WO2020108407A1 - Class of bipiperidine derivatives as antitumor drug - Google Patents

Abstract

Provided is a compound represented by formula (I) serving as an inhibitor of cyclin-dependent kinase 7 (CDK7), a pharmaceutical composition thereof, and a method of using the same. Proposed is a use of the compound or the pharmaceutical composition. Representative compounds show anti-cell proliferation and anti-angiogenic activity. Some compounds are more effective than existing anticancer drugs on the market, such as sunitinib. Accordingly, in some aspects, the compound can be used for preparing drugs for treating abnormal cell proliferation or diseases related to angiogenesis, such as antitumor drugs, leukemia drugs and antiviral drugs.

Description

A class of bipiperidine derivatives as anti-tumor drugs Technical field

The invention belongs to the field of therapeutic compounds. The present invention relates to a class of bispiperidine derivatives. More specifically, the present invention relates to a class of heterocyclic compounds. In some embodiments, 2-[4-(4-piperidinyl)-1-piperidinol and a heterocyclic ring, for example, purine or pyrazole [ 1,5-a]pyrimidines are linked. The compounds of the present invention can inhibit kinases. In some aspects, the invention also relates to pharmaceutical compounds and the use of these compounds to treat diseases associated with kinases (CDK7 and CLKs.) that are inhibited by a class of compounds. In some aspects, the kinase-related diseases inhibited by the compounds of the present invention may be proliferative diseases, such as cancer and viral diseases.

Background technique

Deregulation of protein kinases, especially cyclin-dependent kinases (CDK), will cause uncontrolled cell cycle, leading to proliferative diseases such as cancer, leukemia and viral infections. In proliferative diseases, cyclin/CDK activity increases. Therefore, inhibition of cyclin/CDK activity can limit uncontrolled proliferation. A large number of CDKs inhibitors have been reported (Cancer Biology & Medicine 2017, 14: 348-362.) Recently, three inhibitors of CDK4 and CDK6 have entered the market (Future Med Chem. 2018; 10: 1369-1388). However, CDK7 inhibitors are not yet available, and the importance of developing CDK7 inhibitors is due to the role of CDK7 in the cell cycle and as a transcription kinase. During the cell cycle, CDK7 controls the activities of CDK1, CDK2, CDK4, and CDK6. As a transcription kinase, CDK7 forms a trimeric complex-transcription factor TFIIH with MAT1 and cyclin H (Protein Sci. 2018; 27: 1018-1037.). As a CDK7 inhibitor, BS-181 was the first to be studied in detail. It is a selective CDK7 inhibitor, but it can inhibit CDK2 to a lesser extent. It can inhibit tumor growth in a dose-dependent manner (Drug Des Devel Ther. 2016; 10:1181-1189). But the compound has not entered the stage of drug development. Recent studies have shown that this compound can reduce collagen-induced arthritis in mice by inhibiting NF-kB activation (Clin Exp. Med. 2015; 15:269-275).

Among the CDK7 inhibitors, the researchers measured the antiviral activity of LDC4297 based on the pyrazoline skeleton. The CDK7 inhibitor has broad-spectrum antiviral activity at nanomolar concentrations (Antimicrob Agents Chemother. 2015 59: 2062-71). It has moderate activity against the retroviral family (HIV1), and it is an effective inhibitor of most herpesvirus families, especially cytomegalovirus. ICEC0942 is another selective inhibitor of oral effective CDK7 for the treatment of cancer (Mol Cancer Ther. 2018; 17: 1156-1166.). Another inhibitor of CDK7 is THZ1. This compound is a covalent CDK inhibitor. The researchers conducted a more detailed study of the mechanism of its binding to CDK7 by synthesizing its dihydro analog (Nat Commun. 201; 8: 14290.). The covalent binding site is cysteine outside the ATP pocket. YKL-1-116 is another kind of CDK7 covalent inhibitor. It shows good anti-proliferative activity and can sensitize other anti-proliferative agents, such as 5-fluorouracil (Structural Group 1).

Structural group 1 known CDK inhibitors

CDC-like kinase (CKS) can also be inhibited by the compounds of the present invention. These kinases play key roles in alternative splicing as splicing kinases. CLK2 inhibitors can inhibit tumor development in xenograft mouse models in which cells overexpress MYC.

Summary of the invention

This subject involves a new class of bipiperidine derivatives and their use as anti-tumor, leukemia and antiviral drugs. In some embodiments, the present invention links bipiperidine to a nitrogen heterocycle, for example, purine or pyrazole[1,5-a]pyrimidine, to obtain kinase inhibitors, especially selective inhibitors of CDK7 and CLK. As described herein, representative compounds of the invention exhibit anti-cell proliferation and anti-angiogenic activity. Accordingly, in some aspects, the compounds of the present invention can be used in the preparation of treatments for abnormal cell proliferation, or diseases related to vascular proliferation, such as the preparation of anti-tumor, leukemia and antiviral drugs.

In one aspect, the present invention provides a compound represented by formula (G), or a pharmaceutically acceptable salt thereof:

And/or at least one pharmaceutically acceptable salt thereof, wherein

A is C or N;

E is C or N;

Q is CH or N

R is selected from: C _1-6 alkyl, C _3-6 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, each of which alkyl, and cycloalkyl are unsubstituted or contain At least one, such as 1, 2, 3, or 4, substituents, preferably, wherein each substituent is independently selected from halogen (e.g., F), hydroxy, and alkoxy, wherein alkoxy is a chain or ring shape;

Ar is selected from substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl;

R ¹⁰ , R ¹¹ , R ¹² and R ¹⁰⁰ are each independently selected from: H, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, halogen (for example, F) , OH, and substituted or unsubstituted C _1-6 alkoxy;

L is selected from: substituted or unsubstituted C _2-6 alkylene;

L ^{1 is} selected from: substituted or unsubstituted C _1-6 alkylene;

R ^{13 is} selected from: hydrogen and oxygen protecting groups;

R ^{14 is} selected from: hydrogen and nitrogen protecting groups;

m and n are independently integers of 0-4.

In some embodiments, in formula (G), preferably, A is C, E is N, and preferably, Q is also N.

In some embodiments, in formula (G), preferably, E is C, A is N, preferably, Q is CR ¹⁰⁰ , and more preferably, Q is CH.

In some embodiments, in formula (G), preferably, E is C and both A and Q are N.

In some embodiments, R in formula (G) is preferably an unsubstituted C _1-4 alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , Tert-butyl.

In some embodiments, R in formula (G) is preferably an unsubstituted C _3-6 cycloalkyl group, for example, cyclopropane, cyclobutane, cyclopentane.

In some embodiments, R in formula (G) is preferably a methyl or ethyl group substituted with 1 to 3 substituents, and more preferably a methyl group substituted with 1 substituent. Further, wherein the substituent may independently be fluorine, cyclopropyl, cyclobutyl, or oxetanyl.

R in formula (G) is most preferably the group shown in formulas (1)-(7):

In some embodiments, Ar in formula (G) is preferably a substituted or unsubstituted phenyl group. In some embodiments, Ar is unsubstituted phenyl in formula (G). In some embodiments, Ar is substituted phenyl in formula (G), for example, it contains at least one substituent, such as 1, 2, 3, 4 or 5 substituents, preferably 1, 2 Or 3, wherein each substituent is independently selected from halogen (such as F, Cl, Br), CN, substituted or unsubstituted C _1-4 alkyl (for example, halogen substituted or unsubstituted C _1-4 alkyl ), hydroxy, substituted or unsubstituted alkoxy (for example, halogen substituted or unsubstituted alkoxy), carbonic acid amide group, amide group (for example, acetamido group), sulfonamide group and sulfonimide group. In this context, when the substituent is a carbonic acid amide group, an amide group, a sulfonamide group, or a sulfonimide group, the substituent group may be connected to the substituted group by a nitrogen atom therein, or by a carbon atom (such as C=O), the sulfur atom (such as SO ₂ ) is connected to the substituted group.

In some embodiments, Ar in formula (G) is preferably selected from formulas (8)-(33):

Among them, in the substituents (20)-(33), each R ¹ and R ^{2 is} independently selected from hydrogen, C _1-8 alkyl (eg C _1-4 alkyl), C _3-6 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, aryl and heteroaryl, wherein each alkyl, and cycloalkyl is unsubstituted or contains at least one substituent, such as 1, 2, 3 or 4 substituents, preferably wherein each substituent is independently selected from hydroxyl and alkoxy.

In some embodiments, Ar in formula (G) is preferably a substituted or unsubstituted heteroaryl. As used herein, "heteroaryl" refers to a monocyclic (eg, five- or six-membered) or polycyclic (eg, benzo) having at least one carbon atom and one or more independently selected nitrogen, oxygen, or sulfur atoms Ring) Heteroaromatic ring. Representative examples of monocyclic heteroaryl groups include, but are not limited to: furanyl (including but not limited to: furan-2-yl), imidazolyl (including but not limited to: IH-imidazol-1-yl), Isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridyl (for example: pyridin-4-yl, pyridin-2-yl and pyridin-3-yl), pyridazinyl, Pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl (including but not limited to: thiophen-2-yl and thiophen-3-yl ), triazolyl and triazinyl. Representative examples of polycyclic heteroaryl groups include, but are not limited to: indole, benzofuran, benzothiazole, benzothiophene, and the like.

