Heterocyclic compound of bifunctional chimera for targeted degradation of androgen receptor and use thereof

Abstract

Provided are a heterocyclic compound of a bifunctional chimera for targeted degradation of an androgen receptor, and a use thereof. Specifically provided are a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a use thereof in treating diseases related to androgen receptors. The described compound can target and degrade androgen receptors in prostate cancer cells and inhibit the proliferation of prostate cancer cells, while also showing good metabolic stability and pharmacokinetic properties.

Description

A bifunctional chimeric heterocyclic compound for targeting degradation of androgen receptor and its use Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs, as well as the use of such compounds as androgen receptor (AR) degraders. Background Art

[0002] The androgen receptor (AR) is a nuclear hormone receptor structurally divided into an N-terminal activation domain (NTD), a DNA-binding domain (DBD), and a ligand-binding domain (LTD). It regulates the expression of genes that drive prostate cancer, making AR inhibition an effective treatment for prostate cancer. Currently available AR inhibitors, such as enzalutamide and bicalutamide, primarily exert their inhibitory effects by interacting with the AR ligand-binding domain (LTD). However, some patients develop resistance to AR during treatment due to AR splice variants (AR-Vs) lacking the LTD. Preclinical studies have shown that AR splice variants can accelerate the progression of enzalutamide-resistant prostate cancer, making addressing AR resistance a key clinical concern. Furthermore, a growing body of research suggests that AR plays a crucial role in hormone-related diseases such as alopecia, acne, and benign prostatic hyperplasia (BPH).

[0003] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. Such compounds can be recognized by the cell's proteasome, causing the degradation of the target protein, and can effectively reduce the content of the target protein in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology can be applied to the treatment of various diseases. This technology has also received widespread attention in recent years. Arvinas has developed an AR protein degrader ARV-110 for the treatment of metastatic castration-resistant prostate cancer (mCRPC). It is currently in the second phase of clinical research and development, and the latest clinical data show good efficacy and safety.

[0004] Currently, approved anti-androgen receptor drugs on the market include enzalutamide, bicalutamide, and apalutamide. However, approximately 15% to 25% of prostate cancer patients do not respond to anti-androgen drugs, and approved drugs show excellent anti-cancer effects in the initial stage of administration, but continuous use will produce drug resistance, making them difficult to use again. Therefore, it is necessary to develop new targeted androgen receptor degraders for the treatment of diseases mediated by androgen receptors. Summary of the Invention

[0005] The present invention provides a novel compound with excellent efficacy, high bioavailability, and enhanced safety that inhibits and degrades the androgen receptor for use in treating androgen receptor-mediated diseases such as cancer, inflammatory diseases, or autoimmune diseases. The compound of the present invention exhibits excellent androgen receptor inhibition and / or degradation activity, good pharmacokinetic properties and bioavailability, oral administration, and a good safety profile. Therefore, the compound of the present invention has promising clinical application prospects.

[0006] In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I).

[0007] in:

[0008] ARB is the androgen receptor recognition / binding part, L is the linker part, and U is the ubiquitin protease recognition / binding part; these three parts are connected by chemical bonds;

[0009] The ARB is

[0010] Ring A is C 3-8 Cycloalkyl, heterocyclic group composed of 3-8 atoms, C 6-10 Aryl or heteroaryl composed of 5-12 atoms, wherein the C 3-8 Cycloalkyl, heterocyclic group composed of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent;

[0011] Ring B is C 6-10Aryl or heteroaryl composed of 5-12 atoms, wherein the C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent;

[0012] R 1a 、R 1b 、R 1c 、R 1d and R 1e Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, heterocyclic group composed of 3-8 atoms, C 6-10 Aryl or heteroaryl composed of 5-12 atoms, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, heterocyclic group composed of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 is substituted with a haloalkoxy substituent; or

[0013] R 1a 、R 1b and the carbon atoms to which they are attached, or R 1e 、R 1d Together with the carbon atom to which they are attached, they form C 3-8 A carbocyclic group, a heterocyclic group consisting of 3 to 8 atoms, or a heteroaryl group consisting of 5 to 10 atoms, wherein the C 3-8The carbocyclyl, heterocyclyl of 3-8 atoms and heteroaryl of 5-10 atoms optionally contain 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur or nitrogen, and are optionally substituted by 1, 2, 3 or 4 heteroatoms independently selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent;

[0014] L is wherein ring C and ring D are each independently a heterocyclic group consisting of 3 to 8 atoms, 6-10 Aryl or heteroaryl composed of 5-12 atoms, the heterocyclic group composed of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 is substituted by a haloalkoxy substituent; or D is absent;

[0015] L 1 For bonds, -O-, -S-, -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, -(CR a R b ) n -、-O-(CR a R b ) n -、-(CR a R b ) n -O-, -NR c -(CR a R b ) n -or-(CR a R b ) n -NR c -;

[0016] R a and R b Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy or C 1-6 haloalkoxy;

[0017] R c H, D, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0018] U is selected Its dotted lines represent single or double bonds;

[0019] R 2 and R 3 For H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0020] R 4a and R 4b Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0021] R 5a 、R 5b and R 5c Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or heterocyclic group consisting of 3-8 atoms, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Alkoxy, C 3-8 The cycloalkyl and the heterocyclic group consisting of 3-8 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent;

[0022] R 6 、R 7 、R 8 and R 9 Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0023] n is 1, 2, 3, 4, or 5;

[0024] p is 1, 2, 3, 4, or 5;

[0025] q is 1, 2, 3, 4, or 5;

[0026] t is 1, 2, 3, 4, or 5;

[0027] u is 1, 2, 3, 4, or 5;

[0028] Wherein, the compound represented by the formula (I) does not include the following compounds:

[0029] In some embodiments, L is a substructure of one of the following: wherein the substructures are each independently optionally replaced by 1, 2, 3, 4 or 5 selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 The left and right connection sites on the substructure of L can be connected to the ARB part or the U part in formula (I) respectively.

[0030] In some embodiments, ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl , naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3;

[0031] Ring B is phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein said phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3.

[0032] In some embodiments, R 1a 、R 1b 、R 1c 、R 1d and R 1e Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, C 6-10 Aryl or heteroaryl composed of 5-10 atoms, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 substituted by a haloalkoxy substituent;

[0033] R 1a 、R 1b and the carbon atoms to which they are attached, or R 1e 、R 1d Together with the carbon atoms to which they are attached, they form C 3-6 A carbocyclic group, a heterocyclic group consisting of 3 to 6 atoms, or a heteroaryl group consisting of 5 to 6 atoms, wherein the C 3-6 The carbocyclyl, heterocyclyl of 3-6 atoms and heteroaryl of 5-6 atoms optionally contain 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur or nitrogen, and are optionally substituted by 1, 2, 3 or 4 heteroatoms independently selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 The alkyl group is substituted with a haloalkoxy substituent.

[0034] In some embodiments, R 4a and R 4b Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

[0035] R 5a 、R 5b and R 5cEach independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl or heterocyclic group consisting of 3-6 atoms, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and the heterocyclic group consisting of 3-6 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 The alkyl group is substituted with a haloalkoxy substituent.

[0036] In some embodiments, R 2 and R 3 Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

[0037] R 6 、R 7 、R 8 and R 9 Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy.

[0038] In some embodiments, R 1a 、R 1b 、R 1c 、R1d and R 1e Each is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine alkyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl , propargyl, propynyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, 1,2,4-oxadiazole, 1,3 , 4-oxadiazole, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3;

[0039] R 1a 、R 1b and the carbon atoms to which they are attached, or R 1e 、R 1dand together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropene, cyclobutene, cyclopentene, cyclohexene, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropene, cyclobutene, cyclopentene, cyclohexene, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. and pyridazinyl, optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, F, Cl, Br, I, -NO, -CN, -OH, -NH, methyl, ethyl, n-propyl, isopropyl, -CHF, -CF, -CHCF, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF and -OCF.

[0040] In some embodiments, R 4a and R 4b Each is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 or -OCF3;

[0041] R 5a 、R 5b and R 5cEach is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl , propargyl, propynyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3.

[0042] In some embodiments, R 2 and R 3 Each is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 or -OCF3;

[0043] R 6 、R 7 、R 8 and R 9 Each is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 or -OCF3.

[0044] In some embodiments, the present invention relates to a compound represented by formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII).

[0045] Among them, R 1a 、R 1b 、R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 、R 2 、R 3 、R 4a 、R 4b 、R 5a 、R 5b 、R 5c 、R 6 、R 7 、R 8 、R 9 , p, q, t and u each independently have the meanings as described in the present invention.

[0046] On the other hand, the present invention relates to a pharmaceutical composition comprising a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII) disclosed in the present invention.

[0047] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

[0048] In another aspect, the present invention relates to the use of the compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII) disclosed in the present invention or a pharmaceutical composition thereof in the preparation of a medicament for preventing, treating or alleviating diseases mediated by androgen receptors.

[0049] In some embodiments, the androgen receptor-mediated disease is cancer, acne, hirsutism, sebaceous gland enlargement, alopecia, or Kennedy's disease.

[0050] In other embodiments, the cancer is prostate cancer, breast cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, or melanoma.

[0051] On the other hand, the present invention relates to methods for preparing, isolating and purifying compounds represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII).

[0052] Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as they do not conflict.

[0053] The foregoing description only summarizes certain aspects of the present invention, but is not intended to be limiting. These and other aspects will be described in more detail and fully below. All references in this specification are incorporated herein by reference in their entirety. In the event of a discrepancy between the disclosure of this specification and a reference, the disclosure of this specification shall prevail.

[0054] Detailed description of the present invention

[0055] Definitions and General Terms

[0056] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0057] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0058] Unless otherwise indicated, the following definitions used in the present invention shall apply. For purposes of the present invention, chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0059] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiment.

[0060] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0061] The term "chiral molecule" refers to a molecule that is non-superimposable on its mirror image; whereas "achiral molecule" refers to a molecule that is superimposable on its mirror image.

[0062] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0063] The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers, which mixture lacks optical activity.

[0064] The term "diastereoisomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0065] The stereochemical definitions and conventions used herein generally follow those of SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0066] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0067] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, such as a racemate or a mixture of diastereoisomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0068] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0069] Any racemate of the resulting final product or intermediate can be separated into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separating the diastereomeric salts obtained. The racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed.Robert E.Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0070] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization.

[0071] "Pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0072] The term "optionally substituted with" can be used interchangeably with the term "unsubstituted or substituted with," meaning that the structure is unsubstituted or substituted with one or more substituents described herein, including, but not limited to, D, F, Cl, Br, I, N3, -CN, -NO2, -NH2, -OH, -SH, -COOH, -CONH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-alkyl, -C(=O)-alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, hydroxyalkyl, cyanoalkyl, aminoalkyl, (alkoxy)-alkylene, (alkylamino)-alkylene, (cycloalkyl)-alkylene, (heterocyclyl)-alkylene, (aryl)-alkylene, (heteroaryl)-alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

[0073] In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a specified substituent. Unless otherwise indicated, a substituent may be substituted at every possible position in the group. When more than one position in a given structure can be substituted with one or more of the specified substituents, the substituents may be the same or different at every possible position in the structure.

[0074] In addition, it should be noted that, unless otherwise explicitly stated, the description methods used in the present invention such as "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0075] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers, for example, to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0076] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0077] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0078] Throughout this specification, substituents of the compounds disclosed herein are disclosed by group class or range. It is specifically noted that the present invention includes each independent subcombination of the individual members of these group classes and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0079] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0080] The term "D" refers to a single deuterium atom.

[0081] The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0082] The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salts; or the hydrogen on the nitrogen atom in the heterocyclic ring is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR' (such as NR' in N-substituted pyrrolidinyl, R' is a substituent described in the present invention).

[0083] As used herein, the term "alkyl" or "alkyl group" refers to a saturated, linear or branched, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 6 carbon atoms; in other embodiments, the alkyl group contains 1 to 4 carbon atoms; and in still other embodiments, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), and the like.

[0084] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp 2Double bond, wherein the alkenyl group can be optionally substituted with one or more substituents described herein, including "cis" and "trans" orientations, or "E" and "Z" orientations. In some embodiments, the alkenyl group contains 2-8 carbon atoms; in other embodiments, the alkenyl group contains 2-6 carbon atoms; in yet other embodiments, the alkenyl group contains 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), 1-propenyl (i.e., propenyl, -CH=CH-CH3), and the like.

[0085] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing 2-12 carbon atoms, wherein at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, is present, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms; in yet other embodiments, the alkynyl group contains 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (i.e., propynyl, -C≡C-CH3), and the like.

[0086] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; and in yet other embodiments, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein.

[0087] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), and the like.

[0088] The term "haloalkyl" means an alkyl group substituted by one or more halogen atoms, wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CHFCH3, -CH2CH2F, -CF2CH3, -CH2CF2CHF2, etc. In some embodiments, C1-C6 haloalkyl includes fluorine-substituted C1-C6 alkyl; in other embodiments, C1-C4 haloalkyl includes fluorine-substituted C1-C4 alkyl; in yet other embodiments, C1-C2 haloalkyl includes fluorine-substituted C1-C2 alkyl.

[0089] The term "haloalkoxy" means an alkoxy group substituted by one or more halogen atoms, wherein the alkoxy group has the meaning as described herein, such examples include, but are not limited to, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCHFCH3, -OCH2CH2F, -OCF2CH3, -OCH2CF2CHF2, etc. In some embodiments, C1-C6 haloalkoxy includes fluorine-substituted C1-C6 alkoxy; in other embodiments, C1-C4 haloalkoxy includes fluorine-substituted C1-C4 alkoxy; in yet other embodiments, C1-C2 haloalkoxy includes fluorine-substituted C1-C2 alkoxy.

[0090] The term "jk atoms" or "jk-membered" means that the cyclic group is composed of jk ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P; j and k are each independently any non-zero natural number, and k>j; "jk" includes j, k, and any natural number in between. For example, "3-8 atoms" or "3-8-membered", "3-6 atoms" or "3-6-membered", "5-10 atoms" or "5-10-membered", "5-6 atoms" or "5-6-membered" means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7, or 8), 3-6 (i.e., 3, 4, 5, or 6), 5-10 (i.e., 5, 6, 7, 8, 9, or 10), or 5-6 (i.e., 5 or 6) ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P. For another example, piperidinyl is a 6-atom heterocyclic group or a 6-membered heterocyclic group, while pyridinyl is a 6-atom heteroaryl group or a 6-membered heteroaryl group.

[0091] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. The bicyclic or tricyclic ring system may include fused rings, bridged rings and spiro rings. In some embodiments, the cycloalkyl group contains 3 to 10 carbon atoms, such as C3- C 10 In some embodiments, the cycloalkyl group contains 3-8 carbon atoms, such as C3-C8 cycloalkyl; in some other embodiments, the cycloalkyl group contains 3-6 carbon atoms, such as C3-C6 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. 3- C8 cycloalkyl includes C3-C6 cycloalkyl; the C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group is optionally substituted with one or more substituents described herein.

[0092] The term "carbocyclyl" or "carbocycle" refers to a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbobicyclic groups, fused carbobicyclic groups and bridged carbobicyclic groups. Suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclopropene, cyclobutyl, cyclobutene, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.

[0093] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein the bicyclic or tricyclic ring system may include fused, bridged and spiro rings, wherein one or more ring atoms are independently replaced by a heteroatom, wherein the heteroatom has the meaning as described herein. In some embodiments, the heterocyclyl group is a monocyclic heterocyclyl group consisting of 3-8 ring atoms (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S, wherein S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, and PO2); in other embodiments, the heterocyclyl group is a monocyclic heterocyclyl group consisting of 3-6 ring atoms (2-5 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S, wherein S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, and PO2); in other embodiments, the heterocyclyl group is a bicyclic heterocyclyl group consisting of 7-12 ring atoms (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S, wherein S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, and PO2). The heterocyclyl group is optionally substituted with one or more substituents described herein.

[0094] The ring atoms of the heterocyclic group can be carbon groups or heteroatom groups. In this case, the -CH2- group of the ring is optionally replaced by -C(=O)-, the sulfur atom of the ring is optionally oxidized to S-oxide, and the nitrogen atom of the ring is optionally oxidized to N-oxygen compound. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Base, thiazolin Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like. The heterocyclic group is optionally substituted with one or more substituents described herein.

[0095] The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic and each ring system comprises a ring composed of 3-7 atoms. Aryl groups are typically, but not necessarily, attached to the parent molecule via the aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups can include phenyl, indenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents as described herein.

[0096] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring consisting of 5-7 atoms. The heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring", "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, the 5-10 atom heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

[0097] Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, yl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl , 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also include the following bicyclic rings, but are by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0098] As described in the present invention, the substructure of the group L has two connection sites that can be connected to the rest of the molecule, and the connection methods of the two connection sites can be interchanged. For example, when the linker part L is When, the general formula (I) of the present invention represents that the mm linker on L is connected to the androgen receptor recognition / binding portion ARB, and the other nn linker is connected to the ubiquitin protease recognition / binding portion U, as shown in formula a; or represents that the mm linker on X is connected to the ubiquitin protease recognition / binding portion U, and the other nn linker is connected to the androgen receptor recognition / binding portion ARB, as shown in formula b.

[0099] The term "protecting group" or "PG" refers to a substituent that is attached to an amino group to block or protect a specific functionality, typically when reacting with another functional group. For example, an "amino-protecting group" refers to a substituent attached to an amino group to block or protect the amino functionality in a compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz), and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent attached to a hydroxy group to block or protect the hydroxy functionality. Suitable protecting groups include trialkylsilyl, acetyl, benzoyl, and benzyl. "Carboxyl protecting group" refers to a substituent of the carboxyl group used to block or protect the functionality of the carboxyl group. Typical carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference may be made to: Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Kocienski et al., Protecting Groups, Thieme, Stuttgart, 2005.

[0100] The term "prodrug" as used herein refers to a compound that is converted in vivo into a compound represented by Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII). Such conversion is affected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissues. The prodrug compound of the present invention may be an ester. In the prior art, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, such as these phosphate ester compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound.

[0101] "Metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0102] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., "Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19." Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4The present invention also contemplates quaternary ammonium salts formed by compounds of any group containing N. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates and aromatic sulfonates. Although other salts can be used, for example, to separate or purify products, non-toxic physiologically acceptable salts are preferred.

[0103] The salts may be formed by conventional means, for example by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble or in a solvent such as one in which water is removed in vacuo, or by freeze-drying, or by exchanging the anion of an existing salt for another anion on a suitable ion exchange resin.

[0104] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0105] When the solvent is water, the term "hydrate" may be used. In some embodiments, one molecule of the compound of the present invention may be associated with one water molecule, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be associated with more than one water molecule, such as a dihydrate; and in still other embodiments, one molecule of the compound of the present invention may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.

[0106] The term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing, arresting, or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In yet other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0107] The terms "prevent" or "prevention" refer to a reduction in the risk of acquiring a disease or disorder (i.e., halting the development of at least one clinical symptom of a disease in a subject who may be at risk or predisposed to the disease but has not yet experienced or displayed symptoms of the disease).

[0108] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are encompassed within the scope of the invention.

[0109] In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated and included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, the stereoisomers of the structure are unambiguous and defined.

[0110] The "nitrogen oxides" of the compounds of the present invention are also included within the scope of the present invention. The nitrogen oxides of the compounds of the present invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperatures, or by reaction with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0111] The compound shown in formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII) may exist in the form of a salt. In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal treated therewith. In other embodiments, the salt is not necessarily a pharmaceutically acceptable salt and can be an intermediate for preparing and / or purifying the compound shown in formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII) and / or for separating the enantiomers of the compound shown in formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII).

[0112] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic moiety using conventional chemical methods. Generally speaking, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0113] Any structural formula given herein is also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 I.

[0114] In another aspect, the present invention relates to intermediates for preparing compounds represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII).

[0115] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, solvent, or a combination thereof. In other embodiments, the pharmaceutical composition can be in liquid, solid, semisolid, gel, or spray form.

[0116] Description of the compounds of the present invention

[0117] The present invention provides a compound capable of inhibiting and degrading androgen receptors, a pharmaceutically acceptable salt thereof, a pharmaceutical preparation, and a composition thereof, for use in treating androgen receptor-mediated diseases such as cancer, inflammatory diseases, or autoimmune diseases. The compound of the present invention has good activity in inhibiting and / or degrading androgen receptors, good pharmacokinetic properties and bioavailability, oral administration, and good safety.

[0118] In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I).

[0119] in,

[0120] The ARB is

[0121] L is

[0122] U is selected Its dotted lines represent single or double bonds;

[0123] Each R 1a 、R 1b 、R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 、R 2 、R 3 、R 4a 、R 4b 、R 5a 、R 5b 、R 5c 、R 6 、R 7 、R 8 、R 9 , p, q, t and u independently have the meanings as described in the present invention; the compound represented by formula (I) does not include the following compounds:

[0124] On the other hand, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I).

[0125] Among them, ARB is the androgen receptor recognition / binding part, L is the linker part, and U is the ubiquitin protease recognition / binding part; these three parts are connected by chemical bonds;

[0126] The ARB is

[0127] L is

[0128] U is selected Its dotted lines represent single or double bonds;

[0129] Each R 1a 、R 1b 、R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 、R 2 、R 3 、R 4a 、R 4b 、R 5a 、R 5b 、R 5c 、R 6 、R 7 、R 8 、R 9 , p, q, t and u independently have the meanings as described in the present invention;

[0130] The compound represented by the formula (I) does not include the following compounds:

[0131] In some embodiments, Ring A is C 3-8 Cycloalkyl, heterocyclic group composed of 3-8 atoms, C 6-10 Aryl or heteroaryl composed of 5-12 atoms, wherein the C 3-8 Cycloalkyl, heterocyclic group composed of 3-8 atoms, C 6-10The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 The alkyl group is substituted with a haloalkoxy substituent.

[0132] In some embodiments, Ring A is C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, C 6-10 Aryl or heteroaryl composed of 5-10 atoms, wherein the C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 The alkyl group is substituted with a haloalkoxy substituent.

[0133] In other embodiments, Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl , thiophene, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3.

[0134] In some embodiments, Ring B is C 6-10 Aryl or heteroaryl composed of 5-12 atoms, wherein the C 6-10The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 The alkyl group is substituted with a haloalkoxy substituent.

