CN110746399B

CN110746399B - Compound with androgen receptor degrading activity

Info

Publication number: CN110746399B
Application number: CN201910658388.7A
Authority: CN
Inventors: 舒永志; 王峰; 林军; 罗冯军; 顾磊
Original assignee: Shanghai Meizer Pharmaceuticals Co ltd
Current assignee: Shanghai Meizer Pharmaceuticals Co ltd
Priority date: 2018-07-23
Filing date: 2019-07-21
Publication date: 2022-04-22
Anticipated expiration: 2039-07-21
Also published as: CN110746399A; WO2021012659A1

Abstract

The invention provides a compound with an activity of degrading Androgen Receptor (AR), in particular to a compound shown as a formula I; wherein, the definition of each group is described in the specification. The compound has good Androgen Receptor (AR) degradation activity, and can be used for preparing medicaments for treating AR expression related diseases.

Description

Compound with androgen receptor degrading activity

Technical Field

The invention belongs to the field of medicines, and particularly relates to a novel compound and application thereof in degradation of Androgen Receptor (AR). These compounds degrade AR and are useful as AR inhibitors or degradants for the treatment of diseases such as prostate cancer.

Background

Prostate cancer has become an important disease threatening the health of men. Prostate cancer is the most prevalent male tumor in north america and europe, second only to lung cancer. The annual incidence of prostate cancer also increases at a rate of around 10% in china. The growth of prostate cancer is almost entirely dependent on the Androgen Receptor (AR) pathway, which has become a focus of research in the biomedical field as a target for androgens to exert biological effects.

Some prostate cancer patients can be cured by surgery. However, about 30% of prostate cancer patients relapse due to distant metastasis of cancer cells, resulting in advanced disease. For patients with such advanced disease, androgen deprivation therapy may be used, i.e.: castration is combined with antiandrogen medication. Castration reduces circulating levels of androgens and the activity of Androgen Receptors (ARs). Antiandrogen therapy competitively binds to androgens to block Androgen Receptor (AR) function. This therapy, while effective initially, rapidly fails to convert to hormone refractory prostate cancer.

In recent years, overexpression of AR has been identified as the cause of hormone refractory prostate cancer formation. Overexpression of AR leads to the development of hormone-sensitive prostate cancer into hormone-refractory prostate cancer, and AR is therefore a therapeutic target for hormone-refractory prostate cancer. And overexpression of AR in hormone refractory prostate cancer can convert anti-androgen antagonists into agonists, which is a significant reason why prostate cancer cannot be prevented from developing later in androgen ablation therapy.

The search for drugs with stronger AR antagonism and less AR agonistic activity is an important direction for the development of a therapeutic hormone refractory prostate cancer, for example: enzalutamide, marketed in 2012, for the treatment of prostate cancer, metastatic castration resistant prostate cancer. While approximately 20% to 40% of prostate cancer patients are intrinsically drug resistant to enzalutamide, those prostate cancer patients who are initially sensitive to enzalutamide will eventually develop drug resistance after long term treatment.

In recent years, AR has also become a new target for treating breast cancer, and clinical trials of enzalutamide for treating breast cancer have entered secondary clinical studies. In addition, more and more studies have shown that AR also plays an important role in hormone-related diseases such as whelk, alopecia, benign prostatic hypertrophy, etc.

Disclosure of Invention

The invention aims to provide a compound which can degrade AR and can be used as an AR inhibitor or a degradation agent for treating diseases such as prostatic cancer and the like.

In a first aspect of the present invention, there is provided a compound represented by the following formula I, an isomer, a prodrug, or a pharmaceutically acceptable salt thereof:

wherein:

w is C with or without substituents_5-12Aryl, C with or without substituents_5-12Heteroaryl, C with or without substituents_3-13And C with or without substituents_3-12With or without substituents, straight-chain or branched C_1-6Alkoxy, straight-chain or branched C with or without substituents_2-6Alkenyl, or straight-chain or branched C with or without substituents_2-6An alkynyl group;

x1, X2 are each independently selected from: n, CR^x；

X3 is selected from: o, S, NR^x1；

Y1 is absent or selected from: o, S, NR^Y、C＝O、C＝S、CONR^Y、NR^YCO、SO₂、SO₂NR^Y、SO、CR^Y1R^Y2；

Y2, Y3 are each independently absent or selected from: CH (CH)₂、O、S、NR^Y、C＝O、C＝S、CONR^Y、NR^YCO、SO₂、SO₂NR^Y、SO、(CR^Y1R^Y2)_g3-12 membered substituted or unsubstituted saturated or unsaturated cycloalkyl or heterocyclic alkyl, substituted or unsubstituted aryl or heteroaryl; wherein g is an integer between 0 and 9;

R、R^x、R^x1、R^Y、R^Y1、R^Y2each independently selected from: H. c_1-6Alkyl, halogen, CF₃Hydroxyl, nitro, amino, CN, C_1-6Alkoxy, cycloalkyl, heterocycloalkyl, or any two of R, R^x、R^x1、R^Y、R^Y1、R^Y2Interconnected and carbon atoms connected theretoTogether form a 3-12 membered saturated or unsaturated ring or heterocycle;

m is an integer between 0 and 5;

n is an integer between 0 and 5;

l is selected from the following structures:

wherein:

represents a single bond;

represents a single bond, a double bond or a triple bond;

w1, A, Z, W2 are each independently absent or selected from: o, NR^W1、NR^W1-CO、CO-NR^W1、SO、SO₂、NR^W1-SO₂、SO₂-NR^W1、C(＝O)-O、O-(C＝O)、C(＝O)、CH＝CH、C≡C、O(CH₂)_h、NH(CH₂)_h、(CR^W2 ₂)_h、(CH₂CH₂O)_h、(OCH₂CH₂)_h、NR^W1-CO-(CH₂)_h、CO-NR^W1-(CH₂)_h、CO-NR^W1-(CH₂)_h-O, a 3-12 membered substituted or unsubstituted saturated or unsaturated cyclic or heterocyclic hydrocarbon, substituted or unsubstituted aromatic or heteroaromatic ring; wherein R is^W1Selected from H, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6An acyl group; wherein R is^W2Selected from H, hydroxyl, amino, cyano, carboxyl, ester group, halogen, substituted or unsubstituted C_1-6Alkyl, alkoxy, acyl, 3-12 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted aryl or heteroaryl; wherein h is an integer between 0 and 30;

b is absent or selected from: o, C, CH₂、C＝O、S、NR^B1、NR^B1-C(＝O)、C(＝O)-NR^B1、C(＝O)-O、O-C(＝O)-O、NR^B1-C(＝O)-O、O-C(＝O)-NR^B1、NR^B1-C(＝O)-NR^B2C with or without substituents_1-12The alkyl group of (1), 3-12 membered substituted or unsubstituted cyclic or heterocyclic hydrocarbon, substituted or unsubstituted aromatic ring or heteroaromatic ring; wherein R is^B1、R^B2Each independently selected from H, C with or without substituents_1-8Hydrocarbyl radical, C_3-12Cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

r' is selected from: H. cyano, carboxyl, halogen, C with or without substituents_1-8Alkyl, alkoxycarbonyl, aryl or heteroaryl of (a);

a is an integer between 0 and 30;

d is selected from D1 or D2, and the structure is as follows:

in formula D1:

R₁、R₂each independently selected from: H. OH, amino, cyano, halogen, nitro, trifluoromethyl, C with or without substituents_1-8Hydrocarbyl, C with or without substituents_1-8A hydrocarbyloxy group;

