CN116693502A - Heterocyclic amine menin-MLL interaction inhibitor, preparation method and application thereof - Google Patents

Heterocyclic amine menin-MLL interaction inhibitor, preparation method and application thereof Download PDF

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CN116693502A
CN116693502A CN202310193997.6A CN202310193997A CN116693502A CN 116693502 A CN116693502 A CN 116693502A CN 202310193997 A CN202310193997 A CN 202310193997A CN 116693502 A CN116693502 A CN 116693502A
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compound
leukemia
alkyl
independently selected
mll
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祝辉
王健航
王艳峰
赵杰斌
王颖
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Chengdu Shuoder Pharmaceutical Co ltd
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    • 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
    • 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/02—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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a preparation method and application thereof. The compounds are useful as agents in the treatment of diseases and conditions, including cancer, other diseases mediated by the men-MLL interaction.

Description

Heterocyclic amine menin-MLL interaction inhibitor, preparation method and application thereof
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a novel heterocyclic amine (menin-MLL) interaction inhibitor, a preparation method and medical application thereof.
Background
Mixed lineage leukemia rearrangement (mixed lineage leukemia-rearranged, MLL-r) is an acute leukemia with a poor prognosis, caused by spontaneous translocation of the MLL1 gene. The translocation-generated MLL-r fusion protein binds with high affinity to the nucleoprotein Menin, which interacts with the MLL to cause leukemia to occur by driving specific transcription programs.
There is currently no Acute Myelogenous Leukemia (AML) drug or therapy cohort for MLL-r or NPM1 mutations, the presence of MLL fusion proteins is a sign of poor prognosis of leukemia, MLL-r leukemia patients respond poorly to currently available therapies, and overall survival rates for 5 years are approximately 35%; translocation of the MLL gene is associated with a 13-34% reduction in the 5 year disease-free survival of children, with an average five year survival of only 5-10% for AML adult patients with MLL-r. The overall survival rate of NPM1 mutant AML was about 50% for 5 years. In addition, AML recurrence rates are high, with about 50% of patients relapsing within 1-2 years, and most of the relapsed AML eventually turns into relapsed/refractory AML, for which no effective treatment regimen exists. AML presents a large molecular heterogeneity and patients carrying different mutations may have distinct prognosis. The direction of AML drug development is to more accurately target different mutations and develop targeted drugs for different mutations.
A Menin-MLL interaction inhibitor belongs to an epigenetic inhibitor and can block the interaction of the MLL fusion protein (MLL-r) in the cells of the Menin and leukemia. There are currently 2 compounds in clinical research, SNDX-5613 is conducting a clinical phase 1/2 study for patients with recurrent/refractory acute leukemia carrying MLL rearrangements or NPM1 mutations, KO-539 is conducting a clinical phase 1 study for patients with recurrent/refractory acute leukemia carrying MLL rearrangements or NPM1 mutations.
In conclusion, the Menin-MLL interaction inhibitor has good application prospect as a drug research and development, and has good clinical requirements for developing a novel high-efficiency low-toxicity Menin-MLL interaction inhibitor.
Disclosure of Invention
The present invention provides a compound of formula (i):
wherein:
ring A is selected from C 6-10 Aryl, C 5-8 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl;
l is selected from:
q is selected from-C (R) q1 R q2 ) -, -C (=o) -, -S (=o) -or-S (=o) 2 -；
R q1 、R q2 Each independently selected from H or C 1 -C 6 An alkyl group;
R 1 、R 2 、R 3 each independently selected from H, -OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkyl, -C (O) NR 1a R 2a 、-S(O)NR 1a R 2a 、-S(O) 2 NR 1a R 2a 、-C(O)R 1a 、-S(O) 2 R 1a 、-NR 1a S(O)R 2a 、-NR 1a S(O) 2 R 2a 、-NR 1a C(O)R 2a 、C 6-10 Aryl, 5-7 membered heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, wherein C 6-10 Aryl, 5-7 membered heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl may optionally be substituted with one or more-OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy or C 1 -C 6 Haloalkyl substitution;
R 1a 、R 2a each at each occurrence is independently selected from H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or 3-6 membered heterocyclyl;
R 4 each at each occurrence is independently selected from H, -OH, halogen, cyano, amino, C 1 -C 6 Alkyl, -C (O) R 4a 、-NHC(O)R 4a 、-C(O)NHR 4a 、-NHS(O)R 4a 、-NHS(O) 2 R 4a 、-S(O) 2 R 4a ；
R 4a Each at each occurrence is independently selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl may optionally be substituted with one or more of-OH, halogen, cyano, -NH 2 、-NHCH 3 or-N (CH) 3 ) 2 Substitution;
n is 0, 1, 2, 3,4, 5 or 6.
