Is CH or N.

In some embodiments of the invention, the compound has the structure of formula V:

wherein R is¹、R²、R³、R⁴、R⁵As defined above with respect to formula (I).

In some embodiments of the invention, the compound of formula V wherein R is¹Selected from:

hydrogen, hydrogen,

R²Selected from the group consisting of chloro, fluoro, methoxy, ethoxy and methyl;

R³and R⁴Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following groups: hydroxy, fluoro, chloro, cyano, halogeno C_1-3Alkyl, halo C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-4Alkoxy, -NR^aR^b4-6 membered heterocyclyl; or

R³And R⁴Are linked to each other to form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring; the 4-6 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: halogen, hydroxy, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-7 membered heterocyclyl, -NR^aR^b；

Preferably, -NR³R⁴Is selected from

And is

R⁵Selected from hydrogen, cyano, -CH₂OH、-COOH、CH₃CONH-、

R⁶Selected from H, halogen, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, said C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy groups may be optionally substituted with one or more of the following groups: halogen, cyano, C_1-3Alkyl radical。

In some embodiments of the invention, the compound of formula V wherein R is¹Is composed of

R²Is an ethoxy group; r³And R⁴Each independently selected from hydrogen and C₁-6 alkyl, preferably, -NR³R⁴Is composed of

R⁵Is selected from CH₃CONH-、

R⁶Selected from H, methyl and fluorine.

In some embodiments of the invention, the compounds of the invention are selected from, but not limited to:

or a stereoisomer, tautomer, stable isotope derivative, metabolite or prodrug thereof, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof.

Preparation method

A second aspect of the invention provides a process for the preparation of a compound of formula V according to the invention,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶As described above;

Q¹and Q²As a leaving group, typical leaving groups include, but are not limited to: a halogen atom such as a chlorine atom, a bromine atom or an iodine atom; or R⁷S(O)_q-a group, wherein q is selected from 1 and 2, and R⁷Represents substituted C_1-6Alkyl, substituted C_3-7Cycloalkyl, substituted 3-7 membered monocyclic heterocycloalkyl, substituted phenyl and substituted 5-6 membered monocyclic arylheterocyclyl, preferably selected from methylsulfonyl, trifluoromethoxy sulfonyl and perfluorobutoxy sulfonyl; q³Is a halogen atom, preferably selected from a bromine atom and an iodine atom;

the method comprises the following steps:

the method comprises the following steps: the compound V-1 reacts with the compound V-2 to obtain a compound V-3

The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dioxane, acetonitrile, dimethylsulfoxide, and any combination thereof, preferably acetonitrile. The reaction is preferably carried out under suitable basic conditions, the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, TEA, DIPEA or cesium carbonate, preferably, the base is selected from DIPEA. The reaction is preferably carried out at a suitable temperature. The temperature is preferably room temperature (20-30 ℃). The reaction is preferably carried out for a suitable time, for example 1 to 3 h.

Step two: the compound V-3 and the compound V-4 are subjected to coupling reaction to obtain a compound V-5

The coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst, such as tris (dibenzylideneacetone) dipalladium, triphenylphosphine palladium, bis (triphenylphosphine) palladium dichloride, palladium acetate, preferably tris (dibenzylideneacetone) dipalladium, bis (triphenylphosphine) palladium dichloride. The base is an inorganic base such as potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium carbonate. Optionally, the coupling reaction is carried out in the presence of an organophosphorus compound derived from biphenyl, the organophosphorus compound being selected from RuPhos, XPhos, SPhos andCPhos, preferably RuPhos. Preferably, the reaction is carried out in a suitable organic solvent which may be selected from dioxane, benzene, toluene and xylene, for example toluene. Preferably, the coupling reaction is carried out under a suitable protective atmosphere (e.g., N)₂Ambient). Preferably, the coupling reaction is carried out at a suitable temperature, which may be, for example, 70-100 ℃, preferably 80 ℃. Preferably, the coupling reaction is carried out for a suitable time, for example 1 to 3h, for example 2 h.

Step three: the compound V-5 reacts with the compound V-6 to obtain a compound V

The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dioxane, acetonitrile, dimethylsulfoxide, and any combination thereof, preferably dimethylsulfoxide. The reaction is preferably carried out under suitable basic conditions, the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, TEA, DIPEA or cesium carbonate, preferably the base is selected from cesium carbonate. The reaction is preferably carried out at a suitable temperature, which may be, for example, from 80 to 150 ℃, preferably 100 ℃. Preferably, the reaction is carried out for a suitable time, for example from 1 to 24h, preferably 12 h.

The term "suitable" as used herein means that the selection of a particular compound or condition will depend on the particular synthetic procedure to be performed and the identity of the molecule or molecules to be transformed, but is within the ability of one skilled in the art. All process/method steps described herein are performed under conditions sufficient to provide the indicated products. Those skilled in the art will appreciate that all reaction conditions (including, for example, reaction solvent, reaction time, reaction temperature, and whether the reaction should be carried out under anhydrous or inert atmosphere, etc.) can be varied to optimize the yield of the desired product, and that such variations are within the ability of those skilled in the art.

The examples provide exemplary methods of preparing compounds of formula (I). One skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of formula (I). Although specific starting materials and reagents are described and discussed in the examples, other starting materials and reagents can be substituted to provide various derivatives and/or reaction conditions. In addition, many of the example compounds produced by the methods described herein may be further modified using conventional chemistry well known to those skilled in the art, with reference to this disclosure.

Pharmaceutical compositions, methods of preparation and methods of treatment

A third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV) or (V) of the present invention, a stereoisomer, a tautomer, or a mixture thereof of said compound, a pharmaceutically acceptable salt, a co-crystal, a polymorph or a solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, and one or more pharmaceutically acceptable carriers.

A fourth aspect of the present invention provides a process for preparing a pharmaceutical composition of the invention, which process comprises combining a compound of formula (I), (II), (III), (IV) or (V) of the invention, a stereoisomer, tautomer or mixture thereof of said compound, a stable isotopic derivative, metabolite or prodrug of said compound, or a pharmaceutically acceptable salt, cocrystal, polymorph or solvate of said compound, with one or more pharmaceutically acceptable carriers.

A fifth aspect of the invention provides a pharmaceutical formulation comprising a compound of formula (I), (II), (III), (IV) or (V) of the invention, a stereoisomer, a tautomer, or a mixture thereof of said compound, a stable isotopic derivative, metabolite or prodrug of said compound, a pharmaceutically acceptable salt, cocrystal, polymorph or solvate of said compound, or a pharmaceutical composition of the invention.

A sixth aspect of the present invention provides a use of a compound represented by formula (I), (II), (III), (IV) or (V) of the present invention, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, a cocrystal, a polymorph or solvate of the compound, a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention, for the preparation of a medicament for the prevention or treatment of a disease associated with TTK activity.

A seventh aspect of the present invention provides a compound represented by formula (I), (II), (III), (IV) or (V) of the present invention, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph or solvate of the compound, a pharmaceutical composition of the present invention or a pharmaceutical preparation of the present invention, for use in the prevention or treatment of a disease associated with TTK activity.

An eighth aspect of the present invention provides a method for preventing or treating a disease associated with TTK activity, the method comprising administering to a subject in need thereof an effective dose of a compound represented by formula (I), (II), (III), (IV) or (V) of the present invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph or solvate of the compound, a pharmaceutical composition of the present invention or a pharmaceutical preparation of the present invention, and optionally including combination with other agents for preventing or treating a disease associated with TTK activity, such as cancer.