R₃selected from H, C with or without substituents_1-8Hydrocarbyl radical, C_3-8Cycloalkyl radical, C_3-8Heterocyclic hydrocarbon radical, C_1-6An acyl group;

x' is selected from: c (R)^X’)₂、C(＝O)、S(＝O)、SO₂(ii) a Wherein R is^X’Each independently selected from: H. with or without substituents C_1-6A hydrocarbyl group; or two R^x’Are connected with each other and form a 3-12 membered saturated or unsaturated carbocyclic or heterocyclic ring (containing 1-3 heteroatoms) together with the carbon atoms connected with the same;

b is 0, 1, 2 or 3;

c is 0, 1, 2, 3, 4 or 5;

in formula D2:

R₄，R₅，R₆，R₈，R₉，R₁₀，R₁₁each independently selected from: H. OH, amino, cyano, halogen, nitro, trifluoromethyl, carboxyl, methyl, tert-butyl, C with or without substituents_1-8Hydrocarbyl, C with or without substituents_1-8Hydrocarbyloxy, C with or without substituents_1-8An ester group;

R₇selected from: h, C with or without substituents_1-8Hydrocarbyl radical, C_3-8Cycloalkyl radical, C_3-8Heterocyclic hydrocarbon radical, C_1-8An acyl group.

W3 is absent or selected from: o, NR^W1、NR^W1-CO、CO-NR^W1、SO、SO₂C (═ O) -O, O- (C ═ O), 3-to 12-membered substituted or unsubstituted cyclic, heterocyclic, aromatic or heteroaromatic rings; wherein R is^W1Selected from: H. c_1-6Alkyl radical, C_1-8An acyl group;

x ", X'" are each independently selected from: o, N, S, respectively;

d is 0, 1, 2, 3, 4, 5, 6 or 7;

e is 0, 1, 2, 3 or 4;

f is 0, 1, 2 or 3.

In a further preferred embodiment of the method,

in the formula I, W is selected from the following group:

wherein the content of the first and second substances,

R₁₂independently selected from: H. hydroxy, amino, halogen, CN, CF₃Nitro, hydrocarbyl, halohydrocarbyl, and halohydrocarbyloxy groups;

R₁₃selected from: halogen, -CN, nitro, -CF₃And haloalkyl;

preferably, W is selected from the group consisting of:

in another preferred embodiment, in the formula I, X1 and X2 are each independently selected from: n, and CH.

In another preferred embodiment, in said formula I, X3 is selected from: o, and S.

In another preferred embodiment, in the formula I, when X1 is N, Y1 is selected from: deletion, CO, and CH₂(ii) a When X1 is CH, Y1 is selected from: o, S, NH are provided.

In another preferred embodiment, in formula I, Y2 is selected from: deletion, C ═ O, (CH)₂)_g(ii) a Wherein g is preferably 1, 2, 3, 4, 5, 6.

In another preferred embodiment, in the formula I, Y3 is preferably: a 3-12 membered saturated or unsaturated cyclic or heterocyclic hydrocarbon (containing 1 to 5 hetero atoms), a substituted or unsubstituted aromatic or heteroaromatic ring which is absent, substituted or unsubstituted.

In another preferred embodiment, the structure of L is as shown in formula L₀Shown in the figure:

formula L₀W1, A, Z, W2 are each independently absent or selected from: o, NH, C (═ O), (CH)₂)_h、CH₂-O、O(CH₂)_h、NH(CH₂)_hAnd a substituted or unsubstituted benzene ring, or pyridine ring; wherein h is preferably an integer between 0 and 10;

b is O;

a is an integer between 0 and 20.

In another preferred embodiment, D is selected from D1 or D2, which has the following structure:

in formula D1:

R₃is H;

x' is C (═ O);

b is 0;

c is 0;

in formula D2:

R₄selected from: t-butyl, methyl, CN, and CF₃；

R₅Is hydrogen;

R₆selected from: hydroxy, methyl, halogen, amino, and CN;

R₇is hydrogen;

R₈，R₉each independently is hydrogen, or methyl;

R₁₁is methyl;

W₃deleted or selected from: NH, and NH-C (═ O);

x' is S;

x' "is O;

d is 1 or 2;

e is 0;

f is 1 or 2.

In another preferred embodiment, in formula I, W is selected from:

wherein R is₁₂Selected from halogen and-CF₃；R₁₃Selected from-CN, and nitro;

in another preferred embodiment, in formula I, W is selected from:

in another preferred embodiment, in formula I, X1 is preferably CH.

In another preferred embodiment, in formula I, X2 is preferably N.

In another preferred embodiment, in formula I, X3 is preferably O.

In another preferred embodiment, in formula I, Y1 is preferably O.

In another preferred embodiment, in the formula I, Y2 is preferably CH₂。

In another preferred embodiment, in said formula I, Y3 is absent or may be selected from substituted or unsubstituted benzene and biphenyl rings.

In another preferred embodiment, in formula I, m is 1.

In another preferred embodiment, in the formula I, R is methyl.

In another preferred embodiment, in formula I, n is 2.

In another preferred embodiment, the structure of L is represented by the following formula L₀Shown in the figure:

formula L₀W1, A, Z, W2 are each independently absent or selected from: o, NH, C (═ O), (CH)₂)_h、CH₂-O、O(CH₂)_h(ii) a Wherein h is preferably an integer between 0 and 8;

said L₀In the formula, B is O;

a is an integer between 0 and 10.

the D1, wherein:

R₃is H;

x' is preferably: c (═ O);

b is 0;

c is 0;

the D2, wherein:

R₄is tert-butyl;

R₅is hydrogen;

R₆is a hydroxyl group;

R₇is hydrogen;

R₈，R₉each independently is hydrogen;

R₁₁is methyl;

w3 is absent or selected from: NH, and NH-C (═ O);

x' is S;

x' "is O;

d is 1;

e is 0;

f is 1.

In another preferred embodiment, the structure of formula I is preferably as shown in formula II below:

in formula II:

Y₃absent, or a substituted or unsubstituted benzene or biphenyl ring;

R₁₂is halogen or-CF₃；

L has the structure as follows₁Shown in the figure:

formula L₁The method comprises the following steps: w₁，A，Z，W₂Each independently is absent or selected from: o, NH, C (═ O) -O, O- (C ═ O), C (═ O), (CH), and₂)_h、O(CH₂)_h、NH(CH₂)_h、(CH₂-CH₂-O)_h、(OCH₂CH₂)_h、NH-CO-(CH₂)_h、CO-NH-(CH₂)_h、CO-NH-(CH₂)_h-O; wherein h is preferably an integer between 0 and 10;

a is preferably an integer between 0 and 10;

d is preferably selected from D1 'or D2', the structure of which is as follows:

in formula D1':

R₁is amino;

x' is C (═ O), or CH₂；

b is 0 or 1;

in formula D2':

w3 is selected from: o, NH-C (═ O), C (═ O) -NH, C (═ O) -O, and O-C (═ O);

R₁₀is methyl, or halogen;

x' is O, or S;

R₁₁is methyl;

e is 0, 1, 2, or 3;

f is 0 or 1.

In another preferred embodiment, the substituent is halogen, cyano, hydroxyl, nitro, amino, halogenated or non-halogenated C1-C6 alkyl, acyl, alkoxy, amino, amido, ester, alkoxycarbonyl, aminocarbonyl.