In certain preferred embodiments, ring A is selected from phenyl, naphthyl, C 5-6 Cycloalkyl, 9-10 membered heteroaryl, or 9-10 membered heterocyclyl.
In certain more preferred embodiments, ring a is selected from phenyl, cyclohexyl, benzimidazolinonyl, benzoxazolinonyl, benzothiazolinonyl, benzimidazolyl, indazolyl, indolyl, or indolonyl.
In certain preferred embodiments, L is selected from:
in certain more preferred embodiments, L is selected from:
wherein, the p end is connected with pyrimidinyl, and the Q end is connected with Q.
In certain preferred embodiments, Q is-CH 2 -or-C (=o) -.
In certain preferred embodiments, R 1 、R 2 、R 3 Each independently selected from H, halogen, -C (O) NR 1a R 2a Or a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl may optionally be substituted with one or more C 1 -C 6 Alkyl substitution; r is R 1a 、R 2a Each at each occurrence is independently selected from H or C 1 -C 3 An alkyl group.
In certain more preferred embodiments, R 1 、R 2 、R 3 Each independently selected from H, fluorine, chlorine, bromine, iodine,
In certain preferred embodiments, R 4 Each at each occurrence is independently selected from H, cyano, amino, C 1 -C 6 Alkyl, -C (O) R 4a 、-NHC(O)R 4a 、-NHS(O) 2 R 4a or-S (O) 2 R 4a ；R 4a Each at each occurrence is independently selected from C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl or C 3-5 Cycloalkyl group, wherein C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl or C 3-5 Cycloalkyl groups may be optionally substituted with one or more halogens.
In certain more preferred embodiments, R 4 Each independently at each occurrence is selected from H, cyano, amino, methyl,
In certain preferred embodiments, n is 0, 1, 2, 3, 4.
In certain more preferred embodiments, n is 0 or 1.
In certain preferred embodiments, the compounds of formula (I) have the following structure:
in certain preferred embodiments, ring A is selected from phenyl, naphthyl, C 5-6 Cycloalkyl, 9-10 membered heteroaryl, or 9-10 membered heterocyclyl;
l is selected from:
q is-CH 2 -or-C (=o) -;
R 1 、R 2 、R 3 each independently selected from H, halogen, -C (O) NR 1a R 2a Or a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl may optionally be substituted with one or more C 1 -C 6 Alkyl substitution; r is R 1a 、R 2a Each at each occurrence is independently selected from H or C 1 -C 3 An alkyl group;
R 4 each at each occurrence is independently selected from H, cyano, amino, C 1 -C 6 Alkyl, -C (O) R 4a 、-NHC(O)R 4a 、-NHS(O) 2 R 4a or-S (O) 2 R 4a ；R 4a Each at each occurrence is independently selected from C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl or C 3-5 Cycloalkyl group, wherein C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl or C 3-5 Cycloalkyl groups may be optionally substituted with one or more halogens;
n is 0, 1, 2, 3, 4.
In certain more preferred embodiments, ring a is selected from phenyl, cyclohexyl, benzimidazolinonyl, benzoxazolinonyl, benzothiazolinonyl, benzimidazolyl, indazolyl, indolyl, or indolonyl;
l is selected from:
wherein, the p end is connected with a pyrimidinyl group, and the Q end is connected with Q;
q is-CH 2 -or-C (=o) -;
R 1 、R 2 、R 3 each independently selected from H, fluorine, chlorine, bromine, iodine,
R 4 Each independently at each occurrence is selected from H, cyano, amino, methyl,
n is 0 or 1.
In certain preferred embodiments, the compound is selected from the group consisting of:
the compounds of the present invention may be prepared in the form of pharmaceutically acceptable salts, including organic acid salts and inorganic acid salts thereof, including but not limited to hydrochloric acid, sulfuric acid, phosphoric acid, biphosphoric acid, hydrobromic acid, hydroiodic acid, and the like, and organic acids including but not limited to acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid salts, maleic acid, citric acid, fumaric acid, tartaric acid, succinic acid, malic acid, camphoric acid, nicotinic acid, salicylic acid, oxalic acid, lactic acid, and the like, according to conventional methods.