In some embodiments, Ar in formula (G) is preferably a substituted or unsubstituted five- or six-membered heteroaryl group, for example, pyrrole or pyridyl. In some embodiments, Ar in formula (G) is preferably a substituted or unsubstituted 5,6- and hexacyclic heteroaryl, for example, indole, benzofuran, benzothiazole, Or benzothiophene. Preferably, wherein the heteroaryl group is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4 or 5 substituents. Further, wherein each substituent is independently selected from halogen (such as F, Cl, Br), CN, substituted or unsubstituted C _1-4 alkyl (for example, halogen substituted or unsubstituted C _1-4 alkyl) , Hydroxyl, substituted or unsubstituted alkoxy (for example, halogen substituted or unsubstituted alkoxy), carbonic acid amide group, amide group (for example, acetamido group), sulfonamide group and sulfonimide group.

In some embodiments, Ar in formula (G) is preferably selected from formulas (34)-(53):

R ¹⁰ is usually H in formula (G). However, in some embodiments, R ¹⁰ in formula (G) may also be other groups, for example, substituted or unsubstituted C _1-6 alkyl, preferably unsubstituted C _1-4 alkyl or substituted by 1 -3 C _1-4 alkyl substituted with F; a substituted or unsubstituted C _3-6 cycloalkyl, preferably unsubstituted or substituted by 1-3 F C _3-6 cycloalkyl; halogen, preferably F or Cl; OH; and substituted or unsubstituted C _1-6 alkoxy, preferably unsubstituted or substituted with 1 to 3 F C _1-6 alkoxy group.

Generally, the piperidine ring in formula (G), except for N substitution, does not contain other ring substituents, that is, the variables m, n are all 0. However, in some embodiments, in formula (G) Each piperidine ring may be further independently substituted with 1-3 substituents. For example, in some embodiments, m is 1, 2, or 3, and R ¹¹ is a substituted or unsubstituted C _1-6 alkyl at each occurrence, preferably an unsubstituted C _1-4 alkyl or substituted 1-3 F-substituted C _1-4 alkyl; substituted or unsubstituted C _3-6 cycloalkyl, preferably unsubstituted or substituted with 1-3 F C _3-6 cycloalkyl; halogen , Preferably F or Cl; OH; and substituted or unsubstituted C _1-6 alkoxy, preferably unsubstituted or substituted with 1-3 F _1-6 alkoxy; more preferably, R ¹¹ At each occurrence is methyl, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, or fluorine. In some embodiments, n is 1, 2, or 3, and each occurrence of R ¹² is a substituted or unsubstituted C _1-6 alkyl group, preferably an unsubstituted C _1-4 alkyl group or a 1- 3 C _1-4 alkyl substituted with F; a substituted or unsubstituted C _3-6 cycloalkyl, preferably unsubstituted or substituted by 1-3 F C _3-6 cycloalkyl; halogen, preferably Is F or Cl; OH; and substituted or unsubstituted C _1-6 alkoxy, preferably unsubstituted or substituted with 1-3 F _1-6 alkoxy; more preferably, R ¹² is Each occurrence is methyl, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, or fluorine. Preferably, the total number of m, n does not exceed 4, most preferably 0.

L in formula (G) is usually an unsubstituted C _2-4 alkylene group, preferably ethylene. In some embodiments, L in formula (G) may also be a substituted C _2-6 alkylene group, preferably a substituted C _2-4 alkylene group, more preferably a substituted C _2-3 Alkylene, for example, ethylene, propylene. When substituted, the alkylene group may be substituted with 1-3 substituents, preferably 1 or 2 substituents. Preferably, wherein each substituent is independently selected from methyl, trifluoromethyl, hydroxy, amino, carboxy, lipid, methoxy, trifluoromethoxy, or fluorine, or two substituents on the same carbon Together =O, or two substituents and their connected atoms together form a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, substituted or unsubstituted benzene ring, or substituted or unsubstituted five-membered or Six-membered heteroaromatic ring.

L ¹ in formula (G) is usually an unsubstituted C _1-4 alkylene group, preferably a methylene group. In some embodiments, L ¹ in formula (G) may also be a substituted C _1-6 alkylene group, preferably a substituted C _1-3 alkylene group, more preferably a substituted C _{1- 2} alkylene, for example, methylene, ethylene. When substituted, the alkylene group may be substituted with 1-3 substituents, preferably 1 or 2 substituents. Preferably, wherein each substituent is independently selected from methyl, trifluoromethyl, hydroxy, amino, carboxy, lipid, methoxy, trifluoromethoxy, or fluorine, or two substituents on the same carbon Together =O, or two substituents and their connected atoms together form a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, substituted or unsubstituted benzene ring, or substituted or unsubstituted five-membered or Six-membered heteroaromatic ring.

R ¹³ is usually hydrogen in formula (G). In some embodiments, R ¹³ in formula (G) may also be another group, for example, an oxygen protecting group. Oxygen protecting groups are well known in the art. Suitable oxygen protecting groups include, but are not limited to, "Protective Groups in Organic Synthesis, TWGreene , PGMWuts, 3 rd edition, John Wiley & Sons, 1999" oxygen protecting group and cited in the literature. For example, oxygen protecting groups include, but are not limited to, substituted or unsubstituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl (eg, 4-methoxybenzyl), methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc.; silicon ethers, such as trimethylsilyl (TMS), triethylsilyl ether (TES), triiso Propylsilyl (TIPS), tert-butyldimethylsilyl ether (TBDMS), etc.; acetals or ketals, such as tetrahydropyranyl (THP); esters, such as formate, acetate, ethyl chloride Ester, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc.; carbonate; sulfate, such as mesylate, benzenesulfonate, para Tosylate, etc.

R ¹⁴ is usually hydrogen in formula (G). In some embodiments, R ¹⁴ in formula (G) may also be another group, for example, a nitrogen protecting group. Nitrogen protecting groups are well known in the art. Suitable nitrogen protecting groups include, but are not limited to, "Protective Groups in Organic Synthesis, TWGreene , PGMWuts, 3 rd edition, John Wiley & Sons, 1999" nitrogen protecting group and cited in the literature. For example, nitrogen protecting groups include, but are not limited to, acetyl, carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl, Fmoc, Boc (tert-butoxycarbonyl), benzoyl (Bz), benzyl , Carbamate, tosyl (Ts) and other sulfonamides such as Nosyl or Nps, p-methoxybenzyl, 3,4-dimethoxybenzyl and trichloroethyl chloroformate.

In compounds of the general formula shown herein (eg, (G) or (I), including (Ia) (Ib), etc.), the appropriate groups R, A, E, Q, R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , m, n, L, L ¹ , and Ar, if applicable, are independently selected. The embodiments described in the present invention can be combined, and such a combination is still within the protection scope of the present invention. For example, where applicable, any one of the variables R, A, EQ, R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , m, n, L, L ^{1 in the} general compound (G) or (I) , And Ar can be defined with any of the other variables R, A, EQ, R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , m, n, L, L ¹ , and Ar described in this article combination. This combination is still within the scope of the present invention.

In one aspect, the present invention provides a compound represented by formula (I)

And/or at least one pharmaceutically acceptable salt thereof, wherein

A is C or N;

E is C or N;

Q is CH or N

R is selected from: C _1-6 alkyl, C _1-6 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, each of which alkyl, and cycloalkyl are unsubstituted or contain At least one, such as 1, 2, 3, or 4, substituents, preferably, wherein each substituent is independently selected from halogen (e.g., F), hydroxy, and alkoxy, wherein alkoxy is a chain or ring Preferably, R is unsubstituted C _1-4 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, unsubstituted C _3-6 cycloalkyl, for example, cyclopropane, cyclobutane, cyclopentane, or methyl or ethyl substituted with 1-3, preferably 1, substituents, wherein the substituent is fluorine, ring Propyl, cyclobutyl, or oxetanyl, more preferably, R is selected from formulas (1) to (7):

Ar is selected from phenyl, wherein phenyl is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4, or 5 substituents, preferably, wherein each substituent is independently selected from halogen (such as F, Cl, Br), CN, halogen substituted or unsubstituted C _1-4 alkyl, hydroxyl, halogen substituted or unsubstituted alkoxy, carbonic acid amide group, amide group (for example, acetamido group), sulfonamide group and Sulfoimide group, preferably, Ar is selected from formulas (8)-(33):

In the substituents 20-33, each R ¹ and R ^{2 are} independently selected from hydrogen, C _1-8 alkyl (eg C _1-4 alkyl), C _3-6 cycloalkyl, C _3-10 cycloalkane -C _1-4 alkyl, aryl and heteroaryl, wherein each alkyl and cycloalkyl is unsubstituted or contains at least one substituent, such as 1, 2, 3 or 4 substituents, preferably Ground, wherein each substituent is independently selected from hydroxyl and alkoxy;

