Heterocyclic Compounds as Androgen Receptor Modulators and Their Applications

Abstract

The present invention relates to a new class of heterocyclic compounds and their applications. The structure of the compounds is shown in Formula I, or optical isomers, isotope derivatives or pharmaceutically acceptable salts of the compounds, or pharmaceutical compositions comprising the compounds. The compounds or pharmaceutical compositions are used as androgen receptor (AR) modulators for treating related diseases, and can be used alone or in combination with other therapeutic agents.

Description

Technical Field

[0001] The present invention relates to a compound represented by formula I, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, a pharmaceutical composition comprising the compound, and the use of the compound as an androgen receptor (AR) modulator. Background Art

[0002] Prostate cancer (PC) is one of the common malignant tumors in the male urogenital system and the second leading cause of male death. In 2016, the number of newly diagnosed PC patients in China was 120,000, and it is estimated that this number will increase to 237,000 by 2030, with a compound annual growth rate of 5% in the number of newly diagnosed patients. The treatment of PC includes prostatectomy, radiotherapy and chemotherapy. After treatment, some patients will have an increase in blood PSA. Despite the implementation of new therapies for recurrent PC, tumor cells still frequently metastasize, which is called metastatic castration-resistant prostate cancer (mCRPC); there are also some PC patients who do not show any distant metastases through traditional imaging examinations and are classified as non-metastatic castration-resistant prostate cancer (nmCRPC). With the increasing incidence of PC, the research on its pathogenesis is also gradually deepening.

[0003] Androgen receptor (AR) is a steroid hormone receptor with a ligand-binding domain, a DNA-binding domain and multiple phosphorylation sites. After binding to the ligand androgen in vivo, AR forms an AR dimer, which is then phosphorylated and transferred from the cytoplasm to the nucleus, and then mediates the transcription and activation of various pathways in the nucleus. In normal adult prostate, AR regulates the dynamic balance of proliferation and apoptosis of prostate epithelial cells. This dynamic balance is disrupted in PC tissues, promoting the proliferation and survival of tumor cells, which is the main cause of the development of prostate cancer. Since AR plays an important role in the development of PC, treating PC by inhibiting AR from entering the nucleus has gradually become a research hotspot, and a series of AR inhibitor drugs have been developed based on this.

[0004] The androgen receptor signaling pathway plays an important role in the occurrence and development of prostate cancer, breast cancer, bladder cancer, etc. Therefore, AR inhibitors targeting AR have emerged one after another. In the treatment of PC, AR inhibitors are often divided into steroidal and non-steroidal types, which are different in chemical structure, pharmacological action and safety. Steroidal AR inhibitors can reduce testosterone levels and bind to other hormone receptors, so cross-reactions are likely to occur. Non-steroidal AR inhibitors used as monotherapy tend to increase the overall testosterone level and are more specific for AR. Although steroidal AR inhibitors were developed earlier than non-steroidal AR inhibitors for the treatment of PC, they have gradually been replaced by non-steroidal AR inhibitors due to their easy occurrence of adverse reactions.

[0005] In recent years, with a deeper understanding of the AR structure and its biological functions, researchers are committed to developing better AR analogs, and a new generation of AR inhibitors without agonist activity are being studied for more effective inhibition of AR.

[0006] In view of the deficiencies of the prior art, the present invention provides a class of AR regulators with a completely new structure, which can reduce the expression of AR, show obvious concentration-dependence and time-dependence on the degradation of AR, and have obvious activity of inhibiting the proliferation of prostate cancer cells. Summary of the Invention

[0007] The present invention provides a compound represented by formula I, its optical isomers, isotope derivatives or pharmaceutically acceptable salts thereof,

[0008]

[0009] wherein,

[0010] Ring A, ring B, ring C, ring D, and ring E are each independently selected from C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl or C 5-10 heteroaryl, each of which is optionally substituted with 0, 1, 2, 3, 4 or 5 R2;

[0011] L is selected from -L4-L3-L2-L1-L0- or -CO-NH-(CH2) p -CO-R0-, provided that when L is selected from -CO-NH-(CH2) p -CO-R0-, one or more of the methylene groups therein are optionally substituted with 1, 2 or 3 O atoms;

[0012] L1, L3, and L5 are each independently selected from a single bond, C 1-6 alkyl, C 2-6 alkenyl, C 2-6Alkynyl, O, S, NH, -CO-, -SO-, -SO2-, -C 1-6 alkyl-O-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-6 alkyl-O- is optionally substituted by 1, 2 or 3 R3;

[0013] L0, L2, L4 are each independently selected from a single bond, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl or C 5-10 heteroaryl, wherein the C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl or C 5-10 heteroaryl is optionally substituted by 1 - 4 R4;

[0014] R0 is selected from -NH-, piperidinyl, cyclohexyl or piperazinyl;

[0015] R1 is selected from H, OH, halogen, NH2, CN, NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino;

[0016] R2, R3, R4 are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, OH, NH2, CN, nitro, carboxyl, C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, OH, NH2, carboxyl, C 3-6 cycloalkyl is optionally substituted by 1 - 3 substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, OH, NH2, CN, nitro, carboxyl; preferably, R2 is independently selected from one or more of halogen (most preferably fluorine or chlorine), cyano or trifluoromethyl. m is selected from 0 or 1, n is selected from 0, 1, 2 or 3, and p is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0017] Preferably, R1 is selected from H, C 1-6 alkyl;

[0018] L1, L3 are independently selected from a single bond or C 1-6 alkyl;

[0019] L5 is selected from a single bond, O, S, NH, -CO-, -SO- or -SO2-;

[0020] L0, L2, and L4 are each independently selected from C 5-6 cycloalkyl, C 5-6 heterocycloalkyl, C 6-10 aryl or C 5-10 heteroaryl;

[0021] Ring A, Ring B, and Ring E are each independently selected from an optionally substituted phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, quinolinyl, isoquinolinyl or quinoxalinyl;

[0022] Ring C is selected from an optionally substituted C 6-10 aryl or C 5-10 heteroaryl;

[0023] Ring D is selected from an optionally substituted C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;

[0024] More preferably,

[0025] L0, L2, and L4 are each independently selected from a single bond, C 5-6 cycloalkyl or C 5-6 heterocycloalkyl;

[0026] Ring A, Ring B, and Ring E are each independently selected from an optionally substituted phenyl or pyridyl;

[0027] Ring C is selected from an optionally substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;

[0028] Ring D is selected from an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydrothienyl or tetrahydropyranyl;

[0029] Even more preferably,

[0030] L0, L2, and L4 are each independently selected from a single bond, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; Ring D is selected from an optionally substituted cyclobutyl, cyclopentyl or cyclohexyl.

[0031] Preferably, L is selected from the following linking groups, which are not particularly defined, and the two linking positions of the following linking groups can be arbitrarily selected for linking. For example, the left part of L in the structure of Formula I can be linked to the left or right side of the following linking groups. Correspondingly, the right part of L in the structure of Formula I can be linked to the right or left side of the following linking groups. Particularly preferably, the left part of L in the structure of Formula I is linked to the left side of the following linking groups, and the right part of L in the structure of Formula I is linked to the right side of the following linking groups. L is preferably:

[0032]

[0033] In another aspect of the present invention, the present invention also provides a compound represented by Formula II, its optical isomers, isotope derivatives or pharmaceutically acceptable salts thereof. The structure represented by Formula II is as follows:

[0034]

[0035] The definitions of the respective groups are as described above.

[0036] In another aspect of the present invention, the present invention also provides a compound represented by Formula III, its optical isomers, isotope derivatives or pharmaceutically acceptable salts thereof. The structure represented by Formula III is as follows:

[0037]

[0038] For Formula III, the definitions of the respective groups are as described above.

[0039] In another aspect of the present invention, the present invention also provides a compound represented by Formula IV, its optical isomers, isotope derivatives or pharmaceutically acceptable salts thereof. The structure represented by Formula IV is as follows:

[0040]

[0041] For Formula IV, the definitions of the respective groups are as described above.

[0042] In another aspect of the present invention, the present invention also provides a compound represented by Formula V, its optical isomers, isotope derivatives or pharmaceutically acceptable salts thereof. The structure represented by Formula V is as follows:

[0043]

[0044] For Formula V, the definitions of the respective groups are as described above.

[0045] In another aspect of the present invention, the present invention also provides a compound represented by Formula VI, its optical isomers, isotope derivatives or pharmaceutically acceptable salts thereof. The structure represented by Formula VI is as follows:

[0046]

[0047] Formula VI, wherein the definitions of the various groups are as described above.

