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CN111808080B - Substituted pyridine or pyrimidine compound, preparation method and medical application thereof - Google Patents

Substituted pyridine or pyrimidine compound, preparation method and medical application thereof Download PDF

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CN111808080B
CN111808080B CN201910292859.7A CN201910292859A CN111808080B CN 111808080 B CN111808080 B CN 111808080B CN 201910292859 A CN201910292859 A CN 201910292859A CN 111808080 B CN111808080 B CN 111808080B
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compound
alkyl
group
pharmaceutically acceptable
alkoxy
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CN111808080A (en
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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
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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Abstract

The present invention relates to substituted pyridine or pyrimidine compounds, to a process for their preparation and to their use in medicine. In particular, the invention relates to a method wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Compounds of formula (I) as defined in X, 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 and medical application thereof
Technical Field
The present invention relates to substituted pyridine or pyrimidine compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
Background
Spindle assembly checkpoints (Spindle Assembly Checkpoint, SAC) are one of the major checkpoints of the cell cycle, SAC monitors the arrangement of chromosomes at the equatorial plate and the separation of the two poles towards the spindle, ensures the adhesion of kinetochore-microtubules and the integrity of mitosis, places all chromosomes on the equatorial plate and enters the late stage after bipolar targeting, ensures precise distribution of chromosomes 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 a spindle microtubule is erroneously connected to a chromosome or spindle assembly is wrong, a spindle check point is activated, and the cell cycle progression is inhibited. Over-expression or non-expression of SAC members has been reported in various cancer types, and in most cases, the expression status of SAC members is correlated with highly proliferative activity and poor prognosis of tumors (Nature Reviews Cancer, vol.10, no.2, pp.102-115,2010).
Threonine/tyrosine kinase (Threonine and Tyrosine Kinase, TTK), also known as Mps1 (Monopolar Spindle), is a key kinase for activation and maintenance of SAC function (Novel TTK kinase inhibitors with potent anti-tu activity. Mol Cancer Ther.15 (4): 583-592.2016). TTK is barely detectable in normal tissues except testes and placenta. However, TTK mRNA levels are elevated in many human cancers, including papillary thyroid, breast, gastric, bronchial and lung cancers and the like (Cancer Res.2007;67 (21): 10148-10158.; clin Cancer Res.2006;12:405-410.; proc Natl Acad Sci USA.2010; 108:5384-5389.). Inhibition of TTK can cause a lack of SAC function, leading to premature mitotic withdrawal, and to severe chromosomal misclassification, ultimately leading to cancer cell death. Thus, TTK inhibitors have great potential for treating tumors.
Compounds are in clinical study phase with Servers-81694 (clinical stage I/II), bayer BAY-1217389 (clinical stage I), university Health Network CFI-402257 (clinical stage I/II) and Boston Pharmaceuticals BOS-172722 (clinical stage I). Patent application WO2009156315/WO2014131739/WO2015070349/WO2014037750 also discloses compounds as TTK inhibitors, but no TTK selective inhibitors have yet been marketed. To better meet the clinical demands, there is a need to develop new high-efficiency low-toxicity TTK selective inhibitors.
Disclosure of Invention
In a first aspect the present invention provides a safe and effective TTK inhibitor having a novel structure, which is 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:
ring a is selected from 6-12 membered aryl, 9-12 membered aryl heterocyclo, and 5-14 membered heteroaryl;
R 1 selected from H, -CN, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl, -C (O) N (R) f )R e and-S (O) 2 N(R f )R e The method comprises the steps of carrying out a first treatment on the surface of the 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, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 3-6 Cycloalkyloxy, 4-7 membered heterocyclyl, -NR a R 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) p R a 、-SO 2 N(R b )R a or-N (R) b )SO 2 R a The halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 3-6 The cycloalkyloxy, 4-7 membered heterocyclyl groups may be optionally substituted with one or more of the following groups: -OH, halogen, -CN, C 1-3 Alkoxy, C 1-4 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy groups;
Wherein R is a And R is b Each independently selected from H, C 1-4 Alkyl and C 3-6 Cycloalkyl group, the C 1-4 Alkyl, C 3-6 Cycloalkyl groups may be optionally substituted with one or more of the following groups: halogen, OH, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-7 membered heterocyclyl, -NR c R 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) p R c 、-SO 2 N(R d )R c or-N (R) d )SO 2 R c ；
R e And R is f Each independently selected from H and C 1-4 Alkyl, said C 1-4 Alkyl groups optionally being halogen or C 1-3 Alkoxy substitution; alternatively, R e And R is f Are linked to each other, together with the nitrogen atom to which they are attached, to form a 4-7 membered heterocyclic ring, which 4-7 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: halogen, OH, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-7 membered heterocyclyl, -NR c R 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) p R c 、-SO 2 N(R d )R c or-N (R) d )SO 2 R c ；
R c And R is d Each independently selected from H and C 1-4 An alkyl group;
p is selected from 0, 1 and 2;
R 2 each independently selected from hydrogen, halogen, cyano, OH, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-3 Haloalkyl and C 1-3 Haloalkoxy groups;
R 3 and R is 4 Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C 1-2 alkyl-C 3-8 Cycloalkyl, phenyl, 4-7 membered heterocyclyl, -C 1-2 Alkyl- (4-7 membered heterocyclyl) and 5-6 membered heteroaryl, said C 1-6 Alkyl, C 3-8 Cycloalkyl, -C 1-2 alkyl-C 3-8 Cycloalkyl, phenyl, 4-7 membered heterocyclyl, -C 1-2 Alkyl- (4-7 membered heterocyclyl), 5-6 membered heteroaryl may be optionally substituted with one or more of the following groups: hydroxy, halogen, cyano, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, -NR a R 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) p R a 、-SO 2 N(R b )R a or-N (R) b )SO 2 R a 4-7 membered heterocyclyl; or alternatively
R 3 And R is 4 Are linked to each other, together with the nitrogen atom to which they are attached, to form 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 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-7 membered heterocyclyl, -NR a R 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) p R a 、-SO 2 N(R a )R b or-N (R) b )SO 2 R 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 aryl heterocyclo and 5-14 membered heteroaryl;
R 5 selected from H, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 1-6 Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, -NR g R h 、-C(＝O)OR h 、-C(＝O)NR g R h 、-NR g C(＝O)NR g R h and-NR g C(＝O)R h The C is 1-6 Alkyl, C 3-8 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 1-6 Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following groups: halogen, OH, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-10 membered heterocyclyl, -NR a R 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) p R a 、-SO 2 N(R b )R a or-N (R) b )SO 2 R a The method comprises the steps of carrying out a first treatment on the surface of the The 4-10 membered heterocyclyl may be optionally substituted with one or more of the following groups: halogen, OH, cyano, nitro, C 1-4 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-8 Cycloalkyl;
wherein R is g And R is h Each independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, said C 1-6 Alkyl, C 3-7 Cycloalkyl radicalsThe 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 1-3 Alkyl, -NH 2 、-NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、-O-(C 1-3 Alkyl group, C 3-6 Cycloalkyl, 4-10 membered heterocyclyl; and R is g And R is h May form, together with the attached nitrogen atom, a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring optionally being substituted with one or more of the following groups: halogen, -OH, cyano, C 1-3 Alkyl, -NH 2 、-NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、-O-(C 1-3 Alkyl group, C 3-6 Cycloalkyl, 4-10 membered heterocyclyl;
R 6 each independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, -NH 2 、-NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 and-O-C 1-6 Alkyl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, -NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 and-O-C 1-6 The alkyl group may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C 1-3 Alkyl, -NH 2 、-NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 and-O-C 1-3 An alkyl group;
when R is 5 And R is 6 When adjacent to ring B, may be linked to form, together with the two atoms of ring B, a 5-8 membered carbocycle or heterocycle which may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C 1-3 Alkyl, -NH 2 、-NH-(C 1-3 Alkyl), -N (C) 1-3 Alkyl group 2 、-O-(C 1-3 Alkyl group, C 3-6 Cycloalkyl, 4-10 membered heterocyclyl;
n is selected from 0, 1, 2 and 3;
when more than one R a 、R b 、R c 、R d 、R e Or R is f When the two are simultaneously present, the two may be the same or different.