In another aspect, the present invention also provides a process for the preparation of a compound of formula (I), including but not limited to:
(1) Scheme 1:
wherein, ring A, L, Q, R 1 、R 2 、R 3 、R 4 And n is as defined above;
PG is a protecting group selected from: cbz, boc, fmoc, alloc, teoc, etc.;
LVG is a leaving group selected from: -I, -Br, -Cl, msO-, tfO-, tsO-, etc.;
1) The raw material S1 reacts with the raw material S2 to generate a compound I-1;
2) The compound I-1 is subjected to oxidation reaction to generate a compound I-2;
3) Carrying out halogenation reaction on the compound I-2 to generate a compound I-3;
4) Removing protecting groups after the compound I-3 reacts with the compound PG-L-H to generate a compound I-4;
5) Reacting the compound I-4 with a compound M1 to obtain a compound shown in a formula (I);
(2) Scheme 2:
wherein, ring A, L, Q, R 1 、R 2 、R 3 、R 4 And n is as defined above; the process for preparing compound I-3 is the same as that of scheme 1; the obtained compound I-3 is directly reacted with a compound M2 to obtain a compound of formula (I).
In another aspect, the present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a disease associated with the men-MLL protein.
Specifically, the disease related to the men-MLL protein refers to mixed leukemia (MLL), MLL-related leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed leukemia (MLL-r), leukemia related to MLL rearrangement or MLL gene rearrangement, acute leukemia, chronic leukemia, lymphoblastic leukemia, myelogenous leukemia, childhood leukemia, acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), acute myelogenous leukemia, acute non-lymphoblastic leukemia, chronic Lymphoblastic Leukemia (CLL), chronic Myelogenous Leukemia (CML), leukemia related to treatment, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), myeloproliferative neoplasia (MPN), plasma cell tumor, multiple myeloma, myelodysplasia, cutaneous T cell lymphoma, lymphoid tumor, hairy cell leukemia, leukemia meningitis, multiple myeloma, hodgkin's lymphoma, and non-malignant lymphoma.
The invention discovers that a novel structure of the men-MLL interaction inhibitor has a structure shown as a formula (I) compound, has good cell inhibition activity and good pharmacokinetic property, and is a new generation of high-efficiency low-toxicity men-MLL interaction inhibitor.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The structure of the compounds was determined by Mass Spectrometry (MS) or nuclear magnetic resonance (1 HNMR).
Nuclear magnetic resonance (1 HNMR) displacement (δ) is given in parts per million (ppm); nuclear magnetic resonance (1 HNMR) was measured using a Bruker AVANCE-400 nuclear magnetic resonance apparatus, the measuring solvent was deuterated dimethyl sulfoxide (DMSO), the internal standard was Tetramethylsilane (TMS), and the chemical shift was given in units of 10-6 (ppm).
The Mass Spectrum (MS) was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: therm, model: finnigan LCQ advantage MAX).
The thin silica gel layer is prepared from tobacco stage yellow sea HSGF254 or Qingdao GF254 silica gel plate.
Column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
In the terms of the present invention, "nitrogen protection" means, for example, connecting the reaction flask to a 1L volume nitrogen balloon.
In the case where no specific explanation is given to the present invention, the solution mentioned in the reaction of the present invention is an aqueous solution.
The term "room temperature" in the present invention means that the temperature is between 10℃and 25 ℃.
Example 1
N-ethyl-2- ((4- ((1- (((1 r,4 r) -4- (ethylsulfanyl) -cyclohexyl) -methyl) piperidin-4-yl) amino) pyrimidin-5-yl) -oxy) -5-fluoro-N-isopropylbenzamide (1)
Example 1
The synthetic route is as follows:
step 1N-Ethyl-5-fluoro-N-isopropyl-2- (pyrimidin-5-yloxy) benzamide (1-1)