Or Ar is selected from heteroaryl, the heteroaryl is preferably a 5- or 6-membered ring heteroaryl, or a 5,6-,6,6-bicyclic heteroaryl, preferably indole, benzofuran, benzo Thiazole, pyrrole, benzothiophene or pyridine, wherein the heteroaryl group is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4 or 5 substituents, preferably each of which is independently selected from Halogen (such as F, Cl, Br), CN, halogen substituted or unsubstituted C _1-4 alkyl, hydroxyl, halogen substituted or unsubstituted alkoxy, carbonic acid amide group, amide group (for example, acetamido group) , Sulfonamide and sulfonimide; preferably, Ar is selected from (34)-(53):

In some embodiments, the present invention provides at least one compound represented by formula (1a) and/or at least one pharmaceutically acceptable salt thereof,

Where R and Ar are as described and preferred in formula (I),

E.g,

R is selected from: C _1-6 alkyl, C _3-6 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, each of which alkyl, and cycloalkyl are unsubstituted or contain At least one substituent, such as 1, 2, 3, or 4 substituents, preferably, wherein each substituent is independently selected from halogen (eg, F), hydroxy, and alkoxy, wherein the alkoxy is chain or ring;

Ar is selected from phenyl, wherein phenyl is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4, or 5 substituents, preferably, wherein each substituent is independently selected from halogen (such as F, Cl, Br), CN, halogen substituted or unsubstituted C _1-4 alkyl, hydroxyl, halogen substituted or unsubstituted alkoxy, carbonic acid amide group, amide group (for example, acetamido group), sulfonamide group and Sulfonylimide;

Or Ar is selected from heteroaryl, wherein the heteroaryl is preferably a 5- or 6-membered ring heteroaryl, or 5,6-, 6,6-pyrocyclic heteroaryl, preferably indole, benzofuran, benzene Thiazole, pyrrole, benzothiophene or pyridine, wherein the heteroaryl group is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4 or 5 substituents, preferably each of which is independently selected From halogen (such as F, Cl, Br), CN, halogen substituted or unsubstituted C _1-4 alkyl, hydroxy, halogen substituted or unsubstituted alkoxy, carbonic acid amide group, amide group (eg, acetamido group) ), sulfonamide and sulfonimide. Preferably, R is selected from (1) to (7); Ar is selected from (8) to (53).

In some embodiments, the present invention provides at least one compound represented by formula (1b) and/or at least one pharmaceutically acceptable salt thereof,

Where R and Ar are as described and preferred in formula (I),

E.g,

R is selected from: C _1-6 alkyl, C _3-6 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, each of which alkyl, and cycloalkyl are unsubstituted or contain At least one substituent, such as 1, 2, 3, or 4 substituents, preferably, wherein each substituent is independently selected from halogen (eg, F), hydroxy, and alkoxy, wherein the alkoxy is chain or ring;

Ar is selected from phenyl, wherein phenyl is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4, or 5 substituents, preferably, wherein each substituent is independently selected from halogen (such as F, Cl, Br), CN, halogen substituted or unsubstituted C _1-4 alkyl, hydroxyl, halogen substituted or unsubstituted alkoxy, carbonic acid amide group, amide group (for example, acetamido group), sulfonamide group and Sulfonylimide;

Or Ar is selected from heteroaryl, wherein the heteroaryl is preferably a 5- or 6-membered ring heteroaryl, or 5,6-, 6,6-hexacyclic heteroaryl, preferably indole, benzofuran, benzene Thiazole, pyrrole, benzothiophene or pyridine, wherein the heteroaryl group is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4 or 5 substituents, preferably each of which is independently selected From halogen (such as F, Cl, Br), CN, halogen substituted or unsubstituted C _1-4 alkyl, hydroxy, halogen substituted or unsubstituted alkoxy, carbonic acid amide group, amide group (eg, acetamido group) ), sulfonamide and sulfonimide. Preferably, R is selected from (1) to (7); Ar is selected from (8) to (53).

In some embodiments, the present invention provides at least one compound represented by formula (1c)

among them

X is N, Y is C, Z is C; or X is C, Y is N, Z is C or X is C, Y is C, Z is N

Where R is as claimed and preferred in claim 1,

E.g,

R is selected from: C _1-6 alkyl, C _3-6 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, each of which alkyl, and cycloalkyl are unsubstituted or contain At least one substituent, such as 1, 2, 3, or 4 substituents, preferably, wherein each substituent is independently selected from halogen (eg, F), hydroxy, and alkoxy, wherein the alkoxy is chain or ring.

In some embodiments, the present invention provides at least one compound represented by formula (1d)

And/or at least one pharmaceutically acceptable salt thereof, wherein

X ¹ is F, Cl or Br;

X ² is F, Cl or Br;

Where R is as described and preferred in formula (I),

E.g,

R can be selected from: C _1-6 alkyl, C _3-6 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, each of which alkyl, and cycloalkyl are unsubstituted or Contains at least one substituent, such as 1, 2, 3, or 4 substituents, preferably, wherein each substituent is independently selected from halogen (eg, F), hydroxy, and alkoxy, wherein alkoxy is chain-like Or ring. Preferably, R is selected from (1) to (7).

In some embodiments, the present invention provides at least one compound represented by formula (1e)

And/or at least one pharmaceutically acceptable salt thereof, wherein

X ¹ is F, X ² is F;

X ¹ is Cl and X ² is Cl;

X ¹ is F and X ² is Cl;

X ¹ is Cl and X ² is F;

R is selected from formulas (4)-(7): see formulas (4)-(7) as follows.

In some embodiments, the present invention provides compounds represented by (1f)-(1p), and/or at least one pharmaceutically acceptable salt thereof:

In one aspect, the present invention proposes a pharmaceutical composition. In some embodiments, the pharmaceutical composition may contain one or more compounds of the present invention (eg, the compound has the general formula G or I (eg, the compound has the general formula 1a, 1b, 1c, 1d, or compound (1e) (1i), or any one or more compounds 2-17), or a pharmaceutically acceptable salt thereof), and any pharmaceutically acceptable excipients.

In one aspect, the invention proposes the use of a compound of the invention or a pharmaceutical composition thereof. As described herein, representative compounds of the invention exhibit anti-cell proliferation and anti-angiogenic activity. Some chemicals are more effective than anticancer drugs already on the market such as sunitinib. Accordingly, in some aspects, the compounds of the present invention can be used in the preparation of treatments for abnormal cell proliferation, or diseases related to vascular proliferation, such as the preparation of anti-tumor, leukemia and antiviral drugs.

In some embodiments, the compounds of the present invention or pharmaceutical compositions thereof can be used to treat abnormal cell proliferation. In some embodiments, the compounds of the present invention or pharmaceutical compositions thereof can be used to treat cancer. In some embodiments, the compounds of the present invention or pharmaceutical compositions thereof can be used to treat leukemia. In some embodiments, the compounds of the present invention or pharmaceutical compositions thereof can be used to treat estrogen receptor positive breast cancer. In some embodiments, the compounds of the present invention or pharmaceutical compositions thereof can be used to treat triple negative breast cancer. In some embodiments, the compounds of the present invention or pharmaceutical compositions thereof can be used to treat acute myeloid leukemia. In some embodiments, the compounds of the present invention or pharmaceutical compositions thereof can be used to treat nasopharyngeal carcinoma. In some embodiments, the compounds of the present invention or pharmaceutical compositions thereof can be used to treat lymphoma. In some embodiments, the compounds of the present invention or pharmaceutical compositions thereof can be used to treat peripheral T-cell lymphoma.

In some embodiments, the pharmaceutical composition contains the compound of the present invention as the only active substance.

In some embodiments, the pharmaceutical composition contains a compound of the present invention and other active substances. In some embodiments, the compound of the present invention or the other active substance may each be present in a separate formulation. In some embodiments, the compound of the present invention and the other active substance may be present in the same formulation. In some embodiments, wherein the other active substance is one or more other anti-tumor drugs, preferably, the other tumor drugs may be selected from: aromatase inhibitors, such as letrozole, selective female Hormone breakdown products, such as fulvestrone, estrogen receptor antagonists, such as fulvestrone, and combinations thereof. In some embodiments, the pharmaceutical composition contains a compound of the invention and an aromatase inhibitor, such as letrozole. In some embodiments, the pharmaceutical composition contains a compound of the invention and a selective estrogen breakdown product, such as fulvestrone. In some embodiments, the pharmaceutical composition contains a compound of the present invention and an estrogen receptor antagonist, such as fulvestrone.

In some embodiments, the present invention also provides a method for treating or preventing diseases. Preferably, the method of treating the disease includes giving an effective dose of one or more compounds of the present invention (eg, the compound has the general formula G or I (eg, the compound has the general formula 1a, 1b, 1c, 1d, or compounds (1e)-(1i), or any one or more compounds 2-17), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition described herein. In some embodiments, the method of treating the disease further comprises giving an effective dose of one or more other active substances to the subject (patient), preferably, wherein the other active substances are other one or more anti-tumor Drugs, preferably, the other tumor drugs may be selected from: aromatase inhibitors, such as letrozole, selective estrogen decomposers, such as fulvestrone, estrogen receptor antagonists, such as fulvestrin Joan, and its combination.

