CN116669729A - Heteroaryl piperidine derivatives and their pharmaceutical compositions and applications - Google Patents

Abstract

The invention belongs to the field of medicine, and in particular relates to a heteroaryl piperidine derivative and its pharmaceutical composition and application. The heteroaryl piperidine derivatives represented by the formula (I) provided by the present invention can not only be prepared into oral preparations, but also have good pharmacokinetic properties.

Description

Heteroaryl piperidine derivatives and their pharmaceutical compositions and applications technical field

The invention belongs to the field of medicine, and in particular relates to a heteroaryl piperidine derivative and its pharmaceutical composition and application.

Background technique

Estrogen receptor (ER) is a transcriptional regulatory protein that mediates ligand activation induced by various biological effects through its interaction with endogenous estrogen. ER contains two subtypes, ERα and ERβ. ERα is mainly distributed in the uterus, ovary, testis, pituitary, kidney, epididymis and adrenal gland, while ERβ is mainly distributed in the prostate, ovary, lung, bladder, brain and blood vessels. Due to the serious side effects of full agonists or full antagonists, the study of selective estrogen receptor modulator SERM came into being. Its "modulator" means that SERM acts as an agonist in certain tissues such as bone, liver, and cardiovascular system ERβ concentration areas, while it acts as an antagonist in other tissues such as breast. It can be an agonist or an antagonist in the uterus (where ERa is more prominent). SERMs currently on the market include Tamoxifen, Raloxifene, Bazedoxifene, Toremifene, etc., but studies have found that SERMs currently on the market still have severe For example, long-term use of tamoxifen and toremifene can cause endometrial hyperplasia, polyps, and endometrial cancer, while common side effects of raloxifene include hot flashes, leg pain, breast tenderness, and venous Embolism, etc. Therefore, the research and development of new compounds is still an urgent problem to be solved.

Selective estrogen receptor down-regulators (SERDs) are a class of drugs that can block the activity of estrogen by inhibiting the function of the two transcriptional activation domains AF1 and AF2 of estrogen receptors. Drugs (full antagonists). Fulvestrant is currently the only SERD drug approved for clinical use in the treatment of ER+ breast cancer, but it has poor druggability, rapid metabolism and must be administered by monthly intramuscular injections, unlike those seen in in vitro studies This limits the effective degradation of ER compared to complete ER degradation (-50% ER degradation in clinical samples).

There is a strong clinical demand for drugs that can inhibit the activity of estrogen receptors, down-regulate the expression level of estrogen receptors, or induce the degradation of estrogen receptors, so as to improve the treatment of early, metastatic, or drug-resistant breast cancer or other estrogen-related diseases. Therapeutic effects in diseases associated with receptor overactivity.

AstraZeneca's WO2018077630A patent discloses a series of SERD compounds, including early clinical drug AZD9833, wherein the structure of AZD9833 is:

Selective estrogen receptor down-regulators have shown certain therapeutic advantages, but it is still necessary to develop more orally available selective estrogen receptors, so that candidate drugs have more excellent properties, such as better efficacy, lower side effects, oral Better absorption, better pharmacokinetic properties, etc., so that it can be better used for the prevention or treatment of estrogen receptor-related diseases.

Contents of the invention

In order to solve the above problems, the present invention provides an oral selective estrogen receptor compound with better pharmacokinetic properties and its pharmaceutical composition and application.

The present invention provides a compound as shown in formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt:

in,

Ring A is selected from

D is CR ₉ or N;

E is CR ₁₀ or N;

R ₁ is selected from H, F, Cl, Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ OP(O)(OH) ₂ , -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHSO ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ N( CH ₃ ) ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH(CH ₃ )CN, -C(CH ₃ ) ₂ CN, -CH ₂ CN, -CO ₂ H, -COCH _3. -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CONHCH ₂ CH ₃ , -CONHCH(CH ₃ ) ₂ , -CON (CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , -NO ₂ , =O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OP(O)(OH) ₂ , -S(O) ₂ N(CH ₃ ) ₂ , -SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₂ OH, cyclopropyl, cyclopropylamido, cyclobutyl, oxetanyl, nitrogen Hetidine, (1-methylazetidin-3-yl)oxy, N-methyl-N-oxetane-3-ylamino, azetidin-1- Cylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanonyl, piperazin-1-yl, morpholinomethyl, morpholino-methanonyl and Morpholino;

R ₂ is selected from H, C ₁ -C ₉ alkyl, C ₃ -C ₉ cycloalkyl, C ₃ -C ₉ heterocyclyl, C ₆ -C ₁₀ aryl, C ₅ -C ₁₀ heteroaryl, - (C ₁ -C ₆ alkylene)-(C ₃ -C ₉ cycloalkyl), -(C ₁ -C ₆ alkylene)-(C ₃ -C ₉ heterocyclyl), C(O)R _b , C(O)N(R _a ) ₂ , SO ₂ R _a and SO ₂ N(R _a ) ₂ , the C ₁ -C ₉ alkyl, C ₃ -C ₉ cycloalkyl, C ₃ -C ₉ heterocyclyl, C ₆ -C ₁₀ aryl, C ₅ -C ₁₀ heteroaryl, -(C ₁ -C ₆ alkylene) -(C ₃ -C ₉ cycloalkyl), -(C ₁ - C ₆ alkylene)-(C ₃ -C ₉ heterocyclyl) optionally substituted with one or more of F, Cl, Br, I, CN, OR _a , N(R _a ) ₂ , C ₁ -C ₉ Alkyl, C ₃ -C ₉ cycloalkyl, C ₃ -C ₉ heterocyclyl, C ₆ -C ₁₀ aryl, C ₅ -C ₁₀ heteroaryl, C(O)R _b , C(O)N (R _a ) ₂ , SO ₂ R _a and SO ₂ N(R _a ) ₂ ;

R ₅ are each the same or different, each independently selected from H, F, Cl, Br, I, alkyl, haloalkyl, alkoxy, haloalkoxy, -CN, -NH ₂ , -NO ₂ , -COOH , -CHO, -OH, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally each independently is selected from alkyl, F, Cl, Br, I, -CN, -NH ₂ , -NO ₂ , -OH, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl One or more substituents in radical and heteroaryl;

R ₇ is H, F, Cl, Br, I, OH or NH ₂ ;

_R8 is F or CN;

R ₉ is H, Cl, F, halogenated C ₁ -C ₆ alkoxy;

R ₁₀ is H, Cl, F, halogenated C ₁ -C ₆ alkoxy;

R _a is selected from H, C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, propargyl, C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ heterocyclyl, the C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, propargyl, C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ heterocyclyl are optionally substituted with one or more groups independently selected from the following groups: F , Cl, Br, I, CN, OH, OCH ₃ and SO ₂ CH ₃ ;

R _b is selected from H, -O(C ₁ -C ₃ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, propargyl, -(C ₁ -C ₆ alkylene)- (C ₃ -C ₆ cycloalkyl), C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ heterocyclyl, the -O(C ₁ -C ₃ alkyl), C ₁ -C ₆ alkyl , C ₂ -C ₈ alkenyl, propargyl, -(C ₁ -C ₆ alkylene)-(C ₃ -C ₆ cycloalkyl), C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ Heterocyclyl is optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -OH, -OCH ₃ , and -SO ₂ CH ₃ ;

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

p is 1, 2 or 3.

