CN115785068A - KIF18A inhibitors - Google Patents
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- CN115785068A CN115785068A CN202211090930.1A CN202211090930A CN115785068A CN 115785068 A CN115785068 A CN 115785068A CN 202211090930 A CN202211090930 A CN 202211090930A CN 115785068 A CN115785068 A CN 115785068A
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Abstract
The invention discloses a KIF18A inhibitor. In particular to a compound shown in a general formula (1) and a preparation method thereof, and application of the compound shown in the general formula (1) and various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as a KIF18A inhibitor in preparation of antitumor drugsIts application is disclosed.
Description
The present application claims priority from chinese patent application 202111064364.2, filed 2021, 9, month 10. The present application refers to the above-mentioned chinese patent application in its entirety.
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a compound with a KIF18A protein inhibition effect, a preparation method thereof and application of the compound in preparing an anti-tumor medicament.
Background
Genomic instability is a common feature of most tumor cells. Most tumor cells have abnormal acquisition or deletion of chromosomes. Chromosomal instability of tumor cells can lead to the interaction of abnormal chromosomes with mitotic spindle microtubules (spindle microtubules), which in turn leads to chromosome segregation errors. Cells with chromosomal instability produce increased spindle microtubule polymerization and decreased spindle microtubule-to-centromere contact switching compared to cells with normal chromosomes. Thus, anti-mitotic therapies directed against the microtubule backbone may be particularly effective for cells with chromosomal instability.
Kinesins are a class of molecular motors that play important roles in cell division and intracellular vesicle and organelle transport. Mitotic kinesins play an important role in spindle assembly, chromosome segregation, centrosome segregation, and kinetics. Human kinesins are classified into 14 subtypes based on the difference in amino acid sequence of a motor domain, and the atpase activity located in the motor domain drives the protein to move unidirectionally along microtubules. The non-motor domain of these proteins is responsible for interacting with substrates, which can be used as substrates by a variety of membranous organelles, signal transduction scaffold systems, and chromosomes. Kinesins gain energy through ATP hydrolysis, moving substrates along polarized microtubules. Thus, kinesins are commonly referred to as "positive-end" or "negative-end" directional motors.
The KIF18A protein belongs to the kinesin-8 subtype. KIF18A protein is overexpressed in various types of cancers, such as lung, ovarian, cervical, breast, pancreatic, prostate, colon, and bladder cancers. Studies suggest that KIF18A affects the movement of the positive end of the mitogen microtubule to control proper chromosome location and spindle tone. In tumor cells with chromosomal instability, abnormal microtubule movement makes such cells particularly dependent on the KIF18A protein to reduce spindle microtubule-to-centromere contact switching and to limit microtubule growth (Nat commun.2021,12, 1213). When KIF18A protein is deleted in tumor cells with chromosomal instability, the center of the cell is fragmented and the mitotic progression is slowed or terminated. These phenomena do not occur in cells with normal chromosomes. Therefore, the activity of KIF18A protein does not have a great influence on the proliferation of normal cells, but is very critical for the growth of chromosome-unstable tumors.
Therefore, the development of KIF18A inhibitors is a new potential approach to combat tumors with chromosomal instability.
Disclosure of Invention
The invention provides a compound shown in a general formula (1) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
in the general formula (1):
x is-CR 4 Or N;
l is- (C = O) -NR 9 -or-NR 9 -(C＝O)-；
R 1 is-CN or-Z-R 10 Wherein Z is a bond, -C 0-4 Hydrocarbyl-, -NR 11 -、-NR 11 SO 2 -、-SO 2 NR 11 -、-NR 11 -S(＝O)(＝NH)-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO 2 -、-C 0-4 hydrocarbyl-O-, - (C = O) NR 11 -, -C (= N-OH) -or-NR 11 (C = O) -; or the group-Z-R 10 is-N = S (= O) - (R) 10 ) 2 Wherein the two R are 10 May be combined with the sulfur atom to which they are each attached to form a saturated or partially saturated 3-, 4-, 5-or 6-membered monocyclic ring containing 0, 1,2 or 3N atoms and 0, 1 or 2 atoms selected from O and S;
R 2 is halogen or a radical-Y-R 12 Wherein Y is a bond, -C 0-4 Alkyl-, -N (C) 0-1 Hydrocarbyl group) -C 0-4 Alkyl-, -C (= O) NR a R a (C 1-4 Alkyl) -, -O-C 0-4 Alkyl-, -S (= O) -, -SO 2 -、-SO 2 NR 12 -or-S (= O) (= NH) -;
R 3 is H, halogen, C 1-8 Hydrocarbyl or C 1-4 A halogenated hydrocarbon group;
R 4 is H, halogen, C 1-8 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -O-C 1-8 Hydrocarbyl or-O-R 4a Wherein R is 4a Is a saturated or partially saturated 3-, 4-, 5-or 6-membered monocyclic ring containing 0, 1,2 or 3N atoms and 0, 1 or 2 atoms selected from O and S;
R 5 is H, halogen, C 1-8 Alkyl or C 1-4 A haloalkyl group;
R 6 is H, halogen, C 1-8 Alkyl radical, C 1-4 Haloalkyl, -OH, -O-R 6a or-O-R 6b ；
R 7 Is H, halogen, C 1-8 Hydrocarbyl or C 1-4 A halogenated hydrocarbon group;
R 8 selected from the group consisting of:
R 13a 、R 13b 、R 13c 、R 13d 、R 13e 、R 13f 、R 13g 、R 13h 、R 13i 、R 13j 、R 13k and R 13l Each independently of the other being H, halogen, R 13m Or R 13n (ii) a Or R 13a And R 13b Pair, R 13c And R 13d Pair, R 13e And R 13f Para, R 13g And R 13h Pair, R 13i And R 13j To or R 13k And R 13l Each of the pairs may be independently spiro-linked to R with the carbon atom to which they are each attached 8 A saturated or partially saturated 3-, 4-, 5-, 6-membered monocyclic ring of rings; wherein the 3-, 4-, 5-, 6-membered monocyclic ring contains 0, 1,2, or 3N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, 6-membered monocyclic ring is substituted with 0, 1,2, or 3 groups selected from: F. cl, br, C 1-6 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -OR a 、-OC 1-4 Halogenated hydrocarbon radicals, CN, -NR a R a Or oxo;
R 9 is H or C 1-6 A hydrocarbyl group;
R 10 is H, R 10a Or R 10b ；
R 11 Is H, R 11a Or R 11b ；
R 12 Is R 12a Or R 12b ；
R 6a 、R 10a 、R 11a 、R 12a Or R 13m Is independently selected in each occurrence from: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-or 12-membered bicyclic ring containing 0, 1,2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, wherein said monocyclic and bicyclic rings may each independently optionally be substituted with 0, 1,2 or 3 of the following groups: F. cl, br, C 1-6 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -OR a 、-OC 1-4 Halogenated hydrocarbon radical, CN, -C (= O) R b 、-C(＝O)OR a 、-C(＝O)NR a R a 、-C(＝NR a )NR a R a 、-OC(＝O)R b 、-OC(＝O)NR a R a 、-OC 2-6 Hydrocarbyl radical NR a R a 、-OC 2-6 Hydrocarbyl radicals OR a 、-SR a 、-S(＝O)R b 、-S(＝O) 2 R b 、-S(＝O) 2 NR a R a 、-NR a R a 、-N(R a )C(＝O)R b 、-N(R a )C(＝O)OR b 、-N(R a )C(＝O)NR a R a 、-N(R a )C(＝NR a )NR a R a 、-N(R a )S(＝O) 2 R b 、-N(R a )S(＝O) 2 NR a R a 、-NR a C 2-6 Hydrocarbyl radical NR a R a 、-NR a C 2-6 Hydrocarbyl OR a 、-C 1-6 Hydrocarbyl radical NR a R a 、-C 1-6 Hydrocarbyl radicals OR a 、-C 1-6 Hydrocarbyl group N (R) a )C(＝O)R b 、-C 1-6 Hydrocarbyl OC (= O) R b 、-C 1-6 Hydrocarbyl C (= O) NR a R a 、-C 1-6 Hydrocarbyl C (= O) OR a 、R 14 And oxo;