In some embodiments of the invention, ring A is selected from the group consisting of 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, R 1 Selected from H, -CN, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl, -C (O) N (R) f )R e and-S (O) 2 N(R f )R e The method comprises the steps of carrying out a first treatment on the surface of the 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, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, -NR a R 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) p R a 、-SO 2 N(R b )R a Or N (R) b )SO 2 R a The C is 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, may be optionally substituted with one or more of the following groups: -OH, halogen, -CN, C 1-3 Alkoxy, C 1-4 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy groups;
wherein R is a And R is b Each independently selected from H, C 1-4 Alkyl and C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups may be optionally substituted with one or more of the following groups: halogen, OH, cyano, nitro, C 1-4 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, 4-7 membered heterocyclyl, -NR c R 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) p R c 、-SO 2 N(R d )R c or-N (R) d )SO 2 R c ；
R e And R is f Each independently selected from H and C 1-4 Alkyl, said C 1-4 Alkyl groups optionally being halogen or C 1-3 Alkoxy substitution; or R is e And R is f Are linked to each other, together with the nitrogen atom to which they are attached, to form a 4-7 membered heterocyclic ring, which 4-7 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: halogen, -OH, cyano, nitro, C 1-4 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-7 membered heterocyclyl, -NR c R 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) p R c 、-SO 2 N(R d )R c or-N (R) d )SO 2 R c ；
R c And R is d Each independently selected from H and C 1-4 An alkyl group;
p is selected from 0, 1 and 2.
In some embodiments of the invention, R 1 Selected from H, -CN, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, -C (O) N (R) f )R e and-S (O) 2 N(R f )R e The method comprises the steps of carrying out a first treatment on the surface of the The 5-6 membered heteroaryl and 5-6 membered heterocyclyl may be optionally substituted with one or more of the following groups: halogen, cyano, nitro, -OH, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, -C (O) R a 、-C(O)N(R b )R a 、-N(R b )C(O)R a 、-S(O) p R a 、-SO 2 N(R b )R a or-N (R) b )SO 2 R a The C is 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl radicalsThe 4-7 membered heterocyclyl may be optionally substituted with one or more of the following groups: -OH, halogen, -CN, C 1-3 Alkoxy, C 1-4 Alkyl, halogenated C 1-3 Alkyl, halogenated C 1-3 An alkoxy group;
wherein R is a And R is b Each independently selected from H and C 1-4 Alkyl, said C 1-4 The alkyl group may be optionally substituted with one or more of the following groups: halogen, OH, cyano, nitro, C 1-4 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-7 membered heterocyclyl, -NR c R d 、-N(R d )OR c 、-C(O)N(R d )R c 、-N(R d )C(O)R c 、-S(O) p R c 、-SO 2 N(R d )R c or-N (R) d )SO 2 R c ；
R e And R is f Each independently selected from H and C 1-4 Alkyl, said C 1-4 Alkyl groups optionally being halogen or C 1-3 Alkoxy substitution; or R is e And R is f Are linked to each other, together with the nitrogen atom to which they are attached, to form a 4-7 membered heterocyclic ring, which 4-7 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: halogen, -OH, cyano, nitro, C 1-4 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, 4-7 membered heterocyclyl, -NR c R d 、-N(R d )OR c 、-C(O)N(R d )R c 、-N(R d )C(O)R c 、-S(O) p R c 、-SO 2 N(R d )R c or-N (R) d )SO 2 R c ；
R c And R is d Each independently selected from H and C 1-4 An alkyl group;
p is selected from 0, 1 and 2.
In some embodiments of the invention, R 1 Selected from H, -CN, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and-C (O) N (R) f )R e The method comprises the steps of carrying out a first treatment on the surface of the The 5-6 membered heteroaryl and 5-6 membered heterocyclyl may optionally be substituted with one or moreThe following groups are substituted: halogen, cyano, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, -C (O) R a 、-C(O)N(R b )R a Or N (R) b )SO 2 R a The C is 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, may be optionally substituted with one or more of the following groups: -OH, halogen, -CN, C 1-3 Alkoxy, C 1-4 Alkyl, halogenated C 1-3 Alkyl, halogenated C 1-3 An alkoxy group;
wherein R is a And R is b Each independently selected from H and C 1-4 Alkyl, said C 1-4 The alkyl group may be optionally substituted with one or more of the following groups: halogen, OH, cyano, C 1-4 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-7 membered heterocyclyl;
R e and R is f Each independently selected from H and C 1-4 Alkyl, said C 1-4 Alkyl groups optionally being halogen or C 1-3 Alkoxy substitution; or R is e And R is f Are linked to each other, together with the nitrogen atom to which they are attached, to form a 4-7 membered heterocyclic ring, which 4-7 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: halogen, OH, cyano, C 1-4 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, 4-7 membered heterocyclyl;
R c and R is d Each independently selected from H and C 1-4 An alkyl group;
p is selected from 0, 1 and 2, preferably p is 2.
In some embodiments of the invention, R 1 Selected from H, -CN, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and the likeOxazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and-C (O) N (R) f )R e The method comprises the steps of carrying out a first treatment on the surface of the The heteroaryl and heterocyclyl groups may be optionally substituted with one or more of the following groups: halogen, cyano, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, C 1-4 Alkyl or C 1-4 An alkoxy group;
R e and R is f Each independently selected from H and C 1-4 Alkyl, said C 1-4 Alkyl groups optionally being halogen or C 1-3 Alkoxy substitution; or R is e And R is f Are linked to each other, together with the nitrogen atom to which they are attached, to form a 4-6 membered heterocyclic ring, which 4-6 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: halogen, -OH, cyano, C 1-4 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkyl or halo C 1-3 An alkoxy group.
In some embodiments of the invention, R 1 Selected from hydrogen,
Preferably, R is relative to the amino group attached to the A ring 1 At bit 4.