[0135] In some embodiments, Ring B is C 6-10 Aryl or heteroaryl composed of 5-10 atoms, wherein the C 6-10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 The alkyl group is substituted with a haloalkoxy substituent.

[0136] In other embodiments, ring B is phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl The radicals are each independently optionally substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3.

[0137] In some embodiments, ring C is a heterocyclic group consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl composed of 5-12 atoms, the heterocyclic group composed of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 The alkyl group is substituted with a haloalkoxy substituent.

[0138] In some embodiments, ring D is a heterocyclic group consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl composed of 5-12 atoms, the heterocyclic group composed of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 The alkyl group is substituted with a haloalkoxy substituent.

[0139] In some embodiments, D is absent.

[0140] In some embodiments, L 1 For bonds, -O-, -S-, -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, -(CR a R b ) n -、-O-(CR a R b ) n -、-(CR a R b ) n -O-, -NR c -(CR a R b ) n -or-(CR a R b ) n -NR c -; among them, each R a 、R b 、R c and n have the meanings as defined in the present invention.

[0141] In some embodiments, R a and R b Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy.

[0142] In some embodiments, R a and R bEach is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 or -OCF3.

[0143] In some embodiments, R c H, D, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl.

[0144] In some embodiments, R c is H, D, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0145] In some embodiments, L is a substructure of one of the following: wherein the substructures are each independently optionally replaced by 1, 2, 3, 4 or 5 selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 The left and right connection sites on the substructure of L can be connected to the ARB part or the U part in formula (I) respectively.

[0146] In some embodiments, R 1a 、R 1b 、R 1c 、R 1d and R 1e Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, heterocyclic group composed of 3-8 atoms, C 6-10 Aryl or heteroaryl composed of 5-12 atoms, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, heterocyclic group composed of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent;

[0147] In some embodiments, R 1a 、R 1b 、R 1c 、R 1d and R 1e Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, C 6-10 Aryl or heteroaryl composed of 5-10 atoms, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 The alkyl group is substituted with a haloalkoxy substituent.

[0148] In other embodiments, R 1a 、R 1b 、R 1c 、R 1d and R 1eEach is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl , propargyl, propynyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3.

[0149] In some embodiments, R 1a 、R 1b and the carbon atoms to which they are attached, or R 1e 、R 1d Together with the carbon atoms to which they are attached, they form C 3-8 A carbocyclic group, a heterocyclic group consisting of 3 to 8 atoms, or a heteroaryl group consisting of 5 to 10 atoms, wherein the C 3-8 The carbocyclyl, heterocyclyl of 3-8 atoms and heteroaryl of 5-10 atoms optionally contain 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur or nitrogen, and are optionally substituted by 1, 2, 3 or 4 heteroatoms independently selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 The alkyl group is substituted with a haloalkoxy substituent.

[0150] In some embodiments, R 1a 、R 1b and the carbon atoms to which they are attached, or R1e 、R 1d Together with the carbon atoms to which they are attached, they form C 3-6 A carbocyclic group, a heterocyclic group consisting of 3 to 6 atoms, or a heteroaryl group consisting of 5 to 6 atoms, wherein the C 3-6 The carbocyclyl, heterocyclyl of 3-6 atoms and heteroaryl of 5-6 atoms optionally contain 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur or nitrogen, and are optionally substituted by 1, 2, 3 or 4 heteroatoms independently selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 The alkyl group is substituted with a haloalkoxy substituent.

[0151] In other embodiments, R 1a 、R 1b and the carbon atoms to which they are attached, or R 1e 、R 1d and together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropene, cyclobutene, cyclopentene, cyclohexene, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropene, cyclobutene, cyclopentene, cyclohexene, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. and pyridazinyl, optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, F, Cl, Br, I, -NO, -CN, -OH, -NH, methyl, ethyl, n-propyl, isopropyl, -CHF, -CF, -CHCF, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF and -OCF.

[0152] In some embodiments, R 2 and R 3 For H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy

[0153] In some embodiments, R 2 and R 3 Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy.

[0154] In other embodiments, R 2 and R 3 Each is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 or -OCF3.

[0155] In some embodiments, R 4a and R 4b Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy.

[0156] In some embodiments, R 4a and R 4b Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy.

[0157] In other embodiments, R 4a and R 4bEach is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 or -OCF3.

[0158] In some embodiments, R 5a 、R 5b and R 5c Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or heterocyclic group consisting of 3-8 atoms, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl and the heterocyclic group consisting of 3-8 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 The alkyl group is substituted with a haloalkoxy substituent.

[0159] In some embodiments, R 5a 、R 5b and R 5c Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl or heterocyclic group consisting of 3-6 atoms, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6The cycloalkyl and the heterocyclic group consisting of 3-6 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 The alkyl group is substituted with a haloalkoxy substituent.

[0160] In other embodiments, R 5a 、R 5b and R 5c Each is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl , propargyl, propynyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3.

[0161] In some embodiments, R 6 、R 7 、R 8 and R 9 Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy

[0162] In some embodiments, R 6 、R 7 、R 8 and R 9Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy.

[0163] In other embodiments, R 6 、R 7 、R 8 and R 9 Each is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 or -OCF3.

[0164] In some embodiments, n is 1, 2, 3, 4, or 5.

[0165] In some embodiments, p is 1, 2, 3, 4, or 5.

[0166] In some embodiments, q is 1, 2, 3, 4, or 5.

[0167] In some embodiments, t is 1, 2, 3, 4, or 5.

[0168] In some embodiments, u is 1, 2, 3, 4, or 5.

[0169] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (II), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (II).

[0170] Among them, each R 1a 、R 1b 、R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 and R 2 Independently have the meanings as described in the present invention.

[0171] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (III), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (III).

[0172] Among them, each R 1a 、R 1b 、R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 and R 3 Independently have the meanings as described in the present invention.

[0173] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (IV), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (IV).

[0174] Among them, each R 1a 、R 1b 、R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 、R 4a and R 4b Independently have the meanings as described in the present invention.

[0175] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (V), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (V).

[0176] Among them, each R 1a 、R 1b 、R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 、R 5a 、R 5b and R 5c Independently have the meanings as described in the present invention.

[0177] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (VI), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (VI).

[0178] Among them, each R 1a 、R 1b 、R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 、R 6 and p independently have the meanings as described herein.

[0179] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (VII), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (VII).

[0180] Among them, each R 1a 、R 1b 、R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 、R 7 and q independently have the meanings as described herein.

[0181] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (VIII), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (VIII).

[0182] Among them, each R 1a 、R 1b 、R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 、R 8 and t independently have the meanings as described herein.

[0183] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (IX), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (IX).

[0184] Among them, R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 、R 9 and u each independently have the meanings as described in the present invention.

[0185] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (X), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (X).

[0186] Among them, R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 、R 9 and u each independently have the meanings as described in the present invention.

[0187] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (XI), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (XI).

[0188] Among them, R x For H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0189] R 1a 、R 1b 、R 1d 、R 1e , Ring A, Ring B, Ring C, Ring D, L 1 、R 9 and u each independently have the meanings as described in the present invention.

[0190] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (XII), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (XII).

[0191] Among them, R x For H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0192] R 1a 、R 1b 、R 1d 、R 1e , Ring B, R 9 and u each independently have the meanings as described in the present invention.

[0193] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (XIII), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (XIII).

[0194] Among them, each R 1a 、R 1b 、R 1c 、R 1d 、R 1e , Ring A, Ring B, Ring D, L 1 、R 9 and u independently have the meanings as described herein.

[0195] In some embodiments, the compound of the present invention is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures, but is in no way limited to:

[0196] On the other hand, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) disclosed in the present invention.

[0197] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

[0198] In another aspect, the present invention relates to use of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) disclosed in the present invention or a pharmaceutical composition thereof in the preparation of a medicament for preventing, treating or alleviating diseases mediated by androgen receptors.

[0199] In some embodiments, the androgen receptor-mediated disease is cancer, acne, hirsutism, sebaceous gland enlargement, alopecia, or Kennedy's disease.

[0200] In other embodiments, the cancer is prostate cancer, breast cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, or melanoma.

[0201] On the other hand, the present invention relates to methods for preparing, isolating and purifying compounds represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII).

[0202] Pharmaceutical compositions, formulations and administration of the compounds of the present invention

[0203] The present invention provides a pharmaceutical composition comprising a compound represented by Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), or a stereoisomer thereof, a racemic or non-racemic mixture of the isomers, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant, or excipient, and optionally, other therapeutic and / or prophylactic ingredients.

[0204] The dosage form in which the compounds used in the methods of the present invention are administered will be determined by the particular compound chosen, the type of pharmacokinetic profile desired for the route of administration, and the condition of the patient.

[0205] Preparations suitable for oral, sublingual, intranasal or injection administration are prepared according to methods well known in the pharmaceutical art and contain at least one active compound. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES (16th ed. 1980).

[0206] In general, the formulations of the present invention include the active ingredient (a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII)), typically mixed with an excipient, diluted with an excipient, or encapsulated in a carrier that can be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material that acts as an excipient, carrier, or medium for the active ingredient. Thus, the formulation can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard capsules, gels, suppositories, sterile injectable solutions, and sterile encapsulated powders.

[0207] In the preparation of a formulation, it may be necessary to grind the active compound to provide an appropriate particle size prior to mixing with the other components. If the active compound is substantially insoluble, it is typically ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size is adjusted by grinding to provide a uniform particle size distribution in the formulation, for example, about 40 mesh. In one embodiment of the invention, the particle size is approximately 0.1-100 μm.

[0208] Suitable carriers, adjuvants, and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel HC et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro AR et al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

[0209] As used herein, a "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, mixture, or vehicle that contributes to the consistency of a dosage form or pharmaceutical composition. Each excipient, when combined, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that could significantly reduce the efficacy of the disclosed compounds upon administration to a patient and / or result in an unpharmaceutically acceptable pharmaceutical composition. Furthermore, each excipient must be pharmaceutically acceptable, e.g., possess a sufficiently high degree of purity.

[0210] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. In addition, pharmaceutically acceptable excipients may be selected based on their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to facilitate the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to facilitate the production of a stable dosage form. Certain pharmaceutically acceptable excipients may be selected to facilitate the carrying or transport of the compound of the invention from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected to enhance patient compliance.

[0211] Some suitable excipient examples include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose. Suitable pharmaceutically acceptable excipients also include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants (such as talc, magnesium stearate and mineral oil), glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives (such as methyl hydroxybenzoate and propyl hydroxybenzoate), stabilizers, surfactants and buffers. Those skilled in the art will recognize that certain pharmaceutically acceptable excipients can serve more than one function, and can provide alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation. The compounds of the invention can be formulated using methods known in the art so as to provide quick, sustained, or delayed release of the active ingredient after administration to a patient.

[0212] The skilled person has the knowledge and skill in this area to enable them to select a suitable pharmaceutically acceptable excipient for the appropriate amount of the present invention. In addition, there are a large number of resources available to the skilled person that describe pharmaceutically acceptable excipients and are used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0213] To prepare pharmaceutical compositions using the compounds described herein, pharmaceutically acceptable carriers can be solid or liquid carriers. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets can contain from about 5% to about 95% active ingredient. Suitable solid carriers are known in the art and include, for example, magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing various compositions can be found in: A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th ed., 1990, Mack Publishing Company Co., Easton, Pennsylvania.

[0214] Various carriers for configuring pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference. The use of any conventional carrier, other than any carrier that is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or by interacting in a deleterious manner with any other ingredient in the pharmaceutically acceptable composition, falls within the scope of the present invention.

[0215] The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some common methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0216] Thus, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or combination thereof, the process comprising mixing the ingredients. Pharmaceutical compositions comprising a compound disclosed herein can be prepared, for example, by mixing at ambient temperature and atmospheric pressure.

[0217] The compounds disclosed herein are generally formulated into dosage forms suitable for administration to a patient via a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0218] It should also be recognized that certain compounds of the present invention may be used therapeutically in free form or, if appropriate, in the form of pharmaceutically acceptable derivatives thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts or derivatives that, when administered to a patient in need thereof, directly or indirectly provide a compound of the present invention or a metabolite or residue thereof.

[0219] In some embodiments, the compounds disclosed herein can be formulated into oral dosage forms. In other embodiments, the compounds disclosed herein can be formulated into inhalation dosage forms. In other embodiments, the compounds disclosed herein can be formulated into nasal dosage forms. In yet other embodiments, the compounds disclosed herein can be formulated into transdermal dosage forms. In still other embodiments, the compounds disclosed herein can be formulated into topical dosage forms.

[0220] The pharmaceutical compositions provided herein can be provided as compressed tablets, tablets, chewable lozenges, fast-dissolving tablets, composite compressed tablets, or enteric-coated, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the effects of gastric acid but dissolves or disintegrates in the intestines, thereby protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which helps mask unpleasant tastes or odors and prevents tablet oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Composite compressed tablets are compressed tablets produced through more than one compression cycle, including multilayer tablets and press-coated or dry-coated tablets.

[0221] Tablet dosage forms can be prepared from the active ingredient in powder, crystal or granular form alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and / or colorants. Flavoring agents and sweeteners are particularly useful in forming chewable tablets and lozenges.

[0222] The pharmaceutical composition provided by the present invention can be provided in soft capsules or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as dry-filled capsule (DFC), consists of two sections, one section inserted into the other, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by adding glycerol, sorbitol or similar polyols. The soft gelatin shells can contain preservatives to prevent microbial growth. Suitable preservatives are those as described in the present invention, including methylparaben and propylparaben, and sorbic acid. The liquid, semisolid and solid dosage forms provided by the present invention can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or sustain dissolution of the active ingredient.

[0223] The pharmaceutical compositions provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in another liquid in the form of small globules, which can be oil-in-water or water-in-oil. Emulsions can include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet-tasting hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and can also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for accurate and convenient administration.

[0224] The pharmaceutical compositions provided by the present invention can be formulated into any dosage form suitable for inhalation administration to a patient, such as a dry powder, an aerosol, a suspension or a solution composition. In some embodiments, the pharmaceutical compositions disclosed herein can be formulated into a dosage form suitable for inhalation administration to a patient using a dry powder. In some further embodiments, the pharmaceutical compositions disclosed herein can be formulated into a dosage form suitable for inhalation administration to a patient via a nebulizer. The dry powder composition delivered to the lungs by inhalation typically comprises a fine powder of the compound disclosed herein and one or more fine powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di- and polysaccharides. Fine powders can be prepared, for example, by micronization and grinding. In general, size-reduced (e.g., micronized) compounds can be prepared by a D 50 values ​​(e.g., measured by laser diffraction).

[0225] Pharmaceutical compositions suitable for transdermal administration can be prepared as discontinuous patches intended to remain in close contact with the patient's epidermis for an extended period of time. For example, the active ingredient can be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

[0226] The pharmaceutical composition that is suitable for topical administration can be formulated into ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.For example, ointment, cream and gel can configure with water or oil base, and applicable thickener and / or gel and / or solvent.Such matrix can comprise, water, and / or oil such as liquid paraffin and vegetable oil (such as peanut oil or castor oil), or solvent such as polyethylene glycol.The thickener and gel that use according to matrix properties comprise soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxyvinyl polyol and cellulose derivative, and / or glyceryl monostearate and / or nonionic emulsifier.

[0227] The compounds of the present invention can also be combined with soluble polymers as targetable drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene glycol polylysine substituted with palmitoyl residues. In addition, the compounds disclosed in the present invention can be combined with a class of biodegradable polymers used in achieving controlled release of drugs, for example, cross-linked or amphiphilic block copolymers of polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.

[0228] Pharmaceutical composition provided by the invention can be administered parenterally by injection, infusion or implantation, for local or systemic administration. Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

[0229] Pharmaceutical composition provided by the invention can be mixed with any dosage form suitable for parenteral administration, including solution, suspension, emulsion, micelle, liposome, microsphere, nanometer system and the solid form that is suitable for making solution or suspension in liquid before injection.Such dosage form can be prepared (referring to Remington:The Science and Practice of Pharmacy, the same) according to conventional method known to those skilled in the art of pharmaceutical science.

[0230] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous carriers, water-miscible carriers, non-aqueous carriers, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, antifreezes, cryoprotectants, thickeners, pH adjusters, and inert gases.

[0231] The pharmaceutical composition provided herein can be administered via rectal suppository. The drug is mixed with a suitable non-irritating excipient (e.g., cocoa butter or a glyceride synthesized from polyethylene glycol), which is solid at room temperature and then liquefies or dissolves in the rectal cavity to release the drug. Due to individual differences, the severity of symptoms can vary significantly, and each drug has unique therapeutic properties. Therefore, the precise administration method, dosage form, and treatment regimen for each individual should be determined by a licensed physician.

[0232] The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed, sustained-pulse-controlled, targeted and programmed release forms.

[0233] Although the compounds of the present invention can be administered directly without any formulation, they are generally administered in the form of pharmaceutical formulations containing pharmaceutically acceptable excipients and at least one active ingredient. These formulations can be administered by a variety of routes, including oral, buccal, rectal, intranasal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal administration. Many of the compounds used in the methods of the present invention are effective as injectable and oral compositions.

[0234] For transdermal administration, a transdermal delivery device ("patch") is needed. This transdermal patch can be used to continuously or intermittently inject a controlled amount of the compound of the present invention. The structure and application of transdermal patches for delivering drugs are well known in the art. For example, see US5,023,252. This patch can be made into a continuous, pulsatile or on-demand release drug.

[0235] The compound represented by Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) or a pharmaceutically acceptable salt thereof is usually administered orally in the form of a pharmaceutical preparation comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of a pharmaceutically acceptable salt, in a pharmaceutically acceptable dosage form. The pharmaceutical preparation used depends on the disease to be treated and the patient, and the pharmaceutical composition can be administered at different doses.

[0236] The pharmaceutical preparations described above having a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) can be prepared for oral administration, in particular in the form of tablets or capsules, and particularly relate to a technology aimed at providing colon-targeted drug release (Patel, MM Expert Opin. Drug Deliv. [Expert Opinion on Drug Delivery] 2011, 8(10), 1247-1258).

[0237] The pharmaceutical formulations of the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII) as described above are conveniently administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA. (1985). The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable excipient as described above.

[0238] Pharmaceutical preparations suitable for oral administration can include one or more physiologically compatible carriers and / or excipients and can be in the form of solid or liquid. Tablets and capsules can be prepared with fillers, binders, lubricants and / or surfactants (such as sodium lauryl sulfate). Liquid compositions can contain conventional additives such as emulsifiers, suspending agents and / or preservatives. Liquid compositions can be encapsulated in, for example, gelatin to provide unit dosage forms. Solid oral dosage forms include tablets, two-stage hard shell capsules and soft elastic gelatin (SEG) capsules. Such two-stage hard shell capsules can be prepared, for example, by filling a compound shown in Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) into hydroxypropyl methylcellulose (HPMC) or a gelatin shell.

[0239] The dry shell formulation typically comprises gelatin at a concentration of about 40% to 60% w / w, water at a concentration of about 30% to 40%, and a plasticizer (such as glycerol, propylene glycol, or sorbitol) at a concentration of about 20% to 30%. Other materials such as dyes, flavorings, preservatives, and opacifiers may also be present. The liquid filler material comprises a solid drug that has been dissolved, solubilized, or dispersed (using a suspending agent such as polyethylene glycol 4000, hydrogenated castor oil, or beeswax) or a liquid drug in a combination of a vehicle or multiple vehicles such as glycols, polyols, vegetable oils, mineral oils, triglycerides, and surfactants.

[0240] As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, an amount sufficient to treat, cure, or alleviate the symptoms of a disease when administered or brought into equilibrium in the body. The effective amount required for a particular treatment regimen depends on a variety of factors, including the disease being treated, the severity of the disease, the activity of the specific drug being used, the route of administration, the clearance rate of the specific drug, the duration of treatment, the use of concomitant medications, the age, weight, sex, diet, and health of the patient. A description of other factors that need to be considered in the art regarding a "therapeutically effective amount" can be found in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8 th ed., Pergamon Press, 1990; Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1990.

[0241] Oral formulations are preferred, particularly tablets or capsules, which can be formulated by methods known to those skilled in the art to provide a dose in the range of 0.1 mg to 1000 mg of active compound.

[0242] In the treatment of humans, a suitable daily dose of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or a pharmaceutically acceptable salt thereof, is about 0.0001 to 100 mg / kg body weight. However, it will be understood that the amount of compound actually administered will be determined by the attending physician based on the circumstances, including the disease being treated, the route of administration selected, the compound or compounds to be administered, the age, weight and response of the particular patient, and the severity of the patient's symptoms, and therefore, the above dosage ranges should not limit the scope of the invention in any way. In some cases, dosage levels below the lower limit of the above dosage ranges may be more appropriate, while in other cases, higher doses that do not produce any side effects may be used, provided that such a larger dose is first divided into several smaller doses for administration throughout the day.

[0243] The term "administration" refers to providing a therapeutically effective amount of a drug to an individual, and administration routes include oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like. Dosage forms include ointments, lotions, tablets, capsules, pills, dispersible powders, granules, suppositories, pills, lozenges, injections, sterile solutions or non-aqueous solutions, suspensions, emulsions, patches, and the like. The active ingredient is compounded with a non-toxic pharmaceutically acceptable carrier (e.g., glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea, dextran, and the like).

[0244] The preferred route of administration will vary depending on clinical circumstances, and dosage must be adjusted based on the patient being treated. The physician will determine the appropriate dosage for each individual patient. The therapeutically effective amount per unit dose depends on body weight, physiology, and the chosen vaccination regimen. The compound per unit dose refers to the weight of the compound per administration, excluding the weight of the vehicle (which is present in the drug).

[0245] The pharmaceutical compositions provided herein can be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials, or syringes. The multiple dose parenteral formulations must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as known and practiced in the art.

[0246] The pharmaceutical composition provided by the present invention can be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or co-formulated with substances that supplement the intended effect.

[0247] In some embodiments, the treatment methods of the present invention comprise administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need thereof. Various embodiments of the present invention include treating the diseases mentioned herein by administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need thereof.

[0248] In some embodiments, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, ear, vaginal, inhalation, and intranasal administration. In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be oral administration. In other embodiments, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be inhalation administration. In some further embodiments, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be intranasal administration.