A ninth aspect of the present invention provides a method for preventing or treating a disease associated with TTK activity, the method comprising administering to a subject in need thereof an effective dose of a compound of formula (I), (II), (III), (IV) or (V) of the present invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph or solvate of the compound, a pharmaceutical composition of the present invention or a pharmaceutical formulation of the present invention, in combination with an antimitotic drug.

Diseases associated with TTK activity described herein include, but are not limited to, tumors including benign tumors and malignant tumors, particularly cancers such as melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, cervical cancer, thyroid cancer, metastases of secondary sites of primary solid tumors, chronic myelogenous leukemia, acute lymphocytic leukemia, papillary thyroid cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colon cancer, and the like.

Definition of

Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to those techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

As used herein, the terms "comprises," "comprising," "has," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

The term "alkyl" as used herein is defined as a straight or branched chain saturated aliphatic hydrocarbon group. For example, as used herein, the term "C₁-C₆Alkyl "refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents.

The term "haloalkyl", as used herein alone or in combination with other groups, refers to an alkyl group as described above wherein one or more hydrogen atoms are replaced by a halogen. For example, the term "C_1-6Haloalkyl "refers to C optionally substituted with one or more (e.g., 1-3) halogens_1-6An alkyl group. The term "C_1-3Haloalkyl "means optionally substituted with one or more (e.g., 1-3) halogensC_1-3An alkyl group. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. Haloalkyl radicals such as-CH₂F、-CHF₂、-CF₃、-CCl₃、-C₂F₅、-C₂Cl₅、-CH₂CF₃、-CH₂Cl or-CH₂CH₂CF₃And the like.

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic ring, including spiro, fused or bridged systems (such as bicyclo [ 1.1.1)]Pentyl, bicyclo [2.2.1]Heptyl, etc.), optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 10 carbon atoms, for example 3 to 8 carbon atoms, 3 to 7 carbon atoms, 3 to 6 carbon atoms or 3 to 5 carbon atoms. For example, as used herein, the term "C₃-C₈Cycloalkyl radicals "and" C_3-8Cycloalkyl "is used interchangeably and refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) having 3 to 8 ring-forming carbon atoms, which is optionally substituted with one or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

The term "alkoxy" as used herein, means an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom, e.g., is C₁-C₆Alkoxy or C₁-C₃An alkoxy group. C₁-C₆Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including isopropoxy, n-propoxy), butoxy (including n-butoxy, isobutoxy, t-butoxy), pentoxy (including n-pentoxy, isopentoxy, neopentoxy), and the like,Hexyloxy (including n-hexyloxy, isohexyloxy), and the like.

The term "haloalkoxy", as used herein alone or in combination with other groups, refers to an alkoxy group as described above wherein one or more hydrogen atoms are replaced by a halogen. For example, the term "C_1-6Haloalkoxy "means C substituted with one or more (e.g., 1,2, or 3) halogens_1-6An alkoxy group. Similarly, the term "C_1-3Haloalkoxy "means C substituted with one or more (e.g., 1,2, or 3) halogens_1-3An alkoxy group. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. Haloalkyl radicals such as-OCH₂F、-OCHF₂、-OCF₃、-OCCl₃、-OC₂F₅、-OC₂Cl₅、-OCH₂CF₃、-OCH₂Cl or-OCH₂CH₂CF₃And the like.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system, and in each case may share two adjacent atoms with one another with a cycloalkyl group to form a cyclic group, the point of attachment may be on the aryl group or on the cycloalkyl group. For example,

for example, as used herein, the terms "6-14 membered aryl" and "C₆-C₁₄Aryl "is used interchangeably and means an aromatic radical containing from 6 to 14 carbon atoms, for example C₆-C₁₂Aryl or C₆-C₁₀Aryl, such as phenyl or naphthyl. Aryl is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO)₂、C₁-C₆Alkyl, etc.).

As used herein, the term "hydroxyalkyl" means that a hydrogen atom of an alkyl group is substituted with one or more hydroxyl groups, e.g., C₁-C₆Hydroxyalkyl or C₁-C₃A hydroxyalkyl group. Example bag thereofIncluding but not limited to hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyhexyl, and the like.

As used herein, the term "arylheterocyclo" refers to a cyclic group formed by an aryl group and a heterocyclyl group that share two adjacent carbon atoms with each other with the point of attachment being on the aryl or heterocyclyl group, wherein the aryl or heterocyclyl group is as defined herein. For example, as used herein, the term "9-12 membered arylheterocyclo" means a group of arylheterocyclo containing 9-12 ring atoms, particularly a phenyl-5-8 membered heterocyclyl, particularly a phenyl-5-6 membered heterocyclyl (9-10 membered benzoheterocyclyl), examples of which include, but are not limited to: indazolyl group,

As used herein, the term "heteroaryl" refers to a monocyclic heteroaryl group or a bicyclic or polycyclic ring system containing at least one heteroaromatic ring (a heteroaromatic ring refers to an aromatic ring system containing at least one heteroatom), having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5, 6, 7, 8, 9 or 10 ring atoms, and which contains at least one heteroatom (e.g. 1,2 or 3) which may be the same or different (e.g. oxygen, nitrogen or sulfur), and which may in each case share two adjacent atoms with each other with the aryl, heterocyclyl or cycloalkyl group to form a fused ring group, the point of attachment of which is on the heteroaromatic ring or other ring. For example, as used herein, the term "5-10 membered heteroaryl" means a heteroaryl group containing 5 to 10 ring atoms, including 5-6 membered heteroaryl, examples thereof include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and fused ring derivatives thereof, fused ring derivatives include, but are not limited to, heteroaryloaryl, heteroaryloaterocyclyl, or heteroaryloaycloalkyl, in particular 5-6 membered heteroaryland 5-6 membered heteroaryl, 5-6 membered heteroarylacenyl, 5-6 membered heteroaryland 5-7 membered heterocyclyl or 5-6 membered heteroarylacen C.₄-C₆Cycloalkyl group (C)In particular 5-6 membered heteroarylocyclobutyl, 5-6 membered heteroarylocyclopentyl, 5-6 membered heteroarylocyclocyclohexyl), examples of which include, but are not limited to, indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, indolyl, dihydrobenzoxazolyl, indolyl, and the like,

And the like.

As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic non-aromatic group having 2, 3, 4,5, 6, 7, 8, 9 carbon atoms in the ring and one or more (e.g., 1,2, 3, or 4) selected from C (═ O), O, S, S (═ O), S (═ O)₂N and NR (R represents a hydrogen atom or a substituent such as, but not limited to, an alkyl group or a cycloalkyl group). As used herein, the term "3-14 membered heterocyclyl" means a heterocyclyl group containing 3-14 ring atoms, including 3-10, 4-8, 4-7, 4-6, or 5-6 membered heterocyclyl groups, examples of which include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl, trithianyl (trithianyl), and the like; and fused ring derivatives thereof including, but not limited to, heterocyclo-heterocyclyl, heterocyclo-cycloalkyl, particularly 3-7 membered heterocyclo-3-7 membered heterocyclyl, 3-7 membered heterocyclo-cycloalkyl, 3-7 membered heterocyclo-C₄-C₆Cycloalkyl groups, examples of which include, but are not limited to, pyrrolidinyl-cyclopropyl, cyclopenta-cyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, piperidinyl-morpholinyl; and bridge or spiro derivatives such as, but not limited to:

and the like.