R 6b 、R 10b 、R 11b 、R 12b or R 13n Is independently selected in each case from: c 1-6 (ii) a hydrocarbyl group, wherein the hydrocarbyl group may be optionally substituted with 0, 1,2,3, 4, or 5 of the following groups: F. cl, br, -R a 、-OR a 、-OC 1-4 Halogenated hydrocarbon groups and CN;
R 14 independently in each instance selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-or 12-membered bicyclic ring containing 0, 1,2 or 3N atoms and 0 or 1 atom selected from O and S, wherein said monocyclic ring and bicyclic ring each independently may be optionally substituted with 0, 1,2 or 3 of the following groups: F. cl, br, C 1-6 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -OR a 、-OC 1-4 Halogenated hydrocarbon group, CN、-C(＝O)R b 、-C(＝O)OR a 、-C(＝O)NR a R a 、-C(＝NR a )NR a R a 、-OC(＝O)R b 、-OC(＝O)NR a R a 、-OC 2-6 Hydrocarbyl radical NR a R a 、-OC 2-6 Hydrocarbyl OR a 、-SR a 、-S(＝O)R b 、-S(＝O) 2 R b 、-S(＝O) 2 NR a R a 、-NR a R a 、-N(R a )C(＝O)R b 、-N(R a )C(＝O)OR b 、-N(R a )C(＝O)NR a R a 、-N(R a )C(＝NR a )NR a R a 、-N(R a )S(＝O) 2 R b 、-N(R a )S(＝O) 2 NR a R a 、-NR a C 2-6 Hydrocarbyl radical NR a R a 、-NR a C 2-6 Hydrocarbyl OR a 、-C 1-6 Hydrocarbyl radicals NR a R a 、-C 1-6 Hydrocarbyl OR a 、-C 1-6 Hydrocarbyl group N (R) a )C(＝O)R b 、-C 1-6 Hydrocarbyl OC (= O) R b 、-C 1-6 Hydrocarbyl C (= O) NR a R a 、-C 1-6 Hydrocarbyl C (= O) OR a And oxo;
R a each occurrence independently is H or R b (ii) a And is
R b In each case independently C 1-6 A hydrocarbyl group, a phenyl group, or a benzyl group, wherein the hydrocarbyl group may be optionally substituted with 0, 1,2, or 3 of the following groups: halogen, -OH, -OC 1-4 Hydrocarbyl, -NH 2 、-NHC 1-4 Hydrocarbyl, -OC (= O) C 1-4 Hydrocarbyl or-N (C) 1-4 Hydrocarbyl) C 1-4 A hydrocarbyl group; and wherein said phenyl and benzyl groups may each independently be optionally substituted with 0, 1,2 or 3 of the following groups: halogen, C 1-4 Hydrocarbyl radical, C 1-3 Halogenated hydrocarbon radicals, -OH, -OC 1-4 Hydrocarbyl, -NH 2 、-NHC 1-4 Hydrocarbyl, -OC (= O) C 1-4 Hydrocarbyl or-N (C) 1-4 Hydrocarbyl) C 1-4 A hydrocarbyl group.
In another preferred embodiment, itIn the general formula (1), when X is-CR 4 When represented by formula (1 a) and formula (1 b):
in another preferred embodiment, wherein in said general formula (1), when X is-CR 4 In which R is 4 Is H, methyl or F, preferably H.
In another preferred example, wherein in the general formula (1), when X is N, it has the formula (1 c) and the formula (1 d):
in another preferred embodiment, wherein in said general formula (1), R 9 Is H, methyl or ethyl, preferably H.
In another preferred embodiment, wherein in the general formula (1), R is 13c 、R 13d 、R 13e 、R 13f 、R 13g 、R 13h 、R 13i 、R 13j 、R 13k And R 13l Each independently of the other being H, halogen, C 1-6 Hydrocarbyl radicals or C 1-4 A halogenated hydrocarbon group; and R is 13a And R 13b R in pair 13a And R 13b The carbon atoms to which they are each attached may combine to form a spiro bond to R 8 A saturated 3-, 4-or 5-membered monocyclic ring of rings; wherein the ring contains 0, 1,2 or 3N atoms and 0, 1 or 2 atoms selected from O and S; preferably, R 13c 、R 13d 、R 13e 、R 13f 、R 13g 、R 13h 、R 13i 、R 13j 、R 13k And R 13l Each independently is H, methyl or ethyl; and R is 13a And R 13b R in pair 13a And R 13b The carbon atoms to which they are each attached may combine to form a spiro bond to R 8 A cyclopropyl, cyclobutyl or cyclopentyl ring of the ring.
In another preferred embodiment, wherein in said general formula (1), the structural unit
Comprises the following steps:
preferably a
In another preferred embodiment, wherein in the general formula (1), Z is a bond, -NH-, -NHSO 2 -、-SO 2 NH-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO 2 -, - (C = O) -, - (C = O) NH-, or-NH (C = O) -.
In another preferred embodiment, wherein in the general formula (1), R is 10 Selected from (a) H; or (b) C 1-6 (ii) a hydrocarbyl group which may be optionally substituted with 0, 1,2 or 3 of the following groups: F. cl, br, -OH or-OCH 3 (ii) a Or (c) when said group-Z-R 10 is-N = S (= O) - (R) 10 ) 2 Wherein the two R are 10 May combine with the sulfur atom to which they are each attached to form a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring containing 0, 1,2 or 3N atoms and 0 or 1 atom selected from O and S, which is substituted with 0, 1,2 or 3 groups selected from: F. cl, br, C 1-6 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -C 1-6 Hydrocarbyl OH, -OCH 3 、-NH 2 Or oxo.
In another preferred embodiment, wherein in the general formula (1), R 1 is-CN or a group-Z-R 10 Wherein Z is a bond, -NH-, -NHSO 2 -、-SO 2 NH-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO 2 -, - (C = O) NH-, or-NH (C = O) -; and R is 10 Selected from the group consisting of:
(a)H；
(b) Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, tetrahydrofuryl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuryl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl,
And wherein each of said rings may each independently be optionally substituted with 0, 1,2 or 3 of the following groups: OH, F, methyl, -CH 2 OH、-C(＝O)OCH 3 、-C(＝O)OC(CH 3 ) 3 、NH 2 CN and oxo; preferably oxetanyl, cyclopropyl; or
(c) OCH by 0, 1,2 or 3 OH, F, -C (= O) OCH 3 、-NH 2 、-NH(CH 3 ) or-N (CH) 3 ) 2 Substituted C 1-6 A hydrocarbyl group; preferably C substituted by 0, 1,2 or 3 OH groups 1-6 A hydrocarbyl group; more preferably a C1-6 hydrocarbyl group substituted with 1 OH group.
In another preferred embodiment, wherein in said general formula (1), wherein said group-Z-R 10 is-N = S (= O) - (R) 10 ) 2 Wherein two R are 10 Pairs may combine with the sulfur atom to which they are each attached to form a saturated or partially saturated 3-, 4-, 5-or 6-membered monocyclic ring containing 0, 1,2 or 3N atoms and 0, 1 or 2 atoms selected from O and S; preferred radicals are the groups-Z-R 10 Selected from the group consisting of:
in another preferred embodiment, wherein in the general formula (1), R 1 Is a group-Z-R 10 Wherein Z is-NHSO 2 -or-SO 2 NH-; and R is 10 Is oxetanyl, cyclopropyl, or R 10 Is C substituted by 0, 1,2 or 3 OH groups 1-6 A hydrocarbyl group; preferably, R 1 Is a radical-Z-R 10 Wherein Z is-NHSO 2 -or-SO 2 NH-, and R 10 is-CH 2 -CH 2 -OH or-CH (CH) 3 )-CH 2 -OH; more preferably Z is-NHSO 2 -, and R 10 is-CH 2 -CH 2 -OH。
In another preferred embodimentWherein in the general formula (1), R is 2 Is halogen or a radical-Y-R 12 Wherein Y is a bond, -NH- (CH) 2 ) 0-4 -or-O- (CH) 2 ) 0-4 -; and R is 12 Is a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-or 12-membered bicyclic ring containing 0, 1,2 or 3N atoms and 0 or 1 atom selected from O and S, wherein said monocyclic and bicyclic rings may each independently optionally be substituted with 0, 1,2 or 3 of the following groups: F. cl, br, C 1-6 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -OH, -OC 1-4 Halogenated hydrocarbon group, CN, R 14 And oxo; or R 12 Is C 1-6 A hydrocarbyl group which may be optionally substituted with 0, 1,2,3, 4 or 5 of the following groups: F. cl, br, -OH, -OC 1-4 A halogenated hydrocarbon group or CN.