[0048] In another aspect of the present invention, the present invention also provides a compound represented by Formula VII, its optical isomers, isotope derivatives or pharmaceutically acceptable salts thereof, and the structure of Formula VII is as follows:

[0049]

[0050] Formula VII, wherein the definitions of the various groups are as described above.

[0051] In another aspect of the present invention, the compounds of the present invention are selected from:

[0052]

[0053]

[0054] The information of the said compound is as follows:

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064] In yet another aspect of the present invention, the present invention also provides a pharmaceutical composition comprising any one of the compounds of the present invention, its optical isomers, isotope derivatives or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients or carriers.

[0065] In yet another aspect of the present invention, the present invention also provides the use of the aforementioned compounds, their optical isomers, isotope derivatives or pharmaceutically acceptable salts or the aforementioned pharmaceutical composition in the preparation of androgen receptor modulators.

[0066] In another aspect of the present invention, the present invention also provides the use of the aforementioned compound, its optical isomers, isotope derivatives or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for treating androgen receptor-related diseases.

[0067] In some embodiments of the present invention, the diseases are cancer, metabolic disorder diseases, cardiovascular and cerebrovascular diseases, hyperlipidemia or obesity.

[0068] In some embodiments of the present invention, the cancer is selected from prostate cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, squamous cell carcinoma, brain cancer, basal cell carcinoma, colorectal cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, testicular cancer, pancreatic cancer, kidney cancer or gastric cancer; leukemia; benign and malignant lymphoma; melanoma; myeloproliferative diseases; sarcoma; thyroid cancer, astrocytoma; Hodgkin's disease, Wilms' tumor or teratocarcinoma.

[0069] In some embodiments of the present invention, the aforementioned benign and malignant lymphoma includes Burkitt's lymphoma and non-Hodgkin's lymphoma; the sarcoma includes Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma and schwannoma.

[0070] Definitions and Explanations

[0071] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without a special definition, but should be understood in accordance with its ordinary meaning.

[0072] The short dash (“-”) not between two letters or symbols indicates the attachment site of the substituent, and the attachment order is arbitrary. However, when the attachment site of the substituent is obvious to those skilled in the art, for example, a halogen substituent, the “-” can be omitted.

[0073] When the R2 substituent on the benzene ring has no fixed structure, it means that R2 can be attached to any position on the benzene ring, and R2 can be 0, 1, 2, 3, 4 or 5.

[0074] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment, suitable for contact with human and animal tissues, without excessive toxicity, irritation, allergic reaction or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0075] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from the compounds with specific substituents discovered in the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, the base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds contain relatively basic functional groups, the acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and similar acids; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either base or acid addition salts.

[0076] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing acid radicals or basic groups by conventional chemical methods. Generally, the preparation method of such salts is to react these compounds in the form of free acids or bases with a stoichiometric amount of appropriate bases or acids in water or an organic solvent or a mixture of both.

[0077] The compounds of the present invention can exist in specific stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, and all these mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may exist in substituents such as alkyl groups. All these isomers and their mixtures are included within the scope of the present invention claimed.

[0078] The present invention also encompasses all suitable isotopic variants of the compounds of the present invention. In this context, isotopic variants of the compounds of the present invention are to be understood as compounds in which at least one atom within the compounds of the present invention is replaced by another atom having the same atomic number but an atomic mass different from the atomic mass commonly found or predominantly present in nature. Examples of isotopes that can be introduced into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine, and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I. Certain isotopic variants of the compounds of the present invention (such as, in particular, those in which one or more radioactive isotopes are introduced) can be used, for example, to study the mechanism of action or distribution of the active substance in the body; because they can be prepared and detected relatively easily, compounds labeled with 3 H- or 14 C-isotopes are particularly suitable for this purpose. In addition, the introduction of an isotope (such as deuterium) can produce certain therapeutic advantages due to the higher metabolic stability of the compound, such as an extended half-life in the body or a reduced effective dose required; such modifications of the compounds of the present invention may thus optionally also represent preferred embodiments of the present invention. Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example, by using the corresponding isotopic modifications of the individual reagents and / or starting compounds according to the specifications given in the following methods and embodiments.

[0079] The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound can be labeled with a radioactive isotope, such as tritium (3H), iodine-125 (125I), or C-14 (14C). For another example, hydrogen can be replaced with deuterium to form a deuterated drug. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has advantages such as reduced toxic and side effects, increased drug stability, enhanced efficacy, and extended drug biological half-life. All transformations of the isotope composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention. "Optional" or "optionally" means that the subsequently described event or condition may but does not necessarily occur, and the description includes the case where the described event or condition occurs and the case where the described event or condition does not occur.

[0080] The term "substituted" or "substituted by" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and variants of hydrogen, as long as the valence state of the specific atom is normal and the resulting compound is stable. The term "optionally substituted" or "optionally substituted by" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents can be arbitrary based on what is chemically achievable.

[0081] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted by 1, 2, 3, 4, or 5 Rs, the group may optionally be substituted by 1, 2, 3, 4, or 5 Rs, and each R in each case has independent options. In addition, combinations of substituents and / or their variants are only permitted if such combinations result in a stable compound.

[0082] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected.

[0083] When it is not specified which atom of the listed substituent is connected to the substituted group, this substituent can be bonded through any of its atoms. For example, a pyridyl group as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0084] When the listed linking group does not specify its connection direction, its connection direction is arbitrary. For example, when the linking group L is -CH2O-, -CH2O- can be connected in the same direction as the reading order from left to right or in the opposite direction to the reading order from right to left. Combinations of the linking group, substituents, and / or their variants are only permitted if such combinations result in a stable compound.

[0085] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring size. For example, a "3- to 6-membered ring" refers to a "ring" composed of 3 to 6 atoms arranged in a ring.

[0086] Unless otherwise specified, the term "C 1-6 alkyl" is used to denote a saturated hydrocarbon group having a straight or branched chain of 1 to 6 carbon atoms. The C 1-6 alkyl includes C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C6 and C5 alkyls, etc.; it can be monovalent (such as CH3), divalent (-CH2-), or polyvalent.

[0087] Unless otherwise specified, the term "C 1-6 alkoxy" denotes those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C 1-6 alkoxy includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C6, C5, C4, and C3 alkoxys, etc. Examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy, and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy, and neopentyloxy), hexyloxy, etc.

[0088] The term "cycloalkyl", either by itself or in combination with other terms, represents a cyclic form of an alkyl, alkenyl, or alkynyl group or a mixture thereof. Additionally, cycloalkyl may contain fused rings, but does not include fused aryl and heteroaryl groups. Unless specifically indicated as unsubstituted, cycloalkyl may be substituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cyclohexynyl, cyclohexadienyl, cyclopentadienyl, cyclopentenyl, cycloheptyl, norbornyl, etc. If the size of the ring is not specified, the cycloalkyl groups described herein contain 3 to 8 ring members or 3 to 6 ring members.

[0089] The term "heterocyclic" or "heterocycloalkyl" or "heterocyclic group" by itself or in combination with other terms represents a cycloalkyl group containing at least one ring carbon atom and at least one ring heteroatom selected from O, N, P, Si, and S, preferably selected from N, O, and S, wherein the ring is non-aromatic but may contain unsaturation. The nitrogen and sulfur atoms in the heterocyclic group may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. In various embodiments, the ring heteroatoms are selected from N, O, and S. Unless otherwise specified, the heterocyclic groups described herein contain 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-5, 4-6, 4-7, 4-8, 5-10, 5-8 ring members, and at least one ring member is a heteroatom selected from N, O, and S; generally, there are no more than 3 of these heteroatoms in the heterocyclic group, and generally no more than 2 of these heteroatoms in a single ring of the heterocyclic group. The heterocyclic group may be fused to other carbocyclic, heterocyclic, or aryl rings. The heterocyclic group may be attached to the rest of the molecule at a ring carbon or a ring heteroatom, and the heterocyclic group may be substituted as described for alkyl groups. Additionally, the heterocycle may contain fused rings, but does not include fused systems containing heteroaryl as part of the fused ring system. Examples of heterocyclic groups include but are not limited to 1-(1,2,5,6-tetrahydropyridyl), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, 1,2,3,4-tetrahydropyridyl, dihydroindole (indoline), tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl, 2-piperazinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidyl (including 1-piperidyl, 2-piperidyl, and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxolanyl, dithiolanyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidyl, or dioxepanyl, etc.