As used herein, the term "fused ring" refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.

The term "substituted" means that one or more (e.g., 1,2, 3, or 4) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency at the present time is not exceeded and the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally substituted with … …," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be optionally replaced individually and/or together with an independently selected optional substituent. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen present) may each be optionally replaced with an independently selected optional substituent.

If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4,5 or 10, under reasonable conditions.

Unless indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

The invention also includes all pharmaceutically acceptable isotopic compounds, which are identical to those of the present invention, except that one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominant in natureAnd (4) replacing. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. hydrogen)²H、³H) (ii) a Isotopes of carbon (e.g. of¹¹C、¹³C and¹⁴C) (ii) a Isotopes of chlorine (e.g. of chlorine)³⁶Cl); isotopes of fluorine (e.g. of fluorine)¹⁸F) (ii) a Isotopes of iodine (e.g. of iodine)¹²³I and¹²⁵I) (ii) a Isotopes of nitrogen (e.g. of¹³N and¹⁵n); isotopes of oxygen (e.g. of¹⁵O、¹⁷O and¹⁸o); isotopes of phosphorus (e.g. of phosphorus)³²P); and isotopes of sulfur (e.g. of³⁵S)。

The term "stereoisomer" denotes an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1,2, 3, or 4) asymmetric centers, they can result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as a mixture of two or more different structural forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, a nitroso-oxime may exist in solution in equilibrium with the following tautomeric forms:

it is understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerization and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio. It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, solvates, metabolites or prodrugs thereof, which upon administration to a patient in need thereof are capable of providing, directly or indirectly, a compound of the present invention or a metabolite or residue thereof. Thus, when reference is made herein to "a compound of the invention," it is also intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. For a review of suitable Salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

By "pharmaceutically acceptable carrier" in the context of the present invention is meant a diluent, adjuvant, excipient, or vehicle that is administered together with a therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that may be employed in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also optionally contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's pharmaceutical sciences (1990).

The compositions of the present invention may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

For these routes of administration, the compositions of the present invention may be administered in suitable dosage forms.

Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups.

The term "effective amount" as used herein refers to an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent.

The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose is from about 0.0001 to about 50mg per kg body weight per day, e.g., from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 3500 mg/day, e.g., about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

The compound of the invention may be present in the pharmaceutical composition in an amount or amount of about 0.01mg to about 1000 mg.

As used herein, unless otherwise specified, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing the progression of, a disorder or condition to which the term applies, or one or more symptoms of such disorder or condition.

As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

The compounds of the invention may be present in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such substances may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by the process of contacting the compounds of the present invention with a mammal for a time sufficient to produce a metabolite thereof.

The present invention further includes within its scope prodrugs of the compounds of the present invention which are certain derivatives of the compounds of the present invention which may themselves have little or no pharmacological activity which, when administered into or onto the body, may be converted to the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", volume 14, ACS Symposium Series (T.Higuchi and V.Stella) and "Bioreversible Carriers in Drug Design," PergamonPress,1987(E.B.Roche editions, American Pharmaceutical Association). Prodrugs of the invention may be prepared, for example, by substituting certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of produgs", described in h. bundgaard (Elsevier, 1985)) for appropriate functional groups present in compounds of the invention.

The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, as described in protective groups in Organic Chemistry, ed.j.f.w.mcomie, Plenum Press, 1973; and T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

As used herein, "room temperature" means 20-30 ℃.

In this application, when chemical names and structural formulae are inconsistent, the structural formulae should be taken as a control unless the context suggests that the chemical name and not the structural formula is correct.

Advantageous effects of the invention

The compound has high inhibitory activity on TTK in cells, and has excellent properties such as good pharmacokinetic property and good safety.

Detailed Description

Examples

The invention is further described below in connection with examples, which are not intended to limit the scope of the invention. Further, specific experimental methods not mentioned in the following examples were carried out according to the usual experimental methods.

The structure of the compound of the invention is determined by nuclear magnetic resonance¹HNMR) and/or Mass Spectrometry (MS) identification.

¹HNMR chemical shifts () are recorded in parts per million (ppm).¹HNMR was determined by JEOL Eclipse 400 NMR spectrometer using deuterated methanol (CD) as solvent₃OD), deuterated chloroform (CDCl)₃) Or hexadeuterated dimethyl sulfoxide (DMSO-d6) with the internal standard Tetramethylsilane (TMS). In nuclear magnetic resonance data, each symbol has the following meaning: s: singlet, d: doublet, t: triplet, q: quartet, dd: doublet, qd: quartet, ddd: double doublet, ddt: double triplet, dddd: double doublet, m: multiplet, br: broad (broad), J: coupling constant, Hz: hertz.

MS was determined using an Agilent 6120B mass spectrometer.

The reaction was monitored by Thin Layer Chromatography (TLC) or LC-MS.

Thin Layer Chromatography (TLC) silica gel plates aluminum plates from Merck were used.

LC-MS instrument: agilent 6125B.

The compound can be separated and purified by a silica gel thick preparation plate for chromatography, silica gel column chromatography, preparative high performance liquid chromatography (Prep-HPLC) and Flash column chromatography (Flash column chromatography).

The chromatography silica gel thick preparation plate adopts a cigarette platform yellow sea HSGF254 type preparation plate.

Column chromatography generally uses Qingdao ocean silica gel of 200-300 meshes as a carrier.

Preparative high performance liquid chromatography (Prep-HPLC) using Agilent 1260 chromatography.

Flash column chromatography used an Agela medium pressure rapid purification preparation system (MP-200).

The microwave reaction used a BiotageInitiator + (400W, RT-300 ℃ C.) microwave reactor.

In the examples, the reaction temperature is, unless otherwise specified, room temperature (20 ℃ C. to 30 ℃ C.).

The reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Texas Chemical, and the like.

The abbreviations in the present invention have the following meanings:

example 1

N-cyclopropyl-4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 1)

The method comprises the following steps: 5-bromo-2-chloro-N-neopentylpyrimidin-4-amine (Compound 1-2)

Compound 1-1(2.28g, 10mmol), neopentylamine (1.03g, 12mmol) and DIPEA (2.64g, 20mmol) were added to acetonitrile (50mL) and reacted at 20 ℃ for 2 hours. Evaporating to dryness, adding water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and concentrating to obtain crude compound 1-2(2.63 g).

ESI-MS(m/z):278.2[M+H]⁺.

Step two: 4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) -N-cyclopropylbenzamide (compound 1-3)

Compound 1-2(1g, 3.59mmol), N-cyclopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (1.24g, 4.31mmol), bis (triphenylphosphine) palladium dichloride (257.1mg, 0.36mmol), Na₂CO₃(776.5mg, 7.18mmol) was added to dioxane (20mL) and reacted at 100 ℃ for 2 hours under nitrogen. Cooled to room temperature, evaporated to dryness, water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the concentrated residue was subjected to silica gel column chromatography (DCM/MeOH ═ 20/1) to give title compound 1-3(1.3 g).

ESI-MS(m/z):359.2[M+H]⁺.