In another preferred embodiment, any of the substituents is selected from the group consisting of: halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy, unsubstituted or halogenated C2-C6 alkoxyalkyl, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C2-C6 alkylcarbonyl, unsubstituted or halogenated C1-C6 alkylene-hydroxy, unsubstituted or C1-C6 alkyl-substituted amine.

In a further preferred embodiment of the method,

represents a single bond.

In another preferred embodiment, each of C_3-8Cycloalkyl is preferably C_3-8A cycloalkyl group.

In another preferred embodiment, each of C_3-8The heterocyclic hydrocarbon group is preferably C_3-8A heterocycloalkyl group.

In another preferred embodiment, Y₃The structure of (c) is preferably:

wherein K is H or halogen, preferably H or F.

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the first aspect, an isomer, a prodrug, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another preferred embodiment, the composition contains an effective amount of the compound of the first aspect, its isomer, prodrug, or pharmaceutically acceptable salt thereof, wherein the effective amount is a therapeutically effective amount or an inhibitory effective amount, preferably 0.01 to 99.99%.

In another preferred embodiment, the pharmaceutical composition further comprises one or more additional antineoplastic agents.

In another preferred embodiment, the pharmaceutical composition is used for inhibiting the activity of Androgen Receptor (AR) or reducing the level of Androgen Receptor (AR).

In another preferred embodiment, the pharmaceutical composition is used for treating diseases related to Androgen Receptor (AR) activity or expression.

In a third aspect of the invention, there is provided the use of a compound according to the first aspect of the invention for:

(a) preparing a medicament for treating diseases related to Androgen Receptor (AR) activity or expression;

(b) preparing Androgen Receptor (AR) targeted inhibitor or degradation agent;

(c) non-therapeutically inhibiting or degrading Androgen Receptor (AR) in vitro;

(d) non-therapeutically inhibiting tumor cell proliferation in vitro; and/or

(e) Treating diseases related to Androgen Receptor (AR) activity or expression.

In another preferred embodiment, the disease includes tumor, prostate enlargement, alopecia, acne, etc.

In another preferred embodiment, the tumor comprises prostate cancer and breast cancer.

In a fourth aspect of the invention, there is provided a process for the preparation of a compound of formula I as described in the first aspect of the invention:

the preparation method of the compound of the formula I comprises the following steps:

step 1: when RE is present₁Is a nucleophilic attack group: amino, hydroxy; RE₂Is halogen or sulfonate; RE₃When the amino and the hydroxyl are protected; and carrying out substitution reaction on the intermediate 1 and the intermediate 2 under an alkaline condition to obtain an intermediate 3.

Step 2: when RE is present₃To a protected amino group, RE₄When the intermediate 3 is halogen, deprotection is carried out to generate amino, and then substitution reaction is carried out with halogen of the intermediate 4 to obtain a product I; when RE is present₃For the alcoholic hydroxyl group to be protected, RE₄In the case of phenolic hydroxyl, the intermediate 3 is deprotected to produce alcoholic hydroxyl, and then Mitsunobu reaction is carried out with the phenolic hydroxyl of the intermediate 4 to obtain the product I.

Wherein W, Y1, Y2, Y3, X1, X2, X3, R, L, D, n, m are as defined above; RE₁、RE₂、RE₃、RE₄When two are connected, one end of the two is (or can be converted and deprotected into) nucleophilic/electrophilic attack group, such as amino, hydroxyl, nitro, boric acid ester or other groups capable of generating C anions and the like with or without protecting groups; the other end is (or can be converted, deprotected to) a leaving group or an electrophilic/nucleophilic reaction acceptor, such as a halogen, sulfonate ester, alcohol, aldehyde, acid halide, sulfonyl halide, michael reaction acceptor, or the like; and the substitution, condensation, addition, coupling and other reactions occur under certain reaction conditions.

In a preferred embodiment, the following synthetic route is adopted:

hydroxyl on the intermediate 1 ' and bromine on the intermediate 2 ' are subjected to substitution reaction in the presence of alkali, and then benzyl is removed through hydrogenation to obtain an intermediate 3 '; the alcoholic hydroxyl group of the intermediate 3 'and the phenolic hydroxyl group of the intermediate 4' are subjected to Mitsunobu reaction to obtain a product III.

The above intermediates 1, 2,4, 1 ', 2 ', 4 ' can be obtained by known synthetic methods or can be easily obtained by commercial purchase.

The preparation process of the above formula I, III does not set any limit to the present invention. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.

In a fifth aspect of the present invention, there is provided a method of inhibiting or degrading Androgen Receptor (AR), comprising the steps of: administering to the subject an inhibitory effective amount of a compound of formula I as described in the first aspect of the invention or a pharmaceutically acceptable salt thereof, or administering to the subject an inhibitory effective amount of a pharmaceutical composition as described in the fourth aspect of the invention.

In another preferred embodiment, the inhibition is an in vitro non-therapeutic inhibition.

In another preferred embodiment, when an inhibitory effective amount of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof is administered to a subject, said inhibitory effective amount is 0.001-500nmol/L, preferably 0.01-200 nmol/L.

In a sixth aspect of the present invention, there is provided a method of treating a disease associated with Androgen Receptor (AR) activity or expression, comprising: administering to a subject a therapeutically effective amount of a compound of formula I according to the first aspect of the invention, or a pharmaceutical composition according to the fourth aspect of the invention.

In another preferred embodiment, the subject is a mammal; preferably, the mammal is a human.

In another preferred embodiment, the disease associated with Androgen Receptor (AR) activity or expression is a tumor (e.g., prostate cancer).

In a seventh aspect of the invention, there is provided a method of inhibiting cell proliferation in vitro, the method comprising: administering to the subject an inhibitory effective amount of a compound of formula I as described in the first aspect of the invention, or a pharmaceutical composition as described in the second aspect of the invention.

In another preferred embodiment, the cell is a tumor cell.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The present inventors have made extensive and intensive studies to prepare a compound having a structure represented by formula I, and have found that it has Androgen Receptor (AR) inhibitory and degrading activity. The compound has extremely low concentration, namely, has inhibitory effect on Androgen Receptor (AR), has extremely excellent inhibitory activity, and can be used for treating diseases related to Androgen Receptor (AR) property or expression quantity, such as tumors. The present invention has been completed based on this finding.

The invention discloses a novel compound and application thereof in inhibiting and degrading Androgen Receptor (AR). These compounds inhibit and degrade the Androgen Receptor (AR) and are useful in the treatment of prostate cancer.

Term(s) for

In the present invention, the term "C_1-8The hydrocarbyl group means a functional group containing only carbon and hydrogen atoms, wherein the number of carbon atoms is 1 to 8. The hydrocarbyl group can be regarded as a radical remaining after the corresponding hydrocarbon loses one hydrogen atom, and can be an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group or the like; the structure can be straight chain, branched chain or cyclic; may be aliphatic or aromatic.

The term "C_1-6Alkyl "refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethylPropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like. May be randomly substituted by one or more halogens or C_1-6Alkoxy substitution.

The term "alkoxy" as used herein includes O-alkyl, wherein "alkyl" is as defined above.

The term "halo" as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.

The compounds of the present invention may contain double bonds. When containing such double bonds, the compounds of the present invention exist in cis, trans, or mixtures thereof.

Halogen as used herein includes fluorine, chlorine, bromine and iodine.