[0090] Unless otherwise specified, the term "aryl" refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., 1-3 rings) fused together. The aryl may contain fused rings, wherein one or more of the rings are optionally cycloalkyl, but does not include heterocyclic or heteroaromatic rings; a fused system containing at least one heteroaromatic ring is called heteroaryl, and a phenyl ring fused to a heterocycle is called a heterocyclic group herein. Aryl includes fused ring systems in which a phenyl ring is fused to a cycloalkyl ring. Examples of aryl include but are not limited to phenyl, 1-naphthyl, tetrahydronaphthalene, dihydro-1H-indene, 2-naphthyl, tetrahydronaphthyl, etc.

[0091] As used herein, the term "heteroaryl" refers to a group containing a monocyclic or two or three fused rings, wherein at least one ring is an aromatic ring containing 1-4 heteroatoms selected from N, O, and S as ring members (i.e., it contains at least one heteroaromatic ring), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. The heteroaryl can be linked to the rest of the molecule through a ring carbon or a ring heteroatom, and if the group is bicyclic or tricyclic, it can be linked through any ring of the heteroaryl. The heteroaryl can contain fused rings, wherein one or more rings are optionally cycloalkyl, heterocycloalkyl, or aryl, provided that at least one ring is a heteroaromatic ring. Non-limiting examples of heteroaryl are 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents of each of the above aryl and heteroaryl ring systems are selected from the following acceptable substituents.

[0092] Aryl and / or heteroaryl generally contain up to 4 substituents (0-4) per ring, and sometimes contain 0-3 or 0-2 substituents. The terms "aryloxy" and "heteroaryloxy" refer to aryl and heteroaryl linked to the rest of the molecule through an oxygen linking group (-O-), respectively.

[0093] Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" should include monohaloalkyl and perhaloalkyl. For example, the term "halo(C1-C4)alkyl" should include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc. The prefix "perhalo" refers to each group in which all available valence bonds are replaced by halogen. For example, "perhaloalkyl" includes -CCl3, -CF3, -CCl2CF3, etc. The terms "perfluoroalkyl" and "perchloroalkyl" are subgroups of perhaloalkyl, in which all available valence bonds are replaced by fluorine and chlorine, respectively. Non-limiting examples of perfluoroalkyl include -CF3 and -CF2CF3. Non-limiting examples of perchloroalkyl include -CCl3 and -CCl2CCl3.

[0094] "Amino" as used herein refers to the group -NH2 or -NRR', where R and R' are independently selected from hydrogen or alkyl (e.g., lower alkyl). The term "arylamino" as used herein refers to the group -NRR', where R is aryl and R' is hydrogen, alkyl or aryl. The term "aralkylamino" as used herein refers to the group -NRR', where R is aralkyl and R' is hydrogen, alkyl, aryl or aralkyl. "Substituted amino" refers to an amino group in which at least one of R and R' is not H, i.e., the amino group bears at least one substituent. The term alkylamino refers to -alkyl-NRR', where R and R' are each independently selected from hydrogen or alkyl (e.g., lower alkyl).

[0095] Unless stereochemistry is explicitly indicated in the chemical structure or chemical name, the chemical structure or chemical name shall include all possible stereoisomers, conformational isomers, rotational isomers and tautomers of the compound. For example, a compound containing a chiral carbon atom shall include the (R) enantiomer and the (S) enantiomer, as well as mixtures of enantiomers, including racemic mixtures; a compound containing two chiral carbons shall include all enantiomers and diastereomers (including (R,R), (S,S), (R,S) and (S,R) isomers).

[0096] In all uses of the compounds of the structural formulas described herein, the present invention also encompasses the use of any or all stereochemical forms, enantiomers, diastereomers, conformational isomers, rotational isomers, tautomers, solvates, hydrates, polymorphs, crystalline forms, non-crystalline forms, salts, pharmaceutically acceptable salts, metabolites and prodrugs of the compounds.

[0097] The pharmaceutical compositions of the present invention contain at least one compound (including pharmaceutically acceptable salts of these compounds) according to any of the embodiments disclosed herein, mixed with at least one pharmaceutically acceptable excipient, carrier or diluent. Preferably, the pharmaceutical composition is a sterile composition, or a composition consisting essentially of or consisting only of the above compounds and one or more pharmaceutically acceptable excipients, carriers and / or diluents. In some embodiments, the pharmaceutical composition contains at least two pharmaceutically acceptable carriers and / or excipients as described herein.

[0098] Certain compounds of the present invention may exist in non-solvated form as well as in solvated form (i.e., solvates). The compounds of the present invention may also include hydrated forms (i.e., hydrates). Generally, the solvate and hydrate forms are equivalent in biological efficacy to the non-solvated form and are all included within the scope of the present invention. The present invention also includes all polymorphs, including crystalline and non-crystalline forms. Generally, for the intended uses of the present invention, all physical forms are available and are intended to be included within the scope of the present invention.

[0099] As used herein, "therapeutically effective amount" refers to an amount capable of producing the desired pharmacological and / or physiological effect. This effect can be prophylactic, capable of completely or partially preventing a disease or its symptoms; and / or can be therapeutic, capable of partially or completely curing a disease and / or side effects associated with the disease. The therapeutically effective amount of the compounds of the present invention generally includes any amount sufficient to inhibit Raf activity that can be detected by any of the experiments described herein, by other CDK or CDK9 kinase activity assays known to those skilled in the art, or by detecting the inhibition or alleviation of cancer symptoms.

[0100] As used herein, the term "pharmaceutically acceptable carrier" and its like refer to adjuvants, binders, diluents, etc. known to those skilled in the art, which are suitable for administration to an individual (e.g., a mammal or non-mammal). Combinations of two or more carriers are also encompassed in the present invention. The pharmaceutically acceptable carriers and any other ingredients described herein can be suitable for the intended route of administration (e.g., oral, parenteral) of a particular dosage form. Such suitability is readily recognizable by those skilled in the art, particularly in accordance with the teachings provided herein. The pharmaceutical compositions described herein contain at least one pharmaceutically acceptable carrier or excipient; preferably, the composition contains at least one carrier or excipient other than water or contains at least one carrier or excipient in addition to water.

[0101] Pharmaceutical excipients can be pharmaceutically acceptable carriers, adjuvants, or excipients, such as those used in the present invention, including any solvent, diluent, or other liquid excipient, dispersing or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form.

[0102] The compounds of the present invention can have systemic and / or local effects. For this purpose, they can be administered in a suitable manner, such as by oral, parenteral, pulmonary, intranasal, sublingual, buccal, buccal, rectal, percutaneous, transdermal, transconjunctival or otic routes, or as implants or stents.

[0103] Suitable for oral administration are dosage forms that, according to the prior art, act to rapidly and / or modulate the release of the compounds of the present invention and contain the compounds of the present invention in crystalline and / or non-crystalline (amorphisized) and / or dissolved forms, such as tablets (uncoated or coated tablets, such as those having an enteric coating or a coating with delayed dissolution or an insoluble coating that controls the release of the compounds of the present invention), tablets that rapidly disintegrate in the mouth, or film / wafers, film / lyophilizates, capsules (e.g., hard capsules or soft capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0104] Parenteral administration can be carried out by bypassing the absorption step (e.g., intravenous, intra - arterial, intracardiac, intraspinal or intralumbar) or including absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Dosage forms suitable for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilized products or sterile powders.

[0105] Dosage forms suitable for other administration routes are, for example, inhalation dosage forms (including powder inhalers, nebulizers), nasal drops, solutions and sprays; tablets, films / nacreous capsules or capsules for buccal, sublingual or sublingual administration; suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g., patches), milks, pastes, foams, powders, implants or stents.

[0106] As used herein, the term "treatment" refers to the administration of one or more pharmaceutical substances, in particular the compounds of formula (I) and / or their pharmaceutically acceptable salts as described herein, to an individual suffering from a disease or having the symptoms of said disease, for the purpose of curing, alleviating, reducing, modifying, treating, improving, ameliorating or affecting said disease or the symptoms of said disease. The term "prevention" as used herein refers to the administration of one or more pharmaceutical substances, in particular the compounds of formula (I) and / or their pharmaceutically acceptable salts as described herein, to an individual having a predisposition to said disease, for the purpose of preventing the individual from contracting the disease. When referring to chemical reactions, the terms "treatment", "contact" and "reaction" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction producing the indicated and / or desired product may not necessarily result directly from the combination of the two initially added reagents, i.e., one or more intermediates may be present in the mixture which ultimately lead to the formation of the indicated and / or desired product.