Step three: n-cyclopropyl-4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 1)

The compound 1-3(0.1g, 0.26mmol), N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) formamide (82.4mg, 0.32mmol), Cs₂CO₃(176mg, 0.53mmol) was dissolved in DMSO (2mL) and reacted at 100 ℃ for 12 hours. After cooling to room temperature, water was added, extraction was carried out with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue after concentration was separated by Prep-HPLC to give title compound 1(31 mg).

ESI-MS(m/z):541.2[M+H]⁺.

1H NMR(400MHz,DMSO)8.66(d,J＝8.4Hz,1H),8.53(s,1H),8.48(d,J＝4.2Hz,1H),7.95(s,1H),7.93(s,1H),7.84(s,1H),7.68(s,1H),7.52(s,1H),7.50(s,1H),7.35(d,J＝1.6Hz,1H),7.31(dd,J＝8.4,1.6Hz,1H),6.47(t,J＝6.3Hz,1H),4.23(q,J＝6.9Hz,2H),3.77(s,3H),3.31(s,2H),2.92–2.84(m,1H),1.44(t,J＝6.9Hz,3H),0.93(s,10H),0.74–0.68(m,2H),0.61–0.56(m,2H).

Example 2

N-cyclopropyl-4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) -2-methylbenzamide (compound 2)

The method comprises the following steps: 4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) -N-cyclopropyl-2-methylbenzamide (compound 2-1)

Compound 1-2(1g, 3.59mmol), N-cyclopropyl-2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (1.30g, 4.31mmol), bis (triphenylphosphine) palladium dichloride (257.1mg, 0.36mmol), Na₂CO₃(776.5mg, 7.18mmol) was added to dioxane (20mL) and reacted at 100 ℃ for 2 hours under nitrogen. Cooled to room temperature, evaporated to dryness, water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the concentrated residue was subjected to silica gel column chromatography (DCM/MeOH ═ 20/1) to give title compound 2-1(1.2 g).

ESI-MS(m/z):373.2[M+H]⁺.

Step two: n-cyclopropyl-4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) -2-methylbenzamide (compound 2)

The compound 2-1(0.1g, 0.26mmol), N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) formamide (82.4mg, 0.32mmol), Cs₂CO₃(176mg, 0.53mmol) was added to DMSO (2mL) and reacted at 100 ℃ for 12 hours. After cooling to room temperature, water was added, extraction was carried out with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue after concentration was separated by Prep-HPLC to give title compound 2(11 mg).

ESI-MS(m/z):555.2[M+H]⁺.

¹H NMR(500MHz,DMSO)8.66(d,J＝8.4Hz,1H),8.54(s,1H),8.31(d,J＝4.2Hz,1H),7.79(s,1H),7.67(s,1H),7.41(d,J＝7.7Hz,1H),7.35(s,1H),7.31(d,J＝8.0Hz,2H),7.27(d,J＝7.8Hz,1H),6.37(t,J＝6.0Hz,1H),4.24(q,J＝6.9Hz,2H),3.77(s,3H),3.32(s,2H),2.88–2.82(m,1H),2.39(s,3H),1.45(t,J＝6.9Hz,3H),0.94(s,9H),0.70(m,2H),0.55(m,2H).

Example 3

N-cyclopropyl-2-fluoro-4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 3)

The method comprises the following steps: 2-fluoro-4- (2-chloro-4 (neopentylamino) pyrimidin-5-yl) -N-cyclopropylbenzamide (compound 3-1)

Compound 1-2(1g, 3.59mmol), N-cyclopropyl-2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (1.62g, 4.31mmol), bis (triphenylphosphine) palladium dichloride (257.1mg, 0.36mmol), Na₂CO₃(776.5mg, 7.18mmol) was added to dioxane (20mL) and reacted at 100 ℃ for 2 hours under nitrogen. Cooled to room temperature, evaporated to dryness, water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the concentrated residue was subjected to silica gel column chromatography (DCM/MeOH ═ 20/1) to give title compound 3-1(1.4 g).

ESI-MS(m/z):377.2[M+H]⁺.

Step two: n-cyclopropyl-2-fluoro-4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 3)

The compound 3-1(0.1g, 0.26mmol), N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) formamide (82.4mg, 0.32mmol), Cs₂CO₃(176mg, 0.53mmol) was added to DMSO (2mL) and reacted at 100 ℃ for 12 hours. After cooling to room temperature, water was added, extraction was carried out with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue after concentration was separated by Prep-HPLC to give the title compound 3(27 mg).

ESI-MS(m/z):559.2[M+H]⁺.

¹H NMR(400MHz,CDCl₃)11.96(s,2H),8.75(d,J＝8.4Hz,1H),8.23(t,J＝8.1Hz,2H),7.76(s,1H),7.37–7.30(m,1H),7.24(d,J＝1.5Hz,1H),7.17(dd,J＝15.8,11.2Hz,1H),7.08(dd,J＝12.2,1.4Hz,2H),6.82(d,J＝9.9Hz,2H),5.18(t,J＝5.8Hz,2H),4.22(q,J＝7.0Hz,1H),3.80(s,1H),3.37(d,J＝6.0Hz,3H),3.01–2.92(m,2H),1.52(t,J＝7.0Hz,2H),0.96(s,4H),0.65(q,J＝6.7Hz,4H).

Example 4

(4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) phenyl) methanol (Compound 4)

The method comprises the following steps: 4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) phenyl) methanol (compound 4-1)

Compounds (1-2 (1g, 3.59mmol), (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanol (1.31g, 4.31mmol), bis (triphenylphosphine) palladium dichloride (257.1mg, 0.36mmol), Na₂CO₃(776.5mg, 7.18mmol) was added to dioxane (20mL) and reacted at 100 ℃ for 2 hours under nitrogen. Cooled to room temperature, evaporated to dryness, water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the concentrated residue was subjected to silica gel column chromatography (DCM/MeOH ═ 20/1) to give title compound 4-1(1.2 g).

ESI-MS(m/z):306.2[M+H]⁺.

Step two: (4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) phenyl) methanol (Compound 4)

The compound 4-1(80mg, 0.26mmol), N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) carboxamide (82.4mg, 0.32mmol), Cs₂CO₃(176mg, 0.53mmol) was added to DMSO (2mL) and reacted at 100 ℃ for 12 hours. After cooling to room temperature, water was added, extraction was carried out with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue after concentration was separated by Prep-HPLC to give the title compound 4(21 mg).

ESI-MS(m/z):488.2[M+H]⁺.

¹H NMR(400MHz,DMSO)8.68(d,J＝8.2Hz,1H),8.54(s,1H),7.79(s,1H),7.65(s,1H),7.53–7.25(m,7H),6.26(s,1H),5.29(d,J＝5.4Hz,1H),4.56(d,J＝5.0Hz,2H),4.23(d,J＝6.7Hz,2H),3.77(s,3H),1.45(t,J＝6.6Hz,3H),0.92(s,9H).

Example 5

4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) benzoic acid (Compound 5)

The method comprises the following steps: 4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) benzoic acid methyl ester (Compound 5-1)

The compound 1-2(5g, 17.95mmol), methyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (3.23g, 17.95mmol), bis (triphenylphosphine) palladium dichloride (1.26g, 1.79mmol), Na₂CO₃(3.80g, 35.90mmol) was added to dioxane (50mL) and water (10mL) and reacted at 110 ℃ for 16 hours under nitrogen. After cooling to room temperature, evaporation to dryness, addition of water, extraction with ethyl acetate, drying of the organic phase over anhydrous sodium sulfate and concentration of the residue by silica gel column chromatography (PE/EA ═ 1/1) gave title compound 5-1(4.0 g).