In another preferred embodiment, wherein in the general formula (1), R 2 Is a saturated 5-or 6-membered monocyclic ring, wherein each of said rings contains 0, 1 or 2N atoms and 0 or 1O atoms, and wherein each of said rings is substituted with 0, 1,2 or 3 groups selected from: F. cl, br, C 1-6 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -OH, -OC 1-4 Halogenated hydrocarbon group, CN, R 14 And oxo.
In another preferred embodiment, wherein in the general formula (1), R 2 Is (a) halogen; (b) group-Y-R 12 Wherein Y is a bond; and R is 12 Is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuryl,
Wherein each said ring is substituted with 0, 1,2 or 3 groups selected from:F. cl, br, methyl, CF 3 、-OH、-OCHF 2 CN and oxo; or (c) a group-Y-R 12 Wherein Y is-NH-, -O- (CH) 2 )-、-O-(CH 2 )-(CH 2 ) -or-O- (CH) 2 )-(CH 2 )-(CH 2 ) -, and wherein R 12 Is composed of
Or R 12 Is C 1-6 A hydrocarbyl group which may be optionally substituted with 0, 1,2,3, 4 or 5 of the following groups: F. cl, br, methyl, CF3, -OH or CN.
In another preferred embodiment, wherein in the general formula (1), R 2 Is morpholinyl or piperidinyl, which morpholinyl and piperidinyl groups may be optionally substituted with 0, 1,2 or 3 of: F. cl, br, methyl, CF 3 、-OH、-OCHF 2 And CN.
In another preferred embodiment, wherein in the general formula (1), R is 2 Is piperidinyl substituted with 1,2 or 3 fluoro groups.
In another preferred embodiment, wherein in the general formula (1), R 2 Comprises the following steps:
in another preferred embodiment, wherein in the general formula (1), R 2 Is morpholinyl substituted by 1,2 or 3 methyl groups.
In another preferred embodiment, wherein in the general formula (1), R 2 Is composed of
In another preferred embodiment, wherein in the general formula (1), R is 10 Selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl or 1,3, 4-oxathiazinoalkyl.
In another preferred embodiment, wherein in the general formula (1), R 3 Is H.
In another preferred embodiment, wherein in the general formula (1), R is 4 Is H or F, preferably H.
In another preferred embodiment, wherein in the general formula (1), R 5 Is H or F, preferably H.
In another preferred embodiment, wherein in the general formula (1), R is 6 Is H or F, preferably H.
In another preferred embodiment, wherein in the general formula (1), R 7 Is H.
In various embodiments of the present invention, the compound of formula (1) has one of the following structures:
another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1), or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as an active ingredient.
The invention also provides application of the compound shown as the general formula (1) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof or the pharmaceutical composition in preparing medicines for treating, regulating or preventing diseases related to KIF18A protein.
Still another object of the present invention is to provide a method for treating, regulating or preventing diseases related to KIF18A protein-mediated diseases, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition.
Through synthesis and careful study of various novel compounds having KIF18A protein inhibitory effect, the inventors found that the compounds of the general formula (1) unexpectedly have strong KIF18A protein inhibitory activity.
It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
Synthesis of Compounds
The following specifically describes the preparation process of the compound of the present invention, but these specific processes do not set any limit to the present invention.
The compounds described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds may be obtained synthetically or from commercial sources, such as, but not limited to, aldrich Chemical co. The compounds described herein and other related compounds having various substituents can be synthesized using well-known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed, vols.A and B (Plenum 2000, 2001), green and Wuts, PROTECTIVE GROUPS IN ORGANIC synthieSIS 3 rd The method in ed., (Wiley 1999). The general method of preparation of the compounds can be varied by the use of appropriate reagents and conditions for introducing different groups into the formulae provided herein.
In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, and the like, are not limited to the following explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains. In one aspect, the invention also provides a process for the preparation of said compounds, wherein the compounds of general formula (1) can be prepared using the following general reaction scheme 1,2,3 or 4:
general reaction scheme 1
Embodiments of the compounds of formula (1) can be prepared according to general reaction scheme 1, wherein R 1 、R 2 、R 3 、R 5 、R 6 、R 7 、R 8 X is as defined above; w 1 Represents fluorine, chlorine, bromine or iodine; h represents hydrogen; n represents nitrogen; r 1 Examples of the reagent include (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetan-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropane-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (10) 2-aminoethyl-1-ol and (11) cyclopropanethiol. As shown in general reaction scheme 1, amidation reaction of compound 1-1 and compound 1-2 to produce compound 1-3, compound 1-3 and R 1 The reagents 1-4 react to produce compounds 1-5.
General reaction scheme 2
Embodiments of the compounds of formula (1) can be prepared according to general reaction scheme 2, wherein R 1 、R 2 、R 3 、R 5 、R 6 、R 7 、R 8 X is as defined above; w 1 Represents fluorine, chlorine, bromine or iodine, H represents hydrogen; n represents nitrogen; r 1 Examples of the reagent include (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetan-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropane-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (10) 2-aminoethyl-1-ol and (11) cyclopropanethiol. As shown in the general reaction scheme 2, the amidation reaction of the compound 2-1 and the compound 2-2 generates the compound 2-3, and the compound 2-3 reacts with R 1 And reacting the reagent 2-4 to generate a compound 2-5.
General reaction scheme 3
Embodiments of the compounds of formula (1) may be prepared according to general reaction scheme 3, wherein R 1 、R 2 、R 3 、R 5 、R 6 、R 7 、R 8 X is as defined above; w 1 Represents fluorine, chlorine, bromine or iodine; h represents hydrogen; n represents nitrogen; p 1 A protecting group which is an ester group; r 1 Examples of the reagent include (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetan-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropane-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (10) 2-aminoethyl-1-ol and (11) cyclopropanethiol. As shown in general reaction scheme 3, compound 3-1 is reacted with R 1 The reagent 3-2 reacts to generate a compound 3-3, and the compound 3-3 removes the ester protecting group P 1 To obtain a compound 3-4, and carrying out amidation reaction on the compound 3-4 and the compound 3-5 to generate a compound 3-6.
General reaction scheme 4
Embodiments of the compounds of formula (1) can be prepared according to general reaction scheme 4, wherein R 1 、R 2 、R 3 、R 5 、R 6 、R 7 、R 8 X is as defined above; w 1 Represents fluorine, chlorine, bromine or iodine; h represents hydrogen; n represents nitrogen; p 2 A protecting group for an amine group; r 1 Examples of the reagent include (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetan-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (10) 2-aminoethyl-1-ol and (11) cyclopropanethiol. As shown in general scheme 4, compound 4-1 is reacted with R 1 The reagent 4-2 reacts to generate a compound 4-3, and the amino protecting group P is removed from the compound 4-3 2 Obtaining a compound 4-4, and carrying out amidation reaction on the compound 4-4 and the compound 4-5 to generate a compound 4-6.
Further forms of the compounds
"pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, which does not abolish the biological activity or properties of the compound and which is relatively non-toxic, e.g., by being administered to an individual without causing unwanted biological effects or interacting in a deleterious manner with any of its components contained therein.
The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some specific aspects, the pharmaceutically acceptable salt is obtained by reacting the compound of formula (1) with an acid, such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, etc., an organic acid, e.g., formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., and an acidic amino acid, e.g., aspartic acid, glutamic acid, etc.