Unless otherwise indicated, alkyl groups and the alkyl portion of alkoxy groups referred to herein may be straight chain, branched chain or cyclic.

In the present invention, the term "cycloalkyl group" refers to a functional group containing both carbon and hydrogen atoms. Including cycloalkyl, cycloalkenyl (containing at least one carbon-carbon double bond), and aryl. They may be monocyclic, bicyclic and polycyclic. They may be spiro or fused rings.

In the present invention, the term "heterocyclic hydrocarbon group" means a functional group containing carbon, hydrogen and at least one heteroatom other than carbon and hydrogen. Including heterocycloalkyl, heterocycloalkenyl (containing at least one carbon-carbon double bond), and heteroaryl. One or more of the ring-forming atoms in the ring is a heteroatom. The heteroatoms may be O, N and S atoms, and various combinations thereof. They may be monocyclic, bicyclic and polycyclic. They may be spiro or fused rings.

As used herein, the term "substituent" includes, but is not limited to, halogen (e.g., fluorine, chlorine, bromine), cyano, hydroxy, amino, C_1-6Hydrocarbyloxy, C_1-6Halogenated hydrocarbon group, C_1-6Acyl radical, C_1-6Sulfonyl, CF₃Nitro, CN, -C ≡ CH, C_1-6Alkyl (straight or branched chain, optionally substituted by 1 or more halogens, C_1-6Alkoxy substituted).

The term "hydrocarbyloxy" as used herein refers to an O-hydrocarbyl group, wherein "hydrocarbyl" is as defined above.

The term "alkoxycarbonyl" as used herein refers to a C (═ O) O-hydrocarbyl group, where "hydrocarbyl" is as defined above.

The term "amine" as used herein refers to N (H or hydrocarbyl 1) (H or hydrocarbyl 2), wherein "hydrocarbyl" is as defined above.

The term "aminocarbonyl" as used herein refers to C (═ O) -amine groups, where "amine groups" are as defined above.

The term "amido", as used herein, refers to an N (H or hydrocarbyl) -C (═ O) -hydrocarbyl group, where the "hydrocarbyl group" is as defined above.

The term "aryl" or "aromatic ring" as used herein refers to a phenyl ring or an optionally substituted phenyl ring system fused to one or more optionally substituted phenyl rings, which is optionally substituted with a substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, di (lower alkyl) aminoalkyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, acyl, aroyl, heteroaroyl, acylamino, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, siloxy optionally substituted with alkoxy, alkyl or aryl, silyl optionally substituted with alkoxy, alkyl or aryl, nitro, cyano, nitro, cyano, amino, mercapto, amino, sulfonyl, di (lower alkyl) aminoalkyl, amino optionally substituted with alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted with alkyl, alkoxy, alkyl or aryl, silyl optionally substituted with alkoxy, alkyl or aryl, nitro, cyano, or a substituted with one or more optionally substituted phenyl rings, Halogen or lower perfluoroalkyl, allowing for a variety of degrees of substitution. Examples of aryl groups include, but are not limited to, phenyl, biphenylyl, 2-naphthyl, 1-anthracenyl, and the like.

The term "heteroaryl" as used herein refers to a 5 to 7 membered aromatic or polycyclic heterocyclic aromatic ring containing one or more nitrogen, oxygen or sulfur heteroatoms wherein nitrogen oxide and sulfur monoxide and sulfur dioxide are permissible aromatic heterocyclic substitutions and optionally substituted with a substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, siloxy optionally substituted with alkoxy, alkyl or aryl, silyl optionally substituted with alkoxy, alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, allowing a variety of degrees of substitution. For polycyclic aromatic ring systems, one or more of the rings may contain one or more heteroatoms. Examples of "heteroaryl" as used herein are furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, quinazoline, benzofuran, benzothiophene, indole, and indazole and the like.

As used herein, the terms "comprising," "including," or "including" mean that the various ingredients may be used together in a mixture or composition of the invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "comprising.

In the present invention, the term "pharmaceutically acceptable" ingredient refers to a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.

In the present invention, the term "effective amount" refers to an amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect. The precise effective amount for a subject will depend upon the size and health of the subject, the nature and extent of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experimentation and can be determined by a clinician.

Herein, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on a group are replaced with a substituent selected from the group consisting of: halogen, unsubstituted or halogenated C_1-6Alkyl, unsubstituted or halogenated C_2-6Acyl, unsubstituted or halogenated C_1-6Alkyl-hydroxy.

Unless otherwise specified, all occurrences of a compound in the present invention are intended to include all possible optical isomers, such as a single chiral compound, or a mixture of various chiral compounds (i.e., a racemate). In all compounds of the present invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.

As used herein, the term "compounds of the invention" refers to compounds of formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid.

Compounds and pharmaceutically acceptable salts thereof

The present invention relates to compounds of formula I or pharmaceutically acceptable salts thereof

A compound of formula I, isomers, prodrugs, pharmaceutically acceptable salts thereof:

wherein:

w is aryl, heteroaryl, bicyclic or diheterocyclic (each independently substituted with one or more of H, halogen, CF₃Hydroxy, nitro, amino, CN, -C [ identical to ] CH, C_1-6Alkyl (straight or branched chain, optionally substituted by 1 or more halogens, C_1-6Alkoxy substituted), C_1-6Alkoxy (straight or branched chain, optionally substituted by one or more halogen, hydroxy, cyano, amino), C_2-6Alkenyl or C_2-6Alkynyl groups);

x1, X2 are each independently selected from: n, CR^x；

X3 is selected from: o, S, NR^x1；

R、R^x、R^x1、R^Y、R^Y1、R^Y2each independently selected from: H. methyl, C_1-6Alkyl (straight or branched chain, optionally substituted with one or more halogens or C_1-6Alkoxy substituted), halogen, CF₃Hydroxyl, nitro, amino, CN, C_1-6Alkoxy, cycloalkyl, heterocycloalkyl, or any two of R, R^x、R^x1、R^Y、R^Y1、R^Y2Are connected with each other and form a 3-12 membered saturated or unsaturated carbocyclic or heterocyclic ring (containing 1-3 heteroatoms) together with the carbon atoms connected with the same;

m is an integer between 0 and 5;

n is an integer between 0 and 5;

l is selected from the following structures:

wherein:

represents a single bond;

represents a single bond, a double bond or a triple bond;

w1, A, Z, W2 are each independently absent or selected from: o, NR^W1、NR^W1-CO、CO-NR^W1、SO、SO₂、NR^W1-SO₂、SO₂-NR^W1、C(＝O)-O、O-(C＝O)、C(＝O)、CH＝CH、C≡C、O(CH₂)_h、NH(CH₂)_h、(CR^W2 ₂)_h、(CH₂CH₂O)_h、(OCH₂CH₂)_h、NR^W1-CO-(CH₂)_h、CO-NR^W1-(CH₂)_h、CO-NR^W1-(CH₂)_h-O, a 3-12 membered substituted or unsubstituted saturated or unsaturated cyclic or heterocyclic hydrocarbon, substituted or unsubstituted aromatic or heteroaromatic ring; wherein R is^W1Is selected from H, C_1-6Alkyl (straight or branched chain, optionally substituted by 1 or more halogen, hydroxy, cyano, amino or C)_1-6Alkoxy substituted), C_1-6Acyl (straight or branched chain, optionally substituted by 1 or more halogen, hydroxy, cyano, amino or C)_1-6Alkoxy substituted); wherein R is^W2Selected from H, hydroxyl, amino, cyano, carboxyl, ester group, halogen, substituted or unsubstituted C_1-6Alkyl, alkoxy, acyl, 3-12 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted aryl or heteroaryl; wherein h is an integer between 0 and 30；

a is an integer between 0 and 30;

d is selected from D1 or D2, and the structure is as follows:

as shown in D1, wherein:

b is 0, 1, 2 or 3;

c is 0, 1, 2, 3, 4 or 5;

as shown in D2, wherein:

W3 is absent or selected from: o, NR^W1、NR^W1-CO、CO-NR^W1、SO、SO₂C (═ O) -O, O- (C ═ O), 3-to 12-membered substituted or unsubstituted cyclic, heterocyclic, aromatic or heteroaromatic rings; wherein R is^W1Selected from: H. c_1-6Alkyl (straight or branched chain, optionally substituted by 1 or more halogen, hydroxy, cyano, amino or C)_1-6Alkoxy substituted), C_1-8An acyl group;

x ", X'" are each independently selected from: o, N, S, respectively;

d is 0, 1, 2, 3, 4, 5, 6 or 7;

e is 0, 1, 2, 3 or 4;

f is 0, 1, 2 or 3.

As the active ingredient, the compound of the present invention, isomers, prodrugs, and pharmaceutically acceptable salts thereof, the following compounds are preferred:

the compound package of the present invention may form pharmaceutically acceptable salts with inorganic acids, organic acids or bases. The inorganic acid includes but is not limited to hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid, etc.; such organic acids include, but are not limited to, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid, propionic acid, and the like; the base includes, but is not limited to, inorganic salts and amines.

The term pharmaceutically acceptable salts refers to those salts which are, according to medical judgment, suitable for use in contact with the tissues of humans and mammals without excessive toxicity, irritation, allergic response, and the like. Pharmaceutically acceptable salts are well known in the art.

The invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula I. Prodrugs include compounds wherein the precursor molecule is covalently bonded to a free carboxyl, hydroxyl, amino or amine group of the compound of formula I via a carbonate, carbamate, amide, alkyl ester, phosphate, phosphoramidate linkage.

Preparation of the Compounds

Preparation method

The process for the preparation of the compounds of formula I according to the invention is described in more detail below, but these particular processes do not limit the invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.

The preparation method of the compound of formula I provided by the invention is as follows.

The following reaction scheme illustrates the preparation of the compounds of the present invention. Unless otherwise indicated, W, Y1, Y2, Y3, X1, X2, X3, R, L, D, n, m in the reaction schemes and subsequent discussion are as defined above; RE₁、RE₂、RE₃、RE₄When two are connected, one end of the two is (or can be converted and deprotected into) nucleophilic/electrophilic attack group, such as amino, hydroxyl, nitro, boric acid ester or other groups capable of generating C anions and the like with or without protecting groups; the other end is (or can be converted, deprotected to) a leaving group or an electrophilic/nucleophilic reaction acceptor, such as a halogen, sulfonate ester, alcohol, aldehyde, acid halide, sulfonyl halide, michael reaction acceptor, or the like; and the substitution, condensation, addition, coupling and other reactions occur under certain reaction conditions.

step 1: when RE is present₁Is a nucleophilic attack group: amino, hydroxy;RE₂is halogen or sulfonate; RE₃When the amino and the hydroxyl are protected; and carrying out substitution reaction on the intermediate 1 and the intermediate 2 under an alkaline condition to obtain an intermediate 3.

Step 2: when RE is present₃To a protected amino group, RE₄When the intermediate 3 is halogen, deprotection is carried out to generate amino, and then substitution reaction is carried out with halogen of the intermediate 4 to obtain a product I; when RE is present₃For the alcoholic hydroxyl group to be protected, RE₄When the intermediate is phenolic hydroxyl, the intermediate 3 is deprotected to generate alcoholic hydroxyl, and then the alcoholic hydroxyl and the phenolic hydroxyl of the intermediate 4 are subjected to Mitsunobu reaction to obtain a product I; in a preferred embodiment, scheme 1 employs the following synthetic route:

Use of compounds of formula I

The compounds of formula I may be used for one or more of the following uses:

(b) preparing Androgen Receptor (AR) targeted inhibitor or degradation agent;

(d) non-therapeutically inhibiting cell proliferation in vitro; and/or

(e) Treating diseases related to Androgen Receptor (AR) activity or expression.

In another preferred embodiment, the disease associated with Androgen Receptor (AR) activity or expression is a tumor.

The compounds of formula I of the present invention are useful for preparing a pharmaceutical composition comprising: (i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

In another preferred embodiment, the effective amount refers to a therapeutically effective amount or an inhibitory effective amount.

The compounds of formula I of the present invention may also be used in methods of inhibiting or degrading the Androgen Receptor (AR), either in vitro non-therapeutically or therapeutically.

In another preferred embodiment, when an inhibitory effective amount of a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof is administered to a subject, said inhibitory effective amount is 0.001-500nmol/L, preferably 0.01-200 nmol/L.

In particular, the present invention also provides a method of treating a disease associated with Androgen Receptor (AR) activity or expression, comprising: administering to the subject a therapeutically effective amount of a compound of formula I, or said pharmaceutical composition comprising a compound of formula I as an active ingredient.

Pharmaceutical compositions and methods of administration

The compound of the present invention and various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound as a main active ingredient are useful for treating, preventing and alleviating diseases associated with Androgen Receptor (AR) activity or expression level, since the compound of the present invention has excellent inhibitory activity against Androgen Receptor (AR). According to the prior art, the compounds of the present invention are useful in the treatment of diseases including tumors and the like.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers

Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 5 to 200 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The main advantages of the invention include:

1. provides a compound shown as a formula I.

2. Provided are an Androgen Receptor (AR) degrading agent with a novel structure, a preparation method and an application thereof, wherein the degrading agent can degrade an Androgen Receptor (AR) so as to inhibit AR activity.

3. Pharmaceutical compositions for treating disorders associated with Androgen Receptor (AR) activity are provided.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.

EXAMPLE 1 preparation of Compound 5

First step of

DL-pantolactone 1(7.81g) was dissolved in anhydrous tetrahydrofuran (200ml), and 60% sodium hydride (3.00g) was added thereto, followed by stirring to effect a reaction, and after completion of gas evolution, 4-fluoro-2- (trifluoromethyl) benzonitrile (9.46g) was added thereto and the reaction was allowed to proceed overnight at room temperature. The reaction solution was concentrated, and the residue was purified by a silica gel column to obtain 10.69g of compound 2 as an off-white solid. Yield: and 63 percent. MS (ESI) 300.1[ M + H]⁺。

Second step of

Compound 2(2.99g) was dissolved in toluene (20ml), 4- (aminomethyl) phenol (1.23g) was added thereto at room temperature, the reaction mixture was heated to react for 16 hours, the reaction mixture was filtered and concentrated, and the residue was purified by a silica gel column to give 2.74g of an off-white solid. The resulting solid was dissolved in pyridine (10ml), methanesulfonyl chloride (1.26g) was added dropwise under ice-water bath, stirring was continued until the raw material was substantially disappeared, the reaction solution was concentrated, methylene chloride (20ml) was added to the residue, which was washed with 1M hydrochloric acid and saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in anhydrous tetrahydrofuran (20ml), and 60% sodium hydride (0.80g) was added in portions and stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride (30ml), extracted with ethyl acetate (20ml x 3), concentrated under reduced pressure, and the residue was purified on a silica gel column to give 1.22g of compound 3 as a white solid in yield: 30 percent. MS (ESI) 403.3[ M-H]^-。