ESI-MS(m/z):334.1[M+H]⁺.

Step two: 4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) benzoic acid (compound 5-2)

Compound 5-1(3.7g, 11.08mmol) was added to MeOH (30mL), water (10mL), NaOH (886.73mg, 22.17mmol) was added, and the reaction was stirred at room temperature for 4 hours. MeOH was removed under reduced pressure, the pH was adjusted to about 4 with 10% hydrochloric acid solution, the precipitate was filtered off with suction, and the filter cake was washed with water and dried to give title compound 5-2(3.0 g).

ESI-MS(m/z):318.1[M-H]^-

Step three: 4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) benzoic acid (Compound 5)

Compound 5-2(100mg, 321.72. mu. mol) and N- (2-ethoxy-4- (4-methyl-1, 2, 4-triazol-3-yl) phenyl) carboxamide (180.97mg, 734.87. mu. mol) were added to DMSO (10mL) and cesium carbonate (305.66mg, 938.13. mu. mol) was added. The temperature is increased to 110 ℃, and the reaction is stirred for 16 h. The reaction mixture was washed with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated residue was purified by Prep-HPLC to give title compound 5(12 mg).

ESI-MS(m/z):502.1[M+H]⁺.

¹H NMR(400MHz,DMSO)8.69～8.67(d,J＝8.4Hz,1H),8.53(s,1H),7.96～7.94(d,J＝7.9Hz,2H),7.81(s,1H),7.64(s,1H),7.36～7.28(m,4H),6.24～6.23(m,1H),4.26～4.21(q,2H),3.77(s,3H),3.31(s,2H),1.46～1.43(t,3H),0.92(s,9H).

Example 6

N- (4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) phenyl) acetamide (Compound 6)

The method comprises the following steps: n- (4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) phenyl) acetamide (Compound 6-1)

Compound 1-2(1g, 3.59mmol), 4-acetamidophenylboronic acid (770mg, 4.31mmol), bis (triphenylphosphine) palladium dichloride (257.1mg, 0.36mmol), Na₂CO₃(776.5mg, 7.18mmol) was added to dioxane (20mL) and reacted at 100 ℃ for 2 hours under nitrogen. Cooled to room temperature, evaporated to dryness, water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the concentrated residue was subjected to silica gel column chromatography (DCM/MeOH ═ 20/1) to give title compound 6-1(1 g).

ESI-MS(m/z):333.2[M+H]⁺.

Step two: n- (4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) phenyl) acetamide (Compound 6)

The compound 6-1(0.1g, 0.30mmol), N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) formamide (82.4mg, 0.32mmol), Cs₂CO₃(176mg, 0.53mmol) was added to DMSO (2mL) and reacted at 100 ℃ for 12 hours. Cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the concentrated residue was isolated by Prep-HPLC to afford title compound 6(5 mg).

ESI-MS(m/z):515.3[M+H]⁺.

¹H NMR(400MHz,DMSO)10.06(s,1H),8.67(d,J＝8.3Hz,1H),8.53(s,1H),7.77(s,1H),7.69(d,J＝7.8Hz,1H),7.62(s,2H),7.56(s,2H),7.34(s,2H),6.27(s,1H),4.23(d,J＝6.3Hz,2H),3.76(s,3H),2.07(s,3H),1.44(t,J＝5.3Hz,3H),0.91(s,9H).

Example 7

N-cyclobutyl-4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 7)

The method comprises the following steps: n-cyclobutyl-4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 7-1)

Compound 5-2(300mg, 938.13. mu. mol), cyclobutylamine (100.08mg, 1.41mmol) were added to DCM (20mL), EDCI (269.76mg, 1.41mmol) and DMAP (343.83mg, 2.81mmol) were added sequentially and stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (PE/EA ═ 1:1) to give compound 7-1(200 mg).

ESI-MS(m/z):373.1[M+H]⁺.

Step two: n-cyclobutyl-4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 7)

Compound 7-1(250mg, 670.44. mu. mol) and N- (2-ethoxy-4- (4-methyl-1, 2, 4-triazol-3-yl) phenyl) carboxamide (388.00mg,1.58mmol) were added to DMSO (10mL) and cesium carbonate (655.32mg,2.01mmol) was added. The temperature is increased to 110 ℃, and the reaction is stirred for 16 h. The reaction mixture was washed with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated residue was purified by Prep-HPLC to give the objective compound 7(55 mg).

ESI-MS(m/z):555.2[M+H]⁺.

¹H NMR(400MHz,DMSO)8.68～8.66(m,2H),8.54(s,1H),7.99～7.97(d,J＝8.2Hz,2H),7.85(s,1H),7.69(s,1H),7.53～7.51(d,J＝8.2Hz,2H),7.35～7.31(t,2H),6.51～6.47(t,1H),4.48～4.42(m,,1H),4.26～4.21(q,2H),3.77(s,3H),3.32(s,2H),2.25～2.23(m,2H),2.14～2.04(m,2H),1.70～1.64(m,2H),1.47～1.43(t,3H),0.94(s,9H).

Example 8

4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) -N-methylbenzamide (Compound 8)

The method comprises the following steps: 4- (2-chloro-4 (neopentylamino) pyrimidin-5-yl) -N-methylbenzamide (compound 8-1)

The compound 1-2(500mg, 1.79mmol), (4- (methylcarbamoyl) phenyl) boronic acid (321.24mg, 1.79mmol), bis (triphenylphosphine) palladium dichloride (125.98mg, 0.18mmol), Na₂CO₃(380.47mg, 3.59mmol) was added to dioxane (20mL) and water (5mL) and reacted at 120 ℃ for 16h under nitrogen. The mixture was cooled to room temperature, evaporated to dryness, and the residue after concentration under reduced pressure was purified by silica gel column chromatography (PE/EA ═ 1:1) to give the title compound 8-1(0.32 g).

ESI-MS(m/z):333.2[M+H]⁺.

Step two: 4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) -N-methylbenzamide (Compound 8)

Compound 8-1(110mg, 330.50. mu. mol) and N- (2-ethoxy-4- (4-methyl-1, 2, 4-triazol-3-yl) phenyl) carboxamide (191.27mg, 776.68. mu. mol) were added to DMSO (10mL) and cesium carbonate (323.05mg, 991.51. mu. mol) was added. The temperature is increased to 110 ℃, and the reaction is stirred for 16 h. The reaction mixture was washed with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated residue was purified by Prep-HPLC to give 60mg of the objective product.

ESI-MS(m/z):515.15[M+H]+.

1H NMR(400MHz,DMSO-d₆):8.67～8.65(d,J＝8.4Hz,1H),8.53(s,1H),8.48～8.47(d,J＝4.5Hz,1H),7.96～7.94(d,J＝8.3Hz,2H),7.85(s,1H),7.68(s,1H),7.53～7.51(d,J＝8.3Hz,2H),7.35～7.30(m,2H),6.50～6.47(t,1H),4.26～4.21(q,2H),3.77(s,3H),2.82～2.81(d,J＝4.5Hz,3H),1.46～1.43(t,3H),0.93(s,9H).