In some embodiments, the aforementioned diseases are associated with CDK7 and/or CLK. In some embodiments, the aforementioned disease is abnormal cell proliferation. In some embodiments, the aforementioned disease is cancer. In some embodiments, the aforementioned disease is leukemia. In some embodiments, the aforementioned disease is estrogen receptor positive breast cancer. In some embodiments, the aforementioned disease is triple negative breast cancer. In some embodiments, the aforementioned disease is acute myeloid leukemia. In some embodiments, the aforementioned disease is nasopharyngeal cancer. In some embodiments, the aforementioned disease is lymphoma. In some embodiments, the aforementioned disease is peripheral T cell lymphoma. In some embodiments, the subject has one or more diseases described herein.

The compound of the present invention and its pharmaceutically acceptable salts can be ingested according to pharmaceutically acceptable administration methods, including oral, transdermal, parenteral, nasal and lung administration methods, or by inhalation and insufflation Ingest. The compound of the present invention may use a pharmaceutically acceptable carrier or diluent, and may be any inert, organic or inorganic material suitable for administration, such as water, gelatin, acacia, lactose, microcrystalline cellulose, starch, sodium starch glycolate , Calcium hydrogen phosphate, magnesium stearate, talc and colloidal silica. The pharmaceutical composition also includes other pharmaceutically active agents and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavoring agents and buffering agents. The compounds of the present invention can be prepared in solid or liquid form, such as tablets, capsules, powders, syrups, aerosols, sterile solutions, suspensions or emulsions.

"Compound of the present invention" includes any compound represented by the general formula G or I (for example, the compound has the general formula 1a, 1b, 1c, 1d, or compounds (1e)-(1i), or any one or more compounds 2-17) , Its pharmaceutically acceptable salts, stereoisomers, isotopic substitutions, etc. The compounds of the present invention may also exist in the form of hydrates or solvates.

The compounds of the present invention may exist in an isotopic tracer or enriched form, which contains one or more atoms whose atomic weight or mass number is different from that of the largest amount of atoms found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine and iodine include but are not limited to: ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²⁵ I. Compounds containing these and/or other isotopes of other atoms are within the scope of the present invention.

The term "cycloalkyl" as used herein refers to a monocyclic or bridged ring carbocyclic system. Monocyclic cycloalkyl is a carbocyclic ring system containing 3 to 10 carbon atoms, zero heteroatoms, saturated or unsaturated (non-aromatic ring). Examples of saturated monocyclic systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The saturated monocyclic ring may contain one or two alkylene bridges, each including one, two, or three carbon atoms, and each bridge connects two non-adjacent carbon atoms of the ring system. Representative examples of such bridged cycloalkyl ring systems include, but are not limited to: bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, Bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.03,7]nonane (octahydro-2,5_ Methylcyclopentadiene or noradamantane) and tricyclo[3.3.1.13,7]decane (adamantane). Some unsaturated monocyclic rings may contain olefinic bonds, with four to ten carbon atoms and zero heteroatoms. Four-membered ring systems have one double bond, five- or six-membered ring systems have one or two double bonds, seven- or eight-membered ring systems have one, two or three double bonds, and nine- or ten-membered rings have one or two , Three or four double bonds. Representative examples of unsaturated monocyclic cycloalkyl include, but are not limited to: cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. The unsaturated monocyclic ring may contain one or two alkylene bridges, each including one, two, or three carbon atoms, and each bridge connects two non-adjacent carbon atoms of the ring system. Representative examples of unsaturated bridged rings containing olefinic bonds include, but are not limited to: 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthyl and 1,6-dihydro-pentacyclopentadiene . Monocyclic and bridged cycloalkyl groups can be connected to the parent molecular moiety through any substitutable atoms contained in the ring system. Preferably, the term "cycloalkyl" as used herein refers to a monocyclic saturated cycloalkyl.

The term "subject to be treated" (or, "patient") refers to an animal undergoing treatment, observation, or experiment, especially a mammal, and more preferably a human.

BRIEF DESCRIPTION

Figure 1 compares the inhibitory effect of compound 9 and sunitinib on HUVECs angiogenesis.

Figure 2 is a comparison of the anti-angiogenic activity of compound 9 and sunitinib in chicken embryo chorioallantoic membranes.

Specific implementation

According to the conditions disclosed in the present invention, experienced researchers can easily prepare the compounds represented by the general formulas G and I.

In some aspects, the present invention provides a method of synthesizing the compound represented by formula (Ia). The method includes the formula (IIa) and 2-[4-(piperidinyl)-1-piperidinyl] ethanol, preferably 3-4 equivalents, obtained by heating the reaction, heating at 120-150 degrees Celsius, Where G ¹ is a leaving group, preferably Cl or F, R and Ar are as described and preferred herein,

Specifically, the synthetic route of the compound represented by formula (Ia) can be as follows.

A synthetic route that uses 2,6-dichloropurine as a starting material to synthesize the compound represented by formula (1a). There are 3 steps in this route. Steps (a) and (b) refer to the literature method (Organic Process Research & Development 2009, 13:641). Step (c) uses 3-4 equivalents of 2-[4-( 4-piperidinyl)-1-piperidinyl]ethanol and compound IIIa are obtained by heating.

Steps for preparing compound Ia above. Reagents and conditions: a: aryl-substituted methylamine, n-butanol, triethylamine, reaction at 90℃ for 1 hour, b: bromoalkane, dimethyl sulfoxide, potassium carbonate, reaction at 18-20℃6 -12 hours; c: 2-[4-(4-piperidinyl)-1-piperidinyl] ethanol reacted at 120-150°C for 3-5 hours.

In some aspects, the present invention provides a method of synthesizing the compound represented by formula (Ib). Preferably, the method comprises reacting formula (IIIa) with 2-[4-(piperidinyl)-1-piperidinyl]ethanol, preferably 3-4 equivalents, by heating, preferably at 120-150 Obtained by heating the reaction at Celsius degrees, where G ² is a leaving group, preferably Cl or F, R and Ar are as described and preferred herein,

Specifically, the synthetic route of the compound represented by formula (Ib) can be as follows.

A synthetic route for synthesizing the compound represented by formula (Ib) using 5,7-dichloro-3-alkyl-pyrazole[1,5-a]pyrimidine as a starting material is as follows:

Preparation of Compound 1a. Reagents and conditions: a: aryl-substituted methylamine, n-butanol, or n-propanol, react at 80°C for 1-2 hours, b: 2-[4-(4-piperidinyl)-1-piperidine Base] ethanol reaction at 120-150 ℃ for 3-5 hours

Example 1

1: Synthesis of 2-[4-(4-piperidinyl)-1-piperidinyl]ethanol 1

The above synthetic route is the preparation of 2-[4-(4-piperidine)-1-piperidine]ethanol. 1. Reagents and conditions: a: 2-bromoethanol, acetone, react at 60°C for 5 hours; b: platinum dioxide, hydrogen at 60 atm, hydrobromic acid, water/ethanol, react at 20°C for 4 days.

This compound is prepared from 4,4'-dipyridine in 2 steps. 4,4'-Dipyridine (15 g, 10 mmol) and 2-bromoethanol (12 g, 10 mmol) were reacted and stirred in 100 ml of acetone at 60°C for 5 hours. After cooling, it was filtered to obtain 10.5 g of crude solid 1-(2-hydroxyethyl-1)-4,4′-bispyridine bromide, which was suspended in 20 ml of acetone, stirred at 60° C. for 1 hour, and filtered. The above operation was repeated twice to remove unreacted 4,4'-dipyridine. 1-(2-Hydroxyethyl-1-1)-4,4′-dipyridinium bromide 1a was isolated in 44% yield. ¹ H NMR (400 MHz, DMSO _d6 ) 3.91 (t, 2H), 4.73 (t, 2H), 8.09 (d, 2H), 8.67 (d, 2H), 8.90 (d, 2H), 8.19 (d, 2H) .

Dissolve 1-(2-hydroxy-1-1)-4,4′-bispyridine bromide, 1a (7.26 g, 20 mmol) in 100 ml of ethanol:water=1:1 mixture, add 8 ml 48% hydrobromic acid and 0.8g platinum dioxide. The mixture was hydrogenated at 20°C and 60 atmospheres for 4 days. After removing the catalyst by filtration, the solution was concentrated under vacuum. The concentrated solution was adjusted to pH=11 with concentrated sodium hydroxide at 0°C, extracted 5 times with 50 ml of dichloromethane, and concentrated to remove dipiperidine ethanol to obtain compound 1. Yield 58%. ¹ H-NMR (400 MHz, DMSO _d6 ) 1.05-1.30 (m, 9H), 1.40 (d, 2H), 2.04 (t, 2H), 2.51 (t, 2H), 2.57 (t, 2H), 2.80 (d , 2H), 3.12 (d, 2H), 3.62 (t, 2H).

Example 2

Synthesis of 2-[4-[1-[6-(phenethylamino)-9-isopropyl-purin-2-yl]-4-piperidin]-1-piperidinyl]ethanol (2). Compound 2 was prepared according to the following reaction formula.