In some embodiments of the invention, R 2 Each independently selected from hydrogen, halogen, cyano, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkoxy groups; preferably, R 2 Each independently selected from chlorine, fluorine, bromine, iodine, cyano, and C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkoxy groups; preferably, R 2 Each independently selected from chlorine, fluorine, C 1-3 Alkoxy and C 1-3 An alkyl group; preferably, R 2 Selected from chlorine, fluorine, methoxy, ethoxy and methyl;
preferably, R is relative to the amino group attached to the A ring 2 In the ortho and/or meta position.
In some embodiments of the invention, R 3 And R is 4 Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C 1-2 alkyl-C 3-8 Cycloalkyl, phenyl, 4-7 membered heterocyclyl, -C 1-2 Alkyl- (4-7 membered heterocyclyl) and 5-6 membered heteroaryl, said C 1-6 Alkyl, C 3-8 Cycloalkyl, -C 1-2 alkyl-C 3-8 Cycloalkyl, phenyl, 4-7 membered heterocyclyl, -C 1-2 Alkyl- (4-7 membered heterocyclyl), 5-6 membered heteroaryl may be optionally substituted with one or more of the following groups: hydroxy, fluoro, chloro, cyano, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, -NR a R 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) p R a 、-SO 2 N(R b )R a 4-7 membered heterocyclyl or-N (R) b )SO 2 R a The method comprises the steps of carrying out a first treatment on the surface of the Or,
R 3 and R is 4 Are linked to each other, together with the nitrogen atom to which they are attached, to form 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 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-7 membered heterocyclyl, -NR a R 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) p R a 、-SO 2 N(R a )R b or-N (R) b )SO 2 R a ；
Preferably, R 3 And R is 4 Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C 1-2 alkyl-C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, -C 1-2 Alkyl- (4-7 membered heterocyclyl) and 5-6 membered heteroaryl, said C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following groups: hydroxy, fluoro, chloro, cyano, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, C 1-4 Alkyl, -NR a R b 、-N(R b )OR a 、-C(O)N(R b )R a 、-S(O) p R a 、-SO 2 N(R b )R a 4-7 membered heterocyclyl, -N (R) b )SO 2 R a The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively
R 3 And R is 4 Are linked to each other, together with the nitrogen atom to which they are attached, to form 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 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-7 membered heterocyclyl, -NR a R 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) p R a 、-SO 2 N(R a )R b or-N (R) b )SO 2 R a ；
Preferably, R 3 And R is 4 Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl, said C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following groups: hydroxy, fluoro, chloro, cyano, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, -NR a R b 4-6 membered heterocyclyl; or,
R 3 and R is 4 Are linked to each other, together with the nitrogen atom to which they are attached, to form 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 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-7 membered heterocyclyl, -NR a R b ；
Preferably, R 3 And R is 4 Each independently selected from hydrogen, C 1-6 Alkyl, -C 1-2 alkyl-C 3-8 Cycloalkyl, C 3-6 Cycloalkyl, -C 1-2 Alkyl- (4-6 membered heterocyclyl), said C 1-6 Alkyl groups may be optionally substituted with one or more hydroxy groups; alternatively, R 3 And R is 4 Are linked to each other, together with the nitrogen atom to which they are attached, to form 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 1-4 Alkoxy (e.g., methoxy);
preferably, -NR 3 R 4 Selected 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 the group consisting of 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 furyl.
In some embodiments of the invention, R 5 Selected from H, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 1-6 Cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, -NR g R h 、-C(＝O)OR h 、-C(＝O)NR g R h 、-NR g C(＝O)NR g R h and-NR g C(＝O)R h The C is 1-6 Alkyl, C 3-8 Cycloalkyl, -O-C 1-6 Alkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following groups: halogen, OH, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy group,4-10 membered heterocyclyl, -NR a R 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) p R a 、-SO 2 N(R b )R a or-N (R) b )SO 2 R a The method comprises the steps of carrying out a first treatment on the surface of the The 4-10 membered heterocyclyl may be optionally substituted with one or more of the following groups: halogen, OH, cyano, nitro, C 1-4 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-8 Cycloalkyl;
wherein R is g And R is h Each independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, said C 1-6 Alkyl, C 3-7 Cycloalkyl, 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 1-3 Alkyl, -NH 2 、-NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、-O-(C 1-3 Alkyl group, C 3-6 Cycloalkyl, 4-10 membered heterocyclyl; and R is g And R is h May form, together with the attached nitrogen atom, a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring optionally being substituted with one or more of the following groups: halogen, -OH, cyano, C 1-3 Alkyl, -NH 2 、-NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、-O-(C 1-3 Alkyl group, C 3-6 Cycloalkyl, 4-10 membered heterocyclyl;
preferably, R 5 Selected from H, cyano, C 1-6 Alkyl, -C (=o) OR h 、-C(＝O)NR g R h 、-NR g C(＝O)NR g R h and-NR g C(＝O)R h ；
Wherein R is g And R is h Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, said C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, and phenyl group,The 5-6 membered heteroaryl group may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C 1-3 Alkyl, -NH 2 、-NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、-O-(C 1-3 Alkyl group, C 3-6 Cycloalkyl, 4-10 membered heterocyclyl;
preferably, R 5 Selected from hydrogen, cyano, C 1-6 Alkyl, -C (=o) OR h 、-C(＝O)NR g R h and-NR g C(＝O)R h Wherein R is g And R is h Each independently selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl group, the C 1-3 Alkyl and C 3-6 Cycloalkyl groups may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C 1-3 Alkyl, -NH 2 、-NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、-O-C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclyl;
preferably, R g And R is h Each independently selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl group, the C 1-3 Alkyl and C 3-6 Cycloalkyl groups may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C 1-3 Alkyl, -NH 2 ；
Preferably, R g And R is h Each independently selected from the group consisting of H, halocyclopropyl, methyl, ethyl, cyclopropyl, and cyclobutyl;
preferably, R 5 Selected from optionally substituted 5-6 membered heteroaryl, halocyclopropylcarbamoyl and cyclopropylcarbamoyl; alternatively, R 5 Selected from hydrogen, cyano, -CH 2 OH、-COOH、CH 3 CONH-、
Preferably, R is relative to the position of attachment of the ring containing X and Y 5 At bit 4.
In some embodiments of the invention, R 6 Each independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, -NH 2 、-NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 and-O-C 1-6 Alkyl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, -NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 and-O-C 1-6 The alkyl group may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C 1-3 Alkyl, -NH 2 、-NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 and-O-C 1-3 An alkyl group; n is selected from 1, 2 and 3;
preferably, R 6 Each independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Haloalkyl and C 1-3 Haloalkoxy, said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Haloalkyl, C 1-3 The haloalkoxy groups may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C 1-3 Alkyl, -NH 2 、-NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 and-O-C 1-3 An alkyl group; n is selected from 1, 2 and 3;
preferably, R 6 Each independently selected from H, halogen, hydroxy, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Haloalkoxy, said C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 The haloalkoxy groups may be optionally substituted with one or more of the following groups: halogen, -OH, cyano, C 1-3 Alkyl, -NH-C 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 and-O-C 1-3 An alkyl group; n is selected from 1, 2 and 3;
preferably, R 6 Each independently selected from H, halogen, C 1-3 Alkyl group、C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Haloalkoxy, said C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 The haloalkoxy groups may be optionally substituted with one or more of the following groups: halogen, cyano, C 1-3 An 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 Y 6 In the ortho or meta position.