Example 9

4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 9)

The method comprises the following steps: 4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 9-1)

Compound 5-2(700mg, 2.19mmol), ammonium chloride (234.18mg, 4.38mmol) were added to DMF (20mL), EDCI (839.25mg, 4.38mmol) and HOBt (591.55mg, 4.38mmol), DIPEA (848.72mg, 6.57mmol) were added sequentially, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, and the precipitate was filtered and dried to give the title compound 9-1(580 mg). ESI-MS (M/z) 319.1[ M + H]⁺.

Step two: 4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 9)

Compound 9-1(200mg, 627.35. mu. mol) and N- (2-ethoxy-4- (4-methyl-1, 2, 4-triazol-3-yl) phenyl) carboxamide (363.06mg,1.47mmol) were added to DMSO (10mL) and cesium carbonate (613.21mg,1.88mmol) was added. The temperature is increased to 110 ℃, and the reaction is stirred for 16 h. The reaction mixture was washed with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated residue was purified by Prep-HPLC to give the title compound 9(25 mg).

ESI-MS(m/z):501.2[M+H]⁺.

¹H NMR(400MHz,DMSO)8.67～8.65(d,J＝8.4Hz,1H),8.54(s,1H),8.03～7.98(m,3H),7.84(s,1H),7.68(s,1H),7.52～7.50(d,J＝8.3Hz,2H),7.40～7.30(m,3H),6.55～6.52(t,1H),4.26～4.21(q,2H),3.77(s,3H),3.31(s,2H),1.46～1.43(t,3H),0.93(s,9H).

Example 10

N-ethyl-4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 10)

The method comprises the following steps: N-Ethyl-4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 10-1)

Compound 5-2(200mg, 625.42. mu. mol), ethylamine hydrochloride (42.29mg, 938.13. mu. mol) was added to DCM (20mL), EDCI (179.84mg, 938.13. mu. mol) and DMAP (229.22mg, 1.88mmol) were added successively, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography (PE/EA ═ 1:1) to give the objective compound 10-1(160 mg).

ESI-MS(m/z):347.1[M+H]⁺.

Step two: n-ethyl-4- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 10)

Compound 10-1(200mg, 576.61. mu. mol) and N- (2-ethoxy-4- (4-methyl-1, 2, 4-triazol-3-yl) phenyl) carboxamide (333.70mg,1.36mmol) were added to DMSO (10mL) and cesium carbonate (563.61mg,1.73mmol) was added. The temperature is increased to 110 ℃, and the reaction is stirred for 16 h. The reaction mixture was washed with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated residue was purified by Prep-HPLC to give the objective compound 10(20 mg).

ESI-MS(m/z):529.3[M+H]⁺.

¹H NMR(400MHz,DMSO)8.67～8.65(d,J＝8.4Hz,1H),8.54～8.51(m,2H),7.97～7.95(d,J＝8.3Hz,2H),7.85(s,1H),7.69(s,1H),7.53～7.51(d,J＝8.3Hz,2H),7.35～7.30(m,2H),6.52～6.49(t,1H),4.26～4.21(q,2H),3.77(s,3H),3.33～3.30(d,4H),1.46～1.43(t,3H),1.16～1.12(t,3H),0.93(s,9H).

Example 11

N²- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -5- (furan-2-yl) -N⁴-neopentyl pyrimidine-2, 4-diamine (Compound 11)

The method comprises the following steps: 2-chloro-5- (furan-2-yl) -N-neopentyl pyrimidin-4-amine (compound 11-1)

Compound 1-2(1g, 3.59mmol), furan-2-boronic acid (482.7mg, 4.31mmol), bis (triphenylphosphine) palladium dichloride (257.1mg, 0.36mmol), Na₂CO₃(776.5mg, 7.18mmol) was added to dioxane (20mL) and reacted at 100 ℃ for 2 hours under nitrogen. Cooled to room temperature, evaporated to dryness, water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (DCM/MeOH ═ 20/1) -to give the title compound 11-1(0.8 g).

ESI-MS(m/z):266.2[M+H]⁺.

Step two: n is a radical of²- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -5- (furan-2-yl) -N⁴-neopentyl pyrimidine-2, 4-diamine (Compound 11)

The compound 11-1(70mg, 0.26mmol), N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) carboxamide (82.4mg, 0.32mmol), Cs₂CO₃(176mg, 0.53mmol) was added to DMSO (2mL) and reacted at 100 ℃ for 12 hours. After cooling to room temperature, water was added, extraction was carried out with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue after concentration was isolated by Prep-HPLC to give title compound 11(22 mg).

ESI-MS(m/z):448.2[M+H]⁺.

¹H NMR(400MHz,CDCl₃)8.76(d,J＝8.4Hz,1H),8.19(d,J＝9.8Hz,2H),7.75(s,1H),7.52(d,J＝1.2Hz,1H),7.35–7.24(m,2H),7.19(dd,J＝8.4,1.6Hz,1H),6.57–6.44(m,2H),6.32(t,J＝5.6Hz,1H),4.20(q,J＝6.9Hz,2H),3.80(s,3H),3.46(d,J＝5.9Hz,2H),1.51(t,J＝7.0Hz,3H),1.03(s,9H).

The separation method comprises the following steps:

the compounds 1-8 in the invention are separated and purified by using active 1260 type HPLC, the column temperature is 25 ℃, and other separation conditions are shown in the following table:

biological evaluation

The following test examples further illustrate the present invention, but these test examples are not meant to limit the scope of the present invention.

Test example 1: TTK kinase in vitro enzymatic activity inhibition assay

The test system comprises:

kinase enzymes: recombinant full-length human TTK, Active (Signalchem, T20-10G-10)

Substrate: native protein, MBP (Signalchem, M42-51N)

The kit comprises: ADP-Glo Kinase Assay (Promega, V9101)

Test parameters are as follows:

TTK concentration: 6nM

MBP concentration: 0.7. mu.M

ATP concentration: 20 μ M

Reaction buffer: 1 Xenzymatic buffer (Cisbio, 62 EZBDFC), 10mM MgCl₂，2mM DTTddH₂O

Reaction time: 37 ℃ for 120 minutes

End time: 25 ℃ for 120 minutes

Detection time: at 25 ℃ for 60 minutes

An enzyme-labeling instrument: BMG PHERAStator luminescences

The test steps are as follows:

adding a mixture of a test group (containing a compound to be tested and TTK enzyme), a solvent group (containing no compound to be tested and TTK enzyme), and a blank group (containing no compound to be tested and no TTK enzyme) with substrates MBP and ATP into a reaction buffer solution, incubating for 120 minutes at 37 ℃, taking 5 mu L of the reaction mixture in the previous step, uniformly mixing with 5 mu L of ADP-Glo reagent, incubating for 120 minutes at 25 ℃, and terminating the enzymatic reaction. Then adding Detection Buffer solution (Detection Buffer) in the kit, incubating for 60 minutes at 25 ℃, putting the reaction plate into an enzyme-linked immunosorbent assay, and reading the chemiluminescence value of each hole in the plate by adopting an end-point method.

Data processing:

using solvent group (containing TTK enzyme and no test compound) as negative control, and performing reverse reactionRelative inhibitory activity of each concentration group was calculated using buffer group (containing no TTK kinase and test compound) as blank control, and the inhibition rate was 100% - (chemiluminescence value of test group-chemiluminescence value of blank group)/(chemiluminescence value of vehicle group-chemiluminescence value of blank group) × 100%. Half maximal Inhibitory Concentration (IC) of the compound was calculated according to a four parameter model fitting curve₅₀)。

And (3) test results:

the inhibition of TTK activity by the compounds was determined as described above and the results are shown in table 1.