Reaction formula for preparation of compound 2, a: benzylamine, triethylamine, n-butanol B, reaction at 90°C, b: 2-bromopropane, potassium carbonate, dimethyl sulfoxide, reaction at 15-18°c: 2-[4-(4-piperidinyl)-1-piperidinyl]ethanol at 140°C for 4 hours

2,6-Dichloropurine (2.31 g, 10 mmol) was dissolved in 50 ml of n-butanol solution, triethylamine (2.2 ml, 16 mmol) was added, and then benzylamine (12 mmol) was added. The mixture was stirred at 90°C for 2 hours. After cooling to 20°C, the precipitated 2-chloro-6-phenylaminopurine was separated by filtration and washed with 5 ml of cold n-butanol. After drying, 2-chloro-6-phenylaminopurine was dissolved in 25 ml of dimethyl sulfoxide, potassium carbonate (14.28 mmol) was added, and then 2-bromopropane (11.70 g, 9.52) was added with stirring at 15-18°C. Mmol). After stirring for 8 hours, the mixture was poured into 60 ml of cold water, and extracted three times with 30 ml of ethyl acetate, the organic phase was washed three times with 20 ml of water, and dried over anhydrous sodium sulfate, the organic phase was concentrated , Crystallization to obtain 2-chloro-6-phenylamino-9-isopropylpurine.

2-chloro-6-phenylamino-9-isopropylpurine was dissolved in dimethyl sulfoxide, compound 1 (0.848 g, 4 mmol) was added, and the mixture was stirred at 140°C for 4 hours. After cooling to 20°C, 20 ml of dichloromethane and 20 ml of water were added. The organic phase was washed three times with 10 ml of water. After drying over anhydrous sodium sulfate, the organic phase was concentrated using dichloromethane/ethanol=98/2 Column chromatography was performed to isolate compound 2 in 75% yield.

¹ H NMR (400 MHz, DMSO _d6 ) 0.86-1.35 (m, 10H), 1.48 (d, 6H), 1.63 (m, 4H), 1.80 (t, 2H), 2.40 (t, 2H), 2.60 (t, 2H), 2.83 (d, 2H), 3.46 (t, 2H), 3.60 (t, 2H), 4.60 (hept, 1H), 4.70 (d, 2H), 7.40 (m, 2H), 7.60 (m, 1H ), 7.80 (s, 1H), 8.00 (brs, 1H).

Example 3

Preparation of 2-[4-[1-[9-isopropyl-6-(3-pyridylmethylamino)-5H-purin-2-yl]-4- Piperidinyl]-1-piperidinyl]ethanol (3).

Compound 3 was prepared by the same method as Compound 2, but using 3-pyridylbenzylamine instead of benzylamine.

1H NMR (400MHz, DMSO _d6 ) 0.95-1.20 (m, 10H), 1.50 (d, 6H), 1.70 (m, 2H), t, 1.98 (t, 2H), 2.23 (t, 2H), 2.72 (t , 2H), 2.94 (d, 2H), 3.49 (t, 2H), 4.60 (hept, H), 4.64 (brs, 2H), 5.92 (brs, 1H), 7.20 (dd, 1H), 7.49 (s, 1H), 7.58 (d, 1H), 8.35 (d, 1H), 8.58 (brs, 1H).

Example 4

Preparation of 2-[4-[1-[6-[(3-chloro-4-fluoro-phenyl)methylamino]-9-isopropyl-5H-purine-2- Group]-4-piperidinyl]-1-piperidinyl]ethanol (4).

Compound 4 was prepared by the same method as Compound 2, but 3-chloro-4-fluorobenzylamine was used instead of benzylamine in the first step.

1H NMR (400MHz, CDCl ₃ ) δppm: 1.15-1.30 (m, 8H), 1.70 (d, 2H), 2.00 (t, 2H), 2.45 (t, 2H), 2.60 (t, 2H), 2.90 (d , 2H), 3.10 (d, 2H), 3.40 (s, 1H), 3.60 (t, 2H), 4.60 (m, 1H), 4.75 (d, 2H), 5.10 (d, 2H), 6.85 (s, 1H), 7.30 (t, 1H), 7.40 (t, 1H), 7.5 (s, 1H), 7.70 (d, 1H), 7.9 (d, 1H).

Example 5

Preparation of 2-[4-[1-[6-(1,3-benzothiazol-2-ylmethylamino)-9-isopropyl-purin-2-yl] -4-piperidinyl]-1-piperidinyl]ethanol (5)

Compound 5 was prepared by the same method as Compound 2. In the first step, 1,3-benzothiazole-2-methylamine was used instead of benzylamine. After reacting with 1:2-[4-(4-piperidinyl)-1-piperidinyl]ethanol, it was purified by silica gel column chromatography using dichloromethane:ethanol:triethylamine=10:10:1.

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.15-1.30 (m, 8H), 1.70 (d, 2H), 2.00 (t, 2H piperidinyl), 2.45 (t, 2H), 2.60 (t, 2H), 2.90 ( d, 2H), 3.10 (d, 2H), 3.4 (s, 1H), 3.6 (t, 2H), 4.60 (m, 1H, 4.75 (d, 2H), 6.85 (s, 1H), 7.30 (t, 1H), 7.40 (t, 1H), 7.5 (s, 1H), 7.70 (d, 1H), 7.9 (d, 1H).

Example 6

Preparation of 2-{1′-[6-(3-chloro-4-fluoro-benzylamino)-9-cyclopropylmethyl-9H-purin-2-yl] -[4,4']bipiperidin-1-yl}-ethanol (6).

Compound 6 was prepared by the same method as Compound 2.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 0.35 (d, 2H), 0.55 (d, 2H), 1.15-1.30 (m, 8H), 1.70 (d, 2H), 1.95 (t, 2H), 2.45 ( t, 2H), 2.65 (t, 2H), 2.90 (d, 2H), 3.10 (d, 2H), 3.6 (t, 2H), 3.65 (s, 1H), 3, 75 (d, 2H), 4.65 (d, 2H), 6.15 (s, 1H), 7.15 (m, 1H), 7.40 (m, 1H), 7.50 (m, 1H).

Example 7

Preparation of N - [3 - ({2- [1 '- (2-hydroxy - ethyl) - [4,4'] Piperidine-1-yl] -9-isopropyl-5,9- Hydrogen-4H- purin -6-ylamino}-methyl)-phenyl]-methanesulfonamide (7)

The synthesis of this compound can refer to Example 5, and compound 7 can be prepared according to the following reaction formula.

Preparation of compound 7, reagents and conditions, a: nitrogen-[4-(aminomethyl)phenyl]methanesulfonamide, triethylamine; b: 2-[4-(4-piperidinyl)-1- Piperidinyl] ethanol at 140 ℃ for 4 hours

Compound 7a raw material synthesis reference J. Med. Chem., 2008, 51, 5229-5242

2,6-Dichloro-9-isopropylpurine was placed in a round-bottom flask, dissolved in n-butanol, and 5 mmoles of nitrogen-[4-(aminomethyl)phenyl]methanesulfonamide and 2 A milliliter of triethylamine was added to the reaction system, the temperature was raised to 80°C, and the reaction was carried out for 2 hours. Afterwards, after monitoring the reaction by thin layer chromatography, the solvent was removed in vacuo and the residue was extracted with dichloromethane. Compound 7b was recrystallized with ether solvent.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.55 (d, 6H), 3.01 (s, 3H), 4.65 (d, 2H), 4.72 (hept, 1H),; 7.23 (d, 2H), 7.35 (d , 2H), 8.45 (s, 1H), 9.82 (t, 1H); 9.70 (s, 1H)

Contain 7b (0.6 g 1,52 mmol) and 2-[4-(4-piperidinyl)-1-piperidinyl] ethanol (1,49 g 7,02 mmol) in the reaction flask and warm up At 150°C, react for 4 hours. After monitoring the reaction by thin layer chromatography, it was cooled to 20°C, deionized water was added, and the mixture was extracted with dichloromethane (5x50 mL). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Compound 7b was purified by column chromatography (ethyl acetate:ethanol=98:2) with a yield of 63%.

¹ H NMR (400 MHz, DMSO _d6 ) δ ppm: 0.95-1.35 (m, 8H), 1.45 (d, 6H), (d, 2H), 1.85 (t, 2H), 2.35 (t, 2H), 2.65 (t , 2H), 2.85 (d, 2H), 2.95 (s, 1H), 3.35 (s, 1H), 4.40 (s, 1H), 4.50 (hept, 1H), 4.70 (d, 2H), 7.15 (d, 2H), 7.35 (d, 2H), 7.8 (s, 1H), 7.9 (s, 1H).

Example 8

Preparation of 2-{1′-[6-(4-chloro-3-fluoro-benzylamino)-9-cyclopentyl 1-9hydro-purin-2-yl]-[4,4′]lianpiper piperidin-1-yl} - ethanol (8)

Compound 8 was prepared by the same method as Compound 2.

¹ H NMR (400 MHz, DMSO _d6 ): 0.85-1.30 (m, 8H), 1.6 (m, 8H), 1.85 (d, 2H), 2.30 (t, 2H), 2.55 (t, 2H), 2.65 (t , 2H), 2.85 (d, 2H), 3.35 (d, 2H), 3.5 (t, 2H), 4.35 (s, 1H), 4.60 (m, 3H), 7.15-7.55 (m, 1H), 7.71 ( s, 1H), 8.05 (s, 1H).