N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide (1.88 g,8.18 mmol), 5-bromopyrimidine (3.98 g,25.05 mmol), cesium carbonate (4.07 g,12.20 mmol) were dissolved in anhydrous DMF and reacted at 130℃for 16h. TLC detection (P/e=2/1) reaction was completed, cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, solvent was recovered by rotary evaporation, and purified by column chromatography to isolate (P/e=8/1 to 2/1) to give 1.21g (yield: 45.8%) of a white solid product. ESI-MS m/z 304.2[ M+H ]] + 。
Step 2 5- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) pyrimidine-1-oxynitride (1-2)
The above intermediate 1-1 (1.11 g,3.55 mmol) was dissolved in anhydrous dichloromethane, m-CPBA (1.87 g,10.68 mmol) was added under ice-bath, the reaction was carried out overnight at room temperature, LC/Ms detection was completed, the reaction solution was washed 1 time with saturated sodium sulfite solution, saturated sodium bicarbonate solution was washed 2 times, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was recovered by rotary evaporation to give 1.02g of crude yellow oil (yield: 88.08%). ESI-MS m/z 320.2[ M+H ]] + 。
Step 3 2- ((4-Chloropyrimidin-5-yl) oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (1-3)
Dissolving the above intermediate 1-2 (1.0 g,3.06 mmol) in chloroform, adding triethylamine (0.65 ml,4.60 mmol) and phosphorus oxychloride (0.5 ml,5.32 mmol) under ice bath, heating in oil bath at 70deg.C for 8 hr, detecting reaction progress by TLC, adding saturated sodium bicarbonate aqueous solution to adjust pH to 8, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, filtering, and rotary evaporating to recoverAnd (3) a solvent. Column chromatography purification separation (P/e=2/1) gave 0.52g (yield: 49.2%) of a yellow oily product. ESI-MS m/z 338.2[ M+H ]] + 。
Step 4- ((5- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (1-4)
The above intermediate 1-3 (0.157 g,0.46 mmol) was dissolved in isopropanol, DIPEA (0.162 ml,0.93 mmol) was added, 4-aminopiperidine-1-carboxylic acid tert-butyl ester (93 mg,0.46 mmol) was reacted for 16h with heating at 70℃after TLC detection, diluted with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was recovered by rotary evaporation to give 0.23g (yield: 97.6%) of crude yellow oil. ESI-MS m/z 502.2[ M+H ]] + 。
Step 5N-Ethyl-5-fluoro-N-isopropyl-2- ((4- (piperidin-4-ylamino) pyrimidin-5-yl) oxy) benzamide (1-5)
The above intermediate 1-4 (0.22 g,0.43 mmol) was dissolved in dichloromethane (4 ml), trifluoroacetic acid (2 ml) was added, the reaction was carried out at room temperature for 2 hours, the LC/Ms detection was completed, saturated brine was added for washing, dichloromethane extraction was added for additional, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was recovered by rotary evaporation to give 0.186g of crude yellow oil, which was directly used in the next step. ESI-MS m/z 402.2[ M+H ]] + 。
Step 6:N-Ethyl-5-fluoro-N-isopropyl-2- ((4- (piperidin-4-amino) pyrimidin-5-yl) oxy) benzamide (1)
The above intermediate 1-5 (0.186 g,0.46 mmol), ((1 r,4 r) -4- ((ethylsulfonylamino) cyclohexyl) -4-methylbenzenesulfonic acid methyl ester (53 mg,1.38 mmol), potassium carbonate (192 mg,1.36 mmol), potassium iodide (7.6 mg,0.046 mmol) were dissolved in DMF, reacted at 80℃for 12h.LC/Ms detection reaction was completed, washed with saturated brine, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was recovered by rotary evaporation, and purified by column chromatography to isolate (D/M=20/1) to give 132mg (yield: 49.8%) of ESI-MS M/z:605.2[ M+H ]] + 。 1 H NMR(400MHz,d 6 -DMSO)δ8.90(s,-S(O) 2 -NH,1H),8.52(s,1H),8.09(d,J＝6.6Hz,1H),7.46–7.20(m,2H),7.06(d,J＝7.8Hz,1H),4.47(br-s,-NH,1H),3.79-3.70(m,3H),3.10(m,1H),2.98-2.90(m,5H),2.87(s,2H),2.08(m,2H),1.94–1.84(m,4H),1.78-1.69(m,4H),1.25-1.20(m,5H),1.18–0.98(m,12H)。
Example 2N-Ethyl-2- ((4- ((1- (((1 r,4 r) -4- (ethylsulfonamide) cyclohexyl) methyl) acridin-3-yl) amino) -pyrimidin-5-yl) oxy) -5-fluoro-N-isopropylbenzamide (2)