In some embodiments, the compound represented by formula (I) is further a compound represented by formula (Ib):

in,

D is CR ₉ or N;

E is CR ₁₀ or N;

R ₇ is H, F, Cl, Br, I, OH or NH ₂ ;

_R8 is F or CN;

R ₉ is H, Cl, F, or halogenated C ₁ -C ₆ alkoxy;

R ₁₀ is H, Cl, F, or halogenated C ₁ -C ₆ alkoxy;

When R ₈ is F, R ₉ and R ₁₀ are not H or F at the same time;

When D is N, E is CR ₁₀ and R ₈ is F, R ₁₀ is not H or F; or when E is N, D is CR ₉ and R ₈ is F, R ₉ is not H or F;

R ₁₁ is Me, F or CH ₂ F;

_R12 is Me, F, _CH2F , _CHF2 , _CF3 , _CH2OMe or _CH2OH ;

R ₁₃ is H or F; or

R ₁₂ and R ₁₃ together with the carbon atoms to which they are attached form a cyclopropyl ring, cyclobutyl ring or oxetane ring;

p is 1, 2 or 3.

In some embodiments, the compound represented by formula (I) is further a compound represented by formula (Ic) or formula (Id):

In some embodiments, D is CR ₉ and E is CR ₁₀ .

In some embodiments, D is CR ₉ and E is N; or D is N and E is CR ₁₀ .

In some embodiments, R ₉ is Cl; or R ₁₀ is Cl.

In some embodiments, R ₉ is H; or R ₁₀ is H.

In some embodiments, R ₉ is F; or R ₁₀ is F.

In some embodiments, R ₉ is -OCHF ₂ or -OCHF ₃ .

In some embodiments, R ₁₀ is -OCHF ₂ or -OCHF ₃ .

In some embodiments, R ₉ is Cl, and R ₁₀ is Cl.

In some embodiments, R ₁₁ is F.

In some embodiments, R ₁₂ is F or CH ₂ OH.

In some embodiments, R ₁₃ is F.

In some embodiments, R ₈ is F.

In some embodiments, R ₇ is H or OH.

In some embodiments, R ₇ is H.

In some embodiments, p is 1.

In some embodiments, p is 2.

In some embodiments, the compound represented by the formula (I) is selected from:

5-(difluoromethoxy)-N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-( 2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine;

N-(3-(difluoromethoxy)-4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9- Tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine;

1-(3-fluoropropyl)-N-(4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9- Tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)-3-(trifluoromethoxy)phenyl)azetidin-3-amine;

5-(Difluoromethoxy)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((6S,8R)-8-methyl-7- (2,2,2-Trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine;

5-(Difluoromethoxy)-N-((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((6S,8R)-8-methyl-7- (2,2,2-Trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine;

(3R,4R)-4-((5-(Difluoromethoxy)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6 ,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-yl)amino)-1-(3-fluoropropyl)pyrrolidine -3-ol;

N-(3-(difluoromethoxy)-5-fluoro-4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7, 8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine;

3-((6S,8R)-6-(2-(difluoromethoxy)-6-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino )Phenyl)-8-methyl-3,6,8,9-tetrahydro-7H-pyrazolo[4,3-f]isoquinolin-7-yl)-2,2-difluoropropane- 1-alcohol;

3-((6S,8R)-6-(3-(Difluoromethoxy)-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridine-2 -yl)-8-methyl-3,6,8,9-tetrahydro-7H-pyrazolo[4,3-f]isoquinolin-7-yl)-2,2-difluoropropane-1 -alcohol;

3-((6S,8R)-6-(2-(difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl) -8-methyl-3,6,8,9-tetrahydro-7H-pyrazolo[4,3-f]isoquinolin-7-yl)-2,2-difluoropropan-1-ol;

N-(3,5-dichloro-4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro- 3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine;

(S)-N-(3,5-dichloro-4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9 -tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;

(3R,4R)-4-((3,5-dichloro-4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7, 8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol;

(R)-N-(3,5-dichloro-4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9 -tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine; or

3-((6S,8R)-6-(2,6-dichloro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-8- Methyl-3,6,8,9-tetrahydro-7H-pyrazolo[4,3-f]isoquinolin-7-yl)-2,2-difluoropropan-1-ol.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound represented by formula (I), formula (Ib), formula (Ic) or formula (Id) and at least A pharmaceutically acceptable excipient.

The present invention also provides the use of the compound represented by formula (I), formula (Ib), formula (Ic) or formula (Id) in the preparation of medicines for treating estrogen receptor-related diseases.

In some embodiments, the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.

The present invention also provides a method for treating estrogen receptor-related diseases in a patient, comprising administering to the patient a therapeutically effective amount of the above formula (I), formula (Ib), formula (Ic) or formula (Id) ) compound shown.

In some embodiments, the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.

definition

The general chemical terms used in the above general structural formulas have their usual meanings.

For example, the terms "halo" and "halogen" as used herein refer to fluorine, chlorine, bromine or iodine, unless otherwise specified. Preferred halo groups include fluorine, chlorine and bromine.

In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. Alkyl groups as used herein may be optionally substituted with one or more substituents. Non-limiting examples of alkyl groups include, for example, alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-( 2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and the like. Similarly, "C _1-8 " in "C _1-8 alkyl" refers to a straight chain or branched chain arrangement containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms group.

Alkenyl and alkynyl groups include straight or branched chain alkenyl and alkynyl groups. Similarly, "C _2-8 alkenyl" and "C _2-8 alkynyl" refer to alkenyl groups containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a straight or branched chain or alkynyl.

"Alkoxy" refers to the oxygen ether form of the aforementioned linear or branched alkyl, ie -O-alkyl.

"Haloalkoxy" means that the aforementioned "alkoxy" is substituted by one or more halogens; non-limiting examples of haloalkoxy groups include, but are not limited to, for example -OCH ₂ F, - OCHF ₂ , -OCF ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , -OCHFCH ₃ , -OCF ₂ CH ₃ , -OCHFCH ₂ F and the like.