In some embodiments of the invention, the compound has the structure of formula II:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 A, 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 furyl, and n is selected from 0 and 1.
In some embodiments of the invention, the compound has the structure of formula III:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 The rings A and n are as defined above for formula (I), X 1 、X 2 、X 3 And X 4 Are CH; alternatively, X 1 、X 2 、X 3 And X 4 One 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 is 1 、R 2 、R 3 、R 4 、R 5 、R 6 X is as defined above for formula (I) 5 CH or N.
In some embodiments of the invention, the compound has the structure of formula V:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 As defined above for formula (I).
In some embodiments of the invention, in the compound of formula V, R 1 Selected from:
hydrogen, hydrogen,
R 2 Selected from chlorine, fluorine, methoxy, ethoxy and methyl;
R 3 and R is 4 Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, said C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl may be optionally substituted with one or more of the following groups: hydroxy, fluoro, chloro, cyano, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, -NR a R b 4-6 membered heterocyclyl; or (b)
R 3 And R is 4 Are linked to each other, together with the nitrogen atom to which they are attached, to form 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 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-7 membered heterocyclyl, -NR a R b ；
Preferably, -NR 3 R 4 Selected from the group consisting of
And is also provided with
R 5 Selected from hydrogen, cyano, -CH 2 OH、-COOH、CH 3 CONH-、
R 6 Selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, said C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 The haloalkoxy groups may be optionally substituted with one or more of the following groups: halogen, cyano, C 1-3 An alkyl group.
In some embodiments of the invention, in the compound of formula V, R 1 Is thatR 2 Is ethoxy; r is R 3 And R is 4 Each independently selected from hydrogen and C 1 -6 alkyl, preferably, -NR 3 R 4 Is->R 5 Selected from CH 3 CONH-、 R 6 Selected from H, methyl and fluoro.
In some embodiments of the invention, the compounds of the invention are selected from, but are 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
In a second aspect the present invention provides a process for the preparation of a compound of formula V according to the invention,
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 As previously described;
Q 1 and Q 2 Typical leaving groups include, but are not limited to: halogen atoms such as chlorine atoms, bromine atoms or iodine atoms; or R is 7 S(O) q -a group wherein q is selected from 1 and 2, and R 7 Represents substituted C 1-6 Alkyl, substituted C 3-7 Cycloalkyl, substituted 3-7 membered monocyclic heterocycloalkyl, substituted phenyl and substituted 5-6 membered monocyclic aromatic heterocyclic groups, preferably selected from methylsulfonyl, trifluoromethylsulfonyl and perfluorobutoxysulfonyl; q (Q) 3 Is a halogen atom, preferably selected from a bromine atom and an iodine atom;
the method comprises the following steps:
step one: the compound V-1 reacts with the V-2 to obtain the 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, with acetonitrile being preferred. The reaction is preferably carried out under suitable alkaline conditions, the base being sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, TEA, DIPEA or cesium carbonate, preferably the base being 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 hours.
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, said organophosphorus compound being selected from RuPhos, XPhos, SPhos and CPhos, 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 in a suitable protective atmosphere (e.g., N 2 Environment). 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 1-3 hours, for example 2 hours.
Step three: the compound V-5 reacts with V-6 to obtain the 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 alkaline conditions, the base being sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, TEA, DIPEA or cesium carbonate, preferably the base being selected from cesium carbonate. The reaction is preferably carried out at a suitable temperature, which may be, for example, 80-150 ℃, preferably 100 ℃. Preferably, the reaction is carried out for a suitable time, for example 1 to 24 hours, preferably 12 hours.
The term "suitable" as used herein means that the choice of a particular compound or condition will depend on the particular synthetic procedure to be performed and the nature of the molecule or molecules to be converted, but such choice 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 performed in an anhydrous or inert atmosphere, etc.) may 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 for preparing compounds of formula (I). Those 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 may be substituted to provide various derivatives and/or reaction conditions. In addition, many of the example compounds prepared by the methods described herein may be further modified using conventional chemistry well known to those skilled in the art with reference to the present disclosure.
Pharmaceutical composition, preparation method and treatment method
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, tautomer or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotopic derivative, metabolite or prodrug of the compound, and one or more pharmaceutically acceptable carriers.
A fourth aspect of the invention provides a process for preparing a pharmaceutical composition of the invention, which comprises combining a compound of formula (I), (II), (III), (IV) or (V) of the invention, a stereoisomer, tautomer or mixture thereof, 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.
A fifth aspect of the present invention provides a pharmaceutical formulation comprising a compound of formula (I), (II), (III), (IV) or (V) of the present invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a pharmaceutical composition of the present invention.
In a sixth aspect, the present invention provides the use of a compound of formula (I), (II), (III), (IV) or (V) according to the invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, a pharmaceutical composition according to the invention or a pharmaceutical formulation according to the invention for the manufacture of a medicament for the prophylaxis or treatment of a disease associated with TTK activity.
A seventh aspect of the present invention provides a compound of formula (I), (II), (III), (IV) or (V) of the present invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, a pharmaceutical composition of the present invention or a pharmaceutical formulation 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 amount of a compound of formula (I), (II), (III), (IV) or (V) of the present invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, a pharmaceutical composition of the present invention or a pharmaceutical formulation of the present invention, and optionally including use in combination with other agents for preventing or treating a disease associated with TTK activity (e.g., 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 amount of a compound of formula (I), (II), (III), (IV) or (V) of the present invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, a pharmaceutical composition of the present invention or a pharmaceutical formulation of the present invention, and including use in combination with an antimitotic drug.
Diseases associated with TTK activity as described herein include, but are not limited to, tumors including benign tumors and malignant tumors, in particular cancers such as melanoma, glioblastoma, ovarian, pancreatic, prostate, lung, breast, renal, cervical, thyroid, metastasis of secondary sites of primary solid tumors, chronic myelogenous leukemia, acute lymphoblastic leukemia, papillary thyroid cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, eosinophilic syndrome, gastrointestinal stromal tumor, colon cancer, and the like.
Definition of the definition
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. 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 "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.
As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon group. For example, as used herein, the term "C 1 -C 6 Alkyl "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) optionally substituted with one or more (such as 1 to 3) suitable substituents.
The term "haloalkyl", when 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 with a halogen. For example, the term "C 1-6 Haloalkyl "means C optionally substituted with one or more (e.g., 1-3) halogens 1-6 An alkyl group. The term "C 1-3 Haloalkyl "means C optionally substituted with one or more (e.g., 1-3) halogens 1-3 An alkyl group. It will be appreciated 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-CH 2 F、-CHF 2 、-CF 3 、-CCl 3 、-C 2 F 5 、-C 2 Cl 5 、-CH 2 CF 3 、-CH 2 Cl or-CH 2 CH 2 CF 3 Etc.