[0107] The compounds or their pharmaceutically acceptable salts as defined in the present invention, or the pharmaceutically acceptable compositions containing them, are effective modulators of the androgen receptor. The compounds of the present invention are expected to be potentially useful agents in the treatment of diseases or medical conditions mediated either alone or in part by the androgen receptor. The compounds of the present invention can cause down - regulation of the androgen receptor and / or are selective agonists, partial agonists, antagonists or partial antagonists of the androgen receptor.

[0108] The compounds of the present invention are preferably suitable for the treatment and / or prevention of androgen receptor - dependent diseases.

[0109] Diseases that can be treated with the compounds of the present invention particularly include cancer and tumor diseases. In the context of the present invention, these diseases particularly include, but are not limited to, the following diseases: breast cancer and breast tumors (breast cancer includes ductal and lobular forms, as well as breast cancer in situ), respiratory tumors (small cell carcinoma and non-small cell carcinoma, bronchial carcinoma), brain tumors (such as tumors of the brain stem and hypothalamus, astrocytoma, ependymoma, glioblastoma, glioma, medulloblastoma, meningioma, and neuroectodermal and pineal tumors), tumors of the digestive organs (esophageal cancer, gastric cancer, gallbladder cancer, small intestine cancer, colon cancer, rectal cancer, and anal cancer), liver tumors (including hepatocellular carcinoma, cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma), tumors of the head and neck (laryngeal cancer, tongue cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer, and oral cancer, oral melanoma), skin tumors (basal cell carcinoma, squamous cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, non-melanoma skin cancer, Merkel cell skin cancer, mast cell tumor), tumors of the supportive and connective tissues (including soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, chondrosarcoma, fibrosarcoma, angiosarcoma, leiomyosarcoma, liposarcoma, lymphosarcoma, and rhabdomyosarcoma), tumors of the eye (including intraocular melanoma and retinoblastoma), tumors of the endocrine and exocrine glands (such as tumors of the thyroid and parathyroid glands, pancreatic cancer, and salivary gland cancer, adenocarcinoma), tumors of the urinary tract (bladder tumors, penile tumors, kidney tumors, renal pelvis tumors, and ureteral tumors), and tumors of the reproductive organs (endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, and uterine cancer in women, and prostate cancer and testicular cancer in men). It also includes proliferative diseases of the blood, lymphatic system, and spinal cord in solid and circulating cell forms, such as leukemia, lymphoma, and myeloproliferative diseases, such as acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia, and AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, and lymphoma in the central nervous system.

[0110] In another embodiment, the compounds of the invention can be administered to an animal (e.g., a human) for treating a variety of conditions and disorders, including (but not limited to) maintaining muscle strength and function (e.g., in the elderly); reversing or preventing frailty or age-related functional decline (“ARFD”) in the elderly (e.g., sarcopenia); treating the catabolic side effects of glucocorticoids; preventing and / or treating bone mass, density or growth reduction (e.g., osteoporosis and osteopenia); treating chronic fatigue syndrome (CFS); chronic myalgia; treating acute fatigue syndrome and muscle loss after elective surgery (e.g., post-operative rehabilitation); accelerating wound healing; accelerating fracture repair (e.g., accelerating the recovery of hip fracture patients); accelerating the healing of complex fractures, such as distraction osteogenesis; joint replacement; preventing the formation of post-operative adhesions; accelerating tooth repair or growth; maintaining sensory function (e.g., hearing, vision, smell and taste); treating periodontal disease; treating post-fracture wasting and wasting associated with chronic obstructive pulmonary disease (COPD), chronic liver disease, AIDS, weightlessness, cancer cachexia, burn and trauma recovery, chronic catabolic states (e.g., coma), eating disorders (e.g., anorexia nervosa) and chemotherapy; treating cardiomyopathy; treating thrombocytopenia; treating growth retardation associated with Crohn's disease; treating short bowel syndrome; treating irritable bowel syndrome; treating inflammatory bowel disease; treating Crohn's disease and ulcerative colitis; treating transplantation-related complications; treating physiological short stature, including growth hormone-deficient children and short stature associated with chronic diseases; treating obesity and obesity-related growth retardation; treating anorexia (e.g., anorexia associated with cachexia or aging); treating hypercortisolism and Cushing's syndrome; Paget's disease; treating osteoarthritis; inducing pulsatile growth hormone release; treating osteochondrodysplasia; treating depression, nervousness, irritability and tension; treating reduced mental energy and low self-esteem (e.g., reduced motivation / confidence); improving cognitive function (e.g., treating dementia, including Alzheimer's disease and short-term memory loss); treating catabolism associated with pulmonary dysfunction and ventilator dependence; treating cardiac dysfunction (e.g., myocardial dysfunction associated with vascular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure); reducing blood pressure; preventing ventricular dysfunction or preventing reperfusion events; treating adults on chronic dialysis; reversing or slowing the catabolic state of aging; slowing or reversing the proteolytic response after trauma (e.g., reversing the catabolic state associated with surgery, congestive heart failure, cardiomyopathy, burns, cancer, COPD, etc.); reducing cachexia and protein loss due to chronic diseases such as cancer or AIDS; treating hyperinsulinemia, including nesidioblastosis; treating immunosuppressed patients; treating wasting associated with multiple sclerosis or other neurodegenerative disorders; promoting myelin repair; maintaining skin thickness; treating metabolic homeostasis and renal homeostasis (e.g., in frail elderly); stimulating osteoblasts; bone remodeling and cartilage growth; regulating food intake;Treating mammals (such as humans) with insulin resistance, including non-insulin-dependent diabetes; treating insulin resistance of the heart; improving sleep quality and correcting the relative deficiency of aging growth hormone secretion caused by increased REM sleep and decreased REM latency; treating hypothermia; treating congestive heart failure; treating lipodystrophy (such as in patients receiving HIV or AIDS treatment such as protease inhibitors); treating muscle atrophy (such as due to lack of physical activity, bed rest or weightlessness); treating musculoskeletal injuries (such as in the elderly); improving overall lung function; treating sleep disorders; treating the catabolic state of long-term critical illness; age-related decrease in testosterone levels in men, male menopause, gonadal hypofunction, male hormone replacement therapy, male and female sexual dysfunction (such as erectile dysfunction, decreased sex drive, decreased sexual satisfaction, hypolibido), urinary incontinence, male and female contraception, hair loss, and enhancing bone and muscle performance / strength.

[0111] In one embodiment, the disorders related to androgen receptors include prostate cancer, benign prostatic hyperplasia and prostate hypertrophy, acne (acne vulgaris), seborrhea, hirsutism, male pattern hair loss and androgenetic alopecia, precocious puberty, polycystic ovary syndrome, sexual perversion, virilization, etc. The compounds of the present invention can also be used to improve ovulation in breeding animals.

[0112] The compounds of the present invention can be used alone or, if desired, in combination with one or more other pharmacologically active substances, provided that such combination does not cause undesirable and unacceptable side effects.

[0113] The following substances may be mentioned as examples of suitable combined active substances: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, ametantrone, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, refametinib (BAY86-9766, RDEA 119), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, levoleucovorin, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, cimelukin, cetuximab, chlorambucil, chlormadinone, chlorambucil, cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, actinomycin D, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dibromospirocholine, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, edrecolomab, edotreotide, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol, epoetin alfa, epoetin beta, esaprostol, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastine, fludarabine, fluorouracil, flutamide, formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxyurea, I-125 seeds (I-125seeds), ibandronic acid, iodine-131 tositumomab, idarubicin, ifosfamide, imatinib, imiquimod, iproplatin, interferon alpha, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidone, lenograstim, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, methyltestosterone, mercaptopurine, methotrexate, methoxsalen, methylaminolevulinate, methyltestosterone, mifamurtide, miltefosine, miloplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed (palladium-103seed), pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim,Peginterferon alfa-2b, Pemetrexed, Pentazocine, Pentostatin, Peplomycin, Phosphoramide mustard, Besipirdine, Pirarubicin, Plerixafor, Plicamycin, Polyglucosamine, Estradiol polyphosphate, Polysaccharide-K, Porfimer sodium, Pradofloxacin, Prednimustine, Procarbazine, Quargal, Radium chloride-223, Raloxifene, Raltitrexed, Ranimustine, Razoxane, Regorafenib, Risedronate, Rituximab, Romidepsin, Romiplostim, Sargramostim, Sipuleucel-T, Sizofiran, Sobuzoxane, Sodium glycididazole, Sorafenib, Streptozocin, Sunitinib, Talaporfin, Tamibarotene, Tamoxifen, Tasonermin, Teceleukin, Tegafur, Tegafur + Gemcitabine + Oteracil, Temoporfin, Temozolomide, Temsirolimus, Teniposide, Testosterone, Tiotropium, Thalidomide, Thiotepa, Thymalfasin, Thioguanine, Tocilizumab, Topotecan, Toremifene, Tositumomab, Trabectedin, Trastuzumab, Treosulfan, Tretinoin, Trilostane, Triptorelin, Triphosphamide, Tryptophan, Ubenimex, Valrubicin, Vandetanib, Vapreotide, Vemurafenib, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Voreloxin, Yttrium-90 glass microspheres, Nocodazole, Nocodazole butyrate, Zoledronic acid, Zorubicin.