In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient may be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

The term "aromatic ring", in the present invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic, fused or condensed ring aromatic group including carbon atoms, or an unsubstituted or substituted heteroatom, for example N, O or S monocyclic, parallel ring or condensed ring aromatic group, when it is a parallel ring or condensed ring, at least one ring has aromaticity. Preferably, the aromatic ring is a 5- to 10-membered monocyclic or bicyclic aromatic ring group. Examples of such aromatic rings include, but are not limited to, phenyl, pyridyl, pyrazolyl, pyrimidinyl, chroman, indolyl.

The term "cycloalkyl" refers to monocyclic and polycyclic ring systems containing only carbon atoms in the ring and which may be optionally substituted with one or more substituents. Cycloalkyl as used herein refers to and includes saturated or unsaturated non-aromatic ring systems. The term cycloalkyl additionally includes bridged, fused and spiro ring systems. Non-limiting examples of cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, spiro[3.4]octyl, bicyclo[2.2.1]heptane, and the like.

The term "heterocyclyl", in the present invention, unless otherwise stated, refers to unsubstituted or substituted monocyclic and polycyclic ring systems consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S , and includes saturated or unsaturated ring systems as well as polycyclic ring systems having unsaturated and/or aromatic moieties. Wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized. The heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. It should be understood that polycyclic heterocycloalkyl groups additionally include fused, bridged and spiro ring systems. A heterocycloalkyl group as used herein may be optionally substituted with one or more substituents. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro Oxadiazolyl.

As used herein, unless otherwise indicated, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic ring system containing carbon ring atoms, at least one ring being aromatic. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl is phenyl.

The term "heteroaryl", in the present invention, unless otherwise stated, refers to an unsubstituted or substituted stable 5-membered or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-membered or 10-membered benzo A fused heteroaromatic ring system or a bicyclic heteroaromatic ring system consisting of carbon atoms and 1 to 4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms can optionally be replaced by Oxygenated, the nitrogen heteroatoms can optionally be quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene Thiadiazolyl, benzotriazolyladenine, quinolinyl or isoquinolinyl.

The term "substituted" means that one or more hydrogen atoms in the group are respectively replaced by the same or different substituents. Typical substituents include, but are not limited to, halogen (F, Cl, Br or I), C _1-8 alkyl, C _3-12 cycloalkyl, -OR ¹ , -SR ¹ , =O, =S, -C (O)R ¹ , -C(S)R ¹ , =NR ¹ , -C(O)OR ¹ , -C(S)OR ¹ , -NR ¹ R ² , -C(O)NR ¹ R ² , Cyano, Nitro, -S(O) ₂ R ¹ , -OS(O ₂ )OR ¹ , -OS(O) ₂ R ¹ , -OP(O)(OR ¹ )(OR ² ); where R ¹ and R ² are independently selected from -H, C _1-6 alkyl, C _1-6 haloalkyl. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy Butyl, isobutoxy, tert-butoxy, -SCH ₃ , -SC ₂ H ₅ , formaldehyde, -C(OCH ₃ ), cyano, nitro, -CF ₃ , -OCF ₃ , amino, dimethyl Amino, methylthio, sulfonyl and acetyl groups.

Examples of substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.

Examples of substituted alkoxy include, but are not limited to, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (superior and subvalent), ferric, ferrous, lithium, magnesium, manganese (superior and subvalent), potassium, sodium, zinc, and the like. Particular preference is given to the ammonium, calcium, magnesium, potassium and sodium salts. Pharmaceutically acceptable non-toxic organic bases from which salts can be derived include primary, secondary and tertiary amines, also cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, halamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

When the compound provided by the present invention is a base, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, isethionic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, Hydroiodic acid, perchloric acid, hydrochloric acid, isethionic acid, propionic acid, glycolic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid , succinic acid, sulfuric acid, 2-naphthalenesulfonic acid, cyclamic acid, salicylic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid, etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.

Since the compound shown in formula (I) will be used as a medicine, preferably, a certain purity is used, for example, at least 60% purity, more suitable purity is at least 75%, particularly suitable purity is at least 98% (% is weight) Compare).

The prodrugs of the compounds of the present invention are included in the protection scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted in vivo into the desired compound. For example, any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application, which can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite or Residues. Particularly preferred derivatives or prodrugs are those compounds which, when administered to a patient, increase the bioavailability of the compounds of the present application (e.g., allow an orally administered compound to be more readily absorbed into the blood), or promote the delivery of the parent compound to a biological organ or Those compounds delivered at a site of action such as the brain or lymphatic system. Therefore, the term "administering" in the treatment methods provided by the present invention refers to the administration of the compounds disclosed in the present invention that can treat different diseases, or the compounds disclosed in the present invention, although not explicitly disclosed, can be converted into compounds disclosed in the present invention after administration to the subject. compounds of compounds. Routine methods for selecting and preparing suitable prodrug derivatives are described, for example, in such books as Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

Clearly, any substituent or variable at a particular position in a molecule is defined independently of other positions in the molecule. It is easy to understand that those skilled in the art can select the substituents or substitution forms of the compounds in the present invention by means of the prior art and the methods described in the present invention, so as to obtain chemically stable and easy-to-synthesize compounds.

The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and optical isomers. The present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.

The above formula (I) does not exactly define the three-dimensional structure of a certain position of the compound. The present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. During the synthesis of such compounds, or using racemization or epimerization procedures well known to those skilled in the art, the products obtained may be mixtures of stereoisomers.

When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and their mixtures.

When the compound represented by formula (I) and its pharmaceutically acceptable salts have solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent forming a solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.

The term "composition", in the present invention, is meant to include products comprising the specified amounts of each of the specified ingredients, as well as any product produced directly or indirectly from the combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients as well as processes for the preparation of the compounds of the invention are also part of the invention. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of the present invention.

The pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories. Although the most suitable mode of administration of the active ingredient in any given case depends on the particular subject to be administered, the nature of the subject and the severity of the condition, the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration). The pharmaceutical compositions of the present invention may conveniently be presented in unit dosage forms and prepared by any methods of preparation well known in the art of pharmacy.