Example 9

Preparation of 2-{1′-[9-cyclopentyl-6-(3,4-difluoro-benzylamino)-9hydrogen-purin-2-yl]-[4,4′]piperidinyl -1-yl}-ethanol (9)

Compound 9 was prepared by the same method as Compound 2.

¹ H NMR (400 MHz, DMSO) δ ppm: 0.85-1.30 (m, 8H), 1.60 (m, 8H), 1.85 (d, 2H), 2.30 (t, 2H), 2.55 (t, 2H), 2.65 (t , 2H), 2.85 (d, 2H), 3.35 (d, 2H), 3.50 (t, 2H), 4.35 (s, 1H), 4.60 (m, 3H), 7.15-7.55 (m 1H), 7.70 (s , 1H), 8.02 (s, 1H).

Example 10

Preparation of [4-[1-[6-[(3,4-difluoro-benzylamino]-9 isopropyl-5H-purin-2-yl]-4-piperidinyl]- 1-piperidine Base] ethanol (10)

Compound 10 was prepared by the same method as Compound 2.

¹ H NMR (400MHZ, CDCl ₃ ) δ 1.05-2.07 (m, 8H), 1.64 (d, 6H), 2.06-2.51 (m, 8H), 2.63 (m, 2H), 3.09 (m, 2H), 3.58 (t, 2H), 4.03 (hept, 1H), 4.61 (t, 2H), 4.67 (t, 2H), 6.37 (s, 1H), 7.04 (d, 2H), 7.17 (d, 1H), 7.43 (s, 1H)

Example 11

Preparation of 2-{1′-[9-cyclopentyl-6-(3-chloro-4-fluoro-benzylamino)-9hydro-purin-2-yl]-[4,4′]piperidine Yl- 1-yl}-ethanol (11)

Compound 11 was prepared by the same method as compound 2.

¹ H NMR (400MHZ, DMSO-d6) δ 1.05-2.07 (m, 8H), 1.64 (d, 6H), 2.06-2.51 (m, 8H), 2.63 (d, 2H), 3.09 (d, 2H) , 3.58 (t, 2H), 4.03 (m, 1H), 4.61 (t, 2H), 4.67 (t, 2H), 7.20 (d, 1H), 7.34 (d, 1H), 7.49 (t, 1H), 7.82(s, 1H), 8.02(s, 1H)

Example 12

Preparation of 2-{1′-[9-cyclopentyl-6-(3,5-difluoro-benzylamino)-9hydro-purin-2-yl]-[4,4′]piperidinyl -1-yl}-ethanol (12)

Compound 12 was prepared by the same method as Compound 2.

¹ H NMR (400MHZ, DMSO-d6) δ 1.05-2.07 (m, 8H), 1.64 (d, 6H), 2.06-2.51 (m, 8H), 2.63 (d, 2H), 3.09 (d, 2H) , 3.58(t, 2H), 4.03(m, 1H), 4.61(t, 2H), 4.67(t, 2H), 7.05(d,, 1H), 7.82(s, 1H), 8.02(s, 1H)

Example 13

Preparation of 2- [4- [1- [6- (benzyl-amino) -9- (cyclobutylmethyl purin-2-yl] -4,4 '] Piperidine-l-yl} - ethanol ( 13)

Compound 13 was prepared by the same method as Compound 2.

¹ H NMR (400MHZ, CDCl ₃ ) δ 1.02-1.45 (m, 7H1), 2.06-2.51 (m, 10H), 2.45 (m, 2H), 2.71 (m, 2H), 2.78 (m, 2H), 2.85 (m, 2H), 3.68 (m, 2H), 4.02 (d, 2H), 4.61 (t, 2H), 4.85 (t, 2H), 5.79 (s, 1H, NH), 7.29-7.39 (m, 6H)

Example 14

Preparation of 2-[4-[1-[3-ethyl-7-[(3-fluorophenyl)methylamino]pyrazole[1,5-a]pyrimidin-5-yl]-4,4′ ] piperidine-l-yl} - ethanol (14)

Compound 14 was prepared according to the following reaction formula.

Preparation reagents and conditions of compound 14: a: 3-fluorobenzylamine, triethylamine, isopropanol; b: 2-[4-(4-piperidinyl)-1-piperidinyl]ethanol at 140° React for 4 hours.

Place 14a in a reaction flask, dissolve with 20 ml of isopropanol, add 3-fluorobenzylamine (3.00 ml, 20 mmol), triethylamine (5.6 ml, 40 mmol), warm to 80°C and react 3 hour. After the reaction was monitored by thin layer chromatography, it was cooled to 20°C, deionized water was added, and the mixture was extracted 5 times with 50 ml of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Compound 14b was purified by column chromatography (ethyl acetate:ethanol=9:1) with a yield of 92%.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.20 (t, 3H), 2.65 (q, 2H), 3.30 (d, 2H), 4.45 (d, 2H), 5.75 (s, 1H), 6.75 (t, 1H), 6.80-7.35 (m, H), 7.75 (s, 1H).

Put compound 14b (0.5 g, 1.6 mmol) and 2-[4-(4-piperidinyl)-1-piperidinyl]ethanol (1,63 g, 7,70 mmol) in the reaction flask, The temperature was raised to 150°C and the reaction was carried out for 5 hours. Cool to 20°C. After adding water, it was extracted 4 times with 25 ml of ethyl acetate, the organic phase was dried and the solvent was removed. With the same ratio of the above column chromatography eluent, 71% of pure product can be obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.15-1.30 (m, 8H, 1.70 (d, 2H), 2.15 (t, 2H), 2.55 (m, 2H), 2.80 (t, 2H), 2.90 (d , 2H), 3.15 (d, 2H), 3.55 (s, 1H) 3.65 (t, 2H), 4.55 (d, 2H), 5.30 (s, 1H), 6.5 (m, 1H, 7.00-7.45 (m, 4H), 7.7 (s, 1H)

Example 15

Preparation of 2- [4- [l- [6 - [(3-fluorophenyl) methyl amino] -5H- purin-9-isopropyl-2-yl] -4-piperidinyl] -1 Piperidinyl)ethanol (15)

Compound 15 was prepared by the same method as Compound 2.

δ 1.05-2.07 (m, 8H), 1.64 (d, 6H), 2.06-2.51 (m, 8H), 2.63 (m, 2H), 3.09 (m, 2H), 3.58 (t, 2H), 4.03 ( hept, 1H), 4.61 (t, 2H), 4.67 (t, 2H), 6.97-7.45 (m, 4H), 8.05 (s, 1H)

Example 16

Preparation of 2-[4-[1-[6-[(4-chloro-3-fluorophenyl)methylamino]-9-isopropyl-5H-purin-2-yl]-4 -piperidinyl ]-1-piperidinyl]ethanol 1(16)

Compound 16 was prepared by the same method as Compound 2.

¹ H NMR (400MHZ, CDCl ₃ ) δ 1.05-2.06 (m, 8H), 1.65 (d, 6H), 2.06-2.54 (m, 8H), 2.65 (m, 2H), 3.10 (m, 2H), 3.58 (t, 2H), 4.04 (hept, 1H), 4.62 (t, 2H), 4.67 (t, 2H), 7.22 (d, 1H), 7.35 (d, 1H), 7.47 (t, 1H), 7.84 (s, 1H), 8.05 (s, 1H)

Example 17: - piperidine [(3---fluorophenyl) methyl amino-purin-2-yl] -4-piperidinyl] -1 Preparation of 2- [4- [1- [9-cyclopentyl-6 ] Ethanol (17)

Compound 17 was prepared by the same method as Compound 2.

¹ H NMR (400MHZ, DMSO-d6) δ 1.05-2.06 (m, 8H), 1.66 (d, 6H), 2.04-2.53 (m, 8H), 2.64 (d, 2H), 310 (d, 2H) , 3.59 (t, 2H), 4.03 (m, 1H), 4.62 (t, 2H), 4.67 (t, 2H), 6.99-7.44 (m, 4H), 8.06 (s, 1H)

Example 18

Preparation of 2-[4-[1-[9-isopropyl-6-(3-pyridylmethylamino)-5H-purin-2-yl]-4 -piperidinyl]-1-piperidinyl ] Ethanol (18)

Compound 18 was prepared by the same method as Compound 2.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, J=5.6 Hz, 2H), 8.02 (s, 1H), 7.82 (s, 1H), 7.30 (d, J=5.6 Hz, 2H), 4.54 (t, J = 6.8 Hz, 4H), 3.48 (t, J = 6.4 Hz, 2H), 3.17 (s, 4H), 2.87 (d, J = 11.2 Hz, 2H), 2.56 (m, 2H), 2.36 (t, J=6.4Hz, 2H), 1.87(s, 2H), 1.53(d, J=8.4Hz, 2H), 1.44(d, J=6.8Hz, 6H), 1.16(m, 4H), 0.97 (m, 2H).