References to pharmaceutically acceptable salts are understood to include solvent addition forms or crystalline forms, especially solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of the compounds of formula (1) are conveniently prepared or formed as described herein. For example, the hydrate of the compound of formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, using an organic solvent including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to unsolvated forms for purposes of the compounds and methods provided herein.
In other embodiments, the compounds of formula (1) are prepared in different forms, including, but not limited to, amorphous, pulverized, and nano-sized forms. In addition, the compound of formula (1) includes crystalline forms, and may also be polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
In another aspect, the compounds of formula (1) may exist at chiral centers and/or axial chirality and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers. Each chiral center or axis chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
The compounds of the invention may be present inThe one or more atoms comprising the compound include unnatural proportions of atomic isotopes at the atoms. For example, the compound may be labeled with a radioisotope, such as tritium ( 3 H) Iodine-125 (1) 125 I) And C-14 ( 14 C) .1. The For another example, deuterium can be used to replace a hydrogen atom to form a deuterated compound, the bond formed by deuterium and carbon is stronger than the bond formed by common hydrogen and carbon, and compared with an undeuterated medicament, the deuterated medicament has the advantages of reducing toxic and side effects, increasing medicament stability, enhancing curative effect, prolonging medicament half-life period in vivo and the like. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
Term(s)
Unless otherwise defined, terms used in this application, including the specification and claims, are defined as follows. It must be noted that, in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. If not otherwise stated, conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. In this application, "or" and "means" and/or "if not otherwise stated.
Unless otherwise specified, "C" is α-β By hydrocarbyl "is meant a hydrocarbyl group containing a minimum of a and a maximum of β carbon atoms in a branched or linear relationship, where a and β represent integers. The hydrocarbyl groups described in this section may also contain one or two double or triple bonds. C 0 The designation of hydrocarbyl represents a direct bond. C 1-6 Examples of hydrocarbyl groups include, but are not limited to, the following:
unless otherwise specified, "C α-β Halogenated hydrocarbyl "means a hydrocarbyl group as described above in which any number (at least one) of the hydrogen atoms attached to the hydrocarbyl chain are replaced with F, cl, br, or I.
Unless otherwise specified, "oxo" and "thio" mean = O (e.g., carbonyl) and = S (e.g., thiocarbonyl), respectively.
Unless otherwise specified, "halo" or "halogen" means a halogen atom selected from F, cl, br, and I.
Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom. Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens. Preferred alkoxy groups are selected from OCH 3 、OCF 3 、CHF 2 O、CF 3 CH 2 O、 i- PrO、 n- PrO、 i- BuO、 n- BuO or t- BuO。
Unless otherwise specified, "bicyclic" means a group having two connecting rings. The bicyclic ring can be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (ring atoms include, for example, 1,2 or 3 heteroatoms, such as N, O or S, in addition to carbon atoms). Both rings may be aliphatic (e.g., decalin and norbornane), or may be aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin). Bicyclic rings include (a) spiro compounds in which the two rings share only a single atom (the spiro atom, which is typically a quaternary carbon). Examples of spiro compounds include, but are not limited to:
(b) Fused bicyclic compounds, wherein the two rings share two adjacent atoms. I.e., the rings share a covalent bond, i.e., the bridgehead atoms are directly connected (e.g., alpha-thujaene and decalin). Examples of fused bicyclic rings include, but are not limited to:
and (c) a bridged bicyclic compound in which the two rings share three or more atoms and the two bridgehead atoms are separated by a bridge comprising at least one atom. For example, norbornane, also known as bicyclo [2.2.1] heptane, can be thought of as a pair of cyclopentane rings, each sharing three of their five carbon atoms. Examples of bridged bicyclic rings include, but are not limited to:
unless otherwise specified, "carbocycle" or "carbocyclic" means a ring that is encompassed by itself or in combination with other terms, meaning "C α-β Cyclic forms of hydrocarbyl groups ". Examples of carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinanyl, norcareyl, bicyclo [1.1.1]Pentyl alkyl, bicyclo [2.1.1 ] s]Hexyl and the like.
Unless otherwise specified, "heterocycle" or "heterocyclic" means a ring containing at least one carbon atom and at least one other atom selected from N, O, and S. Examples of heterocycles that may appear in the claims include, but are not limited to, the following:
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
Substituent group' -O-CH 2 -O- "means that two oxygen atoms in the substituent are attached to two adjacent carbon atoms of the heterocycloalkyl, aryl or heteroaryl group, such as:
when the number of one linking group is 0, e.g. - (CH) 2 ) 0 -，Represents that the linking group is a single bond.
When one of the variables is selected from a bond, it means that the two groups to which it is attached are directly linked, for example X-L-Y where L represents a bond means that the structure is actually X-Y.
The term "membered ring" includes any cyclic structure. The term "element" is intended to mean the number of backbone atoms constituting a ring. For example, cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thienyl are five-membered rings.
The term "fragment" refers to a specific part or functional group of a molecule. Chemical moieties are generally considered to be chemical entities contained in or attached to a molecule.
By solid wedge-shaped keys (unless otherwise indicated)
) And wedge-shaped virtual bond: (
) Representing the absolute configuration of a solid center by means of straight solid-line bonds (
) And straight dotted bonds: (
) The relative configuration of the stereocenter is shown, by wavy lines (
) Represents a wedge-shaped solid-line key (
) Or wedge dotted bond (A)
) Or by wavy lines (
) Represents a straight solid-line key (
) Or straight dotted bond: (
)。
Unless otherwise indicated, use
Represents a single bond or a double bond.
Specific pharmaceutical and medical terms
The term "acceptable", as used herein, means that a prescribed component or active ingredient does not unduly adversely affect the health of the general therapeutic target.
The terms "treat," "treatment process," or "therapy" as used herein include alleviating, inhibiting, or ameliorating a symptom or condition of a disease; inhibiting the generation of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or condition, such as controlling the development of a disease or condition; alleviating the disease or symptoms; regression of the disease or symptoms; alleviating a complication caused by the disease or symptom, or preventing or treating a symptom caused by the disease or symptom.
As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom, or condition, particularly severity, delay onset, slow progression, or reduce duration of a condition. Whether fixed or temporary, continuous or intermittent, may be attributed to or associated with administration.
"active ingredient" refers to a compound of the present invention, as well as pharmaceutically acceptable inorganic or organic salts of the compound of the present invention. The compounds of the present invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
The terms "compound", "composition", "medicament" or "drug" are used interchangeably herein and refer to a compound or composition that, when administered to an individual (human or animal), is capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
The term "administering" or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug (produg), derivative (derivative), or analog (analog) of the active compound, and the like.
Although the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain standard deviations found in their respective testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard error of the mean, as considered by those skilled in the art. Except in the experimental examples, or where otherwise explicitly indicated, all ranges, amounts, values and percentages herein used (e.g. to describe amounts of material, length of time, temperature, operating conditions, quantitative ratios and the like) are to be understood as modified by the word "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, these numerical parameters are to be understood as meaning both the number of significant digits indicated and the number resulting from applying ordinary rounding techniques.
Unless defined otherwise herein, the scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Furthermore, as used herein, a singular noun covers a plural of that noun without conflicting context; the use of plural nouns also covers the singular form of such nouns.
Therapeutic use
The invention provides compounds or pharmaceutical compositions of the invention having general formula (1) that are useful for inhibiting KIF18A protein in general, and thus for treating one or more disorders associated with KIF18A protein activity. Thus, in certain embodiments, the present invention provides methods for treating a KIF18A protein-mediated disorder, comprising the step of administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof.
In some embodiments, there is provided a method for the treatment of cancer, the method comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of general structural formula (1). In some embodiments, the cancer is mediated by KIF18A protein. In other embodiments, the cancer is a hematologic cancer and a solid tumor, including, but not limited to, hematologic malignancies (leukemias, lymphomas, myelomas including multiple myeloma, myelodysplastic syndrome, and myeloproliferative family syndrome) and solid tumors (carcinomas such as prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue cancers and osteosarcoma, and interstitial tumors), and the like.