In fact, according to conventional drug mixing techniques, the compound represented by formula (I) of the present invention, or drug prodrug, or metabolite, or pharmaceutically acceptable salt, can be used as an active component, mixed with a drug carrier to form a drug combination things. The pharmaceutical carrier can take a wide variety of forms depending on the mode of administration desired, for example, oral or parenteral (including intravenous). Accordingly, the pharmaceutical compositions of the present invention may be presented as discrete units suitable for oral administration such as capsules, cachets or tablets containing predetermined doses of the active ingredient. Furthermore, the pharmaceutical composition of the present invention may be in the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition, in addition to the common dosage forms mentioned above, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by controlled release and/or delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. In general, such methods include a step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions are prepared by uniform and intimate admixture of the active ingredient with liquid carriers or finely divided solid carriers or a mixture of both. In addition, the product can be easily prepared to a desired appearance.

Therefore, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and the compound shown in formula (I) or its stereoisomer, tautomer, polymorph, solvate, its pharmaceutically acceptable Salts, their prodrugs. The combination of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and one or more other therapeutically active compounds is also included in the pharmaceutical composition of the present invention.

The pharmaceutical carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gaseous carrier. Solid carriers include, but are not limited to, lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid. Liquid carriers include, but are not limited to, syrup, peanut oil, olive oil and water. Gas carriers include, but are not limited to, carbon dioxide and nitrogen. For the preparation of pharmaceutical oral preparations, any pharmaceutically convenient medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. can be used in oral liquid preparations such as suspensions, elixirs, and solutions; and carriers, such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like can be used in oral solid preparations such as powders, capsules and tablets. Considering ease of administration, tablets and capsules are preferred for oral formulations, where solid pharmaceutical carriers are used. Alternatively, tablets may be coated using standard aqueous or non-aqueous formulation techniques.

Tablets containing a compound of this invention or a pharmaceutical composition may be formed by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be obtained by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be obtained by moistening the powdered compound or pharmaceutical composition with an inert liquid diluent and then molding in a suitable machine. Preferably, each tablet contains about 0.05 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of active ingredient. For example, formulations intended for oral administration to humans contain from about 0.5 mg to about 5 g of the active ingredient compounded with suitable and conveniently measured auxiliary materials comprising from about 5% to about 95% of the total pharmaceutical composition. Unit dosage forms generally contain from about 1 mg to about 2 g of active ingredient, typically 2 mg, 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared by adding the active component into water to prepare an aqueous solution or suspension. Suitable surfactants such as hydroxypropylcellulose may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, preservatives may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.

The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems. Furthermore, the above pharmaceutical composition can be prepared in the form of sterile powder for immediate preparation of sterile injection or dispersion. In any event, the final injectable form must be sterile and, for easy syringability, must be fluid. Furthermore, the pharmaceutical composition must be stable during manufacture and storage. Thus, preferably, the pharmaceutical composition is preserved against contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, cream, ointment, lotion, dusting powder or other similar dosage forms. Furthermore, the pharmaceutical composition provided by the present invention can be in a form suitable for use in transdermal drug delivery devices. These preparations can be prepared by using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, by conventional processing methods. As an example, a cream or ointment is prepared with the desired consistency by adding about 5% to 10% by weight of the hydrophilic material and water.

The pharmaceutical composition provided by the invention may be in a form suitable for rectal administration with solid as carrier. Unit dose suppositories are the most typical dosage form. Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories are conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, followed by cooling and moulding.

In addition to the adjuvant components mentioned above, the formulation of the above preparation may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, Thickeners, lubricants and preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that adjust the isotonic pressure between the drug and the blood. The pharmaceutical composition comprising the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, can be prepared in the form of powder or concentrated solution.

Generally, for the treatment of the conditions or disorders indicated above, the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per day per patient. For example, inflammation, cancer, psoriasis, allergies/asthma, disorders and disorders of the immune system, disorders and disorders of the central nervous system (CNS), effective treatment at dosage levels of 0.01 mg/kg body weight to 50 mg/kg body weight per day, or 0.5mg to 3.5g per patient per day.

However, it will be appreciated that lower or higher dosages than those recited above may be required. The specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combinations condition and the severity of the particular disease being treated.

Detailed ways

In order to make the above content more clear and definite, the present invention will use the following examples to further illustrate the technical solution of the present invention. The following examples are only used to illustrate specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the protection scope of the present invention. In the specific implementation of the present invention, technical means or methods that are not specifically described are conventional technical means or methods in the art.

Unless otherwise indicated, all parts and percentages herein are by weight and all temperatures are in degrees Celsius.

The following abbreviations are used in the examples:

DHP: 3,4-dihydro-2H-pyran;

PTSA: p-toluenesulfonic acid;

DCM: dichloromethane;

n-BuLi (2.5M in hexane): n-butyllithium (2.5mol/L n-hexane solution);

HCl (4M in dioxane): hydrochloric acid (1,4-dioxane solution of 4mol/L);

EA: ethyl acetate;

K ₂ CO ₃ : potassium carbonate;

_CH3CN /ACN: acetonitrile;

TFA: trifluoroacetic acid;

Toluene: toluene;

BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine;

Pd ₂ (dba) ₃ : Tris(dibenzylideneacetone)dipalladium;

t-BuONa: sodium tert-butoxide;

DIEA/DIPEA: N,N-Diisopropylethylamine;

DMF: N,N-dimethylformamide;

THF: Tetrahydrofuran;

I ₂ : elemental iodine;

Na ₂ CO ₃ : sodium carbonate;

i-PrMgCl (2M in THF): isopropylmagnesium chloride (2mol/L tetrahydrofuran solution);

BrettPhos Pd G3: Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2' -amino-1,1'-biphenyl-2-yl)palladium(II);

NaH: sodium hydride;

TBDPSCl: tert-butyldiphenylchlorosilane;

_Tf2O : trifluoromethanesulfonic anhydride;

2,6-Lutidine: 2,6-Lutidine;

KI: potassium iodide;

Cs ₂ CO ₃ : cesium carbonate;

CbzCl: benzyl chloroformate;

Acetone: acetone;

Et ₃ N/TEA: Triethylamine;

TosCl: 4-toluenesulfonyl chloride;

Pd(OH) ₂ /C: carbon supported palladium hydroxide;

TBAF: Tetrabutylammonium fluoride;

HOAc: glacial acetic acid;

LC-MS or LCMS: Liquid Chromatography-Mass Spectrometry.

Preparation of Intermediates 1-7

Step 1: Synthesis of Compound 1-2

Into a 500ml single-necked bottle, add compound 1-1 (24.00g, 1eq), DCM (200mL), DHP (15.21g, 1.5eq), PTSA (2.08g, 0.1eq). The reaction was stirred overnight at room temperature. After the reaction was completed, it was washed twice with saturated sodium bicarbonate solution, the organic phase was dried, concentrated, and purified by column chromatography (PE:EA=100:0-50:50) to obtain 33.12 g of compound 1-2.