As used herein, the term "cycloalkyl" refers toSaturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclic, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [ 1.1.1) ]Amyl, 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 "C 3 -C 8 Cycloalkyl radicals "and" C 3-8 Cycloalkyl "is used interchangeably to refer to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having 3 to 8 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) optionally substituted with one or more (such as 1 to 3) suitable substituents, e.g., methyl-substituted cyclopropyl.
As used herein, the term "halo" or "halogen" group is defined to include F, cl, br or I.
As used herein, the term "alkoxy" means an alkyl group, as defined above, e.g., C, attached to the parent molecular moiety through an oxygen atom 1 -C 6 Alkoxy or C 1 -C 3 An alkoxy group. C (C) 1 -C 6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including isopropoxy, n-propoxy), butoxy (including n-butoxy, isobutoxy, tert-butoxy), pentoxy (including n-pentoxy, isopentoxy, neopentoxy), hexoxy (including n-hexoxy, isohexoxy), and the like.
The term "haloalkoxy", when 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 with halogen. For example, the term "C 1-6 Haloalkoxy "refers to C substituted with one or more (e.g., 1, 2 or 3) halogens 1-6 An alkoxy group. Similarly, the term "C 1-3 Haloalkoxy "refers to C substituted with one or more (e.g., 1, 2 or 3) halogens 1-3 An alkoxy group. The book is provided withIt will be appreciated 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 groups such as-OCH 2 F、-OCHF 2 、-OCF 3 、-OCCl 3 、-OC 2 F 5 、-OC 2 Cl 5 、-OCH 2 CF 3 、-OCH 2 Cl or-OCH 2 CH 2 CF 3 Etc.
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 cycloalkyl groups to form a cyclic group, the point of attachment may be on the aryl or on the cycloalkyl. For example, the number of the cells to be processed,for example, as used herein, the terms "6-14 membered aryl" and "C 6 -C 14 Aryl "is used interchangeably and means an aromatic group containing 6 to 14 carbon atoms, e.g. C 6 -C 12 Aryl or C 6 -C 10 Aryl groups 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 、C 1 -C 6 Alkyl, etc.) substitution.
As used herein, the term "hydroxyalkyl" means that the hydrogen atom of an alkyl group is substituted with one or more hydroxyl groups, e.g., C 1 -C 6 Hydroxyalkyl or C 1 -C 3 Hydroxyalkyl groups. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and hydroxyhexyl, among others.
As used herein, the term "aryl-heterocyclyl" refers to a cyclic group formed by aryl and heterocyclyl sharing two adjacent carbon atoms with each other, the point of attachment being on the aryl or heterocyclyl, wherein aryl or heterocyclyl are as defined herein. For example, as used herein, the term "9-12 membered arylalkylheterocyclyl" means a radical of an arylalkylheterocyclyl containing 9-12 ring atoms, particularly a phenyl 5-8 membered heterocyclyl, particularly phenylAnd 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 (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, especially 5, 6, 7, 8, 9 or 10 ring atoms, and which contains at least one (e.g., 1, 2 or 3) heteroatom (e.g., oxygen, nitrogen or sulfur) which may be the same or different, and in each case may share two adjacent atoms with each other with an aryl, heterocyclyl or cycloalkyl group to form a fused ring group, the point of attachment of which is on the heteroaromatic ring or on the other ring. For example, as used herein, the term "5-10 membered heteroaryl" means heteroaryl containing 5 to 10 ring atoms, including 5-6 membered heteroaryl, examples of which 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, as well as fused ring derivatives thereof, including, but not limited to, heteroarylheteroaryl, heteroarylfused heterocyclyl, or heteroarylfused cycloalkyl, particularly 5-6 membered heteroarylfused 5-6 membered heteroaryl, 5-6 membered heteroarylfused phenyl, 5-6 membered heteroarylfused 5-7 membered heterocyclyl, or 5-6 membered heteroarylfused C 4 -C 6 Cycloalkyl (especially 5-6 membered heteroaryl-cyclobutyl, 5-6 membered heteroaryl-cyclopentyl, 5-6 membered heteroaryl-cyclohexyl), examples include but are not limited to indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, Etc.
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 and one or more (e.g., 1, 2, 3, or 4) selected from C (=o), O, S, S (=o), S (=o) in the ring 2 And N and NR (R represents a hydrogen atom or a substituent such as, but not limited to, an alkyl or cycloalkyl group). As used herein, the term "3-14 membered heterocyclyl" means heterocyclyl containing 3-14 ring atoms, including 3-10, 4-8, 4-7, 4-6 or 5-6 membered heterocyclyl, examples of which include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, and the like; and their fused ring derivatives including, but not limited to, heterocyclyl-heterocyclylheterocyclyl, heterocyclyl-heterocyclylcycloalkyl, in particular 3-7 membered heterocyclyl-3-7 membered heterocyclyl, 3-7 membered heterocyclyl-cycloalkyl, 3-7 membered heterocyclyl-C 4 -C 6 Cycloalkyl groups, examples of which include, but are not limited to, pyrrolidinyl-cyclopropyl, cyclopentylazacyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, piperidinyl-morpholinyl; and bridge or spiro derivatives such as, but not limited to:
etc.
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 "substitution" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms 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 optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent any hydrogens are present) may be optionally replaced with an independently selected optional substituent, alone and/or together. If the nitrogen of a substituent is described as optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogens are present) may each be optionally replaced with an independently selected optional substituent.
If substituents are described as "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.
The term "one or more" as used herein means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
As used herein, unless indicated, 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 prevailing in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g 2 H、 3 H) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of carbon (e.g 11 C、 13 C, C is a metal alloy 14 C) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of chlorine (e.g 36 Cl); isotopes of fluorine (e.g 18 F) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of iodine (e.g 123 I, I 125 I) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of nitrogen (e.g 13 N is N 15 N); isotopes of oxygen (e.g 15 O、 17 O and O 18 O)；Isotopes of phosphorus (e.g 32 P) is as follows; isotopes of sulfur (e.g 35 S)。
The term "stereoisomer" refers to 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 produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific 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 (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, nitroso-oximes may exist in solution in equilibrium in the following tautomeric forms:
it is to be understood that the scope of the present application encompasses all such isomers in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.
Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism 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 any ratio of more than one polymorphs. It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives 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 the compounds of the invention or metabolites or residues thereof, either directly or indirectly. 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 invention are known to those skilled in the art.
By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carriers that may be used 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. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, in particular for injections. 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 contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents, as desired. 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 systematically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection, intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic formulation 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 dose" as used herein refers to the amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the condition being treated.
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 doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 50mg, for example about 0.01 to about 10 mg/kg/day per kg body weight per day (single or divided administration). For a 70kg human, this amounts to about 0.007 mg/day to about 3500 mg/day, for example about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforementioned range may be sufficient, while in other cases larger doses may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.