Route of administration
The compound and the pharmaceutically acceptable salt thereof can be prepared into various preparations, wherein the compound or the pharmaceutically acceptable salt thereof contains the compound or the pharmaceutically acceptable salt thereof in a safe and effective dose range and a pharmaceutically acceptable excipient or carrier. Wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the age, condition, course of treatment and other specific conditions of a treated subject.
"pharmaceutically acceptable excipient or carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" as used herein refers to compositionsThe components of (a) can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifiers (e.g. propylene glycol, glycerol, mannitol, sorbitol etc.)
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
When the compounds of the present invention are administered, they may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) Disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such a composition may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using pharmaceutical compositions, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the administration is a pharmaceutically acceptable and effective dose, and the daily dose for a human of 60kg body weight is usually 1 to 2000mg, preferably 50 to 100mg. Of course, the particular dosage will also take into account such factors as the route of administration, the health of the patient, and the like, which are within the skill of the skilled practitioner.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any suitable combination and each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
Detailed Description
The various specific aspects, features and advantages of the compounds, methods and pharmaceutical compositions described above are set forth in detail in the following description, which makes the present invention clear. It should be understood herein that the detailed description and examples, while indicating specific embodiments, are given by way of illustration only. After reading the description of the invention, one skilled in the art can make various changes or modifications to the invention, and such equivalents fall within the scope of the invention as defined in the application.
In all of the embodiments described herein, the first, 1 H-NMR was recorded using a Vian Mercury 400 NMR spectrometer with chemical shifts expressed in delta (ppm); the silica gel used for separation is not specified to be 200-300 meshes, and the mixture ratio of the eluent is volume ratio.
The invention employs the following abbreviations: (Boc) 2 O represents di-tert-butyl dicarbonate; CDCl 3 Represents deuterated chloroform; cs 2 CO 3 Represents cesium carbonate; cuI represents cuprous iodide; etOAc for ethyl acetate; hexane stands for n-Hexane; HPLC for high performance liquid chromatography; meCN represents acetonitrile; DCE represents 1, 2-dichloroethane; DCM represents dichloromethane; DIPEA stands for diisopropylethylamine; 1,4-Dioxane represents 1, 4-Dioxane; DMF represents N, N-dimethylformamide; DMAP for 4- (dimethyl)Amino) pyridine; DMSO represents dimethyl sulfoxide; hr represents hour; HATU stands for N- [ (dimethylamino) -1H-1,2, 3-triazole- [4,5-b]Pyridine-1-methylene]-N-methylmethanamine hexafluorophosphate-N-oxide; IPA stands for isopropanol; min represents minutes; k is 2 CO 3 Represents potassium carbonate; KOAc represents potassium acetate; k 3 PO 4 Represents potassium phosphate; liBH 4 Represents lithium borohydride; min represents min; meOH represents methanol; MS represents mass spectrum; NMR stands for nuclear magnetic resonance; pd/C represents palladium carbon; pd (PPh) 3 ) 4 Represents palladium tetratriphenylphosphine; pd 2 (dba) 3 Represents tris (dibenzylideneacetone) dipalladium (0); PE represents petroleum ether; ruPhos Pd G 3 Representative (2-dicyclohexylphosphino-2 '6' -diisopropoxy-11 ' -biphenyl) [2- (2 ' -amino-11 ' -biphenyl ]]Palladium (II) methanesulfonate; sarcosine represents Sarcosine; TFA represents trifluoroacetic acid; t is 3 P represents 1-propyl phosphoric anhydride; xantPhos stands for 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene; TLC for thin layer chromatography; XPhos stands for 2-dicyclohexylphosphonium-2 ',4',6' -triisopropylbiphenyl.
EXAMPLE 1 Synthesis of Compound 1
Step 1: synthesis of Compound int _ 1-3:
int _1-1 (12.9 g, 100mmol) was dissolved in 1,4 dioxane (150 mL), cesium carbonate (34.2 g, 105mmol) and int _1-2 (12.7 g, 105mmol) were added, the temperature was raised to 80 ℃ for reaction for 24 hours, and LC-MS monitoring indicated that the reaction was complete. The reaction was diluted with water (500 mL), the aqueous phase was extracted with ethyl acetate (500ml × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to give the crude product (19.3 g, yield: 90.1%). The crude product was used directly in the next reaction.
ESI-MS m/z:215[M+H] + 。
And 2, step: synthesis of the Compound int _ 1-5:
int-1-4 (15g, 56.3mmol) was dissolved in methanol (150 mL), concentrated sulfuric acid (2.5 mL) was added, the temperature was raised to 80 ℃ and the reaction was allowed to react for 4 hours, and LC-MS monitoring indicated the end of the reaction. The reaction solution was concentrated under reduced pressure to give a crude product, which was dissolved in ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to give a white solid (14 g, yield: 89%) which was used directly in the next reaction.
ESI-MS m/z:281[M+H] +
And 3, step 3: synthesis of Compound int _ 1-7:
int _1-5 (14g, 49.9mmol) was dissolved in DMSO (100 mL), cesium carbonate (23.4g, 71.7mmol) and int _1-6 (6.98g, 62.8mmol) were added, the temperature was raised to 90 ℃ for 24 hours, and LC-MS monitoring indicated that the reaction was complete. The reaction mixture was diluted with water (500 mL), the aqueous phase was extracted with ethyl acetate (100ml × 3), and the organic phase was dried over anhydrous sodium sulfate. Filtering the organic phase, distilling under reduced pressure to obtain crude product, and subjecting the crude product to column chromatography (SiO) 2 EtOAc: hexane = 1) to give the target product (16.3 g, yield: 88%).
ESI-MS m/z:372[M+H] + 。
And 4, step 4: synthesis of Compound int _ 1-8:
int-1-7 (16.3g, 43.9mmol) was dissolved in a mixed solvent of methanol (100 ml) and water (10 ml), and lithium hydroxide (2.1g, 87.8mmol) was added thereto at room temperature, followed by stirring at room temperature for reaction for 6 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (17 g, crude product). The crude product was used directly in the next reaction.
ESI-MS m/z:358[M+H] +
And 5: synthesis of Compound int _ 1-9:
int-1-8 (2.3g, 6.4 mmol) was dissolved in DMF (20 mL), int-1-3 (1.5g, 7 mmol), DIPEA (1.24g, 9.6 mmol) and HATU (3.65g, 9,6 mmol) were added, and the reaction mixture was stirred at room temperature for 10 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product is subjected to column chromatography (SiO) 2 DCM: meOH = 100) to give a solid (2.5 g, yield: 71%).
ESI-MS m/z:554[M+H] +
Step 6: synthesis of Compound 1:
int-1-10 (168.9mg, 1.35mmol), sarcosine (80.1mg, 0.9mmol), cuprous iodide (85.7mg, 0.45mmol) and potassium phosphate (764.1mg, 3.6mmol) were dissolved in DMF (10 mL), argon was substituted three times, int-1-9 (500mg, 0.9mmol) was added, and the reaction mixture was heated to 100 ℃ under argon for reaction for 3 hours. LC-MS monitoring indicated the reaction was complete. Cooling the reaction solution to room temperature, spin-drying the reaction solution, and performing column chromatography (SiO) 2 EtOAc: hexane = 1) to give a solid (373 mg, yield: 75.3%).
1 H NMR(400MHz,DMSO-d6)δ13.11(s,1H),8.83(d,J＝2.8Hz,1H),8.07–7.83(m,2H),7.19(d,J＝2.1Hz,1H),7.03(dd,J＝8.7,2.1Hz,1H),3.73(t,J＝6.5Hz,2H),3.59(t,J＝5.9Hz,4H),3.26(t,J＝6.5Hz,2H),2.95(d,J＝5.5Hz,4H),2.06(dt,J＝15.7,9.0Hz,4H),1.66(s,4H),0.34(d,J＝25.0Hz,4H).