Example 2
With reference to the preparation method of example 1, intermediate 2- ((4-chloropyrimidin-5-yl) -oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (1-3) was prepared, 1-tert-butoxycarbonyl-3-aminocyclobutylamine was substituted for tert-butyl 4-aminopiperidine-1-carboxylate as a reaction reagent, and purified by the procedure described in example 1. ESI-MS: m/z=577.2 [ M+H ]] + ； 1 H NMR(400MHz,d 6 -DMSO)δ8.92(s,-S(O) 2 -NH,1H),8.50(s,1H),8.08(d,J＝6.6Hz,1H),7.44–7.31(m,2H),7.11(d,J＝7.8Hz,1H),5.01(br-s,-NH,1H),3.76-3.68(m,3H),3.61-3.52(m,4H),3.38(m,1H),2.92-2.83(m,5H),1.79-1.71(m,4H),1.24-1.18(m,5H),1.14–0.97(m,12H)。
Example 3N-Ethyl-2- ((4- (4- ((((1 r,4 r) -4- (ethylsulfonamide) cyclohexyl) methyl) amino) piperidin-1-yl) pyrimidin-5-yl) oxy) -5-fluoro-N-isopropylbenzamide (3)
Example 3
With reference to the preparation method of example 1, intermediate 2- ((4-chloropyrimidin-5-yl) -oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (1-3) was prepared, 4-tert-butoxycarbonylaminopiperidine was substituted for 4-aminopiperidine-1-carboxylic acid tert-butyl ester as the reactant, and purified by the procedure described in example 1. ESI-MS: m/z=605.2 [ M+H ]] + ； 1 H NMR(400MHz,d 6 -DMSO)δ8.88(s,-S(O) 2 -NH,1H),8.43(s,1H),8.06(d,J＝6.8Hz,1H),7.48–7.23(m,2H),7.09(d,J＝6.9Hz,1H),4.90(br-s,-NH,1H),3.77-3.65(m,3H),3.18-3.02(m,5H),2.93-2.82(m,5H),1.95–1.88(m,4H),1.79-1.63(m,4H),1.32-1.24(m,5H),1.20–1.02(m,12H)。
Example 4N-Ethyl-2- ((4- (3- ((((1 r,4 r) -4- (ethylsulfonamide) cyclohexyl) methyl) amino) acridin-1-yl) pyrimidin-5-yl) oxy) -5-fluoro-N-isopropylbenzamide (4)
Example 4
Referring to the procedure for the preparation of example 1, intermediate 2- ((4-chloropyrimidin-5-yl) -oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (1-3) was prepared using 3- (Boc-amino) -azetidine instead of tert-butyl 4-aminopiperidine-1-carboxylate as the reactant and purified by the procedure described in example 1. ESI-MS: m/z=577.3 [ M+H ]] + ； 1 H NMR(400MHz,d 6 -DMSO)δ9.03(s,-S(O) 2 -NH,1H),8.31(s,1H),8.02(d,J＝7.1Hz,1H),7.41–7.32(m,2H),7.16(d,J＝7.2Hz,1H),5.02(br-s,-NH,1H),3.77-3.36(m,8H),2.91-2.53(m,3H),2.33(m,2H),1.77-1.62(m,4H),1.26-1.19(m,5H),1.13–0.96(m,12H)。
Example 5N-Ethyl-2- ((4- ((1- (((1 r,4 r) -4- (ethylsulfonamide) cyclohexyl) methyl) piperidin-4-yl) (methyl) amino) pyrimidin-5-yl) oxy) -5-fluoro-N-isopropylbenzamide (5)
Example 5
Referring to the preparation method of example 1, intermediate 2- ((4-chloropyrimidin-5-yl) -oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (1-3) was prepared using 1-tert-butoxycarbonyl-4-methylaminopiperidine instead of 4-aminopiperidine-1-carboxylic acid tert-butyl ester as the reaction reagent and purified by the procedure described in example 1. ESI-MS: m/z=619.3 [ M+H ]] + ； 1 H NMR(400MHz,d 6 -DMSO)δ9.04(s,-S(O) 2 -NH,1H),8.48(s,1H),8.02(d,J＝6.9Hz,1H),7.43(m,1H),7.27(m,1H),7.04(d,J＝7.0Hz,1H),3.73-3.64(m,3H),3.14-3.08(m,4H),2.99-2.90(m,5H),2.86(s,2H),2.10(m,2H),1.96–1.81(m,4H),1.77-1.60(m,4H),1.26-1.03(m,17H)。
Example 6N-Ethyl-2- ((4- ((1- (((1 r,4 r) -4- (ethylsulfonamide) cyclohexyl) methyl) -4-methylpiperidin-4-yl) amino) pyrimidin-5-yl) oxy) -5-fluoro-N-isopropylbenzamide (6)
Example 6
With reference to the preparation method of example 1, intermediate 2- ((4-chloropyrimidin-5-yl) -oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (1-3) was prepared, tert-butyl 4-amino-4-methylpiperidine-1-carboxylate was substituted for tert-butyl 4-aminopiperidine-1-carboxylate as a reagent, and purification was prepared by the procedure described in example 1. ESI-MS: m/z=619.3 [ M+H ]] + ； 1 H NMR(400MHz,d 6 -DMSO)δ9.01(s,-S(O) 2 -NH,1H),8.53(s,1H),8.11(d,J＝6.8Hz,1H),7.50–7.39(m,2H),7.03(d,J＝6.7Hz,1H),5.06(br-s,-NH,1H),3.73-3.60(m,3H),2.96-2.90(m,5H),2.84(s,2H),2.07(m,2H),1.96–1.88(m,4H),1.77-1.62(m,4H),1.28-1.21(m,5H),1.23–1.04(m,15H)。