[0249] In some embodiments, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be administered once, or several times at different time intervals within a specified time period according to a dosing regimen. For example, the drug is administered once, twice, three times, or four times a day. In some embodiments, the drug is administered once a day. In yet other embodiments, the drug is administered twice a day. The drug can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. The appropriate dosing regimen for the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, which can be determined by a technician. In addition, the appropriate dosing regimen for the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention, including the duration of implementation of the regimen, depends on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the technician. Such technicians should also understand that the appropriate dosing regimen may be required to adjust the individual patient's response to the dosing regimen, or when the individual patient's needs change over time.

[0250] The compounds of the present invention can be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention can be administered separately with other therapeutic agents by the same or different routes of administration, or can be administered with them in the form of the same pharmaceutical composition. This is selected by those skilled in the art based on the actual physical conditions of the patient, such as health, age, weight, etc. If formulated as a fixed dose, such a combination product uses a compound of the present invention (within the dosage range described herein) and other pharmaceutically active agents (within their dosage range).

[0251] Accordingly, in one aspect, the present invention encompasses a combination comprising a quantity of at least one compound of the present invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional therapeutic agents as described above.

[0252] In addition, the compounds of the present invention can be administered in the form of prodrugs. In the present invention, a "prodrug" of a compound of the present invention is a functional derivative that, when administered to a patient, ultimately releases the compound of the present invention in vivo. When administering the compound of the present invention in the form of a prodrug, one skilled in the art may implement one or more of the following methods: (a) altering the onset of action of the compound in vivo; (b) altering the duration of action of the compound in vivo; (c) altering the transport or distribution of the compound in vivo; (d) altering the solubility of the compound in vivo; and (e) overcoming the side effects or other difficulties faced by the compound. Typical functional derivatives used to prepare prodrugs include variants of the compound that are chemically or enzymatically cleaved in vivo. These variants, including those for preparing phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

[0253] Uses of the compounds and pharmaceutical compositions of the present invention

[0254] The compounds and pharmaceutical compositions provided by the present invention can be used to prepare drugs for degrading androgen receptors (ARs), and can also be used to prepare drugs for preventing, treating or alleviating diseases mediated by androgen receptors, especially cancers.

[0255] Specifically, the compound or pharmaceutical composition of the present invention is present in an amount effective to detectably and selectively degrade the androgen receptor (AR).

[0256] The compounds of the present invention can be used for, but are not limited to, preventing, treating, or alleviating diseases mediated by androgen receptors by administering an effective amount of the compounds or pharmaceutical compositions of the present invention to a patient. Such diseases mediated by androgen receptors further include, but are not limited to, cancer, acne, hirsutism, sebaceous gland enlargement, alopecia, or Kennedy's disease.

[0257] The compounds of the present invention can be used for, but are not limited to, preventing, treating, or alleviating cancer, acne, hirsutism, sebaceous gland enlargement, hair loss, or Kennedy's disease by administering an effective amount of the compounds or pharmaceutical compositions of the present invention to a patient. Such cancers further include, but are not limited to, laryngeal cancer, esophageal cancer, gastric cancer, intestinal cancer, liver cancer, kidney cancer, lung cancer, brain cancer, head and neck cancer, squamous cell carcinoma, lymphatic system cancer, thyroid cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, genitourinary tract cancer, breast cancer, blood cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma, and / or monocytic leukemia.

[0258] In addition to being beneficial for human treatment, the compounds and pharmaceutical compositions of the present invention may also be used in veterinary treatment of pets, imported species, and mammals in farm animals. Other examples of animals include horses, dogs, and cats. The compounds of the present invention include pharmaceutically acceptable derivatives thereof.

[0259] General synthetic steps

[0260] To illustrate the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

[0261] Generally, the compounds of the present invention can be prepared by the methods described herein, wherein, unless otherwise indicated, the substituents are as defined in Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII). The following reaction schemes and examples are provided to further illustrate the present invention.

[0262] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0263] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.

[0264] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were dried over sodium reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0265] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0266] The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0267] 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1 H NMR spectra were obtained using CDC13, DMSO-d6, CD3OD, or acetone-d6 as solvents (in ppm) and referenced to TMS (0 ppm) or chloroform (7.26 ppm). When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), ddd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), and tt (triplet of triplets). Coupling constants, J, are expressed in Hertz (Hz).

[0268] Low-resolution mass spectrometry (MS) data were obtained using an Agilent 6120 quadrupole HPLC-M column (Zorbax SB-C18 column, 2.1 x 30 mm, 3.5 μm, 6 min, flow rate 0.6 mL / min). Mobile phase: 5%-95% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid), electrospray ionization (ESI), UV detection at 210 nm / 254 nm.

[0269] Pure compounds were analyzed using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC) with UV detection at 210 nm / 254 nm.

[0270] The following abbreviations are used throughout the present invention: CH2Cl2, DCM dichloromethane mg milligram CDC13 deuterated chloroform g gram DMSO dimethyl sulfoxide mL, ml milliliter DMSO-d6 deuterated dimethyl sulfoxide μL, μl microliter EtOAc, EA ethyl acetate nL, nl nanoliter CH3OH, MeOH methanol min minute CD3OD deuterated methanol h hour nM nanomole PE petroleum ether (60-90°C) μM micromole RT, rt, rt room temperature mmol, mM millimole EDTA ethylenediaminetetraacetic acid M mole per liter Boc, BOC tert-Butyloxycarbonyl ng nanogram DMF N,N-dimethylformamide μg microgram HCl hydrochloric acid CDI N,N'-Carbonyldiimidazole THF Tetrahydrofuran ACN acetonitrile TFA trifluoroacetic acid DIPEA N,N-Diisopropylethylamine wt mass fraction HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0271] The following synthetic schemes describe procedures for preparing compounds disclosed herein.

[0272] Synthesis Scheme 1

[0273] Compound (I) can be synthesized by referring to the method of Synthesis Scheme 1; wherein R x and R y Each independently represents D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 1a 、R 1b 、R 1d 、R 1e and R 9 It has the definition as described in the present invention. Compound (Ia) reacts with 3-aminopiperidine-2,6-dione under suitable conditions (such as triethylamine, 120°C) to obtain compound (Ib); compound (Ib) reacts with tert-butyl piperazine-1-carboxylate under suitable conditions (such as N,N-diisopropylethylamine, 90°C) to obtain compound (Ic); compound (Ic) reacts under acidic conditions (such as the action of hydrogen chloride) to obtain compound (Id); compound (Ie) reacts with di-tert-butyl dicarbonic acid under suitable conditions (such as 50°C) to obtain compound (If); compound (If) reacts with 4-hydroxymethylpiperidine under suitable conditions (such as the action of potassium carbonate and tetrabutylammonium iodide) to obtain compound (Ig); compound (Ig) reacts under suitable conditions (under the action of sulfur trioxide pyridine) to obtain compound (Ih); compound (Ih) reacts with compound (Id) under suitable conditions. The reaction is carried out under suitable conditions (such as the action of sodium triacetoxyborohydride) to obtain compound (Ii); compound (Ii) is reacted under acidic conditions (such as the action of hydrogen chloride) to obtain compound (Ij); compound (Ik) is reacted with tert-butyl (4-hydroxycyclohexyl)carbamate under suitable conditions (such as the action of sodium hydride) to obtain compound (Il); compound (Il) is reacted with hydroxylamine hydrochloride under suitable conditions (such as triethylamine) to obtain compound (Im); compound (Im) is reacted with trimethyl orthoformate under suitable conditions (such as trifluoroacetic acid, 60°C) to obtain compound (In); compound (In) is reacted with under acidic conditions (such as the action of hydrogen chloride) to obtain compound (Io); compound (Io) is reacted with compound (Ij) under suitable conditions (such as the action of HATU, DIPEA) to obtain compound (I).

[0274] Synthesis Scheme 2

[0275] Compound (II) can be synthesized by referring to the method of Synthesis Scheme 2; wherein R x and R y Each independently represents D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 1c 、R 1d 、R 1e and R 9 The compounds (II-a) and (II-b) are reacted with methyl iodide under suitable conditions (such as potassium carbonate) to obtain compound (II-c); compound (II-c) is reacted with tert-butyl (4-hydroxycyclohexyl)carbamate under suitable conditions (such as sodium hydride) to obtain compound (II-d). Compound (II-d) is reacted with compound (Ij) under suitable conditions (such as 1-propylphosphoric anhydride and diisopropylethylamine) to obtain compound (II).

[0276] Synthesis Scheme 3

[0277] Compound (III) can be synthesized by referring to the method of Synthesis Scheme 3; wherein R x and R y Each independently represents D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 1c 、R 1d 、R 1e and R 9 The compound (III-a) is defined as described in the present invention. Compound (III-b) is reacted with methyl iodide under suitable conditions (such as potassium carbonate); Compound (III-b) is reacted with tert-butyl (4-hydroxycyclohexyl)carbamate under suitable conditions (such as sodium hydride) to obtain Compound (III-c); Compound (III-c) is reacted under acidic conditions (such as hydrogen chloride) to obtain Compound (III-d). Compound (III-d) is reacted with Compound (Ij) under suitable conditions (such as 1-propylphosphoric anhydride and diisopropylethylamine) to obtain Compound (III).

[0278] Synthesis Scheme 4

[0279] Compound (IV) can be synthesized by referring to the method of Synthesis Scheme 4; wherein R x 、R y and R z Each independently represents D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 1a 、R 1b 、R 1d 、R 1e and R 9 The compound (Im) is defined as described in the present invention. Compound (IV-a) is reacted with compound (IV-a) under suitable conditions (e.g., 60°C) to obtain compound (IV-b); compound (IV-b) is reacted with compound (IV-c) under acidic conditions (e.g., in the presence of hydrogen chloride); and compound (IV-c) is reacted with compound (Ij) under suitable conditions (e.g., in the presence of HATU or DIPEA) to obtain compound (IV).

[0280] The compounds, pharmaceutical compositions and applications of the present invention are further described below with reference to the examples. Example

[0281] Example 1 N-(1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 1

[0282] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione 1b

[0283] 3-Aminopiperidine-2,6-dione hydrochloride (20.00 g, 121.51 mmol) was dissolved in acetic acid (200 mL), and 5,6-difluoroisobenzofuran-1,3-dione 1a (22.37 g, 121.51 mmol) and triethylamine (27.05 g, 267.32 mmol) were added. The mixture was reacted at 120°C for 3 hours, then cooled to room temperature for 1 hour. The solid was precipitated and filtered. The filter cake was washed with water (100 mL), slurried with water (300 mL), filtered, and dried in vacuo to obtain a purple-gray solid 1b (21.67 g, yield 60.62%).

[0284] MS (ESI, pos.ion) m / z: 295.1 [M+H] + .

[0285] Step 2: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carbamate 1c

[0286] 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione 1b (10.00 g, 33.99 mmol) was dissolved in N-methylpyrrolidone (60 mL). Tert-butyl piperazine-1-carboxylate (6.96 g, 37.39 mmol) and N,N-diisopropylethylamine (10.98 g, 84.98 mmol) were added under a nitrogen atmosphere and reacted at 90°C for 20 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with saturated sodium chloride solution (200 mL) and concentrated. The resulting residue was slurried with ethyl acetate (30 mL), filtered, and the filter cake was dried in vacuo at 45°C to afford 1c (9.65 g, 61.66% yield) as a yellow solid.

[0287] MS (ESI, negative ion) m / z: 459.3 [MH] - .

[0288] Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride 1d

[0289] Dissolve tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carbamate 1c (9.65 g, 20.96 mmol) in a 4M solution of hydrogen chloride in 1,4-dioxane (36 mL). Stir at room temperature overnight, and concentrate the reaction mixture to dryness to afford 1d (8.31 g, 99.92% yield) as a pale yellow solid.

[0290] MS (ESI, pos.ion) m / z: 361.1 [M+H] + .

[0291] Step 4: Synthesis of tert-butyl 6-chloropyridazine-3-carboxylate 1f

[0292] 6-Chloropyridazine-3-carboxylic acid 1e (20 g, 126.15 mmol) and 4-dimethylaminopyridine (7.71 g, 63.08 mmol) were dissolved in tetrahydrofuran (500 mL), and di-tert-butyl dicarbonic acid (36.07 g, 165.26 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated to 50°C and reacted overnight. The reaction system was concentrated under reduced pressure, dissolved in ethyl acetate (200 mL), and washed with water (200 mL × 2). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (V EA / V PE =1 / 10) to give 1f (17.00 g, 62.78% yield) as a white solid.

[0293] Step 5: Synthesis of 1 g of tert-butyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate

[0294] Tert-butyl 6-chloropyridazine-3-carboxylate 1f (17.00 g, 79.20 mmol), 4-hydroxymethylpiperidine (10.95 g, 95.04 mmol), anhydrous potassium carbonate (32.84 g, 237.60 mmol), and tetrabutylammonium iodide (2.93 g, 7.92 mmol) were dissolved in 1,4-dioxane (200 mL) and reacted at 100°C for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Dichloromethane (120 mL) and water (120 mL) were added, stirred, and separated. The organic phase was concentrated to dryness and slurried with dichloromethane (15 mL) and petroleum ether (30 mL). The solid was collected by filtration and dried under vacuum to obtain 1 g of a white solid (20.58 g, 88.58% yield).

[0295] MS (ESI, pos.ion) m / z: 294.1 [M+H] + .

[0296] Step 6: Synthesis of tert-butyl 6-(4-(formyl)piperidin-1-yl)pyridazine-3-carboxylate 1h

[0297] Dissolve 1 g (10.00 g, 34.09 mmol) of tert-butyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate in toluene (28.74 mL). Add dimethyl sulfoxide (18.18 mL) and N,N-diisopropylethylamine (30.84 g, 39.54 mmol) under stirring. Cool to 0°C, then add sulfur trioxide pyridine (16.28 g, 102.27 mmol) and react at 0°C for 0.5 hours. Add water (250 mL) and extract with ethyl acetate (100 mL). Wash the organic phase with water (250 mL × 5) and concentrate. The residue is purified by purifying with dichloromethane / petroleum ether solution (V DCM / V PE=1 / 4, 250 mL) to obtain a light yellow solid 1h (5.33 g, yield 53.66%).

[0298] MS (ESI, pos.ion) m / z: 292.2 [M+H] + .

[0299] Step 7: Synthesis of tert-butyl 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylate 1i

[0300] Dissolve tert-butyl 6-(4-(formyl)piperidin-1-yl)pyridazine-3-carboxylate 1h (0.20 g, 0.69 mmol) in dichloromethane (22 mL), add 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride 1d (0.27 g, 0.69 mmol) under stirring, stir at room temperature for 1 hour, then add sodium triacetoxyborohydride (0.44 g, 2.07 mmol), and react at room temperature for 19 hours. Add water (20 mL), wash the organic phase with saturated sodium chloride solution (20 mL), concentrate, and the resulting residue is purified by silica gel column chromatography (V EA / V PE =2 / 1) to obtain a light yellow solid 1i (0.21 g, yield 48.12%).

[0301] MS (ESI, pos.ion) m / z: 636.2 [M+H] + .

[0302] Step 8: Synthesis of 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 1j

[0303] Dissolve tert-butyl 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylate 1i (0.20 g, 0.31 mmol) in 4M hydrogen chloride in dichloromethane (6 mL). Stir for 2 h, and then concentrate the reaction mixture to dryness to afford 1j (0.18 g, 98.71% yield) as a yellow solid.

[0304] MS (ESI, pos.ion) m / z: 580.5 [M+H] + .

[0305] Step 9: Synthesis of tert-butyl ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamate 1l

[0306] Dissolve tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate (5.00 g, 23.22 mmol) in N,N-dimethylformamide (100 mL), cool to 0°C, add sodium hydride (0.84 mg, 34.83 mmol), then add 2-chloro-4-fluorobenzonitrile 1k (4.33 g, 27.86 mmol), and react at 0°C for 2 hours. Add water (200 mL), extract with ethyl acetate (400 mL), wash the organic phase with saturated sodium chloride solution (200 mL), dry over anhydrous sodium sulfate, filter, and concentrate. The resulting residue is purified by silica gel column chromatography (V EA / V PE =1 / 4) to obtain a white solid 11 (5.59 g, yield 68.62%).

[0307] Step 10: Synthesis of tert-butyl ((1r,4r)-4-(3-chloro-4-(N-hydroxycarbamoyl)phenoxy)cyclohexyl)carbamate

[0308] Dissolve tert-butyl ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamate 1l (0.50 g, 1.43 mmol) in methanol (5.0 mL). Add hydroxylamine hydrochloride (0.30 g, 4.32 mmol) with stirring, followed by the dropwise addition of triethylamine (0.46 g, 4.55 mmol). After completion of the addition, heat the mixture to 75°C and reflux for 13 hours. After TLC monitoring, the reaction mixture was concentrated under reduced pressure to yield 1m (0.53 g, 96.88% yield), a white solid.

[0309] Step 11: Synthesis of tert-butyl (1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)carbamate

[0310] Dissolve tert-butyl ((1r,4r)-4-(3-chloro-4-(N-hydroxycarbamoyl)phenoxy)cyclohexyl)carbamate 1m (0.53 g, 1.38 mmol) in trimethyl orthoformate solution (5.0 mL), add trifluoroacetic acid (0.16 g, 1.42 mmol) dropwise while stirring, and heat to 60°C under nitrogen protection for 16 hours. After the reaction of the raw material is monitored by TLC, water is added to quench (10 mL), and the product is purified by silica gel column chromatography (V EA / V PE =1 / 5) to obtain 1n as a white solid (0.15 g, yield 27.58%).

[0311] Step 12: Synthesis of (1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexane-1-amino hydrochloride 1o

[0312] Tert-butyl (1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)carbamate 1n (0.15 g, 0.38 mmol) was dissolved in 1,4-dioxane solution (1.0 mL), and 4 M 1,4-dioxane hydrochloric acid solution (1.0 mL) was added dropwise with stirring. After the addition was completed, stirring was continued at room temperature under nitrogen protection for 3 hours. After TLC monitoring showed that the raw material had reacted completely, the solvent was directly concentrated under reduced pressure to obtain 1o (0.10 g, yield 79.52%) as a white solid.

[0313] Step 13: Synthesis of N-(1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 1

[0314] 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 1j (0.20 g, 0.34 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.26 g) was added while stirring. ,0.69mmol), stirred for 30 minutes, added (1r,4r)-4-3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexane-1-amino hydrochloride 1o (0.10g, 0.30mmol), and finally added N,N-diisopropylethylamine (0.20mL) dropwise. After the addition was complete, the mixture was stirred at room temperature for 12 hours under nitrogen protection. TLC monitored that the reaction of the raw materials was complete, and water (6mL) was added to the reaction solution to quench it. Solid precipitated, stirred for 10 minutes, filtered, and the filter cake was collected and dried in vacuo. It was purified by silica gel column chromatography (V DCM / V MeOH =9 / 1) to obtain a yellow solid (120 mg crude product), which was then purified by preparative thin layer chromatography (V DCM / V MeOH =40 / 1) to give a yellow solid 1 (70 mg, yield 27.03%).

[0315] MS (ESI, pos.ion) m / z: 856.3 [M+H] + .

[0316] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.11 (s, 1H), 9.72 (s, 1H), 8.58 (d, J = 8.2Hz, 1H), 7.88 (d, J = 8.8Hz, 1H), 7.81 (d, J = 9.5Hz, 1H), 7.73 (d, J = 11 .4Hz,1H),7.46(d,J=7.4Hz,1H),7.34(d,J=9.7Hz,1H),7.28(d,J=2.5Hz,1H),7.16(dd,J=8.8,2.6Hz,1H),5.76(s,1H),5.11(dd,J=12.8, 5.4Hz,1H),4.49(d,J=12.6Hz,3H),3.88(d,J=11.2Hz,1H),3.26(d,J=6.3Hz,3H),3.17-2.97(m,3H),2.90(t,J=15.7Hz,2H),2.23(d,J=6. 9Hz,2H),2.14(d,J=11.6Hz,2H),2.11-2.00(m,2H),2.00-1.81(m,6H),1.66(q,J=12.0Hz,2H),1.55(t,J=11.4Hz,3H),1.24-1.08(m,3H).

[0317] Example 2 N-(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 2

[0318] Step 1: Synthesis of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride 1p

[0319] Dissolve tert-butyl ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamate 1l (2.59 g, 7.38 mmol) in 1,4-dioxane (4 mL). Add 4M hydrogen chloride in 1,4-dioxane (2 mL). Stir overnight, and concentrate the reaction mixture to dryness to obtain 1p (2.11 g, 100% yield), a white solid.

[0320] MS (ESI, pos.ion) m / z: 251.1 [M+H] + .

[0321] Step 2: Synthesis of 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylic acid 1q

[0322] Dissolve 1 g (2.00 g, 6.82 mmol) of tert-butyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate in 1,4-dioxane (5 mL) and add a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL). Stir for 16 h, and concentrate the reaction mixture to dryness to obtain 1q (1.62 g, 100% yield) of a light yellow solid.

[0323] MS (ESI, pos.ion) m / z: 238.2 [M+H] + .

[0324] Step 3: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide 1r

[0325] 6-(4-(Hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylic acid 1q (1.62 g, 6.83 mmol) was dissolved in N,N-dimethylformamide (48 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (5.19 g, 13.66 mmol) was added. Then, 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride 1p (1.96 g, 6.83 mmol) and N,N-diisopropylethylamine (2.65 g, 20.49 mmol) were added, and the mixture was reacted at room temperature for 1 h. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with water (50 mL × 2) and saturated sodium chloride solution (100 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (V EA / V PE =1 / 1) to obtain a reddish-brown solid 1r (2.97 g, yield 92.53%).

[0326] MS (ESI, pos.ion) m / z: 470.1 [M+H] + .

[0327] Step 4: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide 1s

[0328] Dissolve N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide 1r (1.62 g, 6.83 mmol) in toluene (5.75 mL), add dimethyl sulfoxide (3.64 mL) and N,N-diisopropylethylamine (2.65 g, 20.49 mmol) with stirring, cool to 0°C, add sulfur trioxide pyridine (2.03 g, 12.78 mmol), and react at 0°C for 0.5 h. Add water (50 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with water (50 mL × 2) and saturated sodium chloride solution (100 mL) in sequence, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The resulting residue is purified by silica gel column chromatography (V EA / V PE =1 / 1) to give an off-white solid 1s (1.15 g, yield 57.69%). MS (ESI, pos.ion) m / z: 468.4 [M+H] + .