The third step

Compound 3(1.00g), mono TBS protected-1, 6-hexanediol (0.63g), and triphenylphosphine (0.84 g) were dissolved in anhydrous tetrahydrofuran (20ml), and diisopropyl azodicarboxylate (0.75g) was added dropwise under cooling with an ice-water bath. After the addition was complete, the reaction was carried out overnight at room temperature. To the reaction mixture was added 1M diluted hydrochloric acid (20ml), and the mixture was stirred at room temperature for 2 hours. The residue was purified by a silica gel column to give 0.35g of Compound 4 as a colorless oil. Yield: 28 percent. MS (ESI) 505.2[ M + H]⁺。

The fourth step

Compound 4(101mg), 4-hydroxythalidomide (55mg), and triphenylphosphine (63mg) were dissolved in anhydrous tetrahydrofuran (3ml) under a nitrogen atmosphere. Cooling in ice water bath, and droppingDiisopropyl azodicarboxylate (53mg) was added thereto, and after completion of the addition, the temperature was naturally raised to room temperature, followed by reaction overnight. The reaction solution was concentrated, and the residue was purified by silica gel column to give 120mg of compound 5 as a white solid. Yield: 79 percent. MS (ESI) 761.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl3)δ8.32(s,1H),7.77(d,J＝8.4Hz,1H),7.68(t,J＝8.0Hz，1H),7.50(s,1H),7.44(t,J＝7.6Hz，2H),7.22(d,J＝8.4Hz,1H),7.15(d，J＝8.4Hz，2H),6.86(d,J＝6.8Hz),4.95(m,1H),4.60(s,1H),4.44(d,J＝14.4Hz，1H),4.44(dd,J＝14.4，2.4Hz，1H)，4.19(t，J＝6.4Hz,2H),3.97(t，J＝6.4Hz,2H)，3.04(s,2H),2.60-2.93(m,3H),2.12(m,1H),1.91(m,2H),1.84(m,2H),1.69(br,2H),1.58(br,4H),1.25(br,2H),1.18(s,3H),1.12(s,3H)。

EXAMPLE 2 preparation of Compound 11

First step of

Compound 2(5.98g) was dissolved in ethanol (60ml), and 2, 4-dimethoxybenzylamine (10.00g) was added at room temperature, and the reaction mixture was stirred at 60 ℃ for overnight reaction. The reaction solution was concentrated by filtration, and the residue was purified by a silica gel column to obtain 6.44g of an off-white solid. The resulting solid was dissolved in pyridine (50ml), methanesulfonyl chloride (1.89g) was added dropwise under ice-water bath, stirring was continued until the raw material was substantially disappeared, the reaction solution was concentrated, methylene chloride (50ml) was added to the residue, which was washed with 1M hydrochloric acid and saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in anhydrous tetrahydrofuran (50ml), and 60% sodium hydride (1.10g) was added in portions and stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride (50ml), extracted with ethyl acetate (30ml x 3), concentrated under reduced pressure, and the residue was purified on a silica gel column to give 4.00g of compound 6 as a colorless oil in yield: 45 percent. MS (ESI) 449.2[ M + H ]]⁺。

Second step of

Compound 6(4.00g) was dissolved in trifluoroacetic acid (30ml), and triethylsilane (3.11g) was added thereto at room temperature, and the reaction was refluxed overnight. The reaction was concentrated by filtration, water (40ml) was added to the residue, the pH was adjusted to above 9 with solid potassium carbonate, and dichloromethane (20ml) was used3), the organic phases are combined and concentrated under reduced pressure, and the residue is purified on a silica gel column to give 2.39g of compound 7 as a white solid in yield: 90 percent. MS (ESI):299.3[ M + H]⁺。

The third step

Compound 7(2.00g) was dissolved in anhydrous tetrahydrofuran (50ml), 60% sodium hydride (0.54g) was added at room temperature, the mixture was refluxed for 2 hours, cooled to room temperature, bromo ester 8(3.29g) was added, the reflux was overnight, the reaction was quenched with saturated brine (50ml), extracted with ethyl acetate (30ml x 3), and the organic phases were combined and concentrated under reduced pressure. Trifluoroacetic acid (50ml) was added to the residue, and the mixture was stirred at room temperature. The reaction solution was concentrated and purified by a silica gel column to obtain 0.57g of carboxylic acid compound 9 as a colorless oil, yield: 17 percent. MS (ESI) 489.1[ M + H ]]⁺。

The fourth step

Compound 9(100mg) and compound 10(100mg) were added to methylene chloride (4ml), 1-hydroxy-7-azabenzotriazole (36mg), (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (50mg), and triethylamine (60mg) were added at room temperature, the reaction mixture was stirred at room temperature, the reaction mixture was concentrated, and the residue was purified by a silica gel column to give 82mg of compound 11 as a colorless oil with a yield of 44%. MS (ESI):901.0[ M + H]⁺。¹HNMR(400MHz,CDCl3)δ8.68(s,1H),7.74(m,1H),7.40(s,1H),7.28-7.42(m,7H),4.64(t,J＝6.8Hz),4.55(m,3H),4.32(m,1H),3.97-4.05(m,3H)，3.51-3.75(br,12H),3.22-3.50(m,3H),2.51(m,4H),1.98-2.18(br,2H),1.17-1.32(br,8H),0.96(s,9H)。

EXAMPLE 3 preparation of Compound 15

First step of

Compound 2(1.35g) was dissolved in tetrahydrofuran (20ml), and 4- (Boc-amino) benzylamine (1.00g) was added under cooling in an ice-water bath, and the reaction mixture was stirred at 60 ℃ overnight. The reaction mixture was filtered and concentrated, and the residue was purified by means of a silica gel column, 1.98g of the obtained product was dissolved in pyridine (20ml), methanesulfonyl chloride (0.48g) was added dropwise in an ice-water bath, and stirring was continued until the raw material was substantially eliminatedThe reaction mixture was concentrated, methylene chloride (30ml) was added to the residue, which was washed with 1M hydrochloric acid and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in anhydrous tetrahydrofuran (30ml), and 60% sodium hydride (0.30g) was added in portions and stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride (30ml), extracted with ethyl acetate (20ml x 3), concentrated under reduced pressure, and the residue was purified on a silica gel column to give 1.67g of compound 12 as a white solid in yield: 74 percent. MS (ESI) 526.3[ M + Na [)]⁺。

Second step of

Compound 12(1.65g) was dissolved in methylene chloride (10ml), and trifluoroacetic acid (10ml) was added thereto at room temperature, followed by stirring at room temperature overnight. The reaction was concentrated, water (20ml) was added to the residue, pH adjusted to above 9 with solid potassium carbonate, extracted with dichloromethane (20ml x 3), the organic phases combined and concentrated under reduced pressure, and the residue was purified on a silica gel column to give 1.02g of compound 13 as a pale yellow solid, yield: 77 percent. MS (ESI):404.1[ M + H]⁺。

The third step

Compound 13(202mg) and triethylamine (81mg) were dissolved in dichloromethane (5ml), and 5-bromovaleryl chloride (120mg) was added dropwise in an ice-water bath, followed by stirring at room temperature for 3 hours. The reaction solution was concentrated by filtration, and the residue was purified by silica gel column to give 280mg of compound 14 as a pale yellow solid, yield: 99 percent. MS (ESI) 566.1[ M + H ]]⁺。