Example 19

Preparation of 2-[4-[1-[9-isopropyl-6-(3-pyridylmethylamino)-5H-purin-2-yl]-4 -piperidinyl]-1-piperidinyl ] Ethanol (19)

Compound 19 was prepared by the same method as Compound 2.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (d, J=4.4 Hz, 1H), 7.83 (s, 2H), 7.67 (t, J=7.6 Hz, 1H), 7.29 (d, J=8.0 Hz , 1H), 7.20 (t, J = 5.2 Hz, 1H), 5.22 (s, 1H), 4.67 (s, 1H), 4.56 (q, 3H), 3.48 (t, J = 6.0 Hz, 1H), 2.90 (t, J = 10.8 Hz, 1H), 2.83 (d, J = 7.6 Hz, 1H), 2.56 (q, 4H), 2.38 (t, J = 6.0 Hz, 1H), 1.92 (m, 4H), 1.57 (d, J = 11.6 Hz, 2H), 1.46 (d, J = 6.4 Hz, 6H), 1.20 (s, 2H), 1.15 (m, 2H), 1.11 (m, 4H).

Example 20

Preparation: 2-[4-[1-[6-[(3-fluorophenyl)methylamino]-9-methylenecyclopropyl-5H-purin-2-yl]-4 -piperidinyl] -1-piperidinyl)ethanol (20)

Compound 20 was prepared by the same method as Compound 2

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 0.35 (d, 2H), 0.55 (d, 2H), 1.15-1.30 (m, 8H), 1.70 (d, 2H), 1.95 (t, 2H), 2.45 ( t, 2H), 2.65 (t, 2H), 2.90 (d, 2H), 3.10 (d, 2H), 3.6 (t, 2H), 3.65 (s, 1H), 3, 75 (d, 2H), 4.65 (d, 2H), 6.95-7.40 (m, 4H), 8.10 (s, 1H)

Example 21

2-[4-[1-[6-[(4-fluoro-3-chlorophenyl)methylamino]-9 methylenecyclobutyl-5H-purin-2-yl]-4- Piperidinyl]-1-piperidinyl]ethanol (21)

Compound 21 was prepared by the same method as Compound 2

¹ H NMR (400MHZ, CDCl ₃ ) δ 1.02-1.46 (m, 7H), 2.03-2.51 (m, 10H), 2.44 (m, 2H), 2.72 (m, 2H), 2.79 (m, 2H), 2.85 (m, 2H), 3.69 (m, 2H), 4.02 (d, 2H), 4.62 (t, 2H), 4.87 (t, 2H), 5.82 (s, 1H, NH), 7.22 (d, 1H) , 7.34 (d, 1H), 7.49 (t, 1H), 7.81 (s, 1H), 8.05 (s, 1H)

Biological evaluation

Cell lines and culture conditions (Table 1)

Table 1 List of cell lines

Cell proliferation experiment

The inhibitory effect of compounds on cell proliferation was detected by MTT assay. In short, take the cells in the logarithmic growth phase, determine the cell density is 5 × 10 ⁴ cells/mL and inoculate on a 96-well plate, add 100 μL of cell suspension to each well for a certain period of time (suspended cells are cultured for 2 hours, paste Parietal cell culture for 24h). Compounds with different concentrations (10-100,000nM) were added to each well and incubated for 48h, and 20μL of 5mg/mL MTT solution was added to each well to continue incubation for 4h, and then detected using a microplate reader. The control group treated with DMSO was counted as a cell viability value of 100%, and the inhibitory concentration (IC ₅₀ ) was obtained by non-linear regression using GraphPad Prism 4.0. Each experiment final value of three independent experiments IC ₅₀ values measured calculated. The results are shown in Table 2 and Table 3.

Table 2: Activity of the compounds of the present invention to inhibit the proliferation of tumor cells (μM)

To determine the special significance of the compounds of the present invention in triple negative breast cancer (TNBC), the compounds of the present invention were also tested in MDA-MB-231 and MDA-MB-468 cell lines.

Table 3: Activity of the compounds of the present invention to inhibit the proliferation of triple negative breast cancer cells (μM)

CPD.	MDA-MB-231	MDA-MB-468
CPT	19.25±7.27	0.06±0.01
2	3.70±0.91	4.27±0.48
5	3.03±1.31	4.49±0.12
6	3.66±0.83	2.29±0.72
7	37.27±7.77	30.89±1.82
8	2.40±0.38	0.56±0.0005

9	0.29±0.06	0.40±0.03
10	3.69±0.37	2.94±0.21
11	0.70±0.58	3.31±0.73
12	39.23±5.21	34.67±5.29
14	3.62±0.56	3.05±0.27
15	3.31±0.22	4.19±0.73

Kinase inhibition spectrum test, kinase group scan shown in Table 7. Compound 2 was used in this experiment.

Effects of Compounds on Angiogenesis: Angiogenesis Experiment

A 96-well culture plate coated with Matrigel was used to study the vascularization of HUVEC cells. Matrigel (13.9 mg/mL; BD Bioscience, San Jose, CA, USA) was slowly thawed at 4°C. Add 50 μL of Matrigel to a 24-well culture plate, and incubate at 37°C for 30 min for polymerization. HUVEC cells (1×105 cells/well) were suspended in F12 medium containing 10% FBS, 2.05 mM glutamine and 1% penicillin-streptomycin, and then added to Matrigel-coated wells. After incubating at 37°C in a 5% CO 2 environment for 40 min, DMSO or compound 2m (10 nM, 30 nM, 100 nM) was added to the cells. Then, after incubating the plate at 37°C in a 5% CO 2 environment for 12 hours, the luminal formation of the capillary network in each well of the culture plate was photographed with a Nikon Eclipse Ti microscope (Nikon, Tokyo, Japan). The results are shown in Figure 1.

Chicken embryo chorioallantoic membrane vascular experiment

Select 50～66g white-skinned eggs, sterilize them and place them in an incubator for incubation, which is recorded as the first day. From the fourth day onwards, the development of embryos will be checked. Eggs will be irradiated with egg light to eliminate dead eggs and embryos with poorly developed embryos. On the seventh day, the inner shell membrane was torn off to form a false air chamber. Then, the pseudo air chamber is sealed to form a transparent observation window. One day later, 20 μl of compound was added to the carrier. After 3 days of compound action, 1 mL of fixing solution (methanol: acetone = 1:1) was added to the observation window for 15 minutes. .

Compound 9 was used for chicken embryo chorioallantoic membrane assay. The results shown in Figure 2 demonstrate that compound 9 is superior to sunitinib.

Table 4: Activity of the compounds of the present invention to inhibit tumor cell proliferation (μM)

Table 5: Activity of the compounds of the present invention to inhibit tumor cell proliferation (μM)

The following table shows the kinase inhibitory properties of compound 2. This test shows that Compound 2 has high selectivity for kinases. This compound basically inhibits CDK7 and CLK. The experiment was conducted by Nanosyn Inc. Santa Clara 95051 in the United States at a dose of 1 μM and 10 μM of compound 2.

Table 6 Kinase inhibitory properties

Claims (32)

1. A class of bipiperidine derivatives, characterized by: at least one compound represented by formula (I)

   

   And/or at least one pharmaceutically acceptable salt thereof, wherein

   A is C or N;

   E is C or N;

   Q is CH or N

   R is selected from: C _1-6 alkyl, C _3-6 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, each of which alkyl, and cycloalkyl are unsubstituted or contain At least one, such as 1, 2, 3, or 4, substituents, preferably, wherein each substituent is independently selected from halogen (e.g., F), hydroxy, and alkoxy, wherein alkoxy is a chain or ring Preferably, R is unsubstituted C _1-4 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, unsubstituted C _3-6 cycloalkyl, for example, cyclopropane, cyclobutane, cyclopentane, or methyl or ethyl substituted with 1-3, preferably 1, substituents, wherein the substituent is fluorine, ring Propyl, cyclobutyl, or oxetanyl, more preferably, R is selected from (1) to (7):

   

   Ar is selected from phenyl, wherein phenyl is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4, or 5 substituents, preferably, wherein each substituent is independently selected from halogen (such as F, Cl, Br), CN, halogen substituted or unsubstituted C _1-4 alkyl, hydroxyl, halogen substituted or unsubstituted alkoxy, carbonic acid amide group, amide group (for example, acetamido group), sulfonamide group and Sulfoimide group, preferably, Ar is selected from (8)-(33):

   

   In the substituents 20-33, each R ¹ and R ^{2 are} independently selected from hydrogen, C _1-8 alkyl (eg C _1-4 alkyl), C _3-6 cycloalkyl, C _3-10 cycloalkane -C _1-4 alkyl, aryl and heteroaryl, wherein each alkyl and cycloalkyl is unsubstituted or contains at least one substituent, such as 1, 2, 3 or 4 substituents, preferably Ground, wherein each substituent is independently selected from hydroxyl and alkoxy;

   Or Ar is selected from heteroaryl, wherein the heteroaryl is preferably a 5- or 6-membered ring heteroaryl, or 5,6-, 6,6-pyrocyclic heteroaryl, preferably indole, benzofuran, benzene Thiazole, pyrrole, benzothiophene or pyridine, wherein the heteroaryl group is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4 or 5 substituents, preferably each of which is independently selected From halogen (such as F, Cl, Br), CN, halogen substituted or unsubstituted C _1-4 alkyl, hydroxy, halogen substituted or unsubstituted alkoxy, carbonic acid amide group, amide group (eg, acetamido group) ), sulfonamide and sulfonimide; preferably, Ar is selected from (34)-(53):