[0114] Compounds are named according to the conventional naming principles in the art or using software, and commercially available compounds use the supplier catalog names. BRIEF DESCRIPTION OF THE DRAWINGS

[0115] Figure 1 Graph showing the effect of the compounds in the examples on the AR expression level in AR-positive human prostate cancer cells LNCaP;

[0116] Figure 2 Graph showing the results of the inhibition of cell proliferation of human prostate cancer cells LNCaP by the compounds in the examples. DETAILED DESCRIPTION OF THE INVENTION

[0117] The present application will be described in detail below by way of examples, but this does not mean any adverse limitations to the present application. The present application has been described in detail herein, and its specific embodiments have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0118] Preparation of Key Intermediate 12

[0119]

[0120] Dissolve raw material 1 (2.0 g, 9.26 mmol) in dichloromethane (60 mL), add tert-butyl piperazine-1-carboxylate (1.75 g, 9.4 mmol) and triethylamine (2 mL, 14.0 mmol). Stir the reaction mixture at room temperature for 6 h, extract with water (100 mL × 3), wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. After removing the solvent, recrystallize with ethanol to obtain 2.4 g of a light yellow solid with a yield of 80.60%. UPLC-MS calculated for C 16 H 23 N3O4[M+H] + : 321.38, found: 321.92.

[0121]

[0122] Place intermediate 2 (1.5 g, 4.67 mmol) and stannous chloride dihydrate (5.27 g, 23.33 mmol) in ethyl acetate (50 mL) and stir overnight at room temperature. Add saturated aqueous sodium bicarbonate solution (20 mL) and stir vigorously for 1 h. Remove the solid by filtration, extract with ethyl acetate and water, dry the organic phase over anhydrous magnesium sulfate and concentrate to obtain 1.09 g of a yellow solid with a yield of 80.15%. UPLC-MS calculated for C 16 H 25 N3O2[M+H] + : 291.40, found: 291.93.

[0123]

[0124] Dissolve phenyl chloroformate (0.47 mL, 3.74 mmol) in dichloromethane, slowly dropwise add a dichloromethane solution of intermediate 3 (1.09 g, 3.74 mmol) to the solution at 0 °C while stirring, and continue the reaction at 0 °C for 30 min after the addition is complete. Slowly add a dichloromethane solution of triethylamine (0.62 mL, 4.49 mmol), after reacting overnight, add water and dichloromethane for extraction, dry the organic phase with anhydrous magnesium sulfate, evaporate the solvent and then perform column chromatography (V 石油醚 / V 乙酸乙酯 =1 / 1), to obtain 900 mg of a white solid with a yield of 58.48%. UPLC-MS calculated for C 23 H 29 N3O4[M+H] + : 411.50, found: 412.06.

[0125]

[0126] Dissolve intermediate 4 (230 mg, 0.59 mmol) in 1,4-dioxane (10 mL), add hydrazine hydrate (2.95 mmol), and react at 100 °C for 4 h. Detect by TLC that the raw materials have completely reacted. Remove the solvent, cool, and a solid precipitates to obtain the crude product of intermediate 5.

[0127]

[0128] Slowly add POCl3 (1.53 mL, 16.43 mmol) to DMF (1.53 mL) at 0 °C. Dissolve the raw material 6 (1.0 g, 6.57 mmol) in DMF (2.5 mL), and slowly add it to the mixed solution. Transfer to room temperature and react for 1 h, then raise the temperature to 50 °C and react for 1 h. Cool to room temperature, add 14% NaOH / water (3 g / 18 mL) solution, stir and raise the temperature to 75 °C and react for 15 min. Cool to room temperature, acidify the solution with dilute hydrochloric acid to pH = 2 - 3, stir for about 1 h, extract with ethyl acetate, and rotary evaporate the organic phase to obtain a reddish-brown viscous liquid. UPLC-MS calculated for C 10 H 12 O3 [M + H] + : 180.20, found: 180.32.

[0129]

[0130] Dissolve intermediate 7 in acetonitrile (15 mL), add K2CO3 (7.26 g, 52.56 mmol) and benzyl bromide (1.95 mL, 16.43 mmol), reflux and react for 1.5 h. Cool to room temperature, evaporate the solvent to dryness, and separate by column chromatography (V 石油醚 / V 乙酸乙酯 = 20 / 1) to obtain 1.5 g of a pale yellow solid, with a two-step yield of 63.34%. UPLC-MS calculated for C 24 H 24 O3 [M + H] + : 360.45, found: 360.62.

[0131]

[0132] Dissolve intermediate 8 (201 mg, 0.59 mmol) in ethanol (5 mL), add glacial acetic acid (0.04 mL), and slowly add intermediate 5 (195 mg, 0.59 mmol) to the solution under stirring at room temperature. Transfer the reaction to 80 °C and react for 1 h. After the reaction, perform column chromatography (V 二氯甲烷 / V 甲醇== 35 / 1), 290 mg of white solid was obtained with a yield of 71.04%. UPLC-MS calculated for C 41 H 49 N5O5[M+H] + : 691.87, found: 692.10.

[0133]

[0134] Intermediate 9 (290 mg, 0.42 mmol) was added to ethanol (5 mL) to form a suspension. K3Fe(CN)6 (414 mg, 1.26 mmol) and NaOH (84 mg, 2.1 mmol) were added. The reaction was refluxed at 100 °C for 8 h. TLC detected that the raw material reaction was complete. The inorganic residue was filtered off. After evaporating the solvent, column chromatography (V 二氯甲烷 / V 甲醇 == 35 / 1) was used for purification to obtain 284 mg of intermediate with a yield of 98.02%. UPLC-MS calculated for C 41 H 47 N5O5[M+H] + : 689.86, found: 690.11.

[0135]

[0136] Intermediate 10 (280 mg, 0.45 mmol) was dissolved in dichloromethane (20 mL). 4M hydrochloric acid / dioxane solution (1.5 mL) was added. The reaction was stirred at room temperature for 2 h. After TLC detected that the raw material reaction was complete, the solvent was evaporated. It was extracted with ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was evaporated to obtain the crude product of intermediate 11.

[0137]

[0138] The above intermediate 11 was dissolved in methanol (20 mL). An appropriate amount of Pd / C was added. The reaction was stirred at room temperature for 5 h under a H2 atmosphere. After TLC detected that the raw material reaction was complete, it was filtered. The solvent was evaporated to obtain 130 mg of yellow solid. The two-step yield was 75.59%. UPLC-MS calculated for C 22 H 27 N5O3[M+H] + : 409.49, found: 410.13.

[0139] Preparation of Key Intermediate 63

[0140]

[0141] The synthetic route and method refer to Key Intermediate 12, with the raw material replaced from 4-nitrobenzyl bromide to N-Boc-4-nitro-phenethylamine. UPLC-MS calculated for C 18 H 20 N4O3[M+H] + : 341.39, found: 341.52. Preparation of the example:

[0142] Example 1: Synthesis of SQA-701

[0143]

[0144]

[0145] At 0 °C, NaH (60%) (50 mg, 1.23 mmol) was added to a solution of tert-butyl 3-hydroxy-2,2,4,4-(tetramethyl)cyclobutylcarbamate (250 mg, 1.03 mmol) in DMF (20 mL), and the mixture was stirred for 20 min. Raw material 13 (161 mg, 1.03 mmol) was added to the reaction system, and the temperature was raised to room temperature for reaction for 4 h. TLC detected that the raw material reaction was complete. It was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness and then subjected to column chromatography (V 石油醚 / V 乙酸乙酯 = 8 / 1) to obtain 320 mg of white solid, with a yield of 82.00%. UPLC-MS calculated for C 20 H 27 ClN2O3[M+H] + : 378.90, found: 378.92.