The fourth step

Compound 14(280mg) and compound 10(280mg) were dissolved in acetonitrile (10ml) under a nitrogen atmosphere, and anhydrous potassium carbonate (276mg) and NaI (10mg) were added with stirring to conduct a reflux reaction overnight. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified with a silica gel preparation plate, and 4M hydrogen chloride/1, 4-dioxane solution (53. mu.l) was added to the solution obtained by elution, and concentrated to obtain 140mg of compound 15 as an off-white solid. Yield: 30 percent. MS (ESI) 916.3[ M + H ]]⁺。¹HNMR(400MHz,DMSO-d6)δ10.26(s,1H),9.03(s，1H)，8.78(br，1H)，8.61(br，1H)，8.43(br，1H)，8.11(d，J＝8.8Hz，1H)，7.55-7.70(m,4H),7.41(m,5H),7.19(d,J＝8.8Hz，1H),5.30(s，1H)，4.30-4.70(m，6H),4.26(m,2H),4.08(m,1H),3.91(m,1H)，3.51(m,1H)，2.75-3.20(m,5H),2.40(s,3H),2.39(m，2H)，2.19(m，1H)，1.91(m，1H)，1.73(br，1H)，1.54(m，1H)，0.95-1.20(m,13H)。

EXAMPLE 4 preparation of Compound 17

First step of

4-Fluorothalidomide (2.00g) was added to 6-amino-1-hexanol (10.00g), microwave-reacted for 0.5 hour, the reaction solution was diluted with dichloromethane (50ml), washed successively with 0.5M dilute hydrochloric acid, water, saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by a silica gel column to give 0.75g of Compound 16 as a yellow solid in yield: 28 percent. MS (ESI) 374.1[ M + H]⁺。

Second step of

Compound 16(75mg) was dissolved in a 1, 2-dichloroethane (3ml), and dess-martin oxidizer (127mg) was added thereto, and the reaction mixture was stirred at room temperature for 2 hours. Compound 13(81mg) and glacial acetic acid (0.3ml) were stirred at room temperature for 1 h. After cooling in an ice-water bath, sodium triacetoxyborohydride (200mg) was added in portions, reacted at room temperature for 16 hours, concentrated under reduced pressure, and the residue was purified by a silica gel column to give 49mg of compound 17 as a yellow solid, yield: 32 percent. MS (ESI) 759.0[ M + H ]]⁺。¹HNMR(400MHz,CDCl3)δ8.05(s,1H),7.76(d，J＝6.8Hz，1H)，7.50(t，J＝6.0Hz，2H)，7.43(m，1H)，7.10(d，J＝5.2Hz，1H)，7.05(d，J＝6.4Hz，2H)，6.88(d，J＝6.8Hz,1H),6.56(d,J＝6.8Hz，2H),6.23(br，1H)，4.92(m，1H)4.59(s，1H),4.39(d，J＝11.6Hz,1H),4.27(d，J＝11.6Hz,1H),3.28(m,2H),3.11(m,2H)，3.03(m,2H)，2.70-2.93(m,3H),2.10(m,1H),1.21-1.74(m，8H)，1.17(s，3H)，1.12(s，3H)。

EXAMPLE 5 preparation of Compound 18

Compound 18, 8 was synthesized using the procedure of example 10mg, as an off-white solid. MS (ESI) 917.2[ M + H ]]⁺。¹HNMR(400MHz,DMSO-d6)δ9.04(s,1H),8.77(m，1H)，8.57(br，1H),8.45(br，1H)，8.11(d，J＝8.8Hz，1H)，7.68(d,J＝2.4Hz,1H),7.57(m,1H),7.40(s,4H),7.18(d,J＝8.4Hz，2H),6.91(d,J＝8.4Hz,2H),4.60(m，1H)，3.80-4.48(m，10H),3.50(m,1H)，3.09(d,J＝9.6Hz,1H),2.95(d,J-9.6Hz,1H),2.81(m,2H),2.45(s,3H),2.18(m，1H)，1.91(s，3H)，1.70(br，4H)，1.42(m，2H)，0.95-1.37(m,15H)。

EXAMPLE 6 preparation of Compound 19

Compound 19, 26mg, was synthesized as a yellow solid using the procedures of examples 1, 3. MS (ESI):788.2[ M + H]⁺。¹H NMR(400MHz,CDCl3)δ8.22(br,1H),7.76(d,J＝8.4Hz,1H),7.67(t,J＝8.0Hz，1H),7.50(d,J＝2.4Hz,1H),7.44(m,2H),7.21(d,J＝8.4Hz,1H),7.04(d,J＝8.4Hz,2H),6.56(d,J＝8.4Hz,2H),4.58(s,1H),4.37(m，1H),4.29(m,1H)，4.18(t，J＝6.4Hz,2H),3.09(t,J＝6.8Hz,2H),3.04(s,2H),2.64-2.92(m,3H),2.14(m,1H),2.02(m,1H),1.89(m,2H),1.61(br,2H),1.53(br,2H),1.42(br,4H),1.20-1.26(m,4H),1.12(s,3H),1.12(s,3H)。

EXAMPLE 7 preparation of Compound 20

Compound 20, 23mg was synthesized as an off-white solid using the methods of examples 1 and 2. MS (ESI) 931.3[ M + H ]]⁺。¹HNMR(400MHz,CDCl3)δ8.61(s,1H),7.69(d，J＝8.4Hz,1H),7.43(m，1H),7.37(m，1H)，7.30(m，4H)，7.08(d,J＝8.4Hz,2H),6.77(d,J＝8.4Hz，2H),6.09(d,J＝8.8Hz,2H),4.64(m，1H)，4.47(m，3H),4.37(m,1H),4.27(m,2H),4.04(m,1H),3.86(t,J＝6.4Hz,2H),3.67(t,J＝4.8Hz,2H),2.36-2.50(m,6H),2.24(s,3H),2.17(t,J＝6.8Hz，2H)，2.05(m,1H),1.70(m，2H)，1.61(m，2H)，1.21(m，2H)，1.11(s,3H),1.05(s,3H),0.85(s,9H)。

EXAMPLE 8 preparation of Compound 21

Compound 21, 23mg was synthesized as a white solid using the procedures of examples 1 and 2. MS (ESI):731.1[ M + H]⁺。¹H NMR(400MHz,CDCl3)δ8.35(br,1H),7.74(dd,J＝3.2,8.8Hz,1H),7.68(t,J＝8.0Hz，1H),7.48(m,2H),7.41(m，1H),7.26(s,1H),4.95(m,1H),4.58(s,1H),4.34(m，2H),3.94(m,2H)，3.78(t，J＝2.4Hz,2H)，3.63(m,9H),3.44(m,1H),3.32(s,2H),2.69-2.92(m,3H),2.12(m,1H),1.08-1.32(m,6H)。

EXAMPLE 9 preparation of Compound 85

Compound 85, 21mg was synthesized as a white solid using the procedure of example 1. MS (ESI) 749.0[ M + H ]]⁺。¹HNMR(400MHz,DMSO-d6)δ9.42(s,1H),8.11(d,J＝8.8Hz,1H),7.82(dd,J＝7.2,8.4Hz,1H),7.52-7.70(m,3H),7.47(d,J＝7.2Hz,1H),7.07(d,J＝8.4Hz,2H),6.74(d,J＝8.4Hz,2H),5.30(m,1H),4.59(m,1H),4.35(m,2H),3.81(m,2H),3.35-3.60(m,8H)，2.51-3.10(m,3H),2.06(m,1H),1.13(s，3H),1.00(s,3H)。