   
2. The bipiperidine derivative according to claim 1, and/or at least one pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by formula (1a)

   

   Where R and Ar are as described and preferred in claim 1,

   E.g,

   R is selected from: C _1-6 alkyl, C _3-6 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, each of which alkyl, and cycloalkyl are unsubstituted or contain At least one substituent, such as 1, 2, 3, or 4 substituents, preferably, wherein each substituent is independently selected from halogen (eg, F), hydroxy, and alkoxy, wherein the alkoxy is chain or ring;

   Ar is selected from phenyl, wherein phenyl is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4 or 5 substituents, preferably, wherein each substituent is independently selected from halogen, hydroxy, alkyl Oxygen group, carbonic acid amide group, amide group (for example, acetamido group), sulfonamide group and sulfonimide group;

   Or Ar is selected from heteroaryl, the heteroaryl is preferably a 5- or 6-membered ring heteroaryl, or a 5,6-,6,6-bicyclic heteroaryl, preferably indole, benzofuran, benzo Thiazole, pyrrole, benzothiophene and pyridine; wherein heteroaryl is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4 or 5 substituents, preferably each of which is independently selected from Halogen, hydroxyl, alkoxy, carbonic acid amide group, amide group (for example, acetamide group), sulfonamide group and sulfonimide group.
3. The bipiperidine derivative according to claim 1, and/or at least one pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by formula (1b)

   

   Where R and Ar are as described and preferred in claim 1,

   E.g,

   R is selected from: C _1-6 alkyl, C _3-6 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, each of which alkyl, and cycloalkyl are unsubstituted or contain At least one substituent, such as 1, 2, 3, or 4 substituents, preferably, wherein each substituent is independently selected from halogen (eg, F), hydroxy, and alkoxy, wherein the alkoxy is chain or ring;

   Ar is selected from phenyl, wherein phenyl is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4 or 5 substituents, preferably, wherein each substituent is independently selected from halogen, hydroxy, alkyl Oxygen group, carbonic acid amide group, amide group (for example, acetamido group), sulfonamide group and sulfonimide group;

   Or Ar is selected from heteroaryl, the heteroaryl is preferably a 5- or 6-membered ring heteroaryl, or a 5,6-,6,6-bicyclic heteroaryl, preferably indole, benzofuran, benzo Thiazole, pyrrole, benzothiophene and pyridine; wherein heteroaryl is unsubstituted or contains at least one substituent, such as 1, 2, 3, 4 or 5 substituents, preferably each of which is independently selected Halogen, hydroxyl, alkoxy, carbonic acid amide group, amide group (for example, acetamide group), sulfonamide group and sulfonimide group.
4. The bipiperidine derivative according to claim 1, and/or at least one pharmaceutically acceptable salt thereof, wherein the compound is of formula
5. The bipiperidine derivative according to claim 1, and/or at least one pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by formula (1c)

   

   among them

   X is N, Y is C, Z is C; or X is C, Y is N, Z is C or X is C, Y is C, Z is N

   Where R is as claimed and preferred in claim 1,

   E.g,

   R is selected from: C _1-6 alkyl, C _3-6 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, each of which alkyl, and cycloalkyl are unsubstituted or contain At least one substituent, such as 1, 2, 3, or 4 substituents, preferably, wherein each substituent is independently selected from halogen (eg, F), hydroxy, and alkoxy, wherein the alkoxy is chain or ring.
6. The bipiperidine derivative according to claim 1, and/or at least one pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by formula (1d)

   

   among them

   X ¹ is F, Cl or Br;

   X ² is F, Cl or Br;

   Where R is as claimed and preferred in claim 1,

   E.g,

   R is selected from: C _1-6 alkyl, C _3-6 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, each of which alkyl, and cycloalkyl are unsubstituted or contain At least one substituent, such as 1, 2, 3, or 4 substituents, preferably, wherein each substituent is independently selected from halogen (eg, F), hydroxy, and alkoxy, wherein the alkoxy is chain or ring.
7. The bipiperidine derivative according to claim 1, and/or at least one pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by formula (1e)

   

   among them

   X ¹ is F, X ² is F;

   X ¹ is Cl and X ² is Cl;

   X ¹ is F and X ² is Cl;

   X ¹ is Cl and X ² is F;

   R is selected from formulas (4)-(7):

   
8. The compound according to claim 1, and/or at least one pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds represented by formulas (1f)-(1p)

   

   
9. A method for synthesizing the compound represented by formula (Ia) according to claim 2, which comprises combining formula (IIa) with 2-[4-(piperidinyl)-1-piperidinyl]ethanol, preferably 3-4 Equivalents are obtained by heating the reaction, preferably at 120-150 degrees Celsius, wherein G ¹ is a leaving group, preferably Cl or F, R and Ar are as described in claim 1 and preferably,

   
10. A method of synthesizing the compound represented by (Ib) according to claim 3, which comprises combining formula (IIIa) with 2-[4-(piperidinyl)-1-piperidinyl]ethanol, preferably 3-4 Equivalents, obtained by heating reaction, preferably, heating reaction at 120-150 degrees Celsius, wherein G ² is a leaving group, preferably Cl or F, R and Ar are as described in claim 1 and preferably,

    
11. A method for treating abnormal cell proliferation, comprising using an effective dose of a drug for a patient in need, the drug containing at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof.
12. A method for treating cancer, comprising using an effective dose of a medicine for a patient in need, the medicine comprising at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof.
13. A method for treating leukemia, comprising using an effective dose of a medicine for a patient in need, the medicine containing at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof.
14. A method for treating estrogen receptor positive breast cancer, comprising using an effective dose of a medicine for a patient in need, the medicine containing at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof .
15. A method for treating triple-negative breast cancer, comprising using an effective dose of a drug for a patient in need, the drug containing at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof.
16. Use of any one of the compounds described in claims 1-6 and/or a pharmaceutically acceptable salt thereof in the treatment of abnormal cell proliferation, cancer, leukemia, estrogen receptor positive breast cancer, or triple negative breast cancer.
17. Use of any one of the compounds described in claims 1-6 and/or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of abnormal cell proliferation, cancer, leukemia, estrogen receptor positive breast cancer, Or triple negative breast cancer.
18. A pharmaceutical combination comprising at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof and one or more other anti-tumor drugs.
19. A pharmaceutical combination comprising at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof, and an aromatase inhibitor, such as letrozole.
20. A pharmaceutical combination comprising at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof, and a selective estrogen breakdown product, such as fulvestrone.
21. A pharmaceutical combination comprising at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof, and an estrogen receptor antagonist, such as fulvestrone.
22. A method for treating acute myeloid leukemia, comprising using an effective dose of a medicine for a patient in need, the medicine containing at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof.
23. A method for treating nasopharyngeal cancer, comprising using an effective dose of a medicine for a patient in need, the medicine containing at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof.
24. A method for treating lymphoma, comprising using an effective dose of a medicine for a patient in need, the medicine containing at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof.
25. A method for treating peripheral T-cell lymphoma, comprising using an effective dose of a drug for a patient in need, the drug containing at least one compound according to claims 1-6 and/or at least one pharmaceutically acceptable salt thereof.
26. Use of any one of the compounds described in claims 1-6 and/or a pharmaceutically acceptable salt thereof in the treatment of acute myeloid leukemia, nasopharyngeal carcinoma, lymphoma, or peripheral T-cell lymphoma.
27. Use of any one of the compounds described in claims 1-6 and/or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of acute myeloid leukemia, nasopharyngeal carcinoma, lymphoma, or peripheral T cells Lymphoma.
28. The method of any one of claims 9-13 and 20-23, further comprising administering an effective dose of one or more other anti-tumor drugs to patients in need.
29. The method of any one of claims 26, wherein the other anti-tumor drug is selected from the group consisting of aromatase inhibitors, such as letrozole, selective estrogen decomposers, such as fulvestrone, estrogen receptor antagonists , Such as fulvestrone, and combinations thereof.
30. Any one of the compounds described in claims 1-6 and/or a pharmaceutically acceptable salt thereof and one or more other antitumor drugs in the treatment of abnormal cell proliferation, cancer, leukemia, estrogen receptor positive breast cancer, Use in triple negative breast cancer, acute myeloid leukemia, nasopharyngeal carcinoma, lymphoma, or peripheral T-cell lymphoma.
31. The use as claimed in claim 28, wherein the other anti-tumor drugs are selected from: aromatase inhibitors, such as letrozole, selective estrogen breakdown products, such as fulvestrone, estrogen receptor antagonists, such as Fulvestrone, and its combination.
32. Use of any one of the compounds described in claims 1-6 and/or a pharmaceutically acceptable salt thereof and one or more other antitumor drugs in the preparation of a medicament for the treatment of abnormal cell proliferation, cancer , Leukemia, estrogen receptor positive breast cancer, triple negative breast cancer, acute myeloid leukemia, nasopharyngeal carcinoma, lymphoma, or peripheral T cell lymphoma.

    The use as claimed in claim 30, wherein the other anti-tumor drugs are selected from: aromatase inhibitors, such as letrozole, selective estrogen decomposers, such as fulvestrone, estrogen receptor antagonists, such as Fulvestrone, and its combination.

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