ESI-MS m/z:551[M+H] +
EXAMPLE 2 Synthesis of Compound 2
Step 1: synthesis of Compound int _ 2-2:
int-1 (12.9 g, 100mmol) was dissolved in DMSO (150 mL), cesium carbonate (34.2 g, 105mmol) and int-2-1 (10.6 g, 105mmol) were added, the reaction was allowed to warm to 110 ℃ for 24 hours, and LC-MS monitoring indicated the end of the reaction. The reaction was diluted with water (500 mL), the aqueous phase was extracted with ethyl acetate (500ml × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to give the crude product (20 g, yield: 90%). The crude product was used directly in the next reaction.
ESI-MS m/z:195[M+H] + 。
Step 2: synthesis of the Compound int _ 1-5:
int-1-4 (15g, 56.3mmol) was dissolved in methanol (150 mL), concentrated sulfuric acid (2.5 mL) was added, the temperature was raised to 80 ℃ and the reaction was allowed to react for 4 hours, and LC-MS monitoring indicated the end of the reaction. The reaction solution was concentrated under reduced pressure to give a crude product, which was dissolved in ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to give a white solid (14 g, yield: 89%) which was used directly in the next reaction.
ESI-MS m/z:281[M+H] +
And step 3: synthesis of Compound int _ 1-7:
int _1-5 (14g, 49.9mmol) was dissolved in DCesium carbonate (23.4g, 71.7 mmol) and int _1-6 (6.98g, 62.8mmol) were added to MSO (100 mL), and the reaction was allowed to proceed for 24 hours while the temperature was raised to 90 ℃ and the reaction was terminated by LC-MS monitoring. The reaction mixture was diluted with water (500 mL), the aqueous phase was extracted with ethyl acetate (100ml × 3), and the organic phase was dried over anhydrous sodium sulfate. Filtering the organic phase, distilling under reduced pressure to obtain crude product, and subjecting the crude product to column chromatography (SiO) 2 EtOAc: hexane = 1) to give the desired product (16.3 g, yield: 88%).
ESI-MS m/z:372[M+H] + 。
And 4, step 4: synthesis of Compound int _ 1-8:
int-1-7 (16.3g, 43.9mmol) was dissolved in a mixed solvent of methanol (100 ml) and water (10 ml), and lithium hydroxide (2.1g, 87.8mmol) was added thereto at room temperature, followed by stirring at room temperature for 6 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (17 g, crude product). The crude product was used directly in the next reaction.
ESI-MS m/z:358[M+H] +
And 5: synthesis of Compound int _ 2-3:
int-1-8 (2.3g, 6.4 mmol) was dissolved in DMF (20 mL), int-2 (1.36g, 7 mmol), DIPEA (1.24g, 9.6 mmol) and HATU (3.65g, 9,6 mmol) were added, and the reaction mixture was stirred at room temperature for 10 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product is subjected to column chromatography (SiO) 2 DCM: meOH = 100) to give a solid (2.6 g, yield: 76%).
ESI-MS m/z:534[M+H] +
Step 6: synthesis of Compound 2:
int _1-10 (168.9mg, 1.35mmol), sarcosine (80.1mg, 0.9mmol), cuprous iodide (85.7mg, 0.45mmol) and potassium phosphate (764.1mg, 3.6mmol) were dissolved in DMF (10 mL), argon gas was substituted three times, int _2-3 (480mg, 0.9mmol) was added, and the reaction mixture was heated to 100 ℃ under argon protection for 3 hours. LC-MS monitoring indicated the reaction was complete. Cooling the reaction solution to room temperature, spin-drying the reaction solution, and performing column chromatography (SiO) 2 EtOAc: hexane = 1) to give a solid (350 mg, yield: 73%).
ESI-MS m/z:531[M+H] +
Examples 3-132 Synthesis of Compounds 3-132
Using the above synthesis method, target compounds 3-132 in Table 1 can be obtained using different starting materials.
TABLE 1
EXAMPLE 133 in vitro KIF18A enzyme Activity inhibition assay of Compounds of the invention
KIF18A enzyme assay: the KIF18A enzyme activity after treatment with the compound was measured using a microtubule-stimulated ATPase activity assay. The assay measures ADP produced by the atpase reaction. Compounds were serially diluted 2-fold in DMSO over 22 concentration points. Recombinant human KIF18A (1-467 His-tagged) protein was expressed using a baculovirus system. Concentrations of KIF18A protein, microtubules (Microtubules) and ATP in the reaction were optimized for standardized homogenous enzyme assays using an ADP-Glo kinase/ATPase assay kit. Preparation of reaction buffer [ (15mM Tris, pH 7.5), 10mM MgCl 2 0.01% Pluronic F-68, 1. Mu.M paclitaxel and 30. Mu.g/mL porcine microtubules]. To the prepared reaction buffer, compound and KIF18A protein (30 nM) were added and incubated at room temperature for 15min, followed by addition of ATP (Km, 75 μ M) to the reaction mixture and incubation at room temperature for another 15min. Mu.l of ADP-Glo reagent and 2.5. Mu.l of the reaction mixture were mixed and incubated at room temperature for 40min. Add 10. Mu.l ADP-Glo detection reagent and incubate at room temperature for 40min. Luminescence was read using a microplate reader, compared to the DMSO group, and the percent compound inhibition and IC were calculated 50 . The results are shown in Table 2 below.
TABLE 2 inhibitory Activity of Compounds of the invention on KIF18A enzyme (IC) 50 nM)
+ + + + + + + +' denotes IC 50 Less than or equal to 100nM
+ denotes IC 50 Is 100nM to 500nM
+ represents IC 50 Greater than 500nM
As can be seen from the data in Table 2, the compound of the present invention has a good inhibitory activity on the enzymatic activity of KIF 18A.
Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these embodiments are merely illustrative and that many changes or modifications can be made to these embodiments without departing from the principles and spirit of the invention. The scope of the invention is therefore defined by the appended claims.