The compounds of the present invention may be present in the pharmaceutical composition in an amount or amount of about 0.01mg to about 1000mg.
As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing a disorder or condition to which the term applies or one or more symptoms of such disorder or condition.
As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "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, domestic animals 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 a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such materials may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, 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 a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, which, when administered into or onto the body, may be converted into the compounds of the 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. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", vol.14, ACS Symposium Series (T. Higuchi and V. Stilla) and "Bioreversible Carriers in Drug Design," Pergamon Press,1987 (E. B. Roche eds., american Pharmaceutical Association). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g. "Design of Prodrugs", described in h. Bundegaard (Elsevier, 1985) ".
The invention also encompasses compounds of the invention containing a protecting group. During 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 of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, in Protective Groups in Organic Chemistry, ed.J.F.W.McOmie, plenum Press,1973; and those described in 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.
The term "effective dose" as used herein refers to the amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the condition being treated.
As used herein, "room temperature" refers to 20-30deg.C.
In this application, when chemical names and structural formulas are not identical, the structural formulas should be shown unless it can be inferred that the chemical names are correct instead of the structural formulas according to the context.
Advantageous effects of the inventionFruit set
The compound has high inhibition activity on TTK in cells, and has excellent properties such as good pharmacokinetic property, good safety and the like.
Detailed Description
Examples
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention. Moreover, the specific experimental methods not mentioned in the following examples were carried out according to conventional experimental methods.
The structure of the compound of the invention is prepared by nuclear magnetic resonance 1 HNMR) and/or Mass Spectrometry (MS) identification.
1 HNMR chemical shifts (δ) are reported in parts per million (ppm). 1 HNMR was measured by a JEOL Eclipse 400 nuclear magnetic resonance apparatus with deuterated methanol (CD) 3 OD), deuterated chloroform (CDCl) 3 ) Or hexadeuterated dimethyl sulfoxide (DMSO-d 6), with an internal standard of Tetramethylsilane (TMS). In nuclear magnetic resonance data, each symbol has the following meaning: s: single peak, d: double peak, t: triplet, q: quadruplet, dd: double peak, qd: four doublets, ddd: double doublet, ddt: double triplet dddd: double peak, m: multiple peaks, br: broad peak (broad), J: coupling constant, hz: hertz.
MS was determined with Agilent 6120B mass spectrometer.
The reaction monitoring was performed by Thin Layer Chromatography (TLC) or LC-MS.
Thin Layer Chromatography (TLC) silica gel plates were used with aluminum plates produced by Merck.
LC-MS instrument: agilent 6125B.
The compound can be separated and purified by chromatography silica gel thick preparation plate, silica gel column chromatography, preparative high performance liquid chromatograph (Prep-HPLC) and Flash column chromatography.
The chromatographic silica gel thick preparation plate adopts a counter yellow sea HSGF254 type preparation plate.
Column chromatography generally uses 200-300 mesh silica gel of Qingdao ocean as a carrier.
The preparation high performance liquid chromatograph (Prep-HPLC) uses an Agilent 1260 chromatograph.
Flash column chromatography uses the Agela medium pressure Flash purification preparation System (MP-200).
The microwave reaction was carried out using a Biotageinitator+ (400W, RT-300 ℃ C.) microwave reactor.
The reaction temperature was room temperature (20 ℃ C. To 30 ℃ C.) without any particular explanation in examples.
The reagents used in the present invention were purchased from Acros Organics, aldrich Chemical Company, tertbe chemical, etc.
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)
Step one: 5-bromo-2-chloro-N-neopentylpyrimidin-4-amine (Compound 1-2)
Compound 1-1 (2.28 g,10 mmol), pivalic amine (1.03 g,12 mmol), DIPEA (2.64 g,20 mmol) were added to acetonitrile (50 mL) 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 (compounds 1-3)
The compound 1-2 (1 g,3.59 mmol), N-cyclopropyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (1.24 g,4.31 mmol), bis (triphenylphosphine) palladium dichloride (257.1 mg,0.36 mmol), na 2 CO 3 (776.5 mg,7.18 mmol) of dioxygen is addedSix rings (20 mL) were reacted at 100deg.C under nitrogen for 2 hours. 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 chromatographed on silica gel (DCM/meoh=20/1) to give the title compounds 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)
Compounds 1-3 (0.1 g,0.26 mmol), N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) carboxamide (82.4 mg,0.32 mmol), cs 2 CO 3 (176 mg,0.53 mmol) was dissolved in DMSO (2 mL) 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 separated by Prep-HPLC to give the title compound 1 (31 mg).
ESI-MS(m/z):541.2[M+H] + .
1H NMR(400MHz,DMSO)δ8.66(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)
Step one: 4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) -N-cyclopropyl-2-methylbenzamide (compound 2-1)
The compound 1-2 (1 g,3.59 mmol), N-cyclopropyl-2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide1.30g,4.31 mmol), bis (triphenylphosphine) palladium dichloride (257.1 mg,0.36 mmol), na 2 CO 3 (776.5 mg,7.18 mmol) was added to dioxane (20 mL), and the mixture was 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 chromatographed on silica gel (DCM/meoh=20/1) to give the 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)
Compound 2-1 (0.1 g,0.26 mmol), N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) carboxamide (82.4 mg,0.32 mmol), cs 2 CO 3 (176 mg,0.53 mmol) was added to DMSO (2 mL) and reacted at 100℃for 12 hours. Cooled to room temperature, water was added, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and the concentrated residue was separated by Prep-HPLC to give the title compound 2 (11 mg).
ESI-MS(m/z):555.2[M+H] + .
1 H NMR(500MHz,DMSO)δ8.66(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)
Step one: 2-fluoro-4- (2-chloro-4 (neopentylamino) pyrimidin-5-yl) -N-cyclopropylbenzamide (compound 3-1)
The compound 1-2 (1 g,3.59 mmol), N-cyclopropyl-2-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (1.62 g,4.31 mmol), bis (triphenylphosphine) palladium dichloride (257.1 mg,0.36 mmol), na 2 CO 3 (776.5 mg,7.18 mmol) was added to dioxane (20 mL), and the mixture was 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 chromatographed on silica gel (DCM/meoh=20/1) to give the 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)
Compound 3-1 (0.1 g,0.26 mmol), N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) carboxamide (82.4 mg,0.32 mmol), cs 2 CO 3 (176 mg,0.53 mmol) was added to DMSO (2 mL) 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 separated by Prep-HPLC to give the title compound 3 (27 mg).
ESI-MS(m/z):559.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ11.96(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)
Step one: 4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) phenyl) methanol (compound 4-1)
Compound 1-2 (1 g,3.59 mmol), (4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanol (1.31 g,4.31 mmol), bis (triphenylphosphine) palladium dichloride (257.1 mg,0.36 mmol), na 2 CO 3 (776.5 mg,7.18 mmol) was added to dioxane (20 mL), and the mixture was 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 chromatographed on silica gel (DCM/meoh=20/1) to give the 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)
Compound 4-1 (80 mg,0.26 mmol), N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) carboxamide (82.4 mg,0.32 mmol), cs 2 CO 3 (176 mg,0.53 mmol) was added to DMSO (2 mL) 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 separated by Prep-HPLC to give the title compound 4 (21 mg).