Example 7N-Ethyl-2- ((4- ((1- (((1 r,4 r) -4- (ethylsulfonamide) cyclohexyl) methyl) acridin-3-yl) (methyl) amino) pyrimidin-5-yl) oxy) -5-fluoro-N-isopropylbenzamide (7)
Example 7
Referring to the procedure for the preparation of example 1, intermediate 2- ((4-chloropyrimidin-5-yl) -oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (1-3) was prepared using 1-BOC-3-methylaminoazetidine instead of tert-butyl 4-aminopiperidine-1-carboxylate as the reactant and purified by the procedure described in example 1. ESI-MS: m/z=591.2 [ M+H] + ； 1 H NMR(400MHz,d 6 -DMSO)δ8.92(s,-S(O) 2 -NH,1H),8.43(s,1H),8.16(m,1H),7.48(m,1H),7.31(m,1H),7.13(m,1H),3.72-3.66(m,3H),3.60-3.54(m,4H),3.33(m,1H),3.23(m,3H),3.04-2.91(m,5H),1.76-1.61(m,4H),1.26-1.19(m,5H),1.16–0.99(m,12H)。
Example 8N-Ethyl-2- ((4- (5- (((1 r,4 r) -4- (ethylsulfonamide) cyclohexyl) methyl) hexahydropyrrolo [3,4-b ] pyrrol-1 (2H) -yl) pyrimidin-5-yl) oxy) -5-fluoro-N-isopropylbenzamide (8)
Example 8
Reference to the procedure of example 1 gave intermediate 2- ((4-chloropyrimidin-5-yl) -oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (1-3) using 5-BOC-hexahydropyrrolo [3,4-B]Pyrrole was substituted for tert-butyl 4-aminopiperidine-1-carboxylate as a reagent and purified by the procedure described in example 1. ESI-MS: m/z=617.2 [ M+H ]] + 。
Example 9N-Ethyl-2- ((4- ((1- (((1 r,4 r) -4- (ethylsulfanomido) cyclohexyl) methyl) 3-fluoropiperidin-4-yl) amino) pyrimidin-5-yl) oxy) -5-fluoro-N-isopropylbenzamide (9)
Example 9
Referring to the preparation method of example 1, intermediate 2- ((4-chloropyrimidin-5-yl) -oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (1-3) was prepared using 1- (tert-butoxycarbonyl) -3-fluoro-4-aminopiperidine instead of tert-butyl 4-aminopiperidine-1-carboxylate as the reactant and purified by the procedure described in example 1. ESI-MS: m/z=623.2 [ M+H ]] + 。
Test example 1 cell experiment (MV 4-11 cell proliferation inhibition experiment)
Determination of cell viability by CCK-8 reagent
The first day: cell plating
1) The cell suspension in the flask was collected into a 15mL centrifuge tube and the cell solution was centrifuged at 1000rpm for 4min.
2) The supernatant from the centrifuge tube was discarded, and an appropriate amount of fresh complete medium (IMDM+10% FBS+1% P/S) was added to resuspend the cells. mu.L of cell fluid was taken and added to 20. Mu.L of trypan blue and counted.
3) The desired cell suspension volume and complete medium volume were calculated from the viable cell density and the desired number of plated cells. MV4-11 cell plating density was 1 x 104 cells/well, 100. Mu.L/well
4) 100. Mu.L of the above cell suspension was pipetted into a 96-well plate using an electric row gun. A blank well was added with 150. Mu.L of complete medium. The peripheral wells were filled with a suitable volume of PBS to prevent evaporation of the liquid. The culture was carried out in a 96-well plate overnight incubator.
The following day: compound preparation:
1) Compounds dissolved in DMSO were removed and subjected to gradient dilution (96-well PCR plate dilution, columns a, B, etc., in order from left to right, to column J).
Column a initial concentration was 10mM;
b, diluting A, and obtaining 2000 mu M by 2 mu L to 8 mu L of DMSO;
c, diluting B, and obtaining 400 mu M by 2 mu L to 8 mu L of DMSO;
d, diluting C, and obtaining 80 mu M by 2 mu L to 8uL of DMSO;
e, diluting with D, and obtaining 16 mu M from 2uL to 8uL of DMSO;
f, E is taken for dilution, and 2 mu L to 8uL of DMSO is obtained to obtain 3.2 mu M;
g is diluted by F, 2 mu L to 8 mu L DMSO, and 0.64 mu M is obtained;
h, taking G for dilution, and obtaining 0.128 mu M from 2 mu L to 8uL of DMSO;
i is diluted by H, 2 mu L to 8uL DMSO is obtained, and 0.0256 mu M is obtained;
j, diluting with I, and obtaining 0.00512 mu M by 2 mu L to 8uL of DMSO;
the low speed centrifuge was centrifuged at 1000rpm,1 min.