[0329] Step 5: Synthesis of ethyl 2-(3-(2,6-dioxopiperidin-3-yl)ureido)-4-methylthiophene-3-carboxylate 2b

[0330] Ethyl 2-amino-4-methylthiophene-3-carboxylate 2a (5.0 g, 26.99 mmol) and triethylamine (10.92 g, 107.96 mmol) were dissolved in dichloromethane (37.88 mL). CDI (8.75 g, 53.98 mmol) was added and stirred for 3 hours. 3-Aminopiperidine-2,6-dione hydrochloride (4.89 g, 29.69 mmol) was added and stirred for another 12 hours. The mixture was filtered, and the filter cake was rinsed with water (300 mL) and ethyl acetate (150 mL). The filter cake was collected and dried to afford 2b as an off-white solid (6.8 g, 74.23% yield).

[0331] MS (ESI, pos.ion) m / z: 340.3 [M+H] + .

[0332] Step 6: Synthesis of ethyl 5-bromo-2-(3-(2,6-dioxopiperidin-3-yl)ureido)-4-methylthiophene-3-carboxylate 2c

[0333] Ethyl 2-(3-(2,6-dioxopiperidin-3-yl)ureido)-4-methylthiophene-3-carboxylate 2b (1.0 g, 2.95 mmol) was dissolved in DMF (5 mL), cooled to 0°C, and N-bromosuccinimide (0.58 g, 3.25 mmol) was added. The mixture was stirred for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with water (20 mL x 2) and concentrated to dryness to obtain 2c (1.2 g, 97.37%) as a brown oil.

[0334] Step 7: Synthesis of 6-bromo-3-(2,6-dioxopiperidin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 2d

[0335] Ethyl 5-bromo-2-(3-(2,6-dioxopiperidin-3-yl)ureido)-4-methylthiophene-3-carboxylate 2c (1.2 g, 2.87 mmol) was dissolved in 1,4-dioxane (10 mL), potassium tert-butoxide (1.29 g, 11.48 mmol) was added, and the mixture was heated to 50°C with stirring for 4 h. The reaction solution was poured into water (100 mL), the pH was adjusted to 1 with 2M HCl, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with water (50 mL x 2) and concentrated to afford 2d (0.42 g, 39.33% yield).

[0336] MS (ESI, pos.ion) m / z: 372.2 [M+H] + .

[0337] Step 8: Synthesis of tert-butyl 4-(3-(2,6-dioxypiperidin-3-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)piperazine-1-carboxylate 2e

[0338] 6-Bromo-3-(2,6-dioxopiperidin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 2d (2.0 g, 5.37 mmol) was dissolved in N-methylpyrrolidone (30 mL), and tert-butyl piperazine-1-carboxylate (2.00 g, 10.74 mmol) and N,N-diisopropylethylamine (2.08 g, 16.11 mmol) were added and reacted at 90°C for 25 hours. The reaction solution was cooled to room temperature, water (180 mL) was added, and the mixture was extracted with ethyl acetate (180 mL). The organic phase was washed with saturated sodium chloride solution (120 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (V EA / V PE =1 / 1) to afford brown oil 2e (1.5 g, yield 58.46%).

[0339] Step 9: Synthesis of (3-(2,6-dioxopiperidin-3-yl)-5-methyl-6-(piperazin-1-yl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione hydrochloride 2f

[0340] Tert-butyl 4-(3-(2,6-dioxypiperidin-3-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)piperazine-1-carboxylate 2e (1.20 g, 2.51 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (5 mL) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to afford 2f (1.0 g, 96.15% yield) as a brown solid.

[0341] MS (ESI, pos.ion) m / z: 478.5 [M+H] + .

[0342] Step 10: Synthesis of N-(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 2

[0343] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide 1s (0.20 g, 0.43 mmol) and (3-(2,6-dioxopiperidin-3-yl)-5-methyl-6-(piperazin-1-yl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione hydrochloride 2f (0.16 g, 0.43 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 2.5 h. Sodium triacetoxyborohydride (0.27 g, 1.29 mmol) was added and the reaction was continued with stirring for 16 h. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (V EA / V PE =1 / 3) to give an off-white solid 2 (44 mg, yield 12.41%, purity 90.97%).

[0344] MS(ESI,pos.ion)m / z:829.30[M+H] + ;

[0345] 1H NMR (400MHz, CDCl3) δ (ppm) 7.98 (d, J = 9.6Hz, 1H), 7.93 (s, 1H), 7.56 (d, J = 8.7Hz, 1H), 6.99 (t ,J=6.0Hz,2H),6.85(dd,J=8.7,2.3Hz,1H),4.52(s,2H),4.32(t,J=9.6Hz,1H),4.06(d,J=8. 5Hz,1H),3.03(t,J=12.4Hz,2H),2.94-2.74(m,6H),2.60(s,3H),2.34(d,J=17.9Hz,5H),2.1 7(s,6H),1.99-1.87(m,3H),1.68(d,J=11.6Hz,3H),1.55-1.44(m,3H),1.42(d,J=6.9Hz,2H).

[0346] Example 3 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(3-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)-1H-1,2,4-triazol-1-yl)pyridazine-3-carboxamide 3

[0347] Step 1: Synthesis of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide

[0348] 6-Chloropyridazine-3-carboxylic acid (55.0 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.27 g, 0.71 mmol) was added. 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride 1p (0.1 g, 0.35 mmol) and N,N-diisopropylethylamine (0.14 g, 1.05 mmol) were then added. The mixture was reacted at room temperature for 24 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed sequentially with water (30 mL × 2) and saturated sodium chloride solution (30 mL), and concentrated to afford 1t (0.13 g, 95.42% yield) as a white solid.

[0349] MS (ESI, pos.ion) m / z: 391.2 [M+H] + .

[0350] Step 2: Synthesis of tert-butyl 4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-1H-1,2,4-triazole-3-carbonyl)piperazine-1-carboxylate 3a

[0351] Tert-butyl 4-(1H-1,2,4-triazole-3-carbonyl)piperazine-1-carboxylate (140 mg, 0.50 mmol) and 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide 1t (195.63 mg, 0.50 mmol) were dissolved in N,N-dimethylformamide (1 mL). Cesium carbonate (325.82 mg, 1.0 mmol) was added, and the mixture was heated to 65°C and stirred for 8 h. Saturated aqueous sodium chloride solution (5 mL) was added to the reaction mixture, stirred for 0.5 h, filtered, and the filter cake was rinsed with water (1 mL) and dried to obtain 3a as a yellow solid (0.30 g, 94.13% yield).

[0352] MS (ESI, negative ion) m / z: 634.45 [MH] - .

[0353] Step 3: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(3-(piperazine-1-carbonyl)-1H-1,2,4-triazol-1-yl)pyridazine-3-carboxamide trifluoroacetate 3b

[0354] Tert-butyl 4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-1H-1,2,4-triazole-3-carbonyl)piperazine-1-carboxylate 3a (298 mg, 0.47 mmol) was dissolved in dichloromethane (3 mL) and replaced with nitrogen. Trifluoroacetic acid (0.5 mL, 6.73 mmol) was added with stirring and the reaction was continued with stirring for 16 h. The reaction solution was concentrated under reduced pressure, and ethanol (15 mL) was added to the residue for dissolution. The solvent was then concentrated under reduced pressure to afford 3b (304 mg, 100% yield) as a yellow solid.

[0355] Step 4: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(3-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)-1H-1,2,4-triazol-1-yl)pyridazine-3-carboxamide 3

[0356] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(3-(piperazine-1-carbonyl)-1H-1,2,4-triazol-1-yl)pyridazine-3-carboxamide trifluoroacetate 3b (304 mg, 0.47 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione 1b (152 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (3 mL), and diisopropylethylamine (304 mg, 2.35 mmol) was added under stirring. The temperature was raised to 90°C and the reaction was stirred for 5 h. The reaction solution was cooled to room temperature, water (5 mL) was added to the reaction solution, stirred for 0.5 h, and then filtered. The filter cake was washed with water (2 mL), the filter cake was collected and dried, and the obtained crude product was separated and purified by silica gel column chromatography (V DCM / V MeOH =50:1), the eluate was collected and concentrated to give a bluish-yellow solid 3 (230 mg, yield 60.70%).

[0357] MS(ESI,pos.ion)m / z:810.60[M+H] + ;

[0358] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.12 (s, 1H), 9.79 (s, 1H), 9.17 (d, J = 8.1Hz, 1H), 8.46 (d, J = 9.0Hz, 1H), 8.37 (d, J = 9.0Hz, 1H), 7.86 (d, J = 8.8Hz, 1H),7.78(d,J=11.2Hz,1H),7.53(d,J=7.3Hz,1H),7.41(d,J=2.4Hz,1H),7.15(dd,J=8.8,2.4Hz,1H),5.12(dd,J=12.8,5.4Hz,1H),4.56(tt,J =10.0,4.2Hz,1H),3.96(dd,J=7.6,3.7Hz,1H),3.90(d,J=9.5Hz,4H),3.44-3.37(m,2H),3.34(s,2H),2.90(ddd,J=16.7,13.8,5.4Hz,1H),2.6 5-2.53(m,2H),2.18-2.10(m,2H),2.05(dd,J=10.9,5.6Hz,1H),2.00-1.91(m,2H),1.72(dd,J=17.6,7.5Hz,2H),1.55(td,J=13.2,6.7Hz,2H).

[0359] Example 4 N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((2S)-4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)morpholin-2-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide 4

[0360] Step 1: Synthesis of tert-butyl 6-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyridazine-3-carboxylate 4a

[0361] 6-Chloropyridazine-3-carboxylic acid tert-butyl ester 1f (1.00 g, 4.66 mmol), N-Boc-piperazine (0.95 g, 5.13 mmol), anhydrous potassium carbonate (1.93 g, 13.98 mmol) and tetrabutylammonium iodide (0.17 g, 0.47 mmol) were dissolved in 1,4-dioxane (20 mL) and reacted at 100°C for 8 h. The reaction solution was filtered to remove potassium carbonate, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (V PE / V EA =2 / 1) to give a white solid 4a (1.10 g, yield 64.79%).

[0362] MS (ESI, pos.ion) m / z: 365.8 [M+H] + .

[0363] Step 2: Synthesis of 6-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyridazine-3-carboxylic acid 4b

[0364] Tert-butyl 6-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyridazine-3-carboxylate 4a (0.50 g, 1.37 mmol) was dissolved in methanol (10 mL) and water (2 mL), and lithium hydroxide monohydrate (0.23 g, 5.48 mmol) was added. The mixture was allowed to react at room temperature for 15 h. The reaction solution was concentrated, and water (10 mL) was added. The pH was adjusted to 6 with 1M hydrochloric acid. A solid precipitated and was filtered. The filter cake was rinsed with water (10 mL) and dried to afford 4b (0.36 g, 85.10% yield) as a white solid.

[0365] MS (ESI, pos.ion) m / z: 309.2 [M+H] + .

[0366] Step 3: Synthesis of tert-butyl 4-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazine-1-carboxylate 4c

[0367] 6-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)pyridazine-3-carboxylic acid 4b (0.36 g, 1.17 mmol) and N,N-diisopropylethylamine (0.60 g, 4.68 mmol) were dissolved in N,N-dimethylformamide (10 mL). N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.89 g, 2.34 mmol) was added and stirred at room temperature for 10 min. 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride 1p (0.34 g, 1.17 mmol) was then added and reacted at room temperature for 4 hours. Water (100 mL) was added and a solid precipitated. The solid was filtered and the filter cake was rinsed with water (10 mL). The filter cake was collected, dried and purified by silica gel column chromatography (V DCM / V MeOH =50 / 1) to afford 4c as a white solid (0.40 g, yield 63.32%).

[0368] MS (ESI, pos.ion) m / z: 541.2 [M+H] + .

[0369] Step 4: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(piperidin-1-yl)pyridazine-3-carboxamide hydrochloride 4d

[0370] Tert-butyl 4-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazine-1-carboxylate 4c (0.40 g, 0.74 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (4 mL) and stirred at room temperature for 15 h. The reaction mixture was concentrated to afford 4d (0.35 g, 99.17% yield) as a white solid.

[0371] MS (ESI, pos.ion) m / z: 441.3 [M+H] + .

[0372] Step 5: Synthesis of (S)-tert-butyl 2-((4-(6-(((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazin-1-yl)methyl)morpholine-4-carboxylate 4e

[0373] Dissolve N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(piperidin-1-yl)pyridazine-3-carboxamide hydrochloride 4d (0.35 g, 0.73 mmol) and (R)-2-formylmorpholine-4-carboxylic acid tert-butyl ester (0.16 g, 0.73 mmol) in dichloromethane (10 mL), stir at room temperature for 1 hour, then add sodium triacetoxyborohydride (0.46 g, 2.19 mmol), and react at room temperature for 3 hours. Add water (10 mL), extract with DCM (50 mL×3), combine the organic phases, concentrate, and the resulting residue is purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to afford 4e (0.23 g, 49.00% yield) as a pale yellow solid.

[0374] MS (ESI, pos.ion) m / z: 640.4 [M+H] + .

[0375] Step 6: Synthesis of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((R)-morpholin-2-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide hydrochloride 4f

[0376] Tert-butyl (S)-2-((4-(6-(((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazin-1-yl)methyl)morpholine-4-carboxylate 4e (0.24 g, 0.37 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (4 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford 4f (0.20 g, 92.53% yield) as a yellow solid.

[0377] MS (ESI, pos.ion) m / z: 540.4 [M+H] + .

[0378] Step 7: Synthesis of N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((2S)-4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)morpholin-2-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide

[0379] N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((R)-morpholin-2-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide hydrochloride 4f (0.20 g, 0.35 mmol), 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione 1b (0.10 g, 0.35 mmol) and N,N-diisopropylethylamine (0.18 g, 1.40 mmol) were dissolved in N,N-dimethylformamide (5 mL) and heated to 80 ° C for 5 h. Water (30 mL) was added to precipitate a solid, which was filtered and dried. The filter cake was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give a yellow solid 4 (30.0 mg, yield 10.62%).

[0380] MS (ESI, pos.ion) m / z: 814.1 [M+H] + ;

[0381] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.12 (s, 1H), 8.62 (d, J = 8.2Hz, 1H), 7.85 (t, J = 8.9Hz, 2H), 7.77 (d, J = 11.4Hz, 1H), 7.49 (d, J = 7.4Hz ,1H),7.42-7.27(m,2H),7.14(dd,J=8.8,2.4Hz,1H),5.12(dd,J=12.8,5.4Hz,1H),4.54(dt,J=10.0,5.9Hz,1H),3.94(d,J=11.5H z,1H),3.91-3.81(m,2H),3.71(s,4H),3.59(d,J=11.9Hz,1H),3.47(d,J=11.8Hz,1H),3.00(t,J=11.1Hz,1H),2.95-2.85(m,1H), 2.83-2.76(m,1H),2.69-2.51(m,9H),2.14-2.00(m,3H),1.95-1.86(m,2H),1.65(q,J=11.7,10.8Hz,2H),1.52(q,J=10.5Hz,2H).

[0382] Example 5 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 5

[0383] Step 1: Synthesis of tert-butyl 4-(1-benzylpiperidin-4-yl)piperazine-1-carboxylate 5b

[0384] tert-Butyl piperazine-1-carboxylate (5.1 g, 26.95 mmol) was dissolved in tetrahydrofuran (50 mL), and 1-benzylpiperidin-4-one 5a (5.07 g, 27.22 mmol) was added. The pH was adjusted to 6 with acetic acid (15 mL). The mixture was stirred for 0.5 h, cooled to 0°C, and sodium triacetoxyborohydride (3.08 g, 14.55 mmol) was slowly added. The mixture was allowed to react at room temperature for 4 h. The reaction mixture was quenched with sodium bicarbonate solution, and the pH was adjusted to 9-10. The mixture was extracted with ethyl acetate (250 mL × 3). The combined organic phases were washed sequentially with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 5b (9.6 g, 99.09% yield), a yellow liquid.

[0385] Step 2: Synthesis of tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate 5c

[0386] Dissolve tert-butyl 4-(1-benzylpiperidin-4-yl)piperazine-1-carboxylate 5b (3.0 g, 8.34 mmol) in methanol (20 mL). Add 10% Pd / C (1.78 g, 1.67 mmol). Replace the atmosphere with hydrogen three times (using a hydrogen balloon). Stir and continue the reaction at room temperature for 4 hours. TLC analysis confirmed the complete reaction. The mixture was filtered, the filtrate collected, and concentrated under reduced pressure to afford 5c as a yellow oil (2.20 g, 97.83% yield).

[0387] Step 3: Synthesis of tert-butyl 4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidine-1-carboxylate 5d

[0388] 4-(Piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester 5c (0.70 g, 2.60 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 1,2-difluoro-4-nitrobenzene (0.42 g, 2.65 mmol) and triethylamine (0.53 g, 5.2 mmol) were added. The reaction was allowed to react at room temperature for 14 h. The reaction solution was poured into water (30 mL) to quench the reaction solution, and extracted with ethyl acetate (60 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated. The resulting residue was purified by silica gel column chromatography (V PE / V EA =10 / 1) to give a yellow solid 5d (0.38 g, yield 35.8%).

[0389] Step 4: Synthesis of 2-fluoro-4-nitrophenyl-4-piperidin-4-piperazine 5e

[0390] Tert-butyl 4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidine-1-carboxylate 5d (0.38 g, 0.93 mmol) was dissolved in ethyl acetate (3.0 mL). 4 M hydrogen chloride in ethyl acetate (0.70 mL, 2.79 mmol) was added with stirring and allowed to react at room temperature for 6 h. The reaction solution was concentrated to afford 5e (0.32 g, 99.76% yield) as a yellow solid.

[0391] Step 5: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 5f

[0392] 2-Fluoro-4-nitrophenyl-4-piperidin-4-piperazine 5e (0.32 g, 0.93 mmol) was dissolved in N,N-dimethylformamide (4 mL), and potassium carbonate (0.26 g, 1.86 mmol) and 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide 1t (0.38 g, 0.98 mmol) were added. The mixture was reacted at 100°C for 16 h. The reaction solution was cooled to room temperature, quenched with water (20 mL), and extracted with dichloromethane (35 mL x 2). The organic phases were combined and concentrated, and the resulting residue was purified by silica gel column chromatography (100% EtOAc) to afford 5f as a yellow solid (0.20 g, 32.50% yield).

[0393] Step 6: Synthesis of 5 g of 6-(4-(4-(4-amino-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide

[0394] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 5f (0.19 g, 0.29 mmol) was dissolved in ethanol (3 mL). Iron powder (48.59 mg, 0.87 mmol) and ammonium chloride (77.56 mg, 1.45 mmol) in water (1 mL) were added and refluxed at 85°C for 3 h. The reaction solution was cooled to room temperature, diluted with ethanol (20 mL), and filtered through a pad of celite. The filtrate was collected and concentrated. The resulting solid was slurried with water (30 mL), filtered, and the filter cake was dried to obtain 5 g (0.17 g, 93.71% yield) of a yellow solid.

[0395] Step 7: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 5

[0396] 5 g (0.17 g, 0.27 mmol) of 6-(4-(4-(4-amino-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)-N-((1r,4r)-4-3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide was dissolved in N,N-dimethylformamide (3 mL), and 3-bromopiperidine-2,6-dione (0.10 g, 0.54 mmol) and sodium bicarbonate (0.068 g, 0.81 mmol) were added. The mixture was protected by nitrogen and reacted at 70°C for 15 h. The reaction solution was cooled to room temperature and quenched by adding water (20 mL). Solid precipitated and was filtered. The filter cake was washed with water (10 mL × 2), collected and dried, and purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give an off-white solid 5 (20 mg, yield 10.01%).

[0397] MS (ESI, pos.ion) m / z: 744.7 [M+H] + ;

[0398] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.78 (s, 1H), 8.62 (d, J = 8.2Hz, 1H), 7.85 (t, J = 9.1Hz, 2H), 7.41-7 .33(m,2H),7.14(dd,J=8.8,2.5Hz,1H),6.84(t,J=9.3Hz,1H),6.52-6.39(m,2H),5.80(d,J=7.7H z,1H),4.54(s,1H),4.30-4.21(m,1H),3.86(s,1H),3.70(s,4H),3.19(s,3H),2.58(d,J=9.2Hz,3 H), 2.35 (s, 2H), 2.10 (s, 3H), 1.87 (d, J = 11.8Hz, 6H), 1.60 (dt, J = 30.1, 14.7Hz, 7H), 1.23 (s, 1H).

[0399] Example 6 N-(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(4-(S)-2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenylpiperazine-1-carbonyl)piperidin-1-yl)pyridazine-3-carboxamide 6

[0400] Step 1: Synthesis of 1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carboxylic acid 1u

[0401] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide 1r (1.0 g, 2.13 mmol) was dissolved in DCM (10 mL) and Dess-Martin periodinane (1.08 g, 2.56 mmol) was added. The mixture was allowed to react at room temperature for 6 h. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution and saturated sodium thiosulfate solution (V / V = 1 / 1, 25 mL). The mixture was stirred for 30 min and extracted with DCM (50 mL × 2). The combined organic phases were washed sequentially with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford 1u (0.50 g, 48.55% yield) as a yellow solid.

[0402] Step 2: Synthesis of methyl 4-bromo-3-fluorobenzoate 6b

[0403] 4-Bromo-3-fluorobenzoic acid 6a (2.0 g, 9.13 mmol) was dissolved in methanol (20.0 mL), and concentrated hydrochloric acid (0.93 mL, 10.96 mmol) was added. The reaction was allowed to react at 70°C for 16 h. The reaction solution was cooled to room temperature and concentrated. The resulting white solid was slurried with saturated sodium bicarbonate solution (10 mL), filtered, and the filter cake was dried to obtain 6b (1.6 g, 75.18% yield) as a white solid.