Claims (29)
1. A compound represented by the general formula (1) or isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
in the general formula (1):
x is-CR 4 Or N;
l is- (C = O) -NR 9 -or-NR 9 -(C＝O)-；
R 1 is-CN or-Z-R 10 Wherein Z is a bond, -C 0-4 Hydrocarbyl-, -NR 11 -、-NR 11 SO 2 -、-SO 2 NR 11 -、-NR 11 -S(＝O)(＝NH)-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO 2 -、-C 0-4 hydrocarbyl-O-, - (C = O) NR 11 -, -C (= N-OH) -or-NR 11 (C = O) -; or the group-Z-R 10 is-N = S (= O) - (R) 10 ) 2 Wherein said two R are 10 May be combined with the sulfur atom to which they are each attached to form a saturated or partially saturated 3-, 4-, 5-or 6-membered monocyclic ring containing 0, 1,2 or 3N atoms and 0, 1 or 2 atoms selected from O and S;
R 2 is halogen or a radical-Y-R 12 Wherein Y is a bond, -C 0-4 Alkyl-, -N (C) 0-1 Hydrocarbyl group) -C 0-4 Alkyl-, -C (= O) NR a R a (C 1-4 Alkyl) -, -O-C 0-4 Alkyl-, -S (= O) -, -SO 2 -、-SO 2 NR 12 -or-S (= O) (= NH) -;
R 3 is H, halogen, C 1-8 Hydrocarbyl or C 1-4 A halogenated hydrocarbon group;
R 4 is H, halogen, C 1-8 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -O-C 1-8 Hydrocarbyl or-O-R 4a Wherein R is 4a Is a saturated or partially saturated 3-, 4-, 5-or 6-membered monocyclic ring containing 0, 1,2 or 3N atoms and 0, 1 or 2 atoms selected from O and S;
R 5 is H, halogen, C 1-8 Alkyl or C 1-4 A haloalkyl group;
R 6 is H, halogen, C 1-8 Alkyl radical, C 1-4 Haloalkyl, -OH, -O-R 6a or-O-R 6b ；
R 7 Is H, halogen, C 1-8 Hydrocarbyl or C 1-4 A halogenated hydrocarbon group;
R 8 selected from the group consisting of:
R 13a 、R 13b 、R 13c 、R 13d 、R 13e 、R 13f 、R 13g 、R 13h 、R 13i 、R 13j 、R 13k and R 13l Each independently of the other being H, halogen, R 13m Or R 13n (ii) a Or R 13a And R 13b Para, R 13c And R 13d Para, R 13e And R 13f Para, R 13g And R 13h Pair, R 13i And R 13j To or R 13k And R 13l Each of the pairs may be independently spiro-linked to R with the carbon atom to which they are each attached 8 A saturated or partially saturated 3-, 4-, 5-, 6-membered monocyclic ring of rings; wherein the 3-membered, 4-membered, 5-membered,A 6-membered monocyclic ring contains 0, 1,2, or 3N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein said 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring is substituted with 0, 1,2, or 3 groups selected from: F. cl, br, C 1-6 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -OR a 、-OC 1-4 Halogenated hydrocarbon radicals, CN, -NR a R a Or oxo;
R 9 is H or C 1-6 A hydrocarbyl group;
R 10 is H, R 10a Or R 10b ；
R 11 Is H, R 11a Or R 11b ；
R 12 Is R 12a Or R 12b ；
R 6a 、R 10a 、R 11a 、R 12a Or R 13m Is independently selected in each case from: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-or 12-membered bicyclic ring containing 0, 1,2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, wherein said monocyclic ring and bicyclic ring may each independently be optionally substituted with 0, 1,2 or 3 of the following groups: F. cl, br, C 1-6 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -OR a 、-OC 1-4 Halogenated hydrocarbon group, CN, -C (= O) R b 、-C(＝O)OR a 、-C(＝O)NR a R a 、-C(＝NR a )NR a R a 、-OC(＝O)R b 、-OC(＝O)NR a R a 、-OC 2-6 Hydrocarbyl radical NR a R a 、-OC 2-6 Hydrocarbyl OR a 、-SR a 、-S(＝O)R b 、-S(＝O) 2 R b 、-S(＝O) 2 NR a R a 、-NR a R a 、-N(R a )C(＝O)R b 、-N(R a )C(＝O)OR b 、-N(R a )C(＝O)NR a R a 、-N(R a )C(＝NR a )NR a R a 、-N(R a )S(＝O) 2 R b 、-N(R a )S(＝O) 2 NR a R a 、-NR a C 2-6 Hydrocarbyl radicals NR a R a 、-NR a C 2-6 Hydrocarbyl OR a 、-C 1-6 Hydrocarbyl radicals NR a R a 、-C 1-6 Hydrocarbyl OR a 、-C 1-6 Hydrocarbyl group N (R) a )C(＝O)R b 、-C 1-6 Hydrocarbyl OC (= O) R b 、-C 1-6 Hydrocarbyl C (= O) NR a R a 、-C 1-6 Hydrocarbyl C (= O) OR a 、R 14 And oxo;
R 6b 、R 10b 、R 11b 、R 12b or R 13n Is independently selected in each occurrence from: c 1-6 (ii) a hydrocarbyl group, wherein the hydrocarbyl group may be optionally substituted with 0, 1,2,3, 4, or 5 of the following groups: F. cl, br, -R a 、-OR a 、-OC 1-4 Halogenated hydrocarbyl and CN;
R 14 independently in each instance selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-or 12-membered bicyclic ring containing 0, 1,2 or 3N atoms and 0 or 1 atom selected from O and S, wherein said monocyclic ring and bicyclic ring each independently may be optionally substituted with 0, 1,2 or 3 of the following groups: F. cl, br, C 1-6 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -OR a 、-OC 1-4 Halogenated hydrocarbon group, CN, -C (= O) R b 、-C(＝O)OR a 、-C(＝O)NR a R a 、-C(＝NR a )NR a R a 、-OC(＝O)R b 、-OC(＝O)NR a R a 、-OC 2-6 Hydrocarbyl radical NR a R a 、-OC 2-6 Hydrocarbyl OR a 、-SR a 、-S(＝O)R b 、-S(＝O) 2 R b 、-S(＝O) 2 NR a R a 、-NR a R a 、-N(R a )C(＝O)R b 、-N(R a )C(＝O)OR b 、-N(R a )C(＝O)NR a R a 、-N(R a )C(＝NR a )NR a R a 、-N(R a )S(＝O) 2 R b 、-N(R a )S(＝O) 2 NR a R a 、-NR a C 2-6 Hydrocarbyl radical NR a R a 、-NR a C 2-6 Hydrocarbyl OR a 、-C 1-6 Hydrocarbyl radical NR a R a 、-C 1-6 Hydrocarbyl OR a 、-C 1-6 Hydrocarbyl group N (R) a )C(＝O)R b 、-C 1-6 Hydrocarbyl OC (= O) R b 、-C 1-6 Hydrocarbyl C (= O) NR a R a 、-C 1-6 Hydrocarbyl C (= O) OR a And oxo;
R a each occurrence independently is H or R b (ii) a And is
R b In each case independently C 1-6 A hydrocarbyl group, a phenyl group, or a benzyl group, wherein the hydrocarbyl group may be optionally substituted with 0, 1,2, or 3 of the following groups: halogen, -OH, -OC 1-4 Hydrocarbyl, -NH 2 、-NHC 1-4 Hydrocarbyl, -OC (= O) C 1-4 Hydrocarbyl or-N (C) 1-4 Hydrocarbyl) C 1-4 A hydrocarbyl group; and wherein said phenyl and benzyl groups may each independently be optionally substituted with 0, 1,2 or 3 of the following groups: halogen, C 1-4 Hydrocarbyl radical, C 1-3 Halogenated hydrocarbon radicals, -OH, -OC 1-4 Hydrocarbyl, -NH 2 、-NHC 1-4 Hydrocarbyl, -OC (= O) C 1-4 Hydrocarbyl or-N (C) 1-4 Hydrocarbyl) C 1-4 A hydrocarbyl group.
2. The compound according to claim 1, or its isomers, forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein in the general formula (1), when X is-CR 4 When represented by formula (1 a) and formula (1 b):
3. the compound of any one of claims 1-2, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), when X is-CR 4 In which R is 4 Is H, methyl or F, preferably H.
4. The compound according to claim 1, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), when X is N, it has the formula (1 c) and the formula (1 d):
5. the compound according to any one of claims 1 to 4, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R is 9 Is H, methyl or ethyl, preferably H.
6. The compound according to claim 1, wherein in the general formula (1), wherein R is R, or an isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof 13c 、R 13d 、R 13e 、R 13f 、R 13g 、R 13h 、R 13i 、R 13j 、R 13k And R 13l Each independently of the other being H, halogen, C 1-6 Hydrocarbyl radicals or C 1-4 A halogenated hydrocarbon group; and R is 13a And R 13b R in the pair 13a And R 13b The carbon atoms to which they are each attached may combine to form a spiro linkage to R 8 A saturated 3-, 4-or 5-membered monocyclic ring of rings; wherein the ring contains 0, 1,2 or 3N atoms and 0, 1 or 2 atoms selected from O and S; preferably, R 13c 、R 13d 、R 13e 、R 13f 、R 13g 、R 13h 、R 13i 、R 13j 、R 13k And R 13l Each independently is H, methyl or ethyl; and R is 13a And R 13b R in pair 13a And R 13b The carbon atoms to which they are each attached may combine to form a spiro linkage to R 8 A cyclopropyl, cyclobutyl or cyclopentyl ring of the ring.
7. The compound according to any one of claims 1 or 6, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit
Comprises the following steps:
preferably, it is
8. The compound according to any one of claims 1 to 7, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), Z is a bond, -NH-, -NHSO 2 -、-SO 2 NH-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO 2 -, - (C = O) -, - (C = O) NH-, or-NH (C = O) -.