2) Preparation of 3 XCompound (96 well cell culture plate dilution)
The final concentrations were obtained in 3. Mu.L to 197. Mu.L of complete medium in columns B-J using a 10. Mu.L manual lance, respectively: 30000 6000, 1200, 240, 48,9.6,1.92,0.384,0.0768nm; 3. Mu.L DMSO was used as control in 197. Mu.L of complete medium. The shaker was set at 500rpm for 30 min.
Compound treatment:
1) Using a manual lance, the volume was set at 50. Mu.L and the prepared 3 Xcompound solution was pipetted into the corresponding wells with a total culture volume of 150ul per well. The final concentration of compound in 96 well plates was 10uM,2uM,400nM,80nM,16nM,3.2nM,0.64nM,0.128nM,0.0256nM. The shaker was set at 500rpm for 10 min. 2) The laid 96-well plates were placed in a CO2 incubator for 72 hours.
Fifth day: and (3) result detection:
1) Using a lance, the volume was set at 15. Mu.L, and 15. Mu.L/well of CCK-8 assay solution was added.
2) The 96-well cell culture plates were placed in a CO2 incubator and incubated for 4 hours.
3) Reading the 450nm absorption value by using an MD enzyme label instrument, calculating the inhibition rate, and calculating the IC by using a GraphPad 50 Values.
The test results show that the compound IC of the invention 50 The values are less than 100nM, which indicates that the compounds of the invention have good inhibition effect on MV4-11 cells.
It is to be understood that the foregoing detailed description and accompanying examples are merely exemplary and are not to be considered limiting the scope of the invention, which is defined solely by the appended claims and their equivalents. Various alterations and modifications to the disclosed embodiments will be readily apparent to those skilled in the art. Such variations and modifications may be made without departing from the spirit and scope thereof, including but not limited to those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims (10)

1. A compound of formula (i):
wherein:
ring A is selected from C 6-10 Aryl, C 5-8 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl;
l is selected from:
q is selected from-C (R) q1 R q2 ) -, -C (=o) -, -S (=o) -or-S (=o) 2 -；
R q1 、R q2 Each independently selected from H or C 1 -C 6 An alkyl group;
R 1 、R 2 、R 3 each independently selected from H, -OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkyl, -C (O) NR 1a R 2a 、-S(O)NR 1a R 2a 、-S(O) 2 NR 1a R 2a 、-C(O)R 1a 、-S(O) 2 R 1a 、-NR 1a S(O)R 2a 、-NR 1a S(O) 2 R 2a 、-NR 1a C(O)R 2a 、C 6-10 Aryl, 5-7 membered heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, wherein C 6-10 Aryl, 5-7 membered heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl may optionally be substituted with one or more-OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy or C 1 -C 6 Haloalkyl substitution;
R 1a 、R 2a each at each occurrence is independently selected from H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or 3-6 membered heterocyclyl;
R 4 each at each occurrence is independently selected from H, -OH, halogen, cyano, amino, C 1 -C 6 Alkyl, -C (O) R 4a 、-NHC(O)R 4a 、-C(O)NHR 4a 、-NHS(O)R 4a 、-NHS(O) 2 R 4a 、-S(O) 2 R 4a ；
R 4a Each at each occurrence is independently selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl may optionally be substituted with one or more of-OH, halogen, cyano, -NH 2 、-NHCH 3 or-N (CH) 3 ) 2 Substitution; n is 0, 1, 2, 3,4, 5 or 6.
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1,
ring A is selected from phenyl, naphthyl and C 5-6 Cycloalkyl, 9-10 membered heteroaryl, or 9-10 membered heterocyclyl;
preferably, ring a is selected from phenyl, cyclohexyl, benzimidazolinonyl, benzoxazolinonyl, benzothiazolinonyl, benzimidazolyl, indazolyl, indolyl or indolonyl.
3. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1,
l is selected from:
preferably, L is selected from:
wherein, the p end is connected with pyrimidinyl, and the Q end is connected with Q.
4. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 wherein Q is-CH 2 -or-C (=o) -;
or, R 1 、R 2 、R 3 Each independently selected from H, halogen, -C (O) NR 1a R 2a Or a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl may optionally be substituted with one or more C 1 -C 6 Alkyl substitution; r is R 1a 、R 2a Each at each occurrence is independently selected from H or C 1 -C 3 An alkyl group; preferably, R 1 、R 2 、R 3 Each independently selected from H, fluorine, chlorine, bromine, iodine,
Or, R 4 Each at each occurrence is independently selected from H, cyano, amino, C 1 -C 6 Alkyl, -C (O) R 4a 、-NHC(O)R 4a 、-NHS(O) 2 R 4a or-S (O) 2 R 4a ；R 4a Each at each occurrence is independently selected from C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl or C 3-5 Cycloalkyl group, wherein C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl or C 3-5 Cycloalkyl groups may be optionally substituted with one or more halogens; preferably, R 4 Each independently at each occurrence is selected from H, cyano, amino, methyl,
Or n is 0, 1, 2, 3, 4; preferably, n is 0 or 1.
5. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein the compound of formula (I) has the structure:
6. a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1,
ring A is selected from phenyl, naphthyl and C 5-6 Cycloalkyl, 9-10 membered heteroaryl, or 9-10 membered heterocyclyl;
l is selected from:
q is-CH 2 -or-C (=o) -;
R 1 、R 2 、R 3 each independently selected from H, halogen, -C (O) NR 1a R 2a Or a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl may optionally be substituted with one or more C 1 -C 6 Alkyl substitution; r is R 1a 、R 2a Each at each occurrence is independently selected from H or C 1 -C 3 An alkyl group;
R 4 each at each occurrence is independently selected from H, cyano, amino, C 1 -C 6 Alkyl, -C (O) R 4a 、-NHC(O)R 4a 、-NHS(O) 2 R 4a or-S (O) 2 R 4a ；R 4a Each at each occurrence is independently selected from C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl or alkynyl radicalsC 3-5 Cycloalkyl group, wherein C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl or C 3-5 Cycloalkyl groups may be optionally substituted with one or more halogens;
n is 0, 1, 2, 3, 4.
7. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1,
ring a is selected from phenyl, cyclohexyl, benzimidazolinonyl, benzoxazolinonyl, benzothiazolinonyl, benzimidazolyl, indazolyl, indolyl, or indolonyl;
l is selected from:
wherein, the p end is connected with a pyrimidinyl group, and the Q end is connected with Q;
q is-CH 2 -or-C (=o) -;
R 1 、R 2 、R 3 each independently selected from H, fluorine, chlorine, bromine, iodine,R 4 Each occurrence is independently selected from H, cyano, amino, methyl,/v>
n is 0 or 1.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
9. a process for the preparation of a compound of formula (I) according to any one of claims 1 to 8, comprising the steps of:
(1) Scheme 1:
wherein, ring A, L, Q, R 1 、R 2 、R 3 、R 4 And n is as defined in any one of claims 1 to 8;
PG is a protecting group selected from: cbz, boc, fmoc, alloc, teoc, etc.;
LVG is a leaving group selected from: -I, -Br, -Cl, msO-, tfO-, tsO-, etc.;
1) The raw material S1 reacts with the raw material S2 to generate a compound I-1;
2) The compound I-1 is subjected to oxidation reaction to generate a compound I-2;
3) Carrying out halogenation reaction on the compound I-2 to generate a compound I-3;
4) Removing protecting groups after the compound I-3 reacts with the compound PG-L-H to generate a compound I-4;
5) Reacting the compound I-4 with a compound M1 to obtain a compound shown in a formula (I);
(2) Scheme 2:
wherein, ring A, L, Q, R 1 、R 2 、R 3 、R 4 And n is as defined in any one of claims 1 to 8; the process for preparing compound I-3 is the same as that of scheme 1; the obtained compound I-3 is directly reacted with a compound M2 to obtain a compound of formula (I).
10. Use of the compound according to any one of claims 1 to 8 for the preparation of a medicament for the prophylaxis or treatment of a disease associated with the men-MLL protein; preferably, the disease associated with the men-MLL protein comprises mixed leukemia (MLL), MLL-related leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed leukemia (MLL-r), leukemia associated with MLL rearrangement or MLL gene rearrangement, acute leukemia, chronic leukemia, lymphoblastic leukemia, myelogenous leukemia, childhood leukemia, acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), acute myelogenous leukemia, acute non-lymphoblastic leukemia, chronic Lymphoblastic Leukemia (CLL), chronic Myelogenous Leukemia (CML), leukemia associated with treatment, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), myeloproliferative neoplasia (MPN), plasma cell tumor, multiple myeloma, myelodysplasia, cutaneous T cell lymphoma, lymphoid tumor, hairy cell leukemia, meningitis, multiple myeloma, hodgkin's lymphoma, and non-malignant lymphoma.
CN202310193997.6A 2022-03-04 2023-03-03 Heterocyclic amine menin-MLL interaction inhibitor, preparation method and application thereof Pending CN116693502A (en)

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