[0146]

[0147] Intermediate 14 (320 mg, 0.84 mmol) was dissolved in dichloromethane (20 mL), 4M hydrochloric acid / dioxane solution (2.5 mL) was added, and the mixture was stirred at room temperature for 4 h. TLC detected that the raw material reaction was complete, and the solvent was removed to obtain a yellow solid. UPLC-MS calculated for C 15 H 19 ClN2O[M+H] + : 278.78, found: 278.87.

[0148]

[0149] Dissolve raw material 16 (100 mg, 0.63 mmol) in anhydrous tetrahydrofuran, add two drops of DMF and SOCl2 (2 mL, 18 mmol), stir and react at 70 °C for 4 h, and evaporate the solvent to obtain a yellow viscous liquid.

[0150]

[0151] Dissolve intermediate 15 (75 mg, 0.24 mmol) and DIPEA (0.12 mL, 0.71 mmol) in anhydrous dichloromethane (20 mL), stir and react at room temperature for 20 min, add intermediate 17 (51 mg, 0.29 mmol), and stir and react overnight at room temperature under argon protection. After evaporating the solvent, perform column chromatography (V 石油醚 / V 乙酸乙酯 =8 / 1) to obtain 100 mg of a pale yellow solid with a yield of 99.37%. UPLC-MS calculated for C 20 H 20 Cl2N4O2[M+H] + : 419.31, found: 418.91.

[0152]

[0153] Dissolve intermediate 18 (100 mg, 0.24 mmol) together with 4-hydroxymethylpiperidine (33 mg, 0.29 mmol) and DIPEA (0.08 mL, 0.48 mmol) in dichloromethane (20 mL), and stir and react overnight at room temperature. TLC detects that the raw material reaction is complete. After evaporating the solvent, perform column chromatography (V 二氯甲烷 / V 甲醇 =25 / 1) to obtain 100 mg of a yellow solid with a yield of 83.66%. UPLC-MS calculated for C 26 H 32 ClN5O3[M+H] + : 498.02, found: 497.97.

[0154]

[0155] Dissolve intermediate 19 (70 mg, 0.14 mmol) in dichloromethane (20 mL), slowly add DMP (102 mg, 0.24 mmol) to the reaction flask, and stir and react at room temperature for 2 h. TLC detects that the raw material reaction is complete. Wash the organic phase successively with saturated sodium bicarbonate and saturated brine, dry over anhydrous sodium sulfate, and after evaporating the solvent, perform column chromatography (V 二氯甲烷 / V 甲醇= 50 / 1) gave 60 mg of light yellow solid with a yield of 86.05%. UPLC-MS calculated for C 26 H 30 ClN5O3[M+H] + : 496.01, found: 495.91.

[0156]

[0157] Intermediate 20 (50 mg, 0.08 mmol) and Intermediate 12 (40 mg, 0.08 mmol) were dissolved together in DMF (6 mL), two drops of glacial acetic acid were added, and the reaction was stirred at room temperature for 20 min. NaBH(OAc)3 (34 mg, 0.16 mmol) was added, and the reaction was stirred at room temperature overnight. SQA-701 white powdery solid (40 mg) was obtained by preparative liquid chromatography with a yield of 55.62%. UPLC-MS calculated for C 48 H 57 ClN 10 O5[M+H] + : 889.50, found: 889.62.

[0158] Example 2: Synthesis of SQA-702

[0159]

[0160] At 0 °C, NaH (60%) (50 mg, 1.23 mmol) was added to a solution of trans-4-BOC-aminocyclohexanol (222 mg, 1.03 mmol) in DMF (20 mL), and the reaction was stirred for 20 min. Raw material 13 (161 mg, 1.03 mmol) was added to the reaction system, and the temperature was raised to room temperature for 4 h. TLC detected that the raw material reaction was complete. It was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was rotary evaporated and then column chromatographed (V 石油醚 / V 乙酸乙酯 = 5 / 1) to give 280 mg of white solid with a yield of 77.48%. UPLC-MS calculated for C 18 H 23 ClN2O3[M+H] + : 350.84, found: 350.82.

[0161]

[0162] Dissolve intermediate 21 (280 mg, 0.80 mmol) in dichloromethane (20 mL), add 4 M hydrochloric acid / dioxane solution (2.0 mL), stir the reaction at room temperature for 4 h. Monitor the reaction by TLC until the raw materials are completely reacted. Evaporate the solvent to obtain a yellow solid. UPLC-MS calculated for C 13 H 15 ClN2O[M+H] + : 250.73, found: 250.75.

[0163]

[0164] Dissolve intermediate 22 (50 mg, 0.17 mmol) and DIPEA (0.09 mL, 0.52 mmol) in anhydrous dichloromethane (20 mL), stir the reaction at room temperature for 20 min. Add intermediate 17 (36 mg, 0.21 mmol), and stir the reaction at room temperature overnight under argon protection. Evaporate the solvent and then perform column chromatography (V 石油醚 / V 乙酸乙酯 = 5 / 1) to obtain 67 mg of a pale yellow solid with a yield of 99.84%. UPLC-MS calculated for C 18 H 16 Cl2N4O2[M+H] + : 391.25, found: 390.79.

[0165]

[0166] Dissolve intermediate 23 (67 mg, 0.17 mmol), 4-hydroxymethylpiperidine (23 mg, 0.21 mmol) and DIPEA (0.06 mL, 0.34 mmol) in dichloromethane (20 mL), and stir the reaction at room temperature overnight. Monitor the reaction by TLC until the raw materials are completely reacted. Evaporate the solvent and then perform column chromatography (V 二氯甲烷 / V 甲醇 = 25 / 1) to obtain 75 mg of a pale yellow viscous liquid with a yield of 93.87%. UPLC-MS calculated for C 24 H 28 ClN5O3[M+H] + : 469.97, found: 469.96.

[0167]

[0168] Dissolve intermediate 24 (75 mg, 0.15 mmol) in dichloromethane (20 mL), slowly add DMP (126 mg, 0.3 mmol) to the reaction flask, and stir the reaction at room temperature for 2 h. TLC detection shows that the raw material reaction is complete. The organic phase is washed successively with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. Then column chromatography (V 二氯甲烷 / V 甲醇 = 50 / 1) gives 58 mg of white solid with a yield of 82.63%. UPLC-MS calculated for C 24 H 26 ClN5O3 [M + H] + : 467.95, found: 467.90.

[0169]

[0170] Dissolve intermediate 25 (52 mg, 0.11 mmol) and intermediate 12 (45 mg, 0.11 mmol) together in DMF (6 mL), add two drops of glacial acetic acid, stir the reaction at room temperature for 20 min, add NaBH(OAc)3 (46 mg, 0.22 mmol), and stir the reaction at room temperature overnight. Through preparative liquid chromatography, 38 mg of white powdery solid of SQA-702 is obtained with a yield of 40.10%. UPLC-MS calculated for C 46 H 53 ClN 10 O5 [M + H] + : 861.45, found: 861.50.

[0171] Example 3: Synthesis of SQA-703

[0172]

[0173] The synthesis route refers to Example 1, and the raw material 2-chloropyrimidine-5-carboxylic acid in Example 1 is replaced by 6-chloropyridazine-3-carboxylic acid. Through preparative liquid chromatography, 25 mg of white powdery solid of SQA-703 is obtained. UPLC-MS calculated for C 48 H 57 ClN 10 O5 [M + H] + : 889.50, found: 889.50.

[0174] Example 4: Synthesis of SQA-704

[0175]

[0176] The synthetic route refers to Example 2. 65 mg of white powdery solid of SQA-704 was obtained by preparative liquid phase. UPLC-MS calculated for C 47 H 54 ClN9O5[M+H] + : 861.47, found: 861.64.

[0177] Example 5: Synthesis of SQA-705

[0178]

[0179]

[0180] Monomethyl terephthalate (80 mg, 0.28 mmol), HATU (158 mg, 0.42 mmol) and DIPEA (0.24 mL, 1.38 mmol) were dissolved in anhydrous DMF. The reaction was stirred for 15 min under argon protection. A DMF solution of 22 (50 mg, 0.28 mmol) was added, and the reaction was stirred at room temperature overnight. Water and ethyl acetate were added for extraction. The organic phase was washed successively with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (V 石油醚 / V 乙酸乙酯 = 2 / 1) to obtain 77 mg of solid with a yield of 67%. UPLC-MS calculated for C 22 H 21 ClN2O4[M+H] + : 413.88, found: 413.62.