[0404] Step 3: Synthesis of tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate 6c

[0405] Methyl 4-bromo-3-fluorobenzoate 6b (0.50 g, 2.15 mmol) was dissolved in toluene (5.0 mL). 1-Butyl piperazine-1-carboxylate (0.44 g, 2.37 mmol), cesium carbonate (1.40 g, 4.3 mmol), dimethylbisphenylphosphine anthracene (0.37 g, 0.64 mmol) and tris(dibenzylideneacetone)dipalladium (0.20 g, 0.21 mmol) were added in sequence at 10°C. The atmosphere was replaced with nitrogen and refluxed at 110°C for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), filtered, and the filtrate was collected and concentrated. The residue was purified by silica gel column chromatography (V PE / V EA =5 / 1) to afford yellow solid 6c (0.50 g, yield 68.6%).

[0406] Step 4: Synthesis of 4-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid 6d

[0407] Tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate 6c (0.20 g, 0.77 mmol) and tert-butyl piperazine-1-carboxylate (0.15 g, 0.59 mmol) were dissolved in tetrahydrofuran (2.0 mL). 1 M sodium hydroxide solution (1.18 mL, 1.18 mmol) was added, and the atmosphere was replaced with nitrogen. The reaction was allowed to proceed at 60°C for 6 h. The reaction solution was cooled to room temperature, and the pH was adjusted to 5 with 1 N hydrochloric acid solution. Water (15 mL) was then added to precipitate a solid, which was filtered and the filter cake was dried to afford 6d (0.16 g, 83.46% yield) as a white solid.

[0408] Step 5: Synthesis of (S)-tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperidine-1-carboxylate 6e

[0409] 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid 6d (0.16 g, 0.49 mmol) was dissolved in N,N-dimethylformamide (2.0 mL). 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.37 g, 0.98 mmol) was added and reacted at room temperature for 30 min. 3-Aminopiperidine-2,6-dione (0.14 g, 0.29 mmol) and N,N-diisopropylethylamine (0.19 g, 1.47 mmol) were then added. The atmosphere was replaced with nitrogen and the reaction continued at room temperature for 12 h. Water (15 mL) was added to the reaction mixture, which was then filtered and the filter cake was dried to afford 6e (0.19 g, 88.65% yield) as a white solid.

[0410] Step 6: Synthesis of (S)-N-(2,6-dioxopiperidin-3-yl)-3-fluoro-4-(piperidin-1-yl)benzamide hydrochloride 6f

[0411] Dissolve tert-butyl (S)-4-(4-(2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperidine-1-carboxylate 6e (0.19 g, 0.44 mmol) in ethyl acetate (2.0 mL). Add 4 M hydrogen chloride in ethyl acetate (0.33 mL, 1.32 mmol) and react at room temperature for 4 h. The reaction solution was concentrated to afford 6f (0.16 g, 98.67% yield), a white foamy solid.

[0412] Step 7: Synthesis of N-(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(4-(S)-2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenylpiperazine-1-carbonyl)piperidin-1-yl)pyridazine-3-carboxamide 6

[0413] 1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carboxylic acid 1u (0.24 g, 0.49 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.37 g, 0.96 mmol) was added, and the mixture was stirred for 30 min. (S)-N-(2,6-dioxopiperidin-3-yl)-3-fluoro-4-(piperidin-1-yl)benzamide hydrochloride 6f (0.16 g, 0.43 mmol) and N,N-diisopropylethylamine (0.19 g, 1.44 mmol) were added, and the atmosphere was replaced with nitrogen for protection. The reaction was carried out at room temperature for 6 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with DCM (15 mL×2). The combined organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give a yellow solid 6 (30 mg, yield 8.69%).

[0414] MS (ESI, Pos.ion) m / z: 801.3 [M+H] + ;

[0415] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.86 (s, 1H), 8.72 (d, J = 8.3Hz, 1H), 8.60 (d, J = 8.2Hz ,1H),7.84(dd,J=13.3,9.1Hz,2H),7.72-7.65(m,2H),7.38(t,J=6.8Hz,2H),7.14( d,J=8.6Hz,2H),4.52(s,2H),3.76(s,2H),3.64(s,2H),3.15(d,J=12.8Hz,4H),3.0 9(s,4H),2.11(s,4H),1.99-1.88(m,4H),1.77(d,J=12.8Hz,2H),1.67-1.48(m,8H).

[0416] Example 7 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 7

[0417] Step 1: Synthesis of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate 7b

[0418] 1-(4-Bromophenyl)piperazine 7a (1.50 g, 6.22 mmol), triethylamine (1.57 g, 15.55 mmol), and 4-dimethylaminopyridine (76 mg, 0.62 mmol) were dissolved in acetonitrile (30 mL). Boc anhydride (1.49 g, 6.84 mmol) was added and allowed to react at room temperature for 3 h. The reaction solution was poured into water (200 mL) and stirred for crystallization. The mixture was filtered, and the filter cake was rinsed with water (20 mL). The filter cake was collected and dried to obtain an off-white solid 7b (1.75 g, 82.44% yield). MS (ESI, pos. ion) m / z: 341.25 [M+H] + 。

[0419] Step 2: Synthesis of tert-butyl 4-(4-(2,4-dimethoxypyrimidin-5-yl)phenyl)piperazine-1-carboxylate 7c

[0420] 4-(4-bromophenyl)piperazine-1-carboxylic acid tert-butyl ester 7b (0.50 g, 1.47 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (0.41 g, 2.21 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (24 mg, 0.03 mmol) and potassium carbonate (0.61 g, 4.41 mmol) were added to N,N-dimethylformamide (10 mL), replaced with nitrogen protection, and reacted at 100 ° C for 16 hours. The reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (V PE / V EA =9 / 1) to afford an off-white solid 7c (0.32 g, 54.53% yield).

[0421] MS (ESI, pos.ion) m / z: 401.3 [M+H] + .

[0422] Step 3: Synthesis of 5-(4-(piperazin-1-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione hydrochloride 7d

[0423] Tert-butyl 4-(4-(2,4-dimethoxypyrimidin-5-yl)phenyl)piperazine-1-carboxylate 7c (0.32 g, 0.80 mmol) was dissolved in acetic acid (5.0 mL), and 2M aqueous hydrochloric acid (4.0 mL, 2.5 mmol) was added. The reaction was allowed to react at 100°C for 8 h. The reaction solution was cooled to room temperature, and methanol (10 mL) was added. The mixture was stirred for 2 h to allow crystallization. The product was then filtered, and the filter cake was rinsed with methanol (5.0 mL). The filter cake was collected and dried to afford an off-white solid 7d (0.20 g, 81.06% yield).

[0424] MS (ESI, pos.ion) m / z: 273.3 [M+H] + .

[0425] Step 4: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 7

[0426] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(formyl)piperidin-1-yl)pyridazine-3-carboxamide 1s (30.0 mg, 0.064 mmol) and 5-(4-(piperazin-1-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione hydrochloride 7d (21.7 mg, 0.07 mmol) were dissolved in N,N-dimethylacetamide (1.0 mL). After stirring for 1 h, sodium triacetoxyborohydride (40.7 mg, 0.19 mmol) was added and the reaction was carried out at room temperature for 12 h. Water (20 mL) was poured into the reaction solution and stirred for 30 min. Solid precipitated and was filtered. The filter cake was rinsed with water (20 mL) and then dried. The resulting off-white solid was purified by HPLC [eluent: 37% ACN / 63% water (0.01% TFA)] to give an off-white solid 9 (20 mg, 43.07% yield). MS (ESI, pos. ion) m / z: 724.6 [M+H] + ;

[0427] 1H NMR (400MHz, CDCl3) δ (ppm) 11.14 (s, 1H), 10.98 (s, 1H), 8.58 (d, J = 8.2Hz, 1H), 7.85 (d, J = 8.7Hz, 1H), 7.80 (d, J = 9.6Hz, 1H) ,7.48(d,J=4.9Hz,1H),7.43–7.36(m,3H),7.33(d,J=9.7Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),6.91(d,J=8.5Hz,2H),4.50(t ,J=14.7Hz,3H),3.86(d,J=8.0Hz,1H),3.14(d,J=5.9Hz,4H),3.02(t,J=12.5Hz,2H),2.20(d,J=7.1Hz,2H),2.10(d,J=11.7 Hz,2H),1.87(dd,J=25.3,12.7Hz,6H),1.64(q,J=12.2Hz,2H),1.51(d,J=12.0Hz,2H),1.23(s,1H),1.12(q,J=12.1Hz,2H).

[0428] Example 8 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 8

[0429] Step 1: Synthesis of tert-butyl 4-(4-(2,6-dimethoxypyrimidin-4-yl)phenyl)piperazine-1-carboxylate 8b

[0430] 4-Bromo-2,6-dimethoxypyrimidine (0.50 g, 2.28 mmol), (4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)phenyl)boronic acid 8a (1.05 g, 3.42 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (37 mg, 0.05 mmol) and potassium carbonate (0.95 g, 6.84 mmol) were dissolved in N,N-dimethylformamide (25 mL), replaced with nitrogen protection, and reacted at 100°C for 15 h. The reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate (20 mL). The combined filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (V PE / V EA =9 / 1) to afford an off-white solid 8b (0.46 g, 50.32% yield).

[0431] MS (ESI, pos.ion) m / z: 401.3 [M+H] + .

[0432] Step 2: Synthesis of 6-(4-(piperazin-1-yl)phenyl)-pyrimidine-2,4(1H,3H)-dione hydrochloride 8c

[0433] Tert-butyl 4-(4-(2,6-dimethoxypyrimidin-4-yl)phenyl)piperazine-1-carboxylate 8b (0.10 g, 0.25 mmol) was dissolved in acetic acid (5.0 mL), and 2M aqueous hydrochloric acid (4.0 mL, 2.5 mmol) was added. The mixture was reacted at 100°C for 18 h. The reaction solution was cooled to room temperature, adjusted to pH 7 with saturated aqueous sodium bicarbonate, and stirred for 2 h to allow crystallization. The mixture was filtered, and the filter cake was collected and dried to afford an off-white solid 8c (0.20 g, 81.71% yield).

[0434] MS (ESI, pos.ion) m / z: 273.3 [M+H] + .

[0435] Step 3: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)

[0436] (piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 8

[0437] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(formyl)piperidin-1-yl)pyridazine-3-carboxamide 1s (50 mg, 0.11 mmol) and 6-(4-(piperazin-1-yl)phenyl)-pyrimidine-2,4(1H,3H)-dione hydrochloride 8c (37.4 mg, 0.12 mmol) were dissolved in methanol (3.0 mL). After stirring for 10 min, sodium cyanoborohydride (27.3 mg, 0.13 mmol) was added and the reaction was carried out at room temperature for 18 h. Water (30 mL) was added to the reaction solution and stirred for 30 min to precipitate a solid, which was filtered and the filter cake was rinsed with water (20 mL). The filter cake was collected and dried, and the obtained solid was purified by HPLC [eluent: 37% ACN / 63% water (0.01% TFA)] to give an off-white solid 8 (34 mg, yield 43.94%).

[0438] MS (ESI, pos.ion) m / z: 724.6 [M+H] + ;

[0439] 1H NMR (400MHz, DMSO-d6) δ (ppm) 10.91 (d, J = 16.0Hz, 2H), 8.58 (d, J = 8.0Hz, 1H), 7.83 (dd, J = 20. 8,9.3Hz,2H),7.71-7.51(m,2H),7.48-7.23(m,2H),7.14(s,1H),6.98(d,J=8.4Hz,2H),5.74 (s,1H),4.48(d,J=15.7Hz,3H),3.86(s,1H),3.30-3.17(m,4H),3.02(t,J=12.9Hz,2H),2.40 -2.05(m,7H),1.86(d,J=28.3Hz,5H),1.58(dd,J=50.5,12.7Hz,4H),1.18(d,J=43.3Hz,3H).

[0440] Example 9 N-((1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 9

[0441] Step 1: Synthesis of tert-butyl 6-(4-(4-(3-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylate 9a

[0442] At room temperature, 1-(3-fluoro-4-nitrobenzene)-4-(piperidin-4-yl)piperazine hydrochloride 5e (0.50 g, 1.45 mmol), tert-butyl 6-chloropyridazine-3-carboxylate (0.34 g, 1.59 mmol) and N,N-diisopropylethylamine (0.75 g, 5.80 mmol) were dissolved in acetonitrile (5 mL) and heated to 80°C with stirring for 24 hours. The reaction solution was concentrated, and the resulting residue was purified by slurrying with water (20 mL), filtered, and the filter cake was washed with a mixture of petroleum ether and ethyl acetate (V EA / V PE =1 / 9, 10 mL) and filtered to obtain a yellow solid 9a (0.51 g, yield 72.29%).

[0443] MS (ESI, pos.ion) m / z: 487.5 [M+H] + .

[0444] Step 2: Synthesis of tert-butyl 6-(4-(4-(4-amino-3-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylate 9b

[0445] Tert-butyl 6-(4-(4-(3-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylate 9a (0.51 g, 1.05 mmol) and palladium on carbon (0.39 g, 3.65 mmol) were dissolved in methanol (10 mL) and hydrogenated at room temperature for 24 hours with stirring. The mixture was filtered and the filtrate was concentrated to afford 9b (0.45 g, 94.05% yield) as a pale yellow solid.

[0446] MS (ESI, pos.ion) m / z: 457.4 [M+H] + .

[0447] Step 3: Synthesis of tert-butyl 6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylate 9c

[0448] 6-(4-(4-(4-amino-3-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylic acid tert-butyl ester 9b (0.45 g, 0.99 mmol), 3-bromopiperidine-2,6-dione (0.57 g, 2.97 mmol) and sodium bicarbonate (0.83 g, 9.90 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 70 ° C for 25 hours. Water (10 mL) and dichloromethane (10 mL) were added to extract the liquid, and the organic phase was concentrated. The resulting residue was separated and purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to afford a yellow solid 9c (0.39 g, yield 69.71%).

[0449] MS (ESI, pos.ion) m / z: 568.7 [M+H] + .

[0450] Step 4: Synthesis of 6-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylic acid 9d

[0451] Tert-butyl 6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylate 9c (0.44 g, 0.78 mmol) was dissolved in 1,4-dioxane hydrochloric acid solution (4 M, 4 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain 9d (0.39 g, 98.36% yield) as a yellow solid.

[0452] MS (ESI, pos.ion) m / z: 512.5 [M+H] + .

[0453] Step 5: Synthesis of N-((1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)-6-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 9

[0454] (1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexane-1-amine hydrochloride 1o (0.10 g, 0.30 mmol), 6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylic acid 9d (0.15 g, 0.30 mmol) and N,N-diisopropylethylamine (0.16 g, 1.20 mmol) were dissolved in dichloromethane (5 mL), 1-propylphosphonic anhydride (0.38 g, 0.60 mmol, 50% EA solution) was added at 0°C, and then stirred at room temperature for 2 hours. Water (20 mL) and dichloromethane (5 mL) were added to the reaction solution, the liquid was extracted, the organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give an off-white solid 9 (16.0 mg, 13.42% yield) with a purity of 89.46%.

[0455] MS (ESI, pos.ion) m / z: 787.3 [M+H] + ;

[0456] 1 H NMR (400MHz, Chloroform-d) δ (ppm) 8.80 (s, 1H), 8.17 (s, 1H), 8.01 (d, J = 9.6Hz, 1H), 7.91 (t, J = 9.1Hz, 2H), 7. 10(d,J=2.5Hz,1H),7.02(d,J=9.6Hz,1H),6.97-6.84(m,2H),6.49-6.40(m,2H),4.65-4.53(m,3H),4.34(d,J= 10.5Hz,1H),4.05(dd,J=26.2,10.9Hz,2H),3.09(q,J=9.4,6.1Hz,6H),2.93-2.65(m,8H),2.54(ddd,J=11.4,5 .7,3.2Hz,1H),2.22(d,J=11.1Hz,4H),2.08(d,J=12.6Hz,2H),1.65(d,J=12.3Hz,4H),1.50(d,J=11.0Hz,2H).

[0457] Example 10 N-((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)-6-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 10

[0458] Step 1: Synthesis of tert-butyl ((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)carbamate 10b

[0459] Trans-4-Boc-aminocyclohexanol (1.00 g, 4.64 mmol) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydride (0.28 g, 6.96 mmol, 60% wt) was added with stirring at 0°C, followed by 4-fluoro-2-methoxybenzonitrile 10a (0.84 g, 5.57 mmol). The reaction was allowed to react for 6 hours. Water (200 mL) was added to quench the reaction mixture, resulting in the precipitation of a solid. The filter cake was then filtered, rinsed with water (50 mL), and dried to afford 10b (0.95 g, 59.04% yield) as a white solid.

[0460] Step 2: Synthesis of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-methoxybenzonitrile hydrochloride 10c

[0461] Tert-butyl ((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)carbamate 10b (0.20 g, 0.58 mmol) was dissolved in 1,4-dioxane hydrochloride (4 M, 4 mL) and stirred at room temperature for 6 hours. The reaction solution was concentrated to afford 10c (0.16 g, 98.01% yield) as a pale yellow solid. MS (ESI, pos. ion) m / z: 247.2 [M+H] + .

[0462] Step 3: Synthesis of 6-chloro-N-((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)pyridazine-3-carboxamide 10d

[0463] 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-methoxybenzonitrile hydrochloride 10c (0.82 g, 2.90 mmol), 6-chloropyridazine-3-carboxylic acid (0.51 g, 3.19 mmol) and N,N-diisopropylethylamine (1.50 g, 11.60 mmol) were dissolved in dichloromethane (20 mL). 1-Propylphosphonic anhydride (3.69 g, 5.80 mmol, 50% EA solution) was added at 0°C, and then stirred at room temperature for 4 hours. Water (30 mL) and dichloromethane (10 mL) were added to the reaction solution, and the liquid was extracted and separated. The organic phase was dried and the residue was purified by silica gel column chromatography (V PE / V EA =3 / 1) to obtain a white solid 10d (1.09 g, yield 97.17%).

[0464] Step 4: Synthesis of N-((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)-6-(4-(4-(3-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 10e

[0465] 2-Fluoro-4-nitrophenyl-4-piperidin-4-piperazine hydrochloride 5e (0.30 g, 0.87 mmol), 6-chloro-N-((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)pyridazine-3-carboxamide 10d (0.34 g, 0.87 mmol) and potassium carbonate (0.48 g, 3.48 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 100°C for 16 hours. The reaction solution was filtered and concentrated, and the obtained residue was purified by silica gel column chromatography (V DCM / V MeOH =30 / 1) to obtain a yellow solid 10e (0.53 g, yield 92.48%).

[0466] MS (ESI, pos.ion) m / z: 659.4 [M+H] + .

[0467] Step 5: Synthesis of 6-(4-(4-(4-amino-3-fluorophenyl)piperazin-1-yl)piperidin-1-yl)-N-((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)pyridazine-3-carboxamide 10f

[0468] N-((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)-6-(4-(4-(3-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 10e (0.53 g, 0.80 mmol) was dissolved in ethanol (8 mL). Iron powder (0.13 g, 2.40 mmol) and ammonium chloride (0.21 g, 4.00 mmol) in water (2 mL) were added, and the mixture was refluxed at 85°C for 7 hours. The mixture was filtered and the filtrate was concentrated. The resulting residue was slurried with water (20 mL), filtered, and the filter cake was vacuum dried to afford an off-white solid 10f (0.3 g, 59.30% yield).

[0469] MS (ESI, pos.ion) m / z: 629.4 [M+H] + .

[0470] Step 6: Synthesis of N-((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)-6-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 10

[0471] 6-(4-(4-(4-amino-3-fluorophenyl)piperazin-1-yl)piperidin-1-yl)-N-((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)pyridazine-3-carboxamide 10f (0.10 g, 0.16 mmol), 3-bromopiperidine-2,6-dione (92.0 mg, 0.48 mmol) and sodium bicarbonate (0.13 g, 1.60 mmol) were dissolved in N,N-dimethylformamide (2 mL) and heated to 70 ° C with stirring for 21 hours. The reaction solution was quenched with water (10 mL) and a solid precipitated. The filter cake was rinsed with water (10 mL) and dried and then purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give an off-white solid 10 (14 mg, yield 11.90%) with a purity of 90.04%.

[0472] MS (ESI, pos.ion) m / z: 740.4 [M+H] + ;

[0473] 1H NMR(400MHz,Chloroform-d)δ(ppm)8.15(s,1H),8.00(d,J=9.6Hz,1H),7.89(d,J=8.2Hz,1H),7.48(d,J=8.6Hz,1H),7.02(d,J=9.6Hz,1H ),6.89(t,J=9.1Hz,1H),6.58-6.38(m,4H),4.69-4.52(m,3H),4.39-4.31(m,1H),4.11-3.99(m,2H),3.91(s,3H),3.21-3.00(m,6H),2.92 -2.85(m,1H),2.83-2.79(m,3H),2.76(d,J=5.1Hz,1H),2.70(d,J=11.5Hz,1H),2.53(dtd,J=13.0,5.0,2.7Hz,1 H),2.20(dt,J=9.8,5.1Hz,4H),2.10-2.02(m,2H),1.65(dd,J=16.3,7.0Hz,4H),1.54-1.38(m,3H),1.31(s,1H).

[0474] Example 11 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((1-(4-(6-cyano-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-2-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide 11

[0475] Step 1: Synthesis of (1-(4-nitrophenyl)piperidin-4-yl)methanol 11b

[0476] 4-Fluoronitrobenzene (10 g, 70.87 mmol) and 4-piperidinemethanol (16.32 g, 141.74 mmol) were dissolved in DMSO (80 mL) and reacted at 80°C for 22 hours. The reaction solution was cooled to room temperature and quenched by pouring into ice water (160 mL). The mixture was stirred for 1 hour, filtered, and the solid was collected and dried to obtain a yellow solid 11b (16.74 g, 99.97% yield).

[0477] Step 2: Synthesis of 1-(4-nitrophenyl)piperidine-4-carboxaldehyde 11c

[0478] (1-(4-Nitrophenyl)piperidin-4-yl)methanol 11b (3.00 g, 12.70 mmol), dimethyl sulfoxide (0.93 g, 12.7 mmol), and N,N-diisopropylethylamine (11.49 g, 88.90 mmol) were dissolved in dichloromethane (30 mL). Sulfur trioxide (12.13 g, 76.20 mmol) was added at 0°C and allowed to react for 2 hours. Water (30 mL) was added, the layers separated, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 11c as a yellow oil (2.90 g, 97.50% yield).