LC-MS [M+H] ⁺ : 283.

Step 2: Synthesis of compounds 1-4

Into a 1000 mL three-necked flask, add compound 1-2 (23.5 g, 1 eq), THF (200 mL), protect with nitrogen, and cool down to -70°C. Add n-BuLi (2.5M in hexane) (50 mL, 1.5 eq) dropwise thereto, and stir at -70°C for 0.5 hours. A solution of 1-3 (29.54g, 1.5eq) dissolved in THF (200mL) was added dropwise thereto. During the dropwise addition, the internal temperature was controlled below -50°C. After the dropwise addition, the temperature was slowly raised to room temperature and stirred for 2 hours.

After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, concentrated, and purified by column chromatography (PE:EA=100:0-60:40) to obtain 26.80 g of compound 1-4.

LC-MS [M+H] ⁺ : 362.

Step 3: Synthesis of Compounds 1-5

Add compound 1-4 (10.00g, 1eq), EA (80mL), HCl (4M in dioxane, 35mL, 5eq) into a 500mL single-necked bottle, and stir the reaction at room temperature. After the reaction was completed, the reaction solution was filtered, and the filter cake was dried to obtain 5.83 g of compound 1-5.

LC-MS [M+H] ⁺ : 176.

Step 4: Synthesis of Compounds 1-7

In a 50ml single-necked bottle, compound 1-5 (0.500g, 1eq), compound 1-6 (0.786g, 1.2eq), anhydrous potassium carbonate (1.170g, 3eq) were dissolved in acetonitrile (10ml), oil bath The pot was heated to 70°C and stirred overnight. The reaction solution was filtered, the filter cake was rinsed with acetonitrile, the filtrate was collected and concentrated, the residue was dissolved in dichloromethane, washed twice with water, dried over anhydrous sodium sulfate, filtered, the filtrate was purified by column chromatography, and concentrated to obtain 0.600 g of compound 1- 7.

LC-MS [M+H] ⁺ : 258.

Embodiment 3: the preparation of compound 3

Step 1: Synthesis of compound 3-2

Compound 3-1 (16.00 g, 1 eq), H ₂ O (160 mL), Na ₂ CO ₃ (29.24 g, 3 eq), and I ₂ (12.84 g, 1.1 eq) were added to a 500 ml single-necked bottle. The reaction was stirred overnight at room temperature. After completion of the reaction, use 2mol/L HCl solution to adjust the pH of the reaction solution to 1-2. During the dropwise addition, a solid precipitates, stir for 0.5 hours, filter, wash the filter cake with water 2-3 times, collect the filter cake, and dry to obtain 15.70 gCompound 3-2.

LC-MS [M+H] ⁺ : 300/302.

Step 2: Synthesis of Compound 3-4

Into a 250ml single-necked bottle, add compound 3-2 (10.00g, 1eq), acetonitrile (50mL), K ₂ CO ₃ (13.83g, 3eq), compound 3-3 (7.63g, 1.5eq). The reaction was stirred at 85°C for 6 hours. After the reaction was completed, it was filtered, the filtrate was concentrated, and purified by column chromatography (PE:EA=100:0-70:30) to obtain 7.50 g of compound 3-4.

LC-MS [M+H] ⁺ : 350/352.

Step 3: Synthesis of Compound 3-5

Into a 50ml three-neck flask, add compound 3-4 (1.37g, 1eq), THF (14mL), protect with nitrogen, and cool down to 0°C. i-PrMgCl (2.0M in THF) (3.9mL, 2eq) was added dropwise thereto, and after the dropwise addition was completed, the reaction was stirred at 0°C for 1 hour. DMF (0.859g, 3eq) was added thereto, and after the addition was complete, the reaction was stirred at 0°C for 1 hour. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride, extracted with EA, the organic phase was concentrated, and purified by column chromatography (PE:EA=100:0-60:40) to obtain 0.25 g of compound 3-5.

LC-MS [M+H] ⁺ : 252/254.

Step 4: Synthesis of compounds 3-6

Add compound 3-5 (0.16g, 1eq), Toluene (5mL), compound 1-7 (0.16g, 1eq), TFA (0.22g, 3eq) into a 50ml single-necked bottle, and stir at 120°C for 2 hours. After the reaction was completed, EA was diluted, and the organic phase was washed with saturated sodium bicarbonate solution and concentrated to obtain 0.20 g of compound 3-6.

LC-MS [M+H] ⁺ : 493/495.

Step 5: Synthesis of compounds 3-8

Into a 100ml single-necked bottle, add compound 3-7 (2.00g, 1eq), CH ₃ CN (20mL), compound 1-14 (2.40g, 1.1eq), K ₂ CO ₃ (4.82g, 3eq), H ₂ O (5 mL). The reaction was stirred overnight at 70°C. After the reaction was completed, the reaction solution was concentrated, and the residue was extracted with DCM/H ₂ O. The organic phase was washed with water and concentrated to obtain 2.30 g of compound 3-8.

LC-MS [M+H] ⁺ : 233.

Step 6: Synthesis of Compound 3-9

Into a 250ml single-necked bottle, compound 3-8 (2.30g, 1eq), DCM (30mL), HCl (4M in dioxane) (30mL) were added. The reaction was stirred overnight at room temperature. After the reaction was completed, the filter cake was filtered and dried to obtain 1.60 g of compound 3-9.

LC-MS [M+H] ⁺ : 133.

Step 7: Synthesis of compound 3

To a 10ml one-port bottle, add compound 3-6 (0.15g, 1eq), compound 3-9 (125mg, 2eq), BrettPhos Pd G3 (69mg, 0.25eq), t-BuONa (293mg, 10eq), 1,4 -dioxane (5 mL). The temperature was raised to 70°C and the reaction was stirred for 4 hours. After the reaction was completed, it was concentrated and purified by high-pressure preparative liquid phase to obtain 9.4 mg of compound 3.

LC-MS [M+H] ⁺ : 545.

The preparation of embodiment 4 compound 4

Step 1: Synthesis of compound 4-3

In a 50ml single-necked bottle, add compound 4-1 (2.00g, 1eq), DMF (25mL), Cs ₂ CO ₃ (4.86g, 1.5eq), KI (0.20g, 0.12eq), compound 4-2 (2.94 g, 1.5eq), the temperature was raised to 75°C and the reaction was stirred overnight. After the reaction was completed, it was diluted with ethyl acetate, washed with water and saturated brine, the organic phase was dried, concentrated, and purified by column chromatography (PE:EA=100:0-80:20) to obtain 0.50 g of compound 4-3.