[0181]

[0182] Intermediate 40 (70 mg, 0.17 mmol) was dissolved in a tetrahydrofuran solution. Lithium hydroxide (72 mg, 1.7 mmol) and a small amount of water were added, and the reaction was stirred at room temperature overnight. TLC detected that the raw materials had completely reacted. The organic phase was evaporated to dryness. Water and ethyl acetate were added for extraction (the organic phase was discarded). The aqueous phase was adjusted to pH 2-3 with hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate to obtain 60 mg of crude intermediate 40.

[0183]

[0184] Intermediate 40 (60 mg, 0.15 mmol), HATU (86 mg, 0.22 mmol), and DIPEA (0.13 mL, 0.75 mmol) were dissolved in anhydrous DMF, and the reaction was stirred for 15 min under argon protection. A DMF solution of 4-piperidinemethanol (21 mg, 0.18 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was washed successively with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (V 二氯甲烷 / V 甲醇 = 20 / 1) to obtain 57 mg of a white solid with a yield of 76.6%. UPLC-MS calculated for C 27 H 30 ClN3O4 [M+H] + : 497.01, found: 496.98.

[0185] For the remaining synthesis method, refer to Example 2. 47 mg of a white powdery solid of SQA-705 was obtained by preparative liquid chromatography. UPLC-MS calculated for C 49 H 55 ClN8O6 [M+H] + : 888.49, found: 888.24.

[0186] Example 6: Synthesis of SQA-706

[0187]

[0188] The synthetic route was referred to Example 2, and the raw material 2-chloro-4-fluorobenzonitrile in Example 2 was replaced with 2-trifluoromethyl-4-fluorobenzonitrile. 45 mg of a white powdery solid of SQA-706 was obtained by preparative liquid chromatography. UPLC-MS calculated forC 47 H 53 F3N 10 O5 [M+H] + : 896.01, found: 895.88.

[0189] Example 7: Synthesis of SQA-707

[0190]

[0191] Dissolve N-Boc-γ-aminobutyric acid (55 mg, 0.27 mmol), HATU (158 mg, 0.42 mmol) and DIPEA (0.24 mL, 1.38 mmol) in anhydrous DMF, stir the reaction for 15 min under argon protection, add the DMF solution of intermediate 12 (115 mg, 0.28 mmol), and stir the reaction overnight at room temperature. Add water and ethyl acetate for extraction, wash the organic phase successively with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine, dry over anhydrous magnesium sulfate, and perform column chromatography (V 二氯甲烷 / V 甲醇 =15 / 1) to obtain 72 mg of solid, with a yield of 45.1%. UPLC-MS calculated for C 31 H 42 N6O6[M+H] + : 595.72, found: 595.54.

[0192]

[0193] Dissolve intermediate 49 (70 mg, 0.12 mmol) in dichloromethane (20 mL), add 4 M hydrochloric acid / dioxane solution (1.0 mL), stir the reaction for 4 h at room temperature, detect by TLC that the raw material reaction is complete, and remove the solvent to obtain the crude product of intermediate 50.

[0194]

[0195] Dissolve intermediate 40 (40 mg, 0.1 mmol), HATU (57 mg, 0.15 mmol) and DIPEA (0.01 mL, 0.5 mmol) in anhydrous DMF, stir the reaction for 15 min under argon protection, add the DMF solution of intermediate 50 (64 mg, 0.12 mmol), and stir the reaction overnight at room temperature. Add water and ethyl acetate for extraction, wash the organic phase successively with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine, dry over anhydrous magnesium sulfate, and obtain 35 mg of off-white powdery solid of SQA-707 by preparative liquid phase, with a yield of 39.9%. UPLC-MS calculated for C 47 H 51 ClN8O7[M+H] + : 876.43, found: 876.06.

[0196] Example 8: Synthesis of SQA-708

[0197]

[0198]

[0199] The synthetic route refers to Example 7, where the raw material N-Boc-γ-aminobutyric acid in Example 7 is replaced with Boc-5-aminovaleric acid, and 58 mg of white powdery solid of SQA-708 is obtained by preparative liquid chromatography. UPLC-MS calculated for C 48 H 53 ClN8O7[M+H] + : 890.46, found: 890.28.

[0200] Example 9: Synthesis of SQA-709

[0201]

[0202] The synthetic route refers to Example 7, where the raw material N-Boc-γ-aminobutyric acid in Example 7 is replaced with Boc-6-aminohexanoic acid, and 36 mg of off-white powdery solid of SQA-709 is obtained by preparative liquid chromatography. UPLC-MS calculated for C 49 H 55 ClN8O7[M+H] + : 904.49, found: 904.22.

[0203] Example 10: Synthesis of SQA-710

[0204]

[0205] The synthetic steps and treatment methods refer to Example 2, and 26 mg of off-white powdery solid of SQA-710 is obtained by preparative liquid chromatography. UPLC-MS calculated for C 52 H 64 ClN 11 O5[M+H] + : 959.62, found: 960.02.

[0206] Example 11: Synthesis of WCA-814

[0207]

[0208] The synthetic route refers to Examples 2 and 3, and 30 mg of white powdery solid of WCA-814 is obtained by preparative liquid chromatography. UPLC-MS calculated for C 46 H 53 ClN 10 O5[M+H] + : 861.45, found: 861.45.

[0209] Example 12: Synthesis of XLA-721

[0210]

[0211] Dissolve Boc-beta-alanine (57 mg, 0.3 mmol), HATU (171 mg, 0.45 mmol) and DIPEA (0.26 mL, 1.5 mmol) in anhydrous DMF, stir the reaction for 15 min under argon protection, add a DMF solution of intermediate 63 (115 mg, 0.28 mmol), and stir the reaction overnight at room temperature. Add water and ethyl acetate for extraction. The organic phase is washed successively with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (V 二氯甲烷 / V 甲醇 =15 / 1) to obtain 70 mg of solid with a yield of 48.6%. UPLC-MS calculated for C 26 H 33 N5O6[M+H] + : 512.59, found: 512.62.

[0212]

[0213] Dissolve intermediate 64 (70 mg, 0.14 mmol) in dichloromethane (20 mL), add 4 M hydrochloric acid / dioxane solution (1.0 mL), stir the reaction at room temperature for 4 h, and monitor the reaction by TLC until the raw material is completely reacted. Remove the solvent to obtain the crude product of intermediate 65.

[0214]

[0215] The synthesis of intermediate 66 can refer to the preparation method of intermediate 40 in Example 5;

[0216] Dissolve intermediate 66 (42 mg, 0.1 mmol), EDCI (39 mg, 0.2 mmol), HOAT (27 mg, 0.2 mmol) and DIPEA (0.05 mL, 0.3 mmol) in anhydrous DMF, stir the reaction for 10 min under argon protection, add a DMF solution of intermediate 65 (64 mg, 0.12 mmol), and stir the reaction overnight at room temperature. Add water and ethyl acetate for extraction. The organic phase is washed successively with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and white powdery solid of XLA-721 (51 mg) is obtained by preparative liquid chromatography with a yield of 62.1%. UPLC-MS calculated for C 44 H 46 ClN7O7[M+H] + : 821.35, found: 820.34.

[0217] Example 13: Synthesis of XLA-722

[0218]

[0219]

[0220] The synthesis method refers to Example 12, and 22 mg of white powdery solid of XLA-722 was obtained by preparative liquid phase. UPLC-MS calculated for C 42 H 42 ClN7O7[M+H] + : 793.30, found: 792.29.

[0221] Example 14: Synthesis of XLA-723

[0222]

[0223] The synthesis method refers to Example 12, and 36 mg of white powdery solid of XLA-723 was obtained by preparative liquid phase. UPLC-MS calculated for C 43 H 44 ClN7O7[M+H] + : 807.33, found: 806.32.

[0224] Example 15: Synthesis of XLA-724

[0225]

[0226]

[0227] The synthesis method refers to Example 12, and 48 mg of white powdery solid of XLA-724 was obtained by preparative liquid phase. UPLC-MS calculated for C 44 H 46 ClN7O7[M+H] + : 821.35, found: 820.34.

[0228] Example 16: Synthesis of XLA-725

[0229]

[0230] The synthesis method refers to Example 12, and 39 mg of white powdery solid of XLA-725 was obtained by preparative liquid phase. UPLC-MS calculated for C 45 H 48 ClN7O7[M+H]+ : 835.38, found: 834.37.