EXAMPLE 10 preparation of Compound 86

Compound 86, 27mg, was synthesized as a white solid using the procedure of example 1. MS (ESI) 793.1[ M + H ]]⁺。¹HNMR(400MHz,DMSO-d6)δ9.42(s,1H),8.10(d,J＝8.8Hz,1H),7.82(m,1H),7.51-7.68(m,3H),7.47(d,J＝7.2Hz,1H),7.07(d,J＝8.4Hz,2H),6.74(d,J＝8.4Hz,2H),5.17(m,1H),4.57(t,J＝5.6Hz,1H),4.34(m,2H),3.80(m,2H)，3.64(m,2H),3.37-3.56(m,10H)，3.07(d,J＝9.6Hz,1H),2.93(d,J＝9.6Hz,1H),2.74(m,1H),2.05(m,1H),1.13(s，3H),1.00(s,3H)。

EXAMPLE 11 preparation of Compound 87

Compound 87, 51mg, was synthesized as a white solid using the procedure of example 1. MS (ESI) 837.1[ M + H ]]⁺。¹HNMR(400MHz,DMSO-d6)δ9.42(s,1H),8.10(d,J＝8.8Hz,1H),7.82(m,1H),7.52-7.68(m,3H),7.48(d,J＝7.2Hz,1H),7.07(d,J＝8.4Hz,2H),6.74(d,J＝8.4Hz,2H),5.16(m,1H),4.57(m,1H),4.34(m,2H),3.81(m,2H),3.64(m,2H),3.35-3.53(m,14H)，3.07(d,J＝9.6Hz,1H),2.94(d,J＝9.6Hz,1H),2.57-2.80(m,1H),2.04(m,1H),1.13(s，3H),1.00(s,3H)。

Similarly, with reference to the process of the above examples, the compounds in the following table can be obtained:

example 12 in vitro antitumor Activity

The ability of a test compound to inhibit the growth of prostate cancer cells was studied by determining the proliferation inhibition of prostate cancer VCaP cells and LNCaP cells. VCap cells (purchased from ATCC) and LNCaP cells (purchased from ATCC) were seeded into 96-well plates + medium (DMEM + 5% charcol strippod FBS). Test compounds (10. mu.M) and R1881(0.1nM) were added, incubated in a carbon dioxide incubator for 168 hours, and the proliferation inhibitory activity of the cells was determined using the CTG kit. The results are shown in the following table:

the test result shows that: in-vitro anti-tumor research is carried out on the compound to be tested, and experimental results show that the compounds 5, 11, 15, 17, 18, 19 and 20 have remarkable VCaP cell proliferation resistance activity, and the LNCaP cell proliferation resistance activity of the compounds is remarkably superior to that of enzalutamide.

Example 13 detection of AR protein degrading Activity of Compounds Using Western blot

Cell lines: the VCap cell line was cultured in DMEM + 5% Charcol-Stripped FBS at 37 ℃ in a carbon dioxide incubator.

Setting a DMSO control group, an enzalutamide control group and a test compound intervention group (10 mu M), treating for 24 hours, collecting cells, adding 100 mu L of precooled cell lysate, performing ice lysis for 30min, extracting total cell protein, and determining and quantifying the protein concentration by a bicinchoninic acid (BCA) method. Conventionally preparing glue, loading a sample, performing electrophoresis, then transferring a membrane, sealing, respectively adding primary antibody AR, incubating overnight at 4 ℃, adding secondary antibody after rinsing, developing color by ECL developer after rinsing, scanning and imaging by a Bio-Rad gel imaging system, and performing computer software processing and analysis. The control was referenced to glyceraldehyde phosphate dehydrogenase (GAPDH).

And (4) carrying out gray level analysis on each band by using Image J software, and calculating the degradation rate of the compound to be detected for degrading the AR protein. The results are shown in the following table:

remarking: in the above tables, "-" represents no degradation activity, "+ +" represents a degradation rate of 10% -30%, "+++" represents a degradation rate of 30% -50%, and "++++" represents a degradation rate of more than 50%.

The test result shows that: DMSO and enzalutamide controls had no degradation activity against AR, and representative compounds of this invention 5, 11, 15, 17, 18, 19, 20, 85, 86, 158, 159 all showed significant degradation activity against AR.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

wherein:

w is

Wherein R is₁₂Selected from: H. halogen, CN, CF₃And nitro; r₁₃Selected from: halogen, -CN, nitro, and-CF₃；

X1 is CH, X2 is N;

x3 is selected from: o, and S;

y1 is selected from: o, and S;

y2 is CH₂Y3 is phenyl or halogen substituted phenyl;

r is selected from: H. and C_1-6An alkyl group;

m is 1;

n is an integer between 0 and 5;

l is selected from the following structures:

wherein:

-represents a single bond;

represents a single bond;

w1, A, Z, W2 are each independently absent or selected from: o, NH-CO, CO-NH (CR)^W2 ₂)_hWherein R is^W2Selected from H and C_1-6An alkyl group; wherein h is an integer between 0 and 30;

b is absent or selected from: o, CH₂C ═ O, and NH;

r' is H;

a is an integer between 0 and 30;

d is selected from D1 or D2, and the structure is as follows:

in formula D1:

R₁、R₂、R₃each independently is H;

x' is CH₂；

b is 0, 1, 2 or 3;

c is 0, 1, 2, 3, 4 or 5;

in formula D2:

R₄，R₈，R₉，R₁₀each independently is H;

R₅，R₁₁each independently selected from: methyl, and tert-butyl;

R₆selected from: h and OH;

R₇is H;

w3 deletion;

x 'is S, X' is O;

d is 0, 1, 2, 3, 4, 5, 6 or 7;

e is 0, 1, 2, 3 or 4;

f is 0, 1, 2 or 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, in formula I, W is:

and the number of the first and second electrodes,

R₁₂is CF₃；

R₁₃Is CN.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein in formula I: x3 is O.

4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein in formula I:

l has the structure of formula L₀Shown in the figure:

formula L₀W1, A, Z, W2 are each independently absent or selected from: o, NH, C (═ O), and (CH)₂)_h(ii) a Wherein h is preferably an integer between 0 and 10;

b is O;

a is an integer between 0 and 20.

5. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

6. a pharmaceutical composition comprising a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. Use of a compound according to claim 1 for:

(b) preparing Androgen Receptor (AR) targeted inhibitor or degradation agent;

(c) non-therapeutically inhibiting or degrading Androgen Receptor (AR) in vitro; and/or

(d) Non-therapeutically inhibiting prostate cancer cell proliferation in vitro.

8. A method of non-therapeutically inhibiting or degrading the Androgen Receptor (AR) in vitro comprising the steps of: administering to a subject an inhibitory effective amount of a compound of formula I as described in claim 1 or a pharmaceutically acceptable salt thereof, or administering to a subject an inhibitory effective amount of a pharmaceutical composition as described in claim 6.

9. A method of inhibiting prostate cancer cell proliferation in vitro, comprising: administering to a subject in need thereof an inhibitory effective amount of a compound of formula I as defined in claim 1, or a pharmaceutical composition as defined in claim 6.