¹ H NMR (500MHz, DMSO-d6) δ10.22(s, 1H), 7.78(d, J=8.2Hz, 1H), 7.71-7.64(m, 2H), 7.45(t, J=72.9Hz, 1H ).

Step 2: Synthesis of compound 4-4

In a 50ml one-port bottle, dissolve compound 1-7 (0.200g, 1eq), compound 4-3 (0.390g, 1.2eq), TFA (0.266g, 3eq) in toluene (10ml), heat in an oil bath Raise the temperature to 120°C and stir overnight. The reaction solution was concentrated, the residue was dissolved in dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, dried, concentrated, and the residue was purified by column chromatography to obtain 0.230 g Compound 4-4.

LC-MS [M+H] ⁺ : 490.

Step 3: Synthesis of compounds 4-5

In a 50ml single-necked bottle, compound 4-4 (0.230g, 1eq), DHP (0.059g, 1.5eq), PTSA (0.004g, 0.05eq) were dissolved in DCM (5ml), and stirred overnight at room temperature. The reaction solution was washed twice with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by column chromatography to obtain 0.190 g of compound 4-5.

Step 4: Synthesis of compounds 4-6

To a 50ml one-port bottle, add compound 4-5 (190mg, 1eq), compound 3-9 (139mg, 2.5eq), BrettPhos Pd G3 (60mg, 0.2eq), t-BuONa (191mg, 6eq), 1,4 - Dioxane (5 mL), protected by nitrogen, heated to 70° C. and stirred for 2 hours. After the reaction was complete, add ethyl acetate and water, stir and separate the layers, extract the aqueous phase once with ethyl acetate, combine the organic phases, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM:MeOH =100:0-90:10), to obtain 100 mg of compound 4-6.

LC-MS [M+H] ⁺ : 626.

Step 5: Synthesis of Compound 4

Add compound 4-6 (100 mg, 1 eq), DCM (5 mL), TFA (1 mL) into a 50 mL single-necked bottle, and stir the reaction at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, the residue was dissolved in DCM, washed twice with saturated sodium bicarbonate, dried, concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH=100:0-90:10) to obtain 48 mg compound 4.

LC-MS [M+H] ⁺ : 542.

The preparation of embodiment 5 compound 5

According to the synthesis method similar to Example 4, just replace the raw material 4-3 with 5-1.

The preparation of embodiment 7 compound 7

Step 1: Synthesis of compound 7-2

Into a 250ml single-necked bottle, add compound 7-1 (2.00g, 1eq), CH ₃ CN (50mL), K ₂ CO ₃ (4.45g, 3eq), compound 1-14 (2.42g, 1.2eq). The reaction was stirred overnight at 70°C. After the reaction was completed, the reaction solution was concentrated, and the residue was layered with EA/H ₂ O. The organic phase was washed twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.48 g of compound 7-2.

LC-MS [M+H] ⁺ : 247.

Step 2: Synthesis of compound 7-3

Into a 250ml single-necked bottle, compound 7-2 (2.48g, 1eq), EA (30mL), 4M HCl/dioxane (30mL) were added. The reaction was stirred overnight at room temperature. After the reaction was completed, the filter cake was filtered and dried to obtain 1.91 g of compound 7-3 (hydrochloride).

LC-MS [M+H] ⁺ : 147.

Step 3: Synthesis of Compound 7

To a 50ml one-port bottle, add compound 3-6 (100mg, 1eq), compound 7-3 (92mg, 2.5eq), BrettPhos Pd G3 (37mg, 0.2eq), t-BuONa (117mg, 6eq), 1,4 - Dioxane (10 mL), protected by nitrogen, heated to 70° C. and stirred for 2 hours. After the reaction was complete, add ethyl acetate and water, stir and separate the layers, extract the aqueous phase once with ethyl acetate, combine the organic phases, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM:MeOH =100:0-90:10), to obtain 29 mg of compound 7.

LC-MS [M+H] ⁺ : 557.

According to above-mentioned similar method, use corresponding raw material, can synthesize embodiment 1-2, embodiment 6,

Embodiment 8-embodiment 11:

Embodiment 12: the preparation of compound 12

Step 1: Synthesis of compounds 1-9

In a 50ml single-necked bottle, dissolve compound 1-7 (0.600g, 1eq), compound 1-8 (0.886g, 2eq), TFA (0.5mL) in toluene (10ml), heat the oil bath to 120 °C and stirred overnight. The reaction solution was concentrated, the residue was dissolved in dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, dried, concentrated, and the residue was purified by column chromatography to obtain 0.580 g Compounds 1-9.

LC-MS [M+H] ⁺ : 492/494.

Step 2: Synthesis of Compounds 1-10

In a 50ml single-necked bottle, compound 1-9 (0.200g, 1eq), DHP (0.051g, 1.5eq), PTSA (0.0035g, 0.05eq) were dissolved in DCM (5ml), and stirred overnight at room temperature. The reaction solution was washed twice with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by column chromatography to obtain 0.170 g of compound 1-10.

LC-MS [M+H] ⁺ : 576/578.

Step 3: Synthesis of Compounds 1-12

In a 50ml one-port bottle, compound 1-10 (0.125g, 1eq), compound 1-11 (0.0559g, 1.5eq), Pd ₂ (dba) ₃ (0.0397g, 0.2eq), BINAP (0.027g, 0.2 eq), t-BuONa (0.062g, 3eq) was dissolved in toluene (5ml), heated to 100°C under nitrogen protection and stirred overnight. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EA=100:0-50:50) to obtain 0.140 g of compound 1-12.

LC-MS [M+H] ⁺ : 668.

Step 4: Synthesis of Compounds 1-13

Add compound 1-12 (0.140g, 1eq), DCM (5mL), TFA (5mL) into a 50mL single-necked bottle, and stir the reaction at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated to obtain 0.151 g of compound 1-13.

LC-MS [M+H] ⁺ : 484.

Step 5: Synthesis of compound 12

In a 50ml single-necked bottle, compound 1-13 (0.100g, 1eq), compound 1-14 (0.033g, 1.2eq) and DIPEA (0.057g, 3eq) were dissolved in DMF (5ml), and stirred overnight at room temperature. After the reaction was complete, the reaction solution was directly injected into a C18 reverse-phase column (water:acetonitrile=95:5-0:100) to obtain 20.6 mg of compound 12.

LC-MS [M+H] ⁺ : 544.

Embodiment 13: the preparation of compound 13

According to the synthesis method similar to Example 12, the raw materials 1-11 are replaced with 2-11.

According to the method similar to Example 12 and Example 13, using the corresponding raw materials, the Example Compound 14-16 can be synthesized:

Pharmacological experiment

Comparative example 1

The above compound was prepared according to Example 8 of WO2018077630A1.