[0231] Example 17: Synthesis of XLA-726

[0232]

[0233] The synthesis method refers to Example 12, and 23 mg of white powdery solid of XLA-726 was obtained by preparative liquid phase. UPLC-MS calculated for C 46 H 50 ClN7O7 [M+H] + : 849.41, found: 848.42.

[0234] Example 18: Synthesis of XLA-727

[0235]

[0236] The synthesis method refers to Example 12, and 42 mg of white powdery solid of XLA-727 was obtained by preparative liquid phase. UPLC-MS calculated for C 47 H 52 ClN7O7 [M+H] + : 863.44, found: 863.46.

[0237] Example 19: Synthesis of XLA-728

[0238]

[0239] The synthesis method refers to Example 12, and 37 mg of white powdery solid of XLA-728 was obtained by preparative liquid phase. UPLC-MS calculated for C 48 H 54 ClN7O7 [M+H] + : 877.46, found: 877.98.

[0240] Example 20: Synthesis of XLA-729

[0241]

[0242] The synthesis method refers to Example 12, and 40 mg of white powdery solid of XLA-729 was obtained by preparative liquid phase. UPLC-MS calculated for C 49 H 56 ClN7O7 [M+H] + : 891.49, found: 891.26.

[0243] Example 21: Synthesis of XLA-730

[0244]

[0245] The synthesis method refers to Example 12, and 31 mg of white powdery solid of XLA-730 was obtained by preparative liquid phase. UPLC-MS calculated for C 45 H 48 ClN7O9[M+H] + : 867.38, found: 868.42.

[0246] Biological evaluation test

[0247] Test Example 1: Evaluation of the effect of reducing the expression level of androgen receptor (AR)

[0248] The AR-positive human prostate cancer cell line LNCaP was inoculated into a 6-well microplate (Corning) at a density of 3×10 5 / well in RPMI 1640 containing 10% FBS (hereinafter referred to as the evaluation medium) and cultured overnight. The evaluation medium containing the compound of the example was added to the culture so that the final concentration of the compound of the example reached 1 and 10 μmol / L, and the cells were cultured for 24 hours. After 24 hours of culture, the medium was removed, the cells were washed with PBS, and then RIPA lysis buffer containing 1% Protease Inhibitor Cocktail was added. After lysis and centrifugation, the total protein extract was obtained. The protein concentration in the extract was detected by the BCA method; SDS-PAGE was used for protein electrophoresis, and then the protein was transferred to a PVDF (MilliporeSigma IPVH00010) membrane at a constant current of 200 mA for 90 min; the PVDF membrane was placed in 5% non-fat milk and blocked at room temperature for 1 h; Immunoreactions were performed using Anti-Androgen Receptor antibody [EPR1535(2)](HRP)(abcam) and anti-AR-V7 Speccific antibody (Cell Signaling) respectively; after washing the membrane, ECL luminescent solution was added and exposed. The software Image J was used to analyze the gray scale of the bands. The GAPDH protein band was detected as an internal reference for each sample. The degradation rate of AR protein of the compound of the example was calculated according to the gray scale of the protein band.

[0249] The results of LNCaP cells are shown in Figure 1And Table 1. When the reduction effect of AR expression is more than 50%, it is expressed as "reduction". Among the compounds of the present invention, the example compounds SQA-701, SQA-702, SQA-703, SQA-704, SQA-705, SQA-706, SQA-710, and WCA-814 all showed a certain reduction effect on AR expression, and in subsequent experiments, the degradation of the compound on AR showed obvious concentration dependence and time dependence.

[0250] Table 1

[0251]

[0252] Test Example 2: Inhibitory Activity of Androgen-Dependent Prostate Cancer Cell Proliferation

[0253] The androgen receptor-positive human prostate cancer cell line LNCaP was inoculated into a clear-bottom 96-well microplate (Corning) at a density of 4×10 3 / well in RPMI1640 medium containing 5% charcoal-stripped serum (CCS) (hereinafter referred to as the evaluation medium) and cultured for 48 h. In this culture, an evaluation medium containing R1881 (the final concentration of R1881 was 0.1 nmol / L) and an evaluation medium containing the example compound or the comparative compound (Enzalutamide) were added. (The final concentrations of the example or comparative compound were 1.53, 4.6, 13.8, 41.1, 123.4, 370.3, 1111, 3333, and 10000 nmol / L), and after culturing for 96 hours, the number of viable cells was measured. The number of viable cells was measured using WST-1 (Roche). The cell proliferation activity value of 0.1 nmol / L of R1881 was set as 100%, and the cell proliferation activity of only the evaluation medium was set as 0%. The 50% proliferation inhibition concentration (IC 50 value) was calculated using logistic regression based on the measured number of viable cells.

[0254] The results of cell proliferation inhibition are shown in Table 2. The example compounds showed varying degrees of inhibitory activity on prostate cancer cell proliferation. Among them, SQA-710 showed excellent inhibitory activity on tumor cell proliferation, and the maximum half-maximal inhibitory concentration (IC 50 ) was 36.0 nmol / L (LNCaP cell line) and 30.2 nmol / L (22RV1 cell line), respectively. Enzalutamide was used as a positive control, and its IC 50 in the LNCaP cell line was 52 nmol / L, while it was almost ineffective in the 22RV1 cell line.

[0255] Table 2

[0256]

[0257] Experimental Example 3: Preliminary Pharmacodynamic Screening of Compounds on a Mouse Model of Prostate Cancer

[0258] A mouse model was constructed using the human prostate cancer 22RV1 cell line (enzalutamide-resistant), and the mouse strain was balb / c nude mice. The solvent for the compounds in the examples was 20% PEG400 + 6% Cremophor EL + 74% PBS, and the administration was by intraperitoneal injection. The administration cycle was Qod4*weeks, and the administration doses were 5 mg / kg or 10 mg / kg. After 16 days of administration, the tumor volume of the mice was measured, and the experimental results are as Figure 2 shown. Compounds H3 (10 mg / kg), SQA-710 (5 mg / kg and 10 mg / kg), and SQA-814 (5 mg / kg) in the examples showed significant and comparable tumor proliferation inhibitory abilities compared with the Control group, while the compound SQA-702 that was active at the cellular level had poor effects on the mouse model.

[0259] In addition, whether SQA-710 was administered at 5 mg / kg or 10 mg / kg, it showed certain toxicity to the mice, while when SQA-814 was administered at 5 mg / kg, it could ensure the drug effect while having no obvious effect on the body weight of the mice.

[0260] Conclusion

[0261] The compounds in the examples all had a certain effect of reducing the AR expression level in LNCap cells. Among them, SQA-710 had the best AR degradation activity, and its DC 50 was about 20 nM. It could not only dose-dependently inhibit the growth of LNCap cells, but also significantly inhibit the growth of 22RV1 tumor cells resistant to Enzalutamide. In addition, as a small molecule conjugate drug of an AR antagonist and an Hsp90 inhibitor, the tumor inhibitory activity of SQA-710 was higher than that of the two small molecules when applied alone. It can be seen that this conjugate drug played the effect of a similar dual-target inhibitor and produced a synergistic effect.

[0262] When the compounds in the examples were evaluated for their pharmacodynamic effects on the animal model constructed with 22RV1, it was found that SQA-814 had comparable anti-tumor proliferation activity to SQA-710 and also had lower toxicity, and it was worthy of further subsequent research.

[0263] It should be understood that the present invention is not limited to the specific embodiments of the present invention described above, because the specific embodiments can be changed and still fall within the scope of the appended claims.

Claims

1. A compound, its optical isomers or its pharmaceutically acceptable salts, the structure of the compound is shown as formula (Ⅰ): Wherein, R1 is H; R2 is selected from H, halogen, C 1-6 haloalkyl, OH, CN; L is selected from m is 0; ring C is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; ring D is selected from cyclobutyl and cyclohexyl substituted with methyl.

2. The compound according to claim 1, the specific structure of the compound is selected from any one of the following:

3. A pharmaceutical composition, which comprises the compound according to claim 1 or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients or carriers.

4. Use of the compound according to claim 1 or its pharmaceutically acceptable salts or the pharmaceutical composition according to claim 3 in the preparation of an androgen receptor modulator.

5. Use of the compound according to claim 1 or its pharmaceutically acceptable salts or the pharmaceutical composition according to claim 3 in the preparation of a medicament for treating diseases related to androgen receptors.

6. The use according to claim 5, characterized in that The disease is cancer, metabolic disorder disease, cardiovascular and cerebrovascular disease, hyperlipidemia or obesity.

7. The use according to claim 5, characterized in that The cancer is prostate cancer, breast cancer or bladder cancer.

Images