TABLE 1 results of TTK enzyme activity inhibition test

Compound numbering	IC₅₀(nM)
		1	2.9
2	244.0
		3	397.0
6	375.0
		8	56.5
9	320.3
		10	146.8
11	218.4

And (4) conclusion: as can be seen from table 1, the compounds of the present invention have better inhibitory activity against TTK enzyme in vitro tests.

Claims

1. A compound of formula (I) or a stereoisomer, tautomer, stable isotope derivative, metabolite or prodrug thereof, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof,

wherein:

R¹selected from the group consisting of H, -CN, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, 5-6 membered heteroarylo 5-7 membered heterocyclyl, -C (O) N (R)^f)R^eand-S (O)₂N(R^f)R^e(ii) a The 5-6 membered heteroaryl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl may be optionally substituted with one or more of the following groups: halogen, cyano, nitro, OH, halogeno C_1-3Alkyl, halo C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl radical, C_3-6Cycloalkyloxy, 4-7 membered heterocyclyl, -NR^aR^b、-C(O)R^a、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^aor-N (R)^b)SO₂R^aSaid halo C_1-3Alkyl, halo C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl radicals、C_3-6Cycloalkyloxy, 4-7 membered heterocyclyl may be optionally substituted with one or more of the following: -OH, halogen, -CN, C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-3Haloalkyl, C_1-3A haloalkoxy group;

R^cAnd R^dEach independently selected from H and C_1-4An alkyl group;

p is selected from 0, 1 and 2;

R³and R⁴Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl, -C_1-2alkyl-C_3-8Cycloalkyl, phenyl, 4-7 membered heterocyclyl, -C_1-2Alkyl- (4-7 membered heterocyclyl) and 5-6 membered heteroaryl, said C_1-6Alkyl radical, C_3-8Cycloalkyl, -C_1-2alkyl-C_3-8Cycloalkyl, phenyl, 4-7 membered heterocyclyl, -C_1-2Alkyl- (4-7 membered heterocyclyl), 5-6 membered heteroaryl may be optionally substituted with one or more of the following: hydroxy, halogen, cyano, C_1-3Haloalkyl, C_1-3Haloalkoxy, C_1-4Alkyl radical, C_1-4Alkoxy, -NR^aR^b、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^aor-N (R)^b)SO₂R^a4-7 membered heterocyclyl; alternatively, the first and second electrodes may be,

X is selected from N and CH;

y is selected from N and CH;

R⁵selected from H, cyano, C_1-6Alkyl radical, C_3-8Cycloalkyl, -O-C_1-6Alkyl, -O-C_1-6Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, -NR^gR^h、-C(＝O)OR^h、-C(＝O)NR^gR^h、-NR^gC(＝O)NR^gR^hand-NR^gC(＝O)R^hSaid C is_1-6Alkyl radical, C_3-8Cycloalkyl, -O-C_1-6Alkyl, -O-C_1-6Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-10 membered heterocyclyl, -NR^aR^b、-C(O)R^a、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^aor-N (R)^b)SO₂R^a(ii) a The 4-10 membered heterocyclyl may be optionally substituted with one or more of the following: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, C_3-8A cycloalkyl group;

wherein R is^gAnd R^hEach independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, said C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂、-O-(C_1-3Alkyl group), C_3-6Cycloalkyl, 4-10 membered heterocyclyl; and R is^gAnd R^hMay be taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring optionallySubstituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂、-O-(C_1-3Alkyl group), C_3-6Cycloalkyl, 4-10 membered heterocyclyl;

R⁶each independently selected from H, halogen, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-6Alkyl radical, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, -NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-6Alkyl groups may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-3An alkyl group;

n is selected from 0, 1,2 and 3; when more than one R is present^a、R^b、R^c、R^d、R^eOr R^fAnd when occurring at the same time, may be the same or different.

2. A compound of formula (I) according to claim 1 or a stereoisomer, a tautomer, a stable isotopic derivative, a metabolite or a prodrug thereof, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof, wherein

Ring A is selected from 6-12 membered aryl, 9-12 membered benzoheterocyclyl and 5-14 membered heteroaryl; preferably, ring A is selected from 6-12 membered aryl and 5-14 membered heteroaryl; preferably, ring a is phenyl.

3. A compound of formula (I) according to claim 1 or 2 or a stereoisomer, a tautomer, a stable isotopic derivative, a metabolite or a prodrug thereof, or a pharmaceutically acceptable salt, a co-crystal, a polymorph or a solvate thereof, wherein

R¹Selected from the group consisting of H, -CN, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, 5-6 membered heteroarylo 5-7 membered heterocyclyl, -C (O) N (R)^f)R^eand-S (O)₂N(R^f)R^e(ii) a The 5-6 membered heteroaryl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl may be optionally substituted with one or more of the following groups: halogen, cyano, nitro, OH, halogeno C_1-3Alkyl, halo C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl, 4-7 membered heterocyclyl, -NR^aR^b、-C(O)R^a、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^aOr N (R)^b)SO₂R^aSaid C is_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl, 4-7 membered heterocyclyl may be optionally substituted with one or more of the following: -OH, halogen, -CN, C_1-3Alkoxy radical, C_1-4Alkyl radical, C_1-3Haloalkyl, C_1-3A haloalkoxy group;

R^cAnd R^dEach independently selected from H and C_1-4An alkyl group; p is selected from 0, 1 and 2.

4. A compound of formula (I) according to any one of claims 1 to 3, or a stereoisomer, tautomer, stable isotope derivative, metabolite or prodrug thereof, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof, wherein R is²Each independently selected from hydrogen, halogen, cyano, C_1-3Alkoxy radical, C_1-3Alkyl and C_1-3A haloalkoxy group; preferably, R²Each independently selected from chlorine, fluorine, bromine, iodine, cyano, C_1-3Alkoxy radical, C_1-3Alkyl and C_1-3A haloalkoxy group; preferably, R²Each independently selected from chlorine, fluorine, C_1-3Alkoxy and C_1-3An alkyl group; preferably, R²Selected from chlorine, fluorine, methoxy and ethoxyA group and a methyl group;

5. A compound of formula (I) according to any one of claims 1 to 4 or a stereoisomer, a tautomer, a stable isotope derivative, a metabolite, or a prodrug thereof, or a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate thereof, wherein

R³And R⁴Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl, -C_1-2alkyl-C_3-8Cycloalkyl, phenyl, 4-7 membered heterocyclyl, -C_1-2Alkyl- (4-7 membered heterocyclyl) and 5-6 membered heteroaryl, said C_1-6Alkyl radical, C_3-8Cycloalkyl, -C_1-2alkyl-C_3-8Cycloalkyl, phenyl, 4-7 membered heterocyclyl, -C_1-2Alkyl- (4-7 membered heterocyclyl), 5-6 membered heteroaryl may be optionally substituted with one or more of the following: hydroxy, fluoro, chloro, cyano, C_1-3Haloalkyl, C_1-3Haloalkoxy, C_1-4Alkyl radical, C_1-4Alkoxy, -NR^aR^b、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^a4-7 membered heterocyclyl or-N (R)^b)SO₂R^a(ii) a Alternatively, the first and second electrodes may be,

R³and R⁴Are linked to each other to form, together with the nitrogen atom to which they are attached, a 4-7 membered heterocyclic ring; the 4-7 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: halogen, hydroxy, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, 4-7 membered heterocyclyl, -NR^aR^b、-C(O)R^a、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^a)R^bor-N (R)^b)SO₂R^a。

6. A compound of formula (I) according to any one of claims 1-5 or a stereoisomer, tautomer, stable isotope derivative, metabolite or prodrug thereof, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof, wherein X is selected from N and CH, preferably X is N; y is selected from N and CH, preferably Y is N.