Embodiment A: cell proliferation experiment

The cell titer-glo luminescent viability assay kit (Promega, Cat#G7573) was used to detect the inhibitory activity of the compound on the breast cancer cell line MCF7. Cells in the logarithmic growth phase were taken, digested with trypsin, seeded in a 96-well cell culture plate at a cell density of 2000/well, and incubated overnight in a humid incubator at 37°C and 5% CO ₂ . The next day, compounds were formulated in DMSO and serially diluted, and added to cells in a 96-well plate at the following final concentrations: 1000, 333, 111, 37, 12, 4.1, 1.4, 0.45, 0.15 nM. The same volume of DMSO was added to control wells as a solvent control. Cells were co-incubated with compounds for 5 days, and 50 μl of celltiter-glo working solution was added to each well at room temperature, and shaken for 10 minutes in the dark. Chemiluminescence signals were read using PerkinElmer EnVision. Use the nonlinear regression equation Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) of Graph Pad Prism 8.0 software to fit the half-maximum inhibitory concentration IC ₅₀ of cell growth inhibition, part of the examples The specific results are shown in Table 1.

Table 1

Example B: Target degradation experiment

In-Cell Western method was used to detect the degradation activity of the compounds on ER protein in MCF7 and T47D cells. Cells in the logarithmic growth phase were collected, digested with trypsin and collected, inoculated in a 384-well plate, and incubated overnight at 37°C and 5% CO ₂ . Serially dilute the compound with DMSO, and add 120nL/well compound solution (DMSO final concentration is 0.5%) to the orifice plate, so that the final concentration of the compound is 100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.001nM and incubated overnight. Cells were fixed, permeabilized and blocked after washing with PBS. Use ER rabbit primary antibody and GAPDH mouse primary antibody to incubate at room temperature, wash 3 times with PBST, incubate with goat anti-rabbit (800CW) and goat anti-mouse (680RD) fluorescent secondary antibodies at room temperature in the dark, and wash 3 times with PBST, After centrifuging at 1000rpm for 1min to discard the supernatant, read with Odyssey Clx, and use the nonlinear regression equation Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) to perform fitting to obtain IC ₅₀ , see Table 2 for the specific results of some embodiments.

Table 2

Embodiment C: rat pharmacokinetic test

Detection method: 6 male SD rats (150-300g). They were randomly divided into 2 groups with 3 rats in each group. Among the 6 rats of each group, 3 single intravenous injections of the embodiment compound of 1mg/kg, and the other 3 single oral administration of the embodiment compound of 10mg/kg, respectively in 5min (only for intravenous administration) , 15min, 30min, 1h, 2h, 4h, 7h, 24h, blood was collected through the orbital venous plexus, centrifuged and the plasma was separated, and stored in a -80°C refrigerator for later use.

After the above plasma sample was precipitated with acetonitrile, the supernatant was taken and mixed with water 1:1, and 10 μL was taken for LC-MS/MS detection. The limit of quantification of the standard curve of the compound in SD rat plasma was 1.00- 1000ng/mL. The test data results are shown in Table 3:

table 3

Embodiment D: mouse pharmacokinetic test

Mouse PK studies (PO 5 mg/kg) were performed using female BALB/c mice (20-30 g) purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. For an oral (PO) dose of 5 mg/kg, the compound concentration is 0.5 mg/mL, ready to use. Oral administration was performed by oral gavage at 10 mL/kg. Blood was collected through the orbital venous plexus of mice, and 100 μL of whole blood was put into K2 _- EDTA tubes at each time point. The blood collection time was 30min, 1h, 2h, 4h, 7h and 24h. The collected whole blood samples were centrifuged to separate the plasma, and stored in a -80°C refrigerator for later use.

After the above plasma samples were precipitated with acetonitrile, the supernatant was taken and mixed with water 1:1, and 10 μL was taken for detection by LC-MS/MS. The limit of quantification of the standard curve of the compound in the plasma of BALB/c mice was 1.00-1000 ng/mL. The test data results are shown in Table 4:

Table 4

While the invention has been fully described by way of the embodiments thereof, it is to be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should all be included within the scope of the appended claims of the present invention.

Claims (24)