[0479] Step 3: Synthesis of tert-butyl 4-((1-(4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate 11d

[0480] 1-(4-Nitrophenyl)piperidine-4-carbaldehyde 11c (2.90 g, 12.38 mmol), 1-tert-butyloxycarbonylpiperazine (3.46 g, 18.57 mmol), and acetic acid (0.74 g, 12.38 mmol) were dissolved in methanol (50 mL) and reacted at room temperature for 0.5 h. The mixture was then cooled to 0°C and sodium triacetoxyborohydride (5.25 g, 24.76 mmol) was added. The mixture was allowed to react naturally at room temperature for 16 h. Saturated sodium bicarbonate solution (50 mL) was added to the reaction mixture, stirred for 0.5 h, and filtered. The filter cake was rinsed with water (30 mL) and dried to afford 11d (3.15 g, 62.90% yield) as a yellow solid.

[0481] MS(ESI,pos.ion)m / z:405.30[M+H] + .

[0482] Step 4: Synthesis of tert-butyl 4-((1-(4-aminophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate 11e

[0483] Tert-butyl 4-((1-(4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate 11d (3.15 g, 7.79 mmol) was dissolved in ethanol (20 mL) and THF (20 mL). Water (5 mL), iron powder (3.05 g, 54.53 mmol), and ammonium chloride (1.25 g, 23.37 mmol) were added and reacted at 65°C for 2 hours. The reaction solution was cooled to room temperature, ethyl acetate (80 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered and the filter cake was rinsed with ethyl acetate (30 mL). The filtrate was collected and saturated sodium bicarbonate solution (20 mL) was added. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an off-white solid 11e (2.92 g, 100% yield).

[0484] MS (ESI, pos.ion) m / z: 375.3 [M+H]+ .

[0485] Step 5: Synthesis of tert-butyl (Z)-4-((1-(4-(2-(1-cyano-2-((ethoxycarbonyl)amino)-2-oxoethylidene)hydrazine)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate 11f

[0486] Tert-butyl 4-((1-(4-aminophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate 11e (2.4 g, 6.41 mmol) was dissolved in water (5 mL) and acetic acid (15 mL). Sodium nitrite (0.53 g, 7.69 mmol) was added at 0°C and stirred for 0.5 hour. 18-Crown ether-6 (0.85 g, 3.21 mmol) and N-cyanoacetylurea (1.20 g, 7.69 mmol) were added and reacted at room temperature for 2 hours. The solution was adjusted to pH 8 with saturated sodium bicarbonate solution, and ethyl acetate (100 mL) was added. The layers were separated, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 11f (3.47 g, 99.97% yield) as a black solid.

[0487] Step 6: Synthesis of 11 g of tert-butyl 4-((1-(4-(6-cyano-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0488] (Z)-tert-Butyl 4-((1-(4-(2-(1-cyano-2-((ethoxycarbonyl)amino)-2-oxoethylidene)hydrazine)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate 11f (3.47 g, 6.41 mmol) and sodium acetate (1.58 g, 19.23 mmol) were dissolved in 1,4-dioxane (30 mL) and reacted at 90°C for 6 hours. The reaction solution was concentrated and the resulting residue was separated and purified by silica gel column chromatography (V DCM / V MeOH =30 / 1) to give 11 g (1.45 g, 45.67% yield) of a brown solid.

[0489] MS (ESI, pos.ion) m / z: 496.0 [M+H] + .

[0490] Step 7: Synthesis of 3,5-dioxo-2-(4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 11h

[0491] 11 g (0.20 g, 0.40 mmol) of tert-butyl 4-((1-(4-(6-cyano-3,5-dioxo-1,2,4-triazine-2(3H)-yl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate was dissolved in dichloromethane (3 mL), and a hydrochloric acid ethyl acetate solution (0.10 g, 2.80 mmol, 4 mol / L) was added. The mixture was reacted at room temperature and filtered. The filter cake was collected and dried to give a brown solid 11h (0.15 g, 93.99% yield).

[0492] Step 8: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((1-(4-(6-cyano-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-2-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide 11

[0493] 3,5-dioxo-2-(4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 11h (0.15 g, 0.38 mmol), 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide 1t (0.22 g, 0.57 mmol), and potassium carbonate (0.21 g, 1.52 mmol) were dissolved in acetonitrile (10 mL) and reacted at 82°C for 12 hours. The reaction solution was cooled to room temperature, water (60 mL) was added, stirred for 1 hour, filtered, the filter cake was collected and dried, and then purified by silica gel column chromatography (V DCM / V MeOH =30 / 1) to obtain a yellow solid 11 (0.11 g, yield 36.90%) with a purity of 96.72%.

[0494] MS (ESI, pos.ion) m / z: 750.0 [M+H] + .

[0495] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.62 (d, J = 8.2Hz, 1H), 7.84 (dd, J = 9.0, 4.7Hz, 2H), 7.38 (s, 1H), 7.35 (d, J =9.7Hz,1H),7.25(d,J=8.6Hz,2H),7.13(d,J=8.8Hz,1H),6.98(d,J=8.8Hz,2H),3.86(d,J=7.9Hz,2H),3 .81-3.67(m,9H),2.73(t,J=11.7Hz,2H),2.24(d,J=6.1Hz,2H),2.09(d,J=9.8Hz,2H),1.89(d,J=10.4Hz ,2H),1.81(d,J=12.6Hz,3H),1.64(dd,J=23.7,11.4Hz,2H),1.50(dd,J=22.0,10.5Hz,2H),1.22(s,3H).

[0496] Example 12 N-((1r,4r)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 12

[0497] Step 1: Synthesis of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate 12b

[0498] 1-(4-Bromophenyl)piperazine 12a (1.50 g, 6.22 mmol), triethylamine (1.57 g, 15.55 mmol), and 4-dimethylaminopyridine (76 mg, 0.62 mmol) were dissolved in acetonitrile (30 mL). Boc anhydride (1.49 g, 6.84 mmol) was added and allowed to react at room temperature for 3 hours. The reaction solution was poured into water (200 mL) and stirred for 30 minutes to crystallize. The mixture was filtered, and the filter cake was rinsed with water (20 mL) and dried to afford an off-white solid 12b (1.75 g, 82.44% yield).

[0499] MS(ESI,pos.ion)m / z:341.25[M+H] + .

[0500] Step 2: Synthesis of tert-butyl 4-(4-(2,4-dimethoxypyrimidin-5-yl)phenyl)piperazine-1-carboxylate 12c

[0501] 4-(4-bromophenyl)piperazine-1-carboxylic acid tert-butyl ester 12b (0.50 g, 1.47 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (0.41 g, 2.21 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (24 mg, 0.03 mmol) and potassium carbonate (0.61 g, 4.41 mmol) were added to N,N-dimethylformamide (10 mL), replaced with nitrogen protection, and reacted at 100 ° C for 16 hours. The reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (V PE / V EA =9 / 1) to afford an off-white solid 12c (0.32 g, 54.53% yield).

[0502] MS (ESI, pos.ion) m / z: 401.3 [M+H] + .

[0503] Step 3: Synthesis of 5-(4-(piperazin-1-yl)phenyl)-pyrimidine-2,4(1H,3H)-dione hydrochloride 12d

[0504] Tert-butyl 4-(4-(2,4-dimethoxypyrimidin-5-yl)phenyl)piperazine-1-carboxylate 12c (0.10 g, 0.25 mmol) was dissolved in acetic acid (5.0 mL), and 2M aqueous hydrochloric acid (4.0 mL, 2.5 mmol) was added. The reaction was allowed to react at 100°C for 8 hours. The reaction solution was cooled to room temperature, methanol (10 mL) was added, and the mixture was stirred for 2 hours to allow crystallization. The product was then filtered, and the filter cake was rinsed with methanol (5.0 mL). The filter cake was collected and dried to obtain an off-white solid 12d (0.20 g, 81.06% yield). MS (ESI, pos. ion) m / z: 273.3 [M+H] + .

[0505] Step 4: Synthesis of N-((1r,4r)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 12

[0506] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(formyl)piperidin-1-yl)pyridazine-3-carboxamide 1s (30.0 mg, 0.064 mmol) and 5-(4-(piperazin-1-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione hydrochloride 12d (21.7 mg, 0.07 mmol) were dissolved in N,N-dimethylacetamide (1.0 mL). After stirring for 1 hour, sodium triacetoxyborohydride (40.7 mg, 0.19 mmol) was added and the mixture was reacted at room temperature for 12 hours. Water (20 mL) was poured into the reaction solution and stirred for 30 minutes. A solid precipitated and was filtered. The filter cake was rinsed with water (20 mL). The filter cake was collected and dried to obtain an off-white solid which was purified by HPLC (37% ACN / 63% water (0.01% TFA)) to give an off-white solid 12 (20 mg, yield 25.84%) with a purity of 96.24%.

[0507] MS (ESI, pos.ion) m / z: 725.6 [M+H] + .

[0508] 1 H NMR (400MHz, CDCl3) δ (ppm) 11.14 (s, 1H), 10.98 (s, 1H), 8.58 (d, J = 8.2Hz, 1H), 7.85 (d, J = 8.7Hz, 1H), 7.80 (d, J = 9.6Hz, 1H) ,7.48(d,J=4.9Hz,1H),7.43–7.36(m,3H),7.33(d,J=9.7Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),6.91(d,J=8.5Hz,2H),4.50(t ,J=14.7Hz,3H),3.86(d,J=8.0Hz,1H),3.14(d,J=5.9Hz,4H),3.02(t,J=12.5Hz,2H),2.20(d,J=7.1Hz,2H),2.10(d,J=11.7 Hz,2H),1.87(dd,J=25.3,12.7Hz,6H),1.64(q,J=12.2Hz,2H),1.51(d,J=12.0Hz,2H),1.23(s,1H),1.12(q,J=12.1Hz,2H).

[0509] Example 13 N-((1r,4r)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 13

[0510] Step 1: Synthesis of tert-butyl 4-(4-(2,6-dimethoxypyrimidin-4-yl)phenyl)piperazine-1-carboxylate 13b

[0511] 4-Bromo-2,6-dimethoxypyrimidine (0.50 g, 2.28 mmol), 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid 13a (1.05 g, 3.42 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (37 mg, 0.05 mmol) and potassium carbonate (0.95 g, 6.84 mmol) were dissolved in N,N-dimethylformamide (25 mL), replaced with nitrogen protection, and reacted at 100°C for 15 hours. The reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate (20 mL). The combined filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (V PE / V EA =9 / 1) to afford an off-white solid 13b (0.46 g, 50.32% yield).

[0512] MS (ESI, pos.ion) m / z: 401.3 [M+H] + .

[0513] Step 2: Synthesis of 6-(4-(piperazin-1-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione hydrochloride 13c

[0514] Tert-butyl 4-(4-(2,6-dimethoxypyrimidin-4-yl)phenyl)piperazine-1-carboxylate 13b (0.10 g, 0.25 mmol) was dissolved in acetic acid (5.0 mL), and aqueous hydrochloric acid (4.0 mL, 2.5 mmol, 2 M) was added. The mixture was reacted at 100°C for 18 hours. The reaction solution was cooled to room temperature, adjusted to pH 7 with saturated aqueous sodium bicarbonate, and stirred for 2 hours to allow crystallization. The mixture was filtered, and the filter cake was collected and dried to afford an off-white solid 13c (0.20 g, 81.71% yield).

[0515] MS (ESI, pos.ion) m / z: 273.3 [M+H] + .

[0516] Step 3: Synthesis of N-((1r,4r)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 13

[0517] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(formyl)piperidin-1-yl)pyridazine-3-carboxamide 1s (50 mg, 0.11 mmol) and 6-(4-(piperazin-1-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione hydrochloride 13c (37.4 mg, 0.12 mmol) were dissolved in methanol (3.0 mL). After stirring for 10 minutes, sodium cyanoborohydride (27.3 mg, 0.13 mmol) was added and the reaction was allowed to react at room temperature for 18 hours. Water (30 mL) was added to the reaction solution and stirred for 30 minutes to precipitate a solid, which was filtered and the filter cake was rinsed with water (20 mL). The filter cake was collected and dried, and the obtained solid was purified by HPLC (37% ACN / 63% water (0.01% TFA)) to give an off-white solid 13, 34 mg, with a yield of 43.94% and an HPLC purity of 97.56%.

[0518] MS (ESI, pos.ion) m / z: 724.6 [M+H] + .

[0519] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.91 (d, J = 16.0Hz, 2H), 8.58 (d, J = 8.0Hz, 1H), 7.83 (dd, J = 20. 8,9.3Hz,2H),7.71-7.51(m,2H),7.48-7.23(m,2H),7.14(s,1H),6.98(d,J=8.4Hz,2H),5.74 (s,1H),4.48(d,J=15.7Hz,3H),3.86(s,1H),3.30-3.17(m,4H),3.02(t,J=12.9Hz,2H),2.40 -2.05(m,7H),1.86(d,J=28.3Hz,5H),1.58(dd,J=50.5,12.7Hz,4H),1.18(d,J=43.3Hz,3H).

[0520] Example 14 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(1r,4r)-4-(3-methoxy-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)pyridazine-3-carboxamide 14

[0521] Step 1: Synthesis of tert-butyl ((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)carbamate 14b

[0522] Tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate (1.00 g, 4.64 mmol) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydride (0.28 g, 6.96 mmol) was added at 0°C, followed by 4-fluoro-2-methoxybenzonitrile 14a (0.84 g, 5.57 mmol). The mixture was reacted at 0°C for 6 hours. Water (200 mL) was added to quench the reaction mixture. The precipitated solid was filtered and the filter cake was dried to afford 14b (0.95 g, 59.04% yield) as a white solid.

[0523] Step 2: Synthesis of tert-butyl ((1r,4r)-4-(4-(N-hydroxycarbamoyl)-3-methoxyphenoxy)cyclohexyl)carbamate 14c

[0524] Tert-butyl ((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)carbamate 14b (0.76 g, 2.19 mmol) was dissolved in methanol (10 mL). Hydroxylamine hydrochloride (0.46 g, 6.57 mmol) and triethylamine (0.71 g, 7.01 mmol) were added, and the mixture was refluxed at 75°C for 17 hours. The reaction solution was concentrated to afford 14c (0.83 g, 99.70% yield) as a white solid.

[0525] MS (ESI, pos.ion) m / z: 380.5 [M+H] + .

[0526] Step 3: Synthesis of tert-butyl ((1r,4r)-4-(3-methoxy-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)carbamate 14d

[0527] Tert-butyl ((1r,4r)-4-(4-(N-hydroxycarbamoyl)-3-methoxyphenoxy)cyclohexyl)carbamate 14c (0.83 g, 2.19 mmol) was dissolved in trimethyl orthoformate solution (8 mL), and trifluoroacetic acid (0.26 g, 2.26 mmol) was added dropwise. Under nitrogen protection, the mixture was reacted at 60°C for 8 hours. Water (20 mL) and dichloromethane (20 mL) were added to the reaction solution, and the liquid was separated by extraction. The organic phase was concentrated, and the resulting residue was purified by column chromatography (V PE / V EA =5 / 1) to afford 14d as a white solid (0.15 mg, 17.61% yield).

[0528] MS(ESI,pos.ion)m / z:412.3[M+Na] + .

[0529] Step 4: Synthesis of (1r,4r)-4-(3-methoxy-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexane-1-amine hydrochloride 14e

[0530] Tert-butyl ((1r,4r)-4-(3-methoxy-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)carbamate 14d (0.15 g, 0.38 mmol) was dissolved in 1,4-dioxane hydrochloride (2 mL, 4 M) and stirred at room temperature for 2 hours. The reaction solution was concentrated to afford 14e (0.12 g, 95.63% yield) as a white solid.

[0531] Step 5: Synthesis of 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(1r,4r)-4-(3-methoxy-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)pyridazine-3-carboxamide 14

[0532] (1r,4r)-4-(3-methoxy-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexane-1-amine hydrochloride 14e (0.12 g, 0.37 mmol), 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 1j (0.24 g, 0.41 mmol) and N,N-diisopropylethylamine (0.19 g, 1.48 mmol) were dissolved in dichloromethane (5 mL), and 1-propylphosphonic anhydride (0.47 g, 0.74 mmol, 50% EA solution) was added at 0°C, and the mixture was stirred at room temperature for 7 hours. Water (20 mL) and dichloromethane (5 mL) were added to the reaction solution, and the organic phase was concentrated. The residue was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give yellow solid 14 (30.0 mg, yield 9.57%) with a purity of 98.29%.

[0533] MS (ESI, pos.ion) m / z: 851.6 [M+H] + .

[0534] 1H NMR (400MHz, Chloroform-d) δ (ppm) 8.72 (s, 1H), 8.24 (s, 1H), 8.00 (dd, J = 9.0, 2.0Hz, 2H), 7.91 (d, J = 8.2Hz, 1H), 7.49 (d ,J=11.0Hz,1H),7.41(d,J=7.2Hz,1H),7.00(d,J=9.6Hz,1H),6.66-6.60(m,2H),4.96(dd,J=12.2,5.3Hz,1H),4.54(d,J= 13.2Hz,2H),4.41-4.34(m,1H),4.13-4.05(m,1H),3.99(s,3H),3.31(s,4H),3.07(t,J=12.6Hz,2H),2.95-2.75(m,3H), 2.64(s,4H),2.32(d,J=6.6Hz,2H),2.28-2.15(m,5H),1.97(d,J=14.0Hz,3H),1.57-1.39(m,3H),1.29(d,J=13.9Hz,3H).

[0535] Example 15 N-((1r,4r)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)amino)methyl)piperidin-1-yl)pyridazine-3-carboxamide 15

[0536] Step 1: Synthesis of 1-(4-nitrophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione 15b

[0537] 1-Fluoro-4-nitrobenzene (2.00 g, 14.17 mmol) and uracil 15a (1.59 g, 14.17 mmol) were added to DMSO (15 mL) and reacted at 80°C for 12 hours. Water (60 mL) was added to the reaction solution, and the pH was adjusted to 5. The solution was filtered, and the filter cake was rinsed with water (50 mL) and dried to obtain a pale yellow solid 15b (2.59 g, 78.36% yield).

[0538] Step 2: Synthesis of 1-(4-aminophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione 15c

[0539] 1-(4-Nitrophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione 15b (2.4 g, 10.29 mmol), ammonium chloride (5.50 g, 102.90 mmol), and iron powder (2.87 g, 51.45 mmol) were added to a mixture of ethanol (15 mL), water (15 mL), and DMF (2 mL) and refluxed at 85°C for 5 hours. The mixture was filtered while hot and rinsed with ethanol (5 mL). The filtrate was concentrated, and the residue was slurried in water (10 mL) for 20 minutes. The residue was then filtered with suction, and the filter cake was dried to obtain 15c (1.56 g, 74.59% yield) as a white solid.

[0540] MS (ESI, pos.ion) m / z: 204.0 [M+H] + .

[0541] Step 3: Synthesis of N-((1r,4r)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)amino)methyl)piperidin-1-yl)pyridazine-3-carboxamide 15

[0542] 1-(4-Aminophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione 15c (0.05 g, 0.25 mmol) and N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(formyl)piperidin-1-yl)pyridazine-3-carboxamide 1s (0.14 g, 0.30 mmol) were added to DCM (5 mL) and reacted at room temperature for 1 hour. Then, sodium triacetylborohydride (0.16 g, 0.75 mmol) was added and the reaction was continued for 4 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give 15 as a white solid (20.0 mg, 11.58% yield) with a purity of 93.37%.

[0543] MS (ESI, pos.ion) m / z: 655.0 [M+H] + .

[0544] 1H NMR (400MHz, DMSO-d6) δ (ppm) 11.33 (s, 1H), 8.61 (d, J = 8.2Hz, 1H), 7.83 (dd, J = 22.4, 9.2Hz, 2H), 7.58 (d,J=7.9Hz,1H),7.44-7.31(m,2H),7.14(dd,J=8.8,2.4Hz,1H),7.05(d,J=8.6Hz,2H),6.62(d,J=8. 5Hz,2H),6.06(t,J=5.8Hz,1H),5.59(d,J=7.8Hz,1H),4.52(d,J=12.5Hz,3H),3.86(d,J=10.7Hz,1H) ,3.08-2.87(m,4H),2.11(d,J=11.6Hz,2H),1.95-1.83(m,4H),1.71-1.42(m,4H),1.29-1.19(m,3H).

[0545] Example 16 6-(4-(((4-(5-fluoro-2,4-dioxo-3H-pyrimidin-1-yl)phenyl)amino)methyl)piperidin-1-yl)-N-((1r,4r)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide 16

[0546] Step 1: Synthesis of 5-fluoro-1-(4-nitrophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione 16b

[0547] 1-Fluoro-4-nitrobenzene (2.00 g, 14.17 mmol) and 5-fluoro-uracil 16a (1.84 g, 14.17 mmol) were added to DMSO (15 mL) and reacted at 80°C for 12 hours. Water (60 mL) was added to the reaction solution, and the pH was adjusted to 5. The solution was filtered, and the filter cake was rinsed with water (50 mL) and dried to obtain a pale yellow solid 16b (2.48 g, 69.66% yield).

[0548] Step 2: Synthesis of 5-fluoro-1-(4-aminophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione 16c

[0549] 5-Fluoro-1-(4-nitrophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione 16b (0.20 g, 0.80 mmol), ammonium chloride (0.43 g, 8.00 mmol), and iron powder (0.22 g, 4.00 mmol) were added to a mixture of ethanol (5 mL), water (5 mL), and DMF (1 mL) and refluxed at 85°C for 5 hours. The mixture was hot filtered, rinsed with ethanol (2 mL), and the filtrate was concentrated to afford 16c (0.12 g, 70.52% yield) as a white solid.

[0550] MS (ESI, pos.ion) m / z: 222.1 [M+H] + .