ESI-MS(m/z):488.2[M+H] + .
1 H NMR(400MHz,DMSO)δ8.68(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)
Step one: 4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) benzoic acid methyl ester (compound 5-1)
Compound 1-2 (5 g,17.95 mmol), methyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (3.23 g,17.95 mmol), bis (triphenylphosphine) palladium dichloride (1.26 g,1.79 mmol), na 2 CO 3 (3.80 g,35.90 mmol) was added to dioxane (50 mL), water (10 mL), and reacted at 110℃for 16 hours under nitrogen. Cooled to room temperature, evaporated to dryness, water was added, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and the concentrated residue was subjected to silica gel column chromatography (PE/ea=1/1) to give the 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 (3.7 g,11.08 mmol) was added to MeOH (30 mL) and water (10 mL), naOH (886.73 mg,22.17 mmol) 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 a 10% hydrochloric acid solution, the precipitate was suction filtered, and the filter cake was washed with water and dried to give the 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 (100 mg, 321.72. Mu. Mol) and N- (2-ethoxy-4- (4-methyl-1, 2, 4-triazol-3-yl) phenyl) carboxamide (180.97 mg, 734.87. Mu. Mol) were added to DMSO (10 mL) and cesium carbonate (305.66 mg, 938.13. Mu. Mol) was added. The temperature is raised to 110 ℃ and the reaction is stirred for 16h. The reaction solution 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 5 (12 mg).
ESI-MS(m/z):502.1[M+H] + .
1 H NMR(400MHz,DMSO)δ8.69～8.67(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)
Step one: n- (4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) phenyl) acetamide (compound 6-1)
Compounds 1-2 (1 g,3.59 mmol), 4-acetamidophenylboronic acid (770 mg,4.31 mmol), bis (triphenylphosphine) palladium dichloride (257.1 mg,0.36 mmol), na 2 CO 3 (776.5 mg,7.18 mmol) was added to dioxane (20 mL), and the mixture was 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 chromatographed on silica gel (DCM/meoh=20/1) to give the 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)
Compound 6-1 (0.1 g,0.30 mmol), N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) carboxamide (82.4 mg,0.32 mmol), cs 2 CO 3 (176 mg,0.53 mmol) was added to DMSO (2 mL) 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 separated by Prep-HPLC to give the title compound 6 (5 mg).
ESI-MS(m/z):515.3[M+H] + .
1 H NMR(400MHz,DMSO)δ10.06(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)
Step one: n-cyclobutyl-4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 7-1)
Compound 5-2 (300 mg, 938.13. Mu. Mol), cyclobutylamine (100.08 mg,1.41 mmol) and EDCI (269.76 mg,1.41 mmol) were added to DCM (20 mL) and DMAP (343.83 mg,2.81 mmol) were added sequentially and stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was chromatographed on a column (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 (250 mg, 670.44. Mu. Mol) and N- (2-ethoxy-4- (4-methyl-1, 2, 4-triazol-3-yl) phenyl) carboxamide (388.00 mg,1.58 mmol) were added to DMSO (10 mL) and cesium carbonate (655.32 mg,2.01 mmol) was added. The temperature is raised to 110 ℃ and the reaction is stirred for 16h. The reaction solution 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 7 (55 mg).
ESI-MS(m/z):555.2[M+H] + .
1 H NMR(400MHz,DMSO)δ8.68～8.66(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)
Step one: 4- (2-chloro-4 (neopentylamino) pyrimidin-5-yl) -N-methylbenzamide (compound 8-1)
Compounds 1-2 (500 mg,1.79 mmol), (4- (methylcarbamoyl) phenyl) boronic acid (321.24 mg,1.79 mmol), bis (triphenylphosphine) palladium dichloride (125.98 mg,0.18 mmol), na 2 CO 3 (380.47 mg,3.59 mmol) was added to dioxane (20 mL) and water (5 mL), nitrogen blanketed, and reacted at 120℃for 16 hours. 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 (110 mg, 330.50. Mu. Mol) and N- (2-ethoxy-4- (4-methyl-1, 2, 4-triazol-3-yl) phenyl) carboxamide (191.27 mg, 776.68. Mu. Mol) were added to DMSO (10 mL) and cesium carbonate (323.05 mg, 991.51. Mu. Mol) was added. The temperature is raised to 110 ℃ and the reaction is stirred for 16h. The reaction solution 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 desired product.
ESI-MS(m/z):515.15[M+H]+.
1H NMR(400MHz,DMSO-d 6 ):δ8.67～8.65(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)
Step one: 4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 9-1)
Compound 5-2 (700 mg,2.19 mmol), ammonium chloride (234.18 mg,4.38 mmol) were added to DMF (20 mL), EDCI (839.25 mg,4.38 mmol) and HOBt (591.55 mg,4.38 mmol), DIPEA (848.72 mg,6.57 mmol) were added sequentially and stirred overnight at room temperature. 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 (200 mg, 627.35. Mu. Mol) and N- (2-ethoxy-4- (4-methyl-1, 2, 4-triazol-3-yl) phenyl) carboxamide (363.06 mg,1.47 mmol) were added to DMSO (10 mL) and cesium carbonate (613.21 mg,1.88 mmol) was added. The temperature is raised to 110 ℃ and the reaction is stirred for 16h. The reaction solution 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] + .
1 H NMR(400MHz,DMSO)δ8.67～8.65(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)
Step one: n-ethyl-4- (2-chloro-4- (neopentylamino) pyrimidin-5-yl) benzamide (compound 10-1)
Compound 5-2 (200 mg, 625.42. Mu. Mol), ethylamine hydrochloride (42.29 mg, 938.13. Mu. Mol) were added to DCM (20 mL), EDCI (179.84 mg, 938.13. Mu. Mol) and DMAP (229.22 mg,1.88 mmol) were added sequentially and stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by 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 (200 mg, 576.61. Mu. Mol) and N- (2-ethoxy-4- (4-methyl-1, 2, 4-triazol-3-yl) phenyl) carboxamide (333.70 mg,1.36 mmol) were added to DMSO (10 mL) and cesium carbonate (563.61 mg,1.73 mmol) was added. The temperature is raised to 110 ℃ and the reaction is stirred for 16h. 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 10 (20 mg).
ESI-MS(m/z):529.3[M+H] + .
1 H NMR(400MHz,DMSO)δ8.67～8.65(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
N 2 - ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -5- (furan-2-yl) -N 4 Neopentyl pyrimidine-2, 4-diamine (compound 11)
Step one: 2-chloro-5- (furan-2-yl) -N-neopentylpyrimidin-4-amine (Compound 11-1)
Will be converted intoCompounds 1-2 (1 g,3.59 mmol), furan-2-boronic acid (482.7 mg,4.31 mmol), bis (triphenylphosphine) palladium dichloride (257.1 mg,0.36 mmol), na 2 CO 3 (776.5 mg,7.18 mmol) was added to dioxane (20 mL), and the mixture was 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 chromatographed (DCM/meoh=20/1) -giving the title compound 11-1 (0.8 g).