A compound as shown in formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt: in, Ring A is selected from D is CR ₉ or N; E is CR ₁₀ or N; R ₁ is selected from H, F, Cl, Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ OP(O)(OH) ₂ , -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHSO ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ N( CH ₃ ) ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH(CH ₃ )CN, -C(CH ₃ ) ₂ CN, -CH ₂ CN, -CO ₂ H, -COCH _3. -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CONHCH ₂ CH ₃ , -CONHCH(CH ₃ ) ₂ , -CON (CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , -NO ₂ , =O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OP(O)(OH) ₂ , -S(O) ₂ N(CH ₃ ) ₂ , -SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₂ OH, cyclopropyl, cyclopropylamido, cyclobutyl, oxetanyl, nitrogen Hetidine, (1-methylazetidin-3-yl)oxy, N-methyl-N-oxetane-3-ylamino, azetidin-1- Cylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanonyl, piperazin-1-yl, morpholinomethyl, morpholino-methanonyl and Morpholino; R ₂ is selected from H, C ₁ -C ₉ alkyl, C ₃ -C ₉ cycloalkyl, C ₃ -C ₉ heterocyclyl, C ₆ -C ₁₀ aryl, C ₅ -C ₁₀ heteroaryl, - (C ₁ -C ₆ alkylene)-(C ₃ -C ₉ cycloalkyl), -(C ₁ -C ₆ alkylene)-(C ₃ -C ₉ heterocyclyl), C(O)R _b , C(O)N(R _a ) ₂ , SO ₂ R _a and SO ₂ N(R _a ) ₂ , the C ₁ -C ₉ alkyl, C ₃ -C ₉ cycloalkyl, C ₃ -C ₉ heterocyclyl, C ₆ -C ₁₀ aryl, C ₅ -C ₁₀ heteroaryl, -(C ₁ -C ₆ alkylene) -(C ₃ -C ₉ cycloalkyl), -(C ₁ - C ₆ alkylene)-(C ₃ -C ₉ heterocyclyl) optionally substituted with one or more of F, Cl, Br, I, CN, OR _a , N(R _a ) ₂ , C ₁ -C ₉ Alkyl, C ₃ -C ₉ cycloalkyl, C ₃ -C ₉ heterocyclyl, C ₆ -C ₁₀ aryl, C ₅ -C ₁₀ heteroaryl, C(O)R _b , C(O)N (R _a ) ₂ , SO ₂ R _a and SO ₂ N(R _a ) ₂ ; R ₅ are each the same or different, each independently selected from H, F, Cl, Br, I, alkyl, haloalkyl, alkoxy, haloalkoxy, -CN, -NH ₂ , -NO ₂ , -COOH , -CHO, -OH, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally each independently is selected from alkyl, F, Cl, Br, I, -CN, -NH ₂ , -NO ₂ , -OH, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl One or more substituents in radical and heteroaryl; R ₇ is H, F, Cl, Br, I, OH or NH ₂ ; _R8 is F or CN; R ₉ is H, Cl, F, halogenated C ₁ -C ₆ alkoxy; R ₁₀ is H, Cl, F, halogenated C ₁ -C ₆ alkoxy; R _a is selected from H, C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, propargyl, C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ heterocyclyl, the C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, propargyl, C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ heterocyclyl are optionally substituted with one or more groups independently selected from the following groups: F , Cl, Br, I, CN, OH, OCH ₃ and SO ₂ CH ₃ ; R _b is selected from H, -O(C ₁ -C ₃ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, propargyl, -(C ₁ -C ₆ alkylene)- (C ₃ -C ₆ cycloalkyl), C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ heterocyclyl, the -O(C ₁ -C ₃ alkyl), C ₁ -C ₆ alkyl , C ₂ -C ₈ alkenyl, propargyl, -(C ₁ -C ₆ alkylene)-(C ₃ -C ₆ cycloalkyl), C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ Heterocyclyl is optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -OH, -OCH ₃ , and -SO ₂ CH ₃ ; m is 0, 1, 2, 3 or 4; p is 1, 2 or 3. The compound according to claim 1, characterized in that, the compound shown in formula (I) is further the compound shown in formula (Ib): in, D is CR ₉ or N; E is CR ₁₀ or N; R ₇ is H, F, Cl, Br, I, OH or NH ₂ ; _R8 is F or CN; R ₉ is H, Cl, F, or halogenated C ₁ -C ₆ alkoxy; R ₁₀ is H, Cl, F, or halogenated C ₁ -C ₆ alkoxy; When R ₈ is F, R ₉ and R ₁₀ are not H or F at the same time; When D is N, E is CR ₁₀ and R ₈ is F, R ₁₀ is not H or F; or when E is N, D is CR ₉ and R ₈ is F, R ₉ is not H or F; R ₁₁ is Me, F or CH ₂ F; _R12 is Me, F, _CH2F , _CHF2 , _CF3 , _CH2OMe or _CH2OH ; R ₁₃ is H or F; or R ₁₂ and R ₁₃ together with the carbon atoms to which they are attached form a cyclopropyl ring, cyclobutyl ring or oxetane ring; p is 1, 2 or 3. The compound according to claim 2, characterized in that the compound represented by formula (I) is further a compound represented by formula (Ic) or formula (Id): The compound according to any one of claims 1-3, wherein D is CR ₉ , and E is CR ₁₀ . The compound according to any one of claims 1-4, wherein D is CR ₉ and E is N; or D is N and E is CR ₁₀ . The compound according to any one of claims 1-5, wherein R ₉ is Cl; or R ₁₀ is Cl. The compound according to any one of claims 1-5, wherein R ₉ is H; or R ₁₀ is H. The compound according to any one of claims 1-5, wherein R ₉ is F; or R ₁₀ is F. The compound according to any one of claims 1-5, characterized in that, R ₉ is -OCHF ₂ or -OCHF ₃ ; or R ₁₀ is -OCHF ₂ or -OCHF ₃ . The compound according to any one of claims 1-5, wherein R ₉ is Cl and R ₁₀ is Cl. The compound according to any one of claims 2-5, wherein R ₁₁ is F. The compound according to any one of claims 2-5, wherein R ₁₂ is F or CH ₂ OH. The compound according to any one of claims 2-5, wherein R ₁₃ is F. The compound according to any one of claims 1-5, wherein R ₈ is F. The compound according to any one of claims 1-5, wherein R ₇ is H or OH. The compound according to any one of claims 1-5, wherein R ₇ is H. The compound according to any one of claims 1-5, wherein p is 1. The compound according to any one of claims 1-5, wherein p is 2. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein the compound represented by the formula (I) is selected from: 5-(difluoromethoxy)-N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-( 2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine; N-(3-(difluoromethoxy)-4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9- Tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine; 1-(3-fluoropropyl)-N-(4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9- Tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)-3-(trifluoromethoxy)phenyl)azetidin-3-amine; 5-(Difluoromethoxy)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((6S,8R)-8-methyl-7- (2,2,2-Trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine; 5-(Difluoromethoxy)-N-((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((6S,8R)-8-methyl-7- (2,2,2-Trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine; (3R,4R)-4-((5-(Difluoromethoxy)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6 ,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-yl)amino)-1-(3-fluoropropyl)pyrrolidine -3-ol; N-(3-(difluoromethoxy)-5-fluoro-4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7, 8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine; 3-((6S,8R)-6-(2-(difluoromethoxy)-6-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino )Phenyl)-8-methyl-3,6,8,9-tetrahydro-7H-pyrazolo[4,3-f]isoquinolin-7-yl)-2,2-difluoropropane- 1-alcohol; 3-((6S,8R)-6-(3-(Difluoromethoxy)-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridine-2 -yl)-8-methyl-3,6,8,9-tetrahydro-7H-pyrazolo[4,3-f]isoquinolin-7-yl)-2,2-difluoropropane-1 -alcohol; 3-((6S,8R)-6-(2-(difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl) -8-methyl-3,6,8,9-tetrahydro-7H-pyrazolo[4,3-f]isoquinolin-7-yl)-2,2-difluoropropan-1-ol; N-(3,5-dichloro-4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro- 3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine; (S)-N-(3,5-dichloro-4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9 -tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine; (3R,4R)-4-((3,5-dichloro-4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7, 8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol; (R)-N-(3,5-dichloro-4-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9 -tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine; or 3-((6S,8R)-6-(2,6-dichloro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-8- Methyl-3,6,8,9-tetrahydro-7H-pyrazolo[4,3-f]isoquinolin-7-yl)-2,2-difluoropropan-1-ol. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-19 and at least one pharmaceutically acceptable Accepted excipients. Use of the compound according to any one of claims 1-19 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20 in the preparation of a medicament for treating estrogen receptor-related diseases. The use according to claim 21, wherein the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer and uterine cancer. A method for treating estrogen receptor-related diseases in a patient, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof Or the pharmaceutical composition described in claim 20. The method according to claim 23, wherein the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer and uterine cancer.