[0551] Step 3: Synthesis of 6-(4-(((4-(5-fluoro-2,4-dioxo-3H-pyrimidin-1-yl)phenyl)amino)methyl)piperidin-1-yl)-N-((1r,4r)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide 16

[0552] 5-Fluoro-1-(4-aminophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione 16c (0.09 g, 0.19 mmol) and N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(formyl)piperidin-1-yl)pyridazine-3-carboxamide 1s (0.04 g, 0.19 mmol) were added to DCM (5 mL) and reacted at room temperature for 1 hour. Then, sodium triacetylborohydride (0.12 g, 0.57 mmol) was added and the reaction was continued for 4 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to obtain a white solid 16 (32.7 mg, yield 21.64%) with a purity of 85.69%. MS (ESI, pos.ion) m / z: 673.3 [M+H] + .

[0553] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.61 (d, J = 8.2 Hz, 1H), 7.86 ( d, J = 8.8 Hz, 1H), 7.80 ( d, J = 9.5 Hz, 1H), 7.72 ( s,1H),7.44-7.31(m,2H),7.14(dd,J=8.8,2.4Hz,1H),7.02(d,J=8.5Hz,2H),6.59(d,J=8.5Hz,2H),5.95 (t,J=5.9Hz,1H),4.52(d,J=12.1Hz,3H),4.05(t,J=6.1Hz,1H),3.87(s,1H),3.12-2.87(m,4H),2.11(d, J=9.0Hz,2H),1.90(d,J=12.1Hz,4H),1.64(q,J=12.0Hz,2H),1.51(q,J=11.0,10.5Hz,2H),1.24(s,3H).

[0554] Example 17 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-((1r,4r)-4-((7-cyano-1-methyl-1H-indazol-4-yl)oxy)cyclohexyl)pyridazine-3-carboxamide 17

[0555] Step 1: Synthesis of 4-fluoro-1-methyl-1H-indazole-7-carbonitrile 17b

[0556] 4-Fluoro-1H-indazole-7-carbonitrile 17a (0.90 g, 5.59 mmol) was dissolved in N,N-dimethylformamide (9 mL), potassium carbonate (2.70 g, 19.56 mmol) and iodomethane (2.38 g, 16.77 mmol) were added, and the mixture was reacted at room temperature for 5 hours. Water (18 mL) was added to the reaction solution, stirred at room temperature for 20 minutes, filtered, and the filter cake was collected and dried. The obtained solid was separated and purified by column chromatography (V PE / V EA =10 / 1) to afford 17b as a white solid (0.68 g, yield 69.51%).

[0557] MS (ESI, pos.ion) m / z: 176.1 [M+H] + .

[0558] Step 2: Synthesis of tert-butyl N-((1r,4r)-4-((7-cyano-1-methyl-1H-indazol-4-yl)oxy)cyclohexyl)carbamate 17c

[0559] Dissolve tert-butyl N-((1r,4r)-4-hydroxycyclohexyl)carbamate (0.71 g, 3.30 mmol) in tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL). Add sodium hydride (0.38 g, 9.42 mmol, 60% in oil) at 0°C under nitrogen protection. After stirring for 10 minutes, add 4-fluoro-1-methyl-1H-indazole-7-carbonitrile 17b (0.55 g, 3.14 mmol) and allow to react at room temperature for 2 hours. Add water (15 mL) at 0°C to quench the mixture. After stirring for 10 minutes, filter, collect the filter cake, and swirl dry. The resulting solid is purified by column chromatography (V PE / V EA =4 / 1) to afford 17c as a white solid (0.45 g, 38.69% yield).

[0560] MS(ESI,pos.ion)m / z:393.2[M+Na] + .

[0561] Step 3: 1-Methyl-4-(((1r,4r)-4-aminocyclohexyl)oxy)-1H-indazole-7-carbonitrile hydrochloride 17d

[0562] tert-Butyl N-((1r,4r)-4-((7-cyano-1-methyl-1H-indazol-4-yl)oxy)cyclohexyl)carbamate 17c (0.45 g, 1.21 mmol) was added to a solution of hydrochloric acid in ethyl acetate (9.1 mL, 4 M). The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was dried to afford an off-white solid 17d (0.37 g, 99.28% yield).

[0563] Step 4: 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-((1r,4r)-4-((7-cyano-1-methyl-1H-indazol-4-yl)oxy)cyclohexyl)pyridazine-3-carboxamide 17

[0564] 1-Methyl-4-(((1r,4r)-4-aminocyclohexyl)oxy)-1H-indazole-7-carbonitrile hydrochloride 17d (0.050 g, 0.16 mmol), 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 1j (0.10 g, 0.18 mmol) and diisopropylethylamine (0.083 g, 0.64 mmol) were dissolved in N,N-dimethylformamide (4.0 mL), cooled to 0°C, and 1-propylphosphonic anhydride (0.20 g, 0.32 mmol, 50% EA solution) was slowly added, and the reaction was carried out at room temperature for 4 hours. Water (10 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL × 3). The organic phase was collected and dried, and the obtained residue was separated and purified by silica gel column chromatography (V DCM / V MeOH =30 / 1) to give a yellow solid 17 (18.0 mg, yield 13.28%) with a purity of 96.65%.

[0565] MS (ESI, pos.ion) m / z: 832.3 [M+H] + .

[0566] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.12 (d, J = 6.7Hz, 2H), 8.01 (d, J = 9.5Hz, 1H), 7.92 (d, J = 8.1Hz, 1H), 7.68 (d, J = 8.2Hz, 1 H),7.50(d,J=11.0Hz,1H),7.41(d,J=7.2Hz,1H),7.01(d,J=9.6Hz,1H),6.56(d,J=8.3Hz,1H),4.96(dd,J=12.2,5. 2Hz,1H),4.54(d,J=10.6Hz,3H),4.36(s,3H),4.12(d,J=8.6Hz,1H),3.08(t,J=12.5Hz,2H),2.98-2.84(m,2H),2.8 4-2.71(m,2H),2.42-2.22(m,6H),2.08(dd,J=62.0,12.1Hz,6H),1.82(dd,J=21.8,10.5Hz,5H),1.58-1.41(m,6H).

[0567] Example 18 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-((1r,4r)-4-((7-cyano-1-methyl-1H-indol-4-yl)oxy)cyclohexyl)pyridazine-3-carboxamide 18

[0568] Step 1: Synthesis of 4-fluoro-1-methyl-1H-indole-7-carbonitrile 18b

[0569] 4-Fluoro-1H-indole-7-carbonitrile 18a (0.40 g, 2.50 mmol) was dissolved in N,N-dimethylformamide (4 mL), and potassium carbonate (0.86 g, 6.25 mmol) and iodomethane (0.71 g, 5.00 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. Water (12 mL) was added to the reaction solution, stirred for 20 minutes, filtered, and the filter cake dried under vacuum to afford 18b (0.34 g, 78.16% yield) as a white solid.

[0570] Step 2: Synthesis of tert-butyl N-((1r,4r)-4-((7-cyano-1-methyl-1H-indol-4-yl)oxy)cyclohexyl)carbamate 18c

[0571] Dissolve tert-butyl N-((1r,4r)-4-hydroxycyclohexyl)carbamate (0.39 g, 1.81 mmol) in N,N-dimethylformamide (3.0 mL) at 0°C under nitrogen protection. Add sodium hydride (0.21 g, 5.16 mmol, 60% in oil). Stir for 10 minutes, then add 4-fluoro-1-methyl-1H-indole-7-carbonitrile 18b (0.30 g, 1.72 mmol). Return the mixture to room temperature and react for 2 hours. Add water (5 mL) at 0°C to quench the mixture. Stir for 10 minutes, filter, collect the filter cake, and purify it by column chromatography (V PE / V EA =4 / 1) to give a white solid 18c (73.0 mg, yield 11.47%). MS (ESI, pos.ion) m / z: 271.2 [M+H] + .

[0572] Step 3: 1-Methyl-4-(((1r,4r)-4-aminocyclohexyl)oxy)-1H-indole-7-carbonitrile hydrochloride 18d

[0573] tert-Butyl N-((1r,4r)-4-((7-cyano-1-methyl-1H-indol-4-yl)oxy)cyclohexyl)carbamate 18c (70.0 mg, 0.19 mmol) was added to a solution of hydrochloric acid in ethyl acetate (1.4 mL, 4 M). The mixture was allowed to react at room temperature for 1 hour. The reaction solution was spin-dried to dryness to afford an off-white solid 18d (58.0 mg, 100% yield).

[0574] MS(ESI,pos.ion)m / z:392.2[M+Na] + .

[0575] Step 4: 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-((1r,4r)-4-((7-cyano-1-methyl-1H-indol-4-yl)oxy)cyclohexyl)pyridazine-3-carboxamide 18

[0576] 1-Methyl-4-(((1r,4r)-4-aminocyclohexyl)oxy)-1H-indole-7-carbonitrile hydrochloride 18d (58.0 mg, 0.19 mmol), 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 1j (0.12 g, 0.21 mmol) and diisopropylethylamine (98.0 mg, 0.76 mmol) were dissolved in N,N-dimethylformamide (4.0 mL), cooled to 0°C, and 1-propylphosphonic anhydride (0.24 g, 0.38 mmol, 50% EA solution) was slowly added, and the reaction was carried out at room temperature for 4 hours. Water (10 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL × 3). The organic phase was collected and dried, and the obtained residue was separated and purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give a yellow solid 18 (20.0 mg, yield 13.28%) with a purity of 95.30%.

[0577] MS (ESI, pos.ion) m / z: 831.4 [M+H] + .

[0578] 1H NMR (400MHz, CDCl3) δ (ppm) 8.50 (s, 1H), 7.99 (d, J = 9.5Hz, 1H), 7.93 (d, J = 8.2Hz, 1H), 7.52-7.45 (m, 2H), 7.40 (d, J = 7.2Hz, 1H),7.01-6.96(m,2H),6.65(d,J=3.2Hz,1H),6.57(d,J=8.3Hz,1H),4.96(dd,J=12.1,5.3Hz,1H),4.55-4.50(m,2H),4.11 (s,3H),3.30(t,J=4.7Hz,4H),3.07(t,J=12.1Hz,2H),2.94-2.72(m,3H),2.64(t,J=4.9Hz,4H),2.32(d,J=6.6Hz,2H),2.2 4(tq,J=7.9,3.9Hz,4H),1.97(d,J=13.5Hz,2H),1.93-1.82(m,4H),1.80-1.74(m,2H),1.52(t,J=10.7Hz,2H),1.30(s,2H).

[0579] Example 19 N-((1r,4S)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((2S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide 19

[0580] Step 1: Synthesis of (2S,5R)-5-(2,4-dioxo-3H-pyrimidin-1-yl)tetrahydrofuran-2-carbaldehyde 19b

[0581] 2',3'-dideoxyuridine 19a (1.00 g, 4.71 mmol) and 2-iodoacylbenzoic acid (1.98 g, 7.06 mmol) were dissolved in acetonitrile (40 mL) and reacted at 80°C for 2 h. The mixture was filtered and the filter cake was washed with acetonitrile (30 mL). The filtrate was concentrated to give 19b (0.99 g, 99.95% yield) as a white solid.

[0582] Step 2: Synthesis of tert-butyl 4-(((2S,5R)-5-(2,4-dioxo-3H-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl)piperazine-1-carboxylate 19c

[0583] (2S,5R)-5-(2,4-dioxo-3H-pyrimidin-1-yl)tetrahydrofuran-2-carbaldehyde 19b (0.80 g, 3.81 mmol) and N-Boc-piperazine (0.78 g, 4.19 mmol) were dissolved in N,N-dimethylformamide (4 mL) and reacted at room temperature for 1 hour. Sodium cyanoborohydride (0.72 g, 11.43 mmol) was then added and allowed to react at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, stirred for 30 minutes, and filtered. The filter cake was washed with water (10 mL) and dried to afford 19c as a yellow solid (1.44 g, 99.45% yield).

[0584] Step 3: Synthesis of 1-((2R,5S)-5-(piperazin-1-ylmethyl)tetrahydrofuran-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione hydrochloride 19d

[0585] Tert-butyl 4-(((2S,5R)-5-(2,4-dioxo-3H-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl)piperazine-1-carboxylate 19c (1.44 g, 3.79 mmol) was dissolved in a solution of hydrogen chloride in 1,4-oxane (20 mL, 4 M) and allowed to react at room temperature for 3 hours. The reaction mixture was filtered and the filter cake was dried to afford 19d (1.10 g, 91.74% yield) as a yellow solid.

[0586] Step 4: N-((1r,4S)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((2S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide 19

[0587] 1-((2R,5S)-5-(piperazin-1-ylmethyl)tetrahydrofuran-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione hydrochloride 19d (0.10 g, 0.32 mmol), 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide 1t (0.14 g, 0.35 mmol) and N,N-diisopropylethylamine (0.12 g, 0.96 mmol) were dissolved in N,N-dimethylformamide (1 mL) and reacted at 100°C for 3 hours. Water (10 mL) was added to the reaction solution, stirred for 20 minutes, filtered, and the filter cake was vacuum dried. The obtained solid was purified by silica gel column chromatography (V DCM / V MeOH =30 / 1) to give a brown solid 19 (18.0 mg, 8.98% yield) with a purity of 96.93%.

[0588] MS (ESI, pos.ion) m / z: 636.3 [M+H]+ ;

[0589] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.29 (s, 1H), 8.63 (d, J = 8.2Hz, 1H), 7.90-7.81 (m, 2H), 7.66 (d, J = 8.1Hz, 1H), 7.41-7.32 ( m,2H),7.14(dd,J=8.8,2.4Hz,1H),6.01(t,J=5.7Hz,1H),5.61(d,J=8.0Hz,1H),4.55(ddd,J=20.5,11.3,6.0Hz,2H),3. 87(qd,J=8.3,5.6,3.8Hz,1H),3.70(t,J=5.1Hz,4H),2.59(hept,J=6.1,5.5Hz,4H),2.47(d,J=5.5Hz,2H),2.36-2.29(m ,1H),2.15-2.05(m,3H),2.03-1.97(m,1H),1.89(dt,J=8.3,3.8Hz,2H),1.76-1.60(m,3H),1.50(dd,J=13.0,9.6Hz,2H).

[0590] Example 20 N-((1r,4S)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((2S,5R)-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide 20

[0591] Step 1: Synthesis of 1-((2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl)dihydropyrimidine-2,4(1H,3H)-dione 20a

[0592] 2',3'-dideoxyuridine 19a (1.00 g, 4.71 mmol) and 10% palladium / carbon (0.40 g) were dissolved in methanol (10 mL). The reaction was switched to hydrogen gas and allowed to react at room temperature for 23 hours. The reaction mixture was filtered and the filtrate was concentrated to afford 20a (1.00 g, 99.06% yield) as a white solid.

[0593] Step 2: Synthesis of (2S,5R)-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)tetrahydrofuran-2-carbaldehyde 20b

[0594] 1-((2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl)dihydropyrimidine-2,4(1H,3H)-dione 20a (1.00 g, 4.67 mmol) and 2-iodoacylbenzoic acid (1.96 g, 7.00 mmol) were dissolved in acetonitrile (40 mL) and reacted at 80°C for 2 hours. The reaction mixture was filtered, the filter cake was washed with acetonitrile (30 mL), and the filtrate was concentrated to obtain 20b (0.99 g, 99.94% yield) as a white solid.

[0595] Step 3: Synthesis of tert-butyl 4-(((2S,5R)-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl)piperazine-1-carboxylate 20c

[0596] (2S,5R)-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)tetrahydrofuran-2-carbaldehyde 20b (1.00 g, 4.71 mmol) and N-Boc-piperazine (0.96 g, 5.18 mmol) were dissolved in N,N-dimethylformamide (5 mL) and reacted at room temperature for 1 hour. Sodium cyanoborohydride (0.89 g, 14.13 mmol) was then added and allowed to react at room temperature for 12 hours. Water (50 mL) and dichloromethane (20 mL) were added to the reaction mixture, and the mixture was separated by extraction. The organic phase was concentrated to afford 20c as a yellow oil (1.60 g, 88.78% yield).

[0597] Step 4: Synthesis of 1-((2R,5S)-5-(piperazin-1-ylmethyl)tetrahydrofuran-2-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride 20d

[0598] Tert-butyl 4-(((2S,5R)-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl)piperazine-1-carboxylate 20c (1.60 g, 4.18 mmol) was dissolved in a solution of hydrogen chloride in 1,4-oxane (22 mL, 4 M) and allowed to react at room temperature for 2 hours. The reaction mixture was filtered and the filter cake was dried to afford 20d (1.10 g, 82.48% yield) as a yellow solid.

[0599] MS (ESI, pos.ion) m / z: 281.2 [M+H] + .

[0600] Step 5: N-((1r,4S)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((2S,5R)-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide 20

[0601] 1-((2R,5S)-5-(piperazin-1-ylmethyl)tetrahydrofuran-2-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride 20d (0.20 g, 0.63 mmol), 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide 1t (0.27 g, 0.69 mmol) and N,N-diisopropylethylamine (0.24 g, 1.89 mmol) were dissolved in N,N-dimethylformamide (2 mL) and reacted at 100°C for 18 hours. Water (10 mL) was added to the reaction solution, stirred for 20 minutes, filtered, and the filter cake was collected and dried. The obtained solid was purified by silica gel column chromatography (V DCM / V MeOH =30 / 1) to give a brown solid 20 (30.0 mg, yield 7.51%) with a purity of 94.27%.

[0602] MS (ESI, pos.ion) m / z: 638.3 [M+H] + .

[0603] 1 H NMR (400MHz, CDCl3) δ (ppm) 9.10 (s, 1H), 8.02 (dd, J = 9.5, 2.7Hz, 1H), 7.90 (d, J = 8.2Hz, 1H), 7.57 (d, J = 8.7Hz, 1H), 7.02 (d,J=2.5Hz,1H),6.87(dd,J=8.7,2.5Hz,1H),6.09(t,J=5.5Hz,1H),5.75(t,J=7.9Hz,1H),4.32(dq,J=10.3,6.6,5.4Hz ,1H),4.13-4.04(m,1H),3.81(q,J=4.4Hz,4H),2.74(q,J=6.0Hz,4H),2.69-2.34(m,3H),2.18(q,J=8.0,5.2Hz,5H),2. 11-2.00(m,2H),1.86(dt,J=12.4,7.8Hz,3H),1.70(tdd,J=13.1,9.9,4.6Hz,3H),1.54-1.44(m,2H),1.30-1.25(m,1H).

[0604] Example 21 N-((1r,4S)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 21

[0605] Step 1: Synthesis of 2-((3S)-2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione 21b

[0606] (3S)-3-Aminopiperidine-2,6-dione hydrochloride 21a (2.00 g, 12.15 mmol) was dissolved in acetic acid (20 mL), and 5,6-difluoro-2-benzofuran-1,3-dione 1a (2.24 g, 12.15 mmol) and triethylamine (2.70 g, 26.73 mmol) were added. The mixture was reacted at 120°C for 3 hours. The reaction mixture was cooled to room temperature and stirred for 1 hour. The mixture was then filtered and the filter cake was washed with water (10 mL). The filter cake was collected, slurried with water (30 mL), filtered, and dried to obtain a purple-gray solid 21b (2.20 g, 61.54% yield).

[0607] Step 2: Synthesis of (S)-tert-butyl 4-(2-(-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate 21c

[0608] 2-((3S)-2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione 21b (2.20 g, 7.48 mmol) was dissolved in N-methylpyrrolidone (10 mL), and tert-butyl piperazine-1-carboxylate (1.53 g, 8.23 ​​mmol) and N,N-diisopropylethylamine (2.42 g, 18.70 mmol) were added. The mixture was reacted at 90°C for 5 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added to precipitate a solid. The solid was filtered, and the filter cake was slurried with water (50 mL), filtered, and dried to obtain a yellow solid 21c (2.50 g, 72.61% yield).

[0609] Step 3: Synthesis of (S)-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride 21d

[0610] Tert-butyl (S)-4-(2-(-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate 21c (2.50 g, 5.43 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (15 mL, 4 M) and allowed to react at room temperature for 5 hours. The reaction mixture was filtered and the filter cake was dried to afford 21d (2.10 g, 97.48% yield) as a green solid.

[0611] Step 4: Synthesis of (S)-tert-butyl 6-(4-((4-(2-(-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylate 21e

[0612] Dissolve tert-butyl 6-(4-(formyl)piperidin-1-yl)pyridazine-3-carboxylate 1h (0.50 g, 1.72 mmol) in dichloromethane (20 mL), add (S)-2-(-2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride 21d (0.68 g, 1.72 mmol) with stirring, react at room temperature for 1 hour, then add sodium triacetoxyborohydride (1.09 g, 5.16 mmol), and react at room temperature for 5 hours. Water (20 mL) was added to the reaction solution, the liquid was separated, the organic phase was washed with saturated sodium bicarbonate solution (20 mL), concentrated, and the resulting residue was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to afford a light yellow solid 21e (0.54 g, 49.50% yield).

[0613] Step 5: Synthesis of (S)-6-(4-((4-(2-(-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 21f

[0614] Tert-butyl 6-(4-((4-(2-((3S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylate 21e (0.54 g, 0.85 mmol) was dissolved in dichloromethane (4 mL). A solution of hydrogen chloride in 1,4-dioxane (4 mL, 4 M) was added and allowed to react at room temperature for 4 hours. The reaction solution was concentrated to afford 21f (0.49 g, 99.53% yield) as a yellow solid.

[0615] Step 6: Synthesis of N-((1r,4S)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 21

[0616] (S)-6-(4-((4-(2-(-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 21f (0.29 g, 0.50 mmol), (1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexane-1-amine hydrochloride 1o (0.15 g, 0.45 mmol) and N,N-diisopropylethylamine (0.23 g, 1.80 mmol) were dissolved in dichloromethane (4 mL), and n-propylphosphonic anhydride (0.29 g, 0.45 mmol, 50% EA solution) was added, and the reaction was carried out at room temperature for 18 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL). The organic phase was concentrated and the residue was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give a yellow solid 21 (125.0 mg, 32.17% yield) with a purity of 99.60%.

[0617] MS (ESI, pos.ion) m / z: 855.2 [M+H] + .