ESI-MS(m/z):266.2[M+H] + .
Step two: n (N) 2 - ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -5- (furan-2-yl) -N 4 Neopentyl pyrimidine-2, 4-diamine (compound 11)
Compound 11-1 (70 mg,0.26 mmol), N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) carboxamide (82.4 mg,0.32 mmol), cs 2 CO 3 (176 mg,0.53 mmol) was added to DMSO (2 mL) and reacted at 100℃for 12 hours. Cooled to room temperature, water was added, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and the concentrated residue was separated by Prep-HPLC to give the title compound 11 (22 mg).
ESI-MS(m/z):448.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.76(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:
in the invention, all the compounds 1-8 are separated and purified by adopting Aglient 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 invention, but are not meant to limit the scope of the invention.
Test example 1: TTK kinase in vitro enzymatic Activity inhibition assay
Test system:
kinase: recombinant full-length human TTK, active (Signalchem, T20-10G-10)
A substrate: native protein, MBP (Signalchem, M42-51N)
The kit comprises: ADP-Glo Kinase Assay (Promega, V9101)
Test parameters:
TTK concentration: 6nM
MBP concentration: 0.7 mu M
ATP concentration: 20 mu M
Reaction buffer: 1 Xenzymatic buffer (Cisbio, 62 EZBFDC), 10mM MgCl 2 ，2mM DTTddH 2 O
Reaction time: 37 ℃ for 120 min
Termination time: 25 ℃,120 minutes
Detection time: 25 ℃,60 minutes
Enzyme-labeled instrument: BMG PHERAstar Luminescence
The test steps are as follows:
the mixture of test group (containing test compound and TTK enzyme), solvent group (containing no test compound and TTK enzyme), blank group (containing no test compound and TTK enzyme) and substrate MBP and ATP are added into reaction buffer solution, incubated for 120 min at 37 deg.C, 5 μl of the previous reaction mixture is taken to be mixed with 5 μl of ADP-Glo reagent, incubated for 120 min at 25 deg.C, and the enzymatic reaction is terminated. Then adding Detection Buffer (Detection Buffer) in the kit, incubating for 60 minutes at 25 ℃, placing the reaction plate in an enzyme-labeling instrument, and reading the chemiluminescent value of each well in the plate by adopting an endpoint method.
And (3) data processing:
with solvent group (containing TTK enzyme, no test compound)) As a negative control, the response buffer group (without TTK kinase and test compound) was used as a blank control, and the relative inhibition activity of each concentration group was calculated with inhibition ratio = 100% - (chemiluminescence value of test group-chemiluminescence value of blank group)/(chemiluminescence value of vehicle group-chemiluminescence value of blank group) ×100%. The half maximal Inhibitory Concentration (IC) of the compound was calculated by fitting a curve according to a four parameter model 50 )。
Test results:
inhibition of TTK activity by the compounds was determined as described above and the results are shown in table 1.
TABLE 1 TTK enzyme Activity inhibition test results
Numbering of compounds IC 50 (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
Conclusion: as can be seen from Table 1, the compounds of the present invention have a good inhibitory activity against TTK enzymes in vitro tests.

Claims (17)

1. A compound of formula (V) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein,
R 1 selected from:
R 2 selected from chlorine, fluorine, methoxy, ethoxy and methyl;
R 3 and R is 4 Each independently selected from hydrogen, C 1-6 Alkyl, said C 1-6 The alkyl group may be optionally substituted with one or more of the following groups: hydroxy, fluoro, chloro;
R 5 selected from-CH 2 OH、-COOH、CH 3 CONH-、
R 6 Selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy groups.
2. A compound of formula (V) according to claim 1 or a stereoisomer thereofOr a pharmaceutically acceptable salt thereof, wherein-NR 3 R 4 Selected from the group consisting of
3. A compound of formula (V) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 Is ethoxy; r is R 3 And R is 4 Each independently selected from hydrogen and C 1-6 An alkyl group; r is R 5 Selected from the group consisting of
R 6 Selected from H, methyl and fluoro.
4. A compound of formula (V) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 3, wherein-NR 3 R 4 Is that
5. The compound of claim 1, selected from the group consisting of:
or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound according to any one of claims 1-5, a stereoisomer of the compound or a mixture thereof, or a pharmaceutically acceptable salt of the compound, and one or more pharmaceutically acceptable carriers.
7. A method of preparing the pharmaceutical composition of claim 6, the method comprising combining a compound according to any one of claims 1-5, a stereoisomer of the compound or a mixture thereof, or a pharmaceutically acceptable salt of the compound with one or more pharmaceutically acceptable carriers.
8. A pharmaceutical formulation comprising a compound according to any one of claims 1-5, a stereoisomer of the compound or a mixture thereof, a pharmaceutically acceptable salt of the compound, or a pharmaceutical composition according to claim 6.
9. Use of a compound according to any one of claims 1-5, a stereoisomer of said compound or a mixture thereof, or a pharmaceutically acceptable salt of said compound, a pharmaceutical composition according to claim 6 or a pharmaceutical formulation according to claim 8 in the manufacture of a medicament for the prevention or treatment of a disease associated with TTK activity.
10. The use according to claim 9, wherein the disease associated with TTK activity is selected from tumors.
11. The use according to claim 10, wherein the tumor is selected from benign tumors and malignant tumors.
12. The use according to claim 10, wherein the tumour is selected from cancer.
13. The use according to claim 10, wherein the tumor is selected from melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, cervical cancer, thyroid cancer, chronic myelogenous leukemia, acute lymphoblastic leukemia, papillary thyroid cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, gastrointestinal stromal tumor, colon cancer.
14. The use according to claim 9, wherein the disease associated with TTK activity is selected from the group consisting of metastasis at a secondary site of a primary solid tumor, eosinophilia syndrome.
15. A process for the preparation of a compound of formula V,
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 As claimed in any one of claims 1 to 5;
Q 1 and Q 2 Is a leaving group; q (Q) 3 Is a halogen atom;
the method comprises the following steps:
step one: the compound V-1 reacts with the V-2 to obtain a compound V-3;
step two: coupling reaction is carried out on the compound V-3 and the compound V-4 to obtain a compound V-5;
step three: the compound V-5 reacts with V-6 to obtain the compound V.
16. The method of claim 15, wherein the leaving group is selected from a halogen atom, or R 7 S(O) q -a group wherein q is selected from 1 and 2, and R 7 Represents substituted C 1-6 Alkyl, substituted C 3-7 Cycloalkyl, substituted 3-7 membered monocyclic heterocycloalkyl, substituted phenyl, and substituted 5-6 membered monocyclic aromatic heterocyclic.
17. The production method according to claim 16, wherein the halogen atom is selected from a chlorine atom, a bromine atom or an iodine atom; the R is 7 S(O) q -the group is selected from methylsulfonyl, trifluoromethylsulfonyl and perfluorobutoxysulfonyl.
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