7. A compound of formula (I) according to any one of claims 1 to 6, or a stereoisomer, a tautomer, a stable isotope derivative, a metabolite, or a prodrug thereof, or a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate thereof,

ring B is selected from 6-12 membered aryl, 9-12 membered arylheterocyclo, and 5-14 membered heteroaryl; preferably, ring B is selected from phenyl and 5-6 membered heteroaryl; preferably, ring B is selected from phenyl and furanyl.

8. A compound of formula (I) according to any one of claims 1 to 7, or a stereoisomer, a tautomer, a stable isotope derivative, a metabolite, or a prodrug thereof, or a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate thereof,

R⁵selected from H, cyano, C_1-6Alkyl radical, C_3-8Cycloalkyl, -O-C_1-6Alkyl, -O-C_1-6Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, -NR^gR^h、-C(＝O)OR^h、-C(＝O)NR^gR^h、-NR^gC(＝O)NR^gR^hand-NR^gC(＝O)R^hSaid C is_1-6Alkyl radical, C_3-8Cycloalkyl, -O-C_1-6Alkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Haloalkyl, C_1-3A halogenated alkoxy group,4-10 membered heterocyclyl, -NR^aR^b、-C(O)R^a、-C(O)OR^a、-OC(O)R^a、-N(R^b)OR^a、-C(O)N(R^b)R^a、-N(R^b)C(O)R^a、-S(O)_pR^a、-SO₂N(R^b)R^aor-N (R)^b)SO₂R^a(ii) a The 4-10 membered heterocyclyl may be optionally substituted with one or more of the following: halogen, OH, cyano, nitro, C_1-4Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, C_3-8A cycloalkyl group;

wherein R is^gAnd R^hEach independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, said C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂、-O-(C_1-3Alkyl group), C_3-6Cycloalkyl, 4-10 membered heterocyclyl; and R is^gAnd R^hMay form, together with the nitrogen atom to which it is attached, a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring being optionally substituted by one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂、-O-(C_1-3Alkyl group), C_3-6Cycloalkyl, 4-10 membered heterocyclyl.

9. A compound of formula (I) according to any one of claims 1 to 8, or a stereoisomer, a tautomer, a stable isotope derivative, a metabolite, or a prodrug thereof, or a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate thereof,

R⁶each independently selected from H, halogen, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-6Alkyl radical, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, -NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-6Alkyl groups may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C_1-3Alkyl, -NH₂、-NH-C_1-3Alkyl, -N (C)_1-3Alkyl radical)₂and-O-C_1-3An alkyl group; n is selected from 1,2 and 3.

10. A compound of formula (I) according to any one of claims 1 to 9, or a stereoisomer, tautomer, stable isotope derivative, metabolite or prodrug thereof, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof, wherein the compound of formula (I) has the structure of formula II:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶A, B and n are as defined for formula (I).

11. A compound of formula II according to claim 10, or a stereoisomer, tautomer, stable isotopic derivative, metabolite or prodrug thereof, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof, wherein ring a is selected from 6-12 membered aryl (e.g. phenyl) and 5-14 membered heteroaryl, ring B is selected from phenyl and furanyl, and n is selected from 0 and 1.

12. A compound of formula (I) according to any one of claims 1 to 9, or a stereoisomer, tautomer, stable isotope derivative, metabolite or prodrug thereof, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof, wherein said compound of formula (I) has the structure of formula III:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶Ring A and n are as defined for formula (I), X¹、X²、X³And X⁴Are all CH; or X¹、X²、X³And X⁴One of them is N, and the others are CH.

13. A compound of formula (I) according to any one of claims 1 to 9, or a stereoisomer, tautomer, stable isotope derivative, metabolite or prodrug thereof, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof, wherein the compound of formula (I) has the structure of formula IV:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶As defined in formula (I), X⁵Is CH or N.

14. A compound of formula (I) according to any one of claims 1 to 9, or a stereoisomer, tautomer, stable isotope derivative, metabolite or prodrug thereof, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof, wherein said compound of formula (I) has the structure of formula V:

wherein R is¹、R²、R³、R⁴、R⁵As defined in formula (I).

15. The method of claim 14Or a stereoisomer, tautomer, stable isotope derivative, metabolite or prodrug thereof, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof, wherein R is¹Selected from:

hydrogen, hydrogen,

Preferably, -NR³R⁴Is selected from

And is

R⁵Selected from hydrogen, cyano, -CH₂OH、-COOH、CH₃CONH-、

R⁶Selected from H, halogen, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy, said C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl, C_1-3Haloalkoxy groups may be optionally substituted with one or more of the following groups: halogen, cyano, C_1-3An alkyl group.

16. A compound of formula V according to claim 15, or a stereoisomer, tautomer, stable isotopic derivative, metabolite or prodrug thereof, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof, wherein R is¹Is composed of

R²Is an ethoxy group; r³And R⁴Each independently selected from hydrogen and C_1-6Alkyl, preferably, -NR³R⁴Is composed of

R⁵Is selected from CH₃CONH-、

R⁶Selected from H, methyl and fluorine.

17. The compound according to any one of claims 1-16, selected from:

18. A pharmaceutical composition comprising a compound according to any one of claims 1-17, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, a co-crystal, a polymorph, or a solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, and one or more pharmaceutically acceptable carriers.

19. A method of making a pharmaceutical composition of the invention, the method comprising combining a compound according to any one of claims 1-17, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, with one or more pharmaceutically acceptable carriers.

20. A pharmaceutical formulation comprising a compound according to any one of claims 1-17, a stereoisomer, a tautomer, or a mixture thereof, a stable isotopic derivative, metabolite, or prodrug of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a pharmaceutical composition according to claim 18.

21. Use of a compound according to any one of claims 1-17, a stereoisomer, a tautomer, or a mixture thereof, a stable isotopic derivative, a metabolite, or a prodrug of said compound, a pharmaceutically acceptable salt, a co-crystal, a polymorph, or a solvate of said compound, a pharmaceutical composition according to claim 18, or a pharmaceutical formulation according to claim 20, in the manufacture of a medicament for the prevention or treatment of a disease associated with TTK activity;

preferably, said diseases associated with TTK activity include, but are not limited to, tumors including benign tumors and malignant tumors, in particular cancers such as melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, cervical cancer, thyroid cancer, metastases of secondary sites of primary solid tumors, chronic myelogenous leukemia, acute lymphocytic leukemia, papillary thyroid cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colon cancer and the like.

22. A process for the preparation of a compound of formula V,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶As claimed in any one of claims 14 to 16;

the method comprises the following steps:

the method comprises the following steps: reacting the compound V-1 with the compound V-2 to obtain a compound V-3;

step two: carrying out coupling reaction on the compound V-3 and the compound V-4 to obtain a compound V-5;

step three: the compound V-5 reacts with the compound V-6 to obtain a compound V.