9. The compound according to any one of claims 1 to 8, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 10 Selected from (a) H; or (b) C 1-6 (ii) a hydrocarbyl group which may be optionally substituted with 0, 1,2 or 3 of the following groups: F. cl, br, -OH or-OCH 3 (ii) a Or (c) when said group-Z-R 10 is-N = S (= O) - (R) 10 ) 2 Wherein the two R are 10 May combine with the sulfur atom to which they are each attached to form a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring containing 0, 1,2 or 3N atoms and 0 or 1 atom selected from O and S, which is substituted with 0, 1,2 or 3 groups selected from: F. cl, br, C 1-6 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -C 1-6 Hydrocarbyl OH, -OCH 3 、-NH 2 Or oxo.
10. The compound according to any one of claims 1 to 9, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 1 is-CN or a group-Z-R 10 Wherein Z is a bond, -NH-, -NHSO 2 -、-SO 2 NH-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO 2 -, - (C = O) NH-, or-NH (C = O) -; and R is 10 Selected from:
(a)H；
(b) Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl,
And wherein each of said rings may each independently optionally be substituted with 0, 1,2 or 3 of the following groups: OH, F, methyl, -CH 2 OH、-C(＝O)OCH 3 、-C(＝O)OC(CH 3 ) 3 、NH 2 CN and oxo; preferably oxetanyl, cyclopropyl; or
(c) OCH by 0, 1,2 or 3 OH, F, -C (= O) OCH 3 、-NH 2 、-NH(CH 3 ) or-N (CH) 3 ) 2 Substituted C 1-6 A hydrocarbyl group; preferably C substituted by 0, 1,2 or 3 OH groups 1-6 A hydrocarbyl group; more preferably C substituted by 1 OH group 1-6 A hydrocarbyl group.
11. The compound of any one of claims 1-7, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein the group-Z-R 10 is-N = S (= O) - (R) 10 ) 2 Wherein two R are 10 To sulfur to which they may be attached respectivelyThe atoms combine to form a saturated or partially saturated 3-, 4-, 5-or 6-membered monocyclic ring containing 0, 1,2 or 3N atoms and 0, 1 or 2 atoms selected from O and S; preference is given to the group-Z-R 10 Selected from:
12. the compound according to any one of claims 1 to 10, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 1 Is a radical-Z-R 10 Wherein Z is-NHSO 2 -or-SO 2 NH-; and R is 10 Is oxetanyl, cyclopropyl, or R 10 Is C substituted by 0, 1,2 or 3 OH groups 1-6 A hydrocarbyl group; preferably, R 1 Is a group-Z-R 10 Wherein Z is-NHSO 2 -or-SO 2 NH-, and R 10 is-CH 2 -CH 2 -OH or-CH (CH) 3 )-CH 2 -OH; more preferably Z is-NHSO 2 -, and R 10 is-CH 2 -CH 2 -OH。
13. The compound according to any one of claims 1 to 12, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 2 Is halogen or a radical-Y-R 12 Wherein Y is a bond, -NH- (CH) 2 ) 0-4 -or-O- (CH) 2 ) 0-4 -; and R is 12 Is a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-or 12-membered bicyclic ring containing 0, 1,2 or 3N atoms and 0 or 1 atom selected from O and S, wherein said monocyclic and bicyclic rings may each independently optionally be substituted with 0, 1,2 or 3 of the following groups: F. cl, br, C 1-6 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -OH, -OC 1-4 Halogenated hydrocarbon group, CN, R 14 And oxo; or R 12 Is C 1-6 A hydrocarbon groupMay be optionally substituted with 0, 1,2,3, 4 or 5 of the following groups: F. cl, br, -OH, -OC 1-4 A halogenated hydrocarbon group or CN.
14. The compound according to any one of claims 1 to 13, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 2 Is a saturated 5-or 6-membered monocyclic ring, wherein each of said rings contains 0, 1 or 2N atoms and 0 or 1O atoms, and wherein each of said rings is substituted with 0, 1,2 or 3 groups selected from: F. cl, br, C 1-6 Hydrocarbyl radical, C 1-4 Halogenated hydrocarbon radicals, -OH, -OC 1-4 Halogenated hydrocarbon group, CN, R 14 And oxo.
15. The compound according to any one of claims 1 to 14, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 2 Is (a) halogen; (b) The radical-Y-R 12 Wherein Y is a bond; and R is 12 Is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuryl,
Wherein each said ring is substituted with 0, 1,2 or 3 groups selected from: F. cl, br, methyl, CF 3 、-OH、-OCHF 2 CN and oxo; or (c) a group-Y-R 12 Wherein Y is-NH-, -O- (CH) 2 )-、-O-(CH 2 )-(CH 2 ) -or-O- (CH) 2 )-(CH 2 )-(CH 2 ) -, and wherein R 12 Is composed of
Or R 12 Is C 1-6 (ii) a hydrocarbyl group which may be optionally substituted with 0, 1,2,3, 4 or 5 of the following groups: F. cl, br, methyl, CF3, -OH or CN.
16. The compound of any one of claims 1-15, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 2 Is morpholinyl or piperidinyl, which morpholinyl and piperidinyl groups may be optionally substituted with 0, 1,2 or 3 of: F. cl, br, methyl, CF 3 、-OH、-OCHF 2 And CN.
17. The compound of any one of claims 1-16, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 2 Is piperidinyl substituted with 1,2 or 3 fluoro groups.
18. The compound of any one of claims 1-15, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 2 Comprises the following steps:
19. the compound of any one of claims 1-16, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 2 Is morpholinyl substituted by 1,2 or 3 methyl groups.
20. The compound of any one of claims 1-15, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound isIn the formula (1), wherein R 2 Is composed of
21. The compound according to any one of claims 1 to 9, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 10 Selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl or 1,3, 4-oxathiazinoalkyl.
22. The compound of any one of claims 1-21, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 3 Is H.
23. The compound of any one of claims 1-22, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 5 Is H or F, preferably H.
24. The compound of any one of claims 1-23, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 6 Is H or F, preferably H.
25. The compound of any one of claims 1-24, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein R is 7 Is H.
26. The compound of any one of claims 1-25, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has one of the following structures:
27. a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a compound of any one of claims 1-26, or an isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, as an active ingredient.
28. Use of a compound of any one of claims 1-26, or isomers, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, or a pharmaceutical composition of claim 27, in the manufacture of a medicament for treating a disease associated with a KIF18A protein-mediated disorder.
29. The use of claim 28, wherein the disease is cancer, and the cancer is hematological cancer and solid tumor.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023198209A1 (en) * | 2022-04-15 | 2023-10-19 | 武汉人福创新药物研发中心有限公司 | Kif18a inhibitor and use thereof |
| WO2024083208A1 (en) * | 2022-10-21 | 2024-04-25 | 杭州邦顺制药有限公司 | Kif18a protein inhibitor |
| WO2024114787A1 (en) * | 2022-12-02 | 2024-06-06 | 深圳众格生物科技有限公司 | Amide or urea compound |
| WO2024146593A1 (en) * | 2023-01-05 | 2024-07-11 | 浙江海正药业股份有限公司 | Aromatic amide derivative, and preparation method therefor and medical use thereof |
| US12084420B2 (en) | 2021-08-26 | 2024-09-10 | Volastra Therapeutics, Inc. | Indoline compounds for inhibiting KIF18A |
-
2022
- 2022-09-07 CN CN202211090930.1A patent/CN115785068A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12084420B2 (en) | 2021-08-26 | 2024-09-10 | Volastra Therapeutics, Inc. | Indoline compounds for inhibiting KIF18A |
| WO2023198209A1 (en) * | 2022-04-15 | 2023-10-19 | 武汉人福创新药物研发中心有限公司 | Kif18a inhibitor and use thereof |
| WO2024083208A1 (en) * | 2022-10-21 | 2024-04-25 | 杭州邦顺制药有限公司 | Kif18a protein inhibitor |
| WO2024114787A1 (en) * | 2022-12-02 | 2024-06-06 | 深圳众格生物科技有限公司 | Amide or urea compound |
| WO2024146593A1 (en) * | 2023-01-05 | 2024-07-11 | 浙江海正药业股份有限公司 | Aromatic amide derivative, and preparation method therefor and medical use thereof |
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