[0618] 1 H NMR (599MHz, CDCl3) δ (ppm) 8.80 (s, 1H), 8.40 (s, 1H), 8.02 (d, J = 9.5Hz, 1H), 7.92 (dd, J = 12.8, 8.5Hz, 2H), 7.54 (d, J = 10.5Hz, 1H),7.45(d,J=7.1Hz,1H),7.10(d,J=2.5Hz,1H),7.01(d,J=9.6Hz,1H),6.94(dd,J=8.8,2.5Hz,1H),4.97(dd,J=12.6,5.4Hz, 1H),4.55(d,J=13.4Hz,2H),4.38-4.33(m,1H),4.08(q,J=10.1,8.8Hz,1H),3.52(s,4H),3.11-3.07(m,2H),2.95-2.91(m,1H) ,2.79(dddd,J=23.2,16.7,13.3,7.0Hz,4H),2.26-2.12(m,7H),2.03(d,J=13.0Hz,3H),1.76-1.66(m,3H),1.55-1.38(m,5H).

[0619] Example 22 N-((1r,4r)-4-((3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)-6-(4-((4-(2-((R)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 22

[0620] Step 1: Synthesis of 2-((3R)-2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione 22b

[0621] (3S)-3-Aminopiperidine-2,6-dione hydrochloride 22a (2.00 g, 12.15 mmol) was dissolved in acetic acid (20 mL), and 5,6-difluoro-2-benzofuran-1,3-dione 1a (2.24 g, 12.15 mmol) and triethylamine (2.70 g, 26.73 mmol) were added. The mixture was allowed to react at 120°C for 3 hours. The reaction mixture was cooled to room temperature and stirred for 1 hour. The mixture was then filtered and the filter cake was washed with water (10 mL). The filter cake was collected, slurried with water (30 mL), filtered, and dried to obtain a purple-gray solid 22b (2.50 g, 69.93% yield).

[0622] Step 2: Synthesis of tert-butyl 4-(2-((3R)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate 22c

[0623] 2-((3R)-2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione 22b (2.50 g, 8.50 mmol) was dissolved in N-methylpyrrolidone (10 mL), and tert-butyl piperazine-1-carboxylate (1.74 g, 9.35 mmol) and N,N-diisopropylethylamine (2.75 g, 21.25 mmol) were added. The mixture was reacted at 90°C for 8 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added to precipitate a solid. The solid was filtered, and the filter cake was slurried with water (50 mL), filtered, and dried to obtain 22c (3.50 g, 89.45% yield) as a yellow solid.

[0624] Step 3: Synthesis of 2-((3R)-2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride 22d

[0625] Tert-butyl 4-(2-((3R)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate 22c (3.50 g, 7.60 mmol) was dissolved in 1,4-dioxane (20 mL, 4 M) hydrogen chloride and allowed to react at room temperature for 5 hours. The reaction mixture was filtered and the filter cake was dried to afford 22d (3.00 g, 97.47% yield) as a green solid.

[0626] Step 4: Synthesis of tert-butyl 6-(4-((4-(2-((3R)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylate 22e

[0627] Dissolve tert-butyl 6-(4-(formyl)piperidin-1-yl)pyridazine-3-carboxylate 1h (0.50 g, 1.72 mmol) in dichloromethane (20 mL), add 2-((3R)-2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride 22d (0.68 g, 1.72 mmol) under stirring, react at room temperature for 1 hour, then add sodium triacetoxyborohydride (1.09 g, 5.16 mmol), and react at room temperature for 5 hours. Water (20 mL) was added to the reaction solution, the liquid was separated, the organic phase was washed with saturated sodium bicarbonate solution (20 mL), concentrated, and the resulting residue was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to afford 22e as a pale yellow solid (0.60 g, 55.00% yield).

[0628] Step 5: Synthesis of 6-(4-((4-(2-((3R)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 22f

[0629] Tert-butyl 6-(4-((4-(2-((3R)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylate 21e (0.60 g, 0.94 mmol) was dissolved in dichloromethane (4 mL). A solution of hydrogen chloride in 1,4-dioxane (4 mL, 4 M) was added and reacted at room temperature for 4 hours. The reaction solution was concentrated to afford 22f (0.54 g, 98.71% yield) as a yellow solid.

[0630] Step 6: Synthesis of N-((1r,4r)-4-((2-chloro-1-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)-6-(4-((4-(2-((3R)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 22

[0631] Tert-butyl 6-(4-((4-(2-((3R)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylate 22f (0.29 g, 0.50 mmol), (1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexane-1-amine hydrochloride 1o (0.15 g, 0.45 mmol) and N,N-diisopropylethylamine (0.23 g, 1.80 mmol) were dissolved in dichloromethane (4 mL), and n-propylphosphoric anhydride (0.29 g, 0.45 mmol, 50% EA solution) was added, and the reaction was carried out at room temperature for 18 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL). The organic phase was concentrated and the residue was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give a yellow solid 22 (88.0 mg, yield 22.65%) with a purity of 96.74%.

[0632] MS (ESI, pos.ion) m / z: 855.2 [M+H] + ;

[0633] 1H NMR (599MHz, CDCl3) δ (ppm) 8.80 (s, 1H), 8.12 (s, 1H), 8.01 (d, J = 9.5Hz, 1H), 7.92 (dd, J = 17.5, 8.5Hz, 2H), 7.51 (d, J = 10. 9Hz,1H),7.42(d,J=7.2Hz,1H),7.10(d,J=2.5Hz,1H),7.01(d,J=9.6Hz,1H),6.95(dd,J=8.7,2.5Hz,1H),4.96(dd,J=12 .6,5.4Hz,1H),4.55(d,J=13.3Hz,2H),4.35(d,J=10.2Hz,1H),4.09(d,J=10.2Hz,1H),3.36(s,4H),3.08(t,J=12.7Hz,2 H),2.89-2.64(m,6H),2.19(dd,J=35.8,10.4Hz,6H),1.99(d,J=12.9Hz,3H),1.50(q,J=11.2Hz,3H),1.36-1.26(m,5H).

[0634] Example 23 N-((1r,4r)-4-((7-cyano-1-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)cyclohexane)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 23

[0635] Step 1: Synthesis of 7-fluoro-3-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile 23b

[0636] 7-Fluoro-3-oxoindene-4-carbonitrile 23a (0.35 g, 2.0 mmol) was dissolved in toluene (5 mL). Sodium borohydride (0.079 g, 2.1 mmol) was added with stirring at room temperature and allowed to react for 1 hour. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were concentrated to afford 23b (0.24 g, 66.94% yield) as a pale yellow solid.

[0637] Step 2: Synthesis of 7-fluoro-3-methoxy-2,3-dihydro-1H-indene-4-carbonitrile 23c

[0638] Sodium hydride (54 mg, 1.35 mmol, 60% in oil) was weighed and a solution of 7-fluoro-3-hydroxyindene-4-carbonitrile 23b (0.22 g, 1.23 mmol) in THF (12 mL) was added dropwise at 0°C. The reaction was continued for 3 hours, and then iodomethane (0.17 g, 1.23 mmol) was added dropwise. The reaction was then stirred at room temperature for 4 hours. Water (12 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (12 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (V PE / V DCM =1 / 3) to afford 23c as a light yellow oil (83 mg, 35.28% yield).

[0639] Step 3: Synthesis of tert-butyl N-((1r,4r)-4-((7-cyano-1-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)cyclohexyl)carbamate 23d

[0640] At 0°C, tert-butyl N-((1r,4r)-4-hydroxycyclohexyl)carbamate (0.097 g, 0.45 mmol) was added to a solution of sodium hydride (0.052 g, 1.29 mmol) in DMF (5 mL) and reacted at room temperature for 50 minutes. Then, a solution of 7-fluoro-3-methoxy-2,3-dihydro-1H-indene-4-carbonitrile 23c (0.083 g, 0.43 mmol) in DMF (5 mL) was added dropwise and the reaction was continued at room temperature for 6 hours. Water (5 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were concentrated, and the resulting residue was purified by silica gel column chromatography (V PE / V EA =4 / 1) to give a white solid 23d (0.035 g, yield 20.86%).

[0641] MS (ESI, pos.ion) m / z: 387.1 [M+H] + .

[0642] Step 4: Synthesis of 3-methoxy-7-(((1r,4r)-4-aminocyclohexyl)oxy)-2,3-dihydro-1H-indene-4-carbonitrile 23e

[0643] Tert-butyl N-((1r,4r)-4-((7-cyano-1-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)cyclohexyl)carbamate 23d (35 mg, 0.091 mmol) was dissolved in a solution of hydrogen chloride in THF (1 mL, 4.0 mol / L) and reacted at room temperature for 1 hour. The reaction solution was dried to afford 23e as a white solid (25.9 mg, 99.87% yield).

[0644] MS(ESI,pos.ion)m / z:287.35[M+H] + .

[0645] Step 5: Synthesis of N-((1r,4r)-4-((7-cyano-1-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)cyclohexane)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 23

[0646] 3-Methoxy-7-(((1r,4r)-4-aminocyclohexyl)oxy)-2,3-dihydro-1H-indene-4-carbonitrile 23e (25 mg, 0.087 mmol), 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 1j (55.5 mg, 0.096 mmol) and DIPEA (44.98 mg, 0.35 mmol) were dissolved in DCM (2 mL), and 1-propylphosphonic anhydride (110.7 mg, 0.17 mmol, 50% EA solution) was slowly added at 0°C and the reaction was carried out at room temperature for 12 minutes. The reaction solution was quenched by adding water (10 mL), extracted with DCM (20 mL × 3), and the combined organic phase was dried by rotary elution. The residue was purified by silica gel column chromatography (V DCM / V MeOH =19 / 1) to give a yellow solid 23 (37 mg, 49.98% yield) with a purity of 96.61%.

[0647] MS (ESI, pos.ion) m / z: 848.3 [M+H] + ;

[0648] 1H NMR (599MHz, CDCl3) δ (ppm) 8.06 (s, 1H), 7.97 (d, J = 9.6Hz, 1H), 7.93 (d, J = 8.3Hz, 1H), 7.49 (d, J = 8.4Hz, 1H), 7.47 (d,J=11.1Hz,1H),7.38(d,J=7.3Hz,1H),6.98(d,J=9.6Hz,1H),6.81(d,J=8.5Hz,1H),5.01-4.89(m,2H),4.51(d ,J=13.4Hz,2H),4.38-4.31(m,1H),4.06(dd,J=12.0,7.0Hz,1H),3.50(s,3H),3.09-2.96(m,3H),2.95-2.87(m,1 H),2.87-2.69(m,3H),2.38-2.25(m,3H),2.24-2.09(m,6H),2.00-1.87(m,3H),1.61(s,13H),1.48-1.42(m,1H).

[0649] Example 24 N-((1r,4r)-4-((7-cyano-1-isopropyl-1H-indol-4-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 24

[0650] Step 1: Synthesis of 4-fluoro-1-isopropyl-1H-indole-7-carbonitrile 24a

[0651] Sodium hydride (0.19 g, 4.8 mmol, 60% wt) was dissolved in DMF (20 mL) at 0°C, and 4-fluoro-1H-indole-7-carbonitrile 18a (0.64 g, 4.0 mmol) was added. The reaction was allowed to proceed for 20 minutes, followed by the addition of 2-iodopropane (0.68 g, 4.0 mmol) and continued at 0°C for 12 hours. Saturated ammonium chloride solution (20 mL) was added to the reaction solution to quench the reaction, which was then extracted with EA (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (V PE / V EA =4 / 1) to afford 24a as a colorless oil (0.34 g, 41.45% yield).

[0652] MS (ESI, pos.ion) m / z: 203.2 [M+H] + .

[0653] Step 2: Synthesis of 1-isopropyl-4-(((1r,4r)-4-aminocyclohexyl)oxy)-1H-indole-7-carbonitrile 24b

[0654] Tert-butyl N-((1r,4r)-4-hydroxycyclohexyl)carbamate (0.45 g, 2.07 mmol) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (0.095 g, 2.39 mmol, 60% in oil) was added at 0°C. After stirring for 1 hour, a solution of 4-fluoro-1-isopropyl-1H-indole-7-carbonitrile 24a (0.32 g, 1.59 mmol) in N,N-dimethylformamide (0.5 mL) was added and the mixture was allowed to react at room temperature for 12 hours. The reaction mixture was quenched with water (5 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford 24b as a white solid (0.24 g, 50.15% yield).

[0655] MS(ESI,pos.ion)m / z:297.95[M+H] + .

[0656] Step 3: Synthesis of N-((1r,4r)-4-((7-cyano-1-isopropyl-1H-indol-4-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 24

[0657] 1-Isopropyl-4-(((1r,4r)-4-aminocyclohexyl)oxy)-1H-indole-7-carbonitrile 24b (85 mg, 0.29 mmol), 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 1j (0.19 g, 0.32 mmol) and diisopropylethylamine (0.15 g, 1.16 mmol) were dissolved in DCM (2.0 mL), cooled to 0°C, and 1-propylphosphoric anhydride (0.37 g, 0.58 mmol, 50% EA solution) was slowly added and reacted at room temperature for 5 hours. Water (10 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL × 3). The organic phase was collected and dried, and the obtained residue was separated and purified by silica gel column chromatography (V DCM / V MeOH =19 / 1) to give a yellow solid 24 (55 mg, yield 22.40%) with a purity of 95.48%.

[0658] MS(ESI,pos.ion)m / z:859.30[M+H] + ;

[0659] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.33 (s, 1H), 7.97 (d, J = 9.5Hz, 1H), 7.90 (d, J = 8.2Hz, 1H), 7.47 (dd, J = 9.5, 3.8Hz, 2H), 7.38 (d, J = 7.1Hz, 1H), 7. 22(d,J=3.4Hz,1H),6.98(d,J=9.6Hz,1H),6.69(d,J=3.4Hz,1H),6.56(d,J=8.3Hz,1H),5.40(p,J=6.6Hz,1H),4.93(dd,J=12.5,5.4Hz,1H) ,4.50(t,J=12.6Hz,3H),4.18-4.02(m,1H),3.29(t,J=4.6Hz,4H),3.11-3.00(m,2H),2.97-2.68(m,3H),2.62(s,4H),2.30(d,J=7.0Hz,2H) ,2.27-2.17(m,4H),2.13(ddd,J=11.2,7.1,4.0Hz,1H),2.00-1.69(m,5H),1.55(d,J=6.6Hz,6H),1.53-1.41(m,2H),1.29(d,J=11.9Hz,2H).

[0660] Example 25 N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((R)-2-((4-(4-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazin-1-yl)methyl)morpholinyl)pyridazine-3-carboxamide 25

[0661] Step 1: Synthesis of (S)-morpholin-2-ylmethanol hydrochloride 25b

[0662] Tert-butyl (S)-2-(hydroxymethyl)morpholine-4-carboxylate 25a (1.00 g, 4.60 mmol) was dissolved in 1,4-dioxane hydrochloride (10 mL, 4 M) and reacted at room temperature for 4 hours. The reaction solution was concentrated to afford 25b (0.70 g, 99.01% yield) as a white solid.

[0663] Step 2: Synthesis of N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-(hydroxymethyl)morpholino)pyridazine-3-carboxamide 25c

[0664] 6-Chloro-N-((1r,3r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide 1t (1.50 g, 3.83 mmol), (S)-morpholin-2-ylmethanol hydrochloride 25b (0.70 g, 4.56 mmol) and potassium carbonate (2.12 g, 15.32 mmol) were dissolved in 1,4-dioxane (20 mL) and reacted at 100°C for 24 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to afford 25c as a yellow solid (1.60 g, 88.43% yield).

[0665] Step 3: Synthesis of N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-formylmorpholino)pyridazine-3-carboxamide 25d

[0666] N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-(hydroxymethyl)morpholino)pyridazine-3-carboxamide 25c (0.10 g, 0.21 mmol) and 2-iodoacylbenzoic acid (88.0 mg, 0.32 mmol) were dissolved in acetonitrile (4 mL) and reacted at 80°C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the organic phase was concentrated to afford 25d as a light yellow oil (99.0 mg, 99.43% yield).

[0667] Step 4: Synthesis of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((R)-2-((4-(4-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazin-1-yl)methyl)morpholinyl)pyridazine-3-carboxamide 25

[0668] N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-formylmorpholino)pyridazine-3-carboxamide 25d (0.10 g, 0.21 mmol) and (S)-N-(2,6-dioxopiperidin-3-yl)-3-fluoro-4-(piperidin-1-yl)benzamide hydrochloride 6f (0.08 g, 0.24 mmol) were dissolved in N,N-dimethylacetamide (2 mL) and reacted at room temperature for 1 hour. Sodium triacetoxyborohydride (0.11 g, 0.51 mmol) was added and reacted at room temperature for 20 hours. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and solid precipitated. The solid was filtered and the collected filter cake was dried and purified by silica gel column chromatography (V DCM / V MeOH =30 / 1) to give 25 as a white solid (28.0 mg, 15.84% yield) with a purity of 91.38%.

[0669] MS (ESI, pos.ion) m / z: 788.3 [M+H] + ;

[0670] 1 H NMR (599MHz, CDCl3) δ (ppm) 8.16 (s, 1H), 8.07 (d, J = 9.4Hz, 1H), 7.98 (t, J = 9. 1Hz,1H),7.92(d,J=5.5Hz,1H),7.58(d,J=8.7Hz,1H),7.44(dd,J=13.9,5.4 Hz,1H),7.02(d,J=8.3Hz,2H),6.88(d,J=8.6Hz,1H),6.74(d,J=7.7Hz,1H), 6.54(d,J=15.6Hz,1H),4.83-4.79(m,1H),4.45(d,J=12.8Hz,1H),4.35(d,J =9.6Hz,1H),4.19(d,J=13.1Hz,1H),4.14(d,J=13.0Hz,1H),4.09(d,J=7.8H z,1H),3.85(s,1H),3.76(t,J=10.8Hz,1H),3.39(s,4H),3.23(t,J=10.8Hz, 1H),2.96-2.92(m,1H),2.87-2.79(m,2H),2.74(s,6H),2.59(s,1H),2.21(t ,J=13.6Hz,4H),1.99-1.94(m,1H),1.53-1.49(m,2H),1.31(t,J=9.0Hz,2H).

[0671] Example 26 N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-((4-(4-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazin-1-yl)methyl)morpholinyl)pyridazine-3-carboxamide 26

[0672] Step 1: Synthesis of (R)-2-hydroxymethylmorpholine hydrochloride 26b

[0673] Tert-butyl (R)-2-(hydroxymethyl)morpholine-4-carboxylate 26a (1.00 g, 4.60 mmol) was dissolved in 1,4-dioxane hydrochloride (7.8 mL, 4 M) and reacted at room temperature for 3 hours. The reaction solution was concentrated to afford 26b (0.70 g, 99.01% yield) as a white solid.

[0674] Step 2: Synthesis of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-(hydroxymethyl)morpholino)pyridazine-3-carboxamide 26c

[0675] 6-Chloro-N-((1r,3r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide 1t (1.00 g, 2.56 mmol), (R)-2-hydroxymethylmorpholine hydrochloride 26b (0.43 g, 2.82 mmol) and potassium carbonate (1.06 g, 7.68 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 100°C for 24 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (V DCM / V MeOH =30 / 1) to afford 26c as a white solid (1.20 g, yield 99.48%).

[0676] MS (ESI, pos.ion) m / z: 472.2 [M+H] + .

[0677] Step 3: Synthesis of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-formylmorpholino)pyridazine-3-carboxamide 26d

[0678] N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-(hydroxymethyl)morpholino)pyridazine-3-carboxamide 26c (0.20 g, 0.42 mmol) and 2-iodoacylbenzoic acid (0.17 g, 0.64 mmol) were dissolved in acetonitrile (6 mL) and reacted at 80°C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the organic phase was concentrated to afford 26d as a light yellow oil (0.19 g, 91.88% yield).

[0679] MS (ESI, pos.ion) m / z: 488.2 [M+H] + .

[0680] Step 4: Synthesis of N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-((4-(4-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazin-1-yl)methyl)morpholinyl)pyridazine-3-carboxamide 26

[0681] N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-formylmorpholino)pyridazine-3-carboxamide 26d (0.19 g, 0.40 mmol) and (S)-N-(2,6-dioxopiperidin-3-yl)-3-fluoro-4-(piperidin-1-yl)benzamide hydrochloride 6f (0.16 g, 0.51 mmol) were dissolved in N,N-dimethylacetamide (2 mL) and reacted at room temperature for 2 hours. Sodium triacetoxyborohydride (0.11 g, 0.51 mmol) was added and reacted at room temperature for 18 hours. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and solid precipitated. The solid was filtered and the collected filter cake was dried and then purified by silica gel column chromatography (V DCM / V MeOH =40 / 1) to give 26 (91.0 mg, 27.64% yield) as a white solid with a purity of 96.46%.

[0682] MS (ESI, pos.ion) m / z: 788.3 [M+H] + ;

[0683] 1 H NMR (599MHz, CDCl3) δ (ppm) 8.16 (s, 1H), 8.07 (d, J = 9.5Hz, 1H), 7.98 (t, J = 9.1Hz ,1H),7.92(d,J=7.8Hz,1H),7.58(d,J=8.7Hz,1H),7.44(dd,J=14.0,5.4Hz,1H) ,7.02(d,J=9.4Hz,2H),6.87(d,J=8.7Hz,1H),6.73(d,J=7.6Hz,1H),6.53(d,J= 16.0Hz,1H),4.84-4.79(m,1H),4.44(d,J=12.6Hz,1H),4.35(d,J=9.9Hz,1H),4 .19(d,J=12.7Hz,1H),4.14(d,J=10.2Hz,1H),4.09(d,J=7.5Hz,1H),3.83(s,1H ),3.76(t,J=10.6Hz,1H),3.38(s,4H),3.23(t,J=10.8Hz,1H),2.96-2.92(m,1H ),2.86-2.78(m,2H),2.71(s,6H),2.54(dd,J=13.1,4.2Hz,1H),2.21(t,J=13.9 Hz,4H),1.97(dt,J=12.7,7.9Hz,1H),1.53-1.47(m,2H),1.29(d,J=22.6Hz,2H).

[0684] Example 27 N-((1r,4r)-4-(3-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 27

[0685] Step 1: Synthesis of tert-butyl ((1r,4r)-4-(3-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)carboxylate 27a

[0686] Dissolve tert-butyl ((1r,4r)-4-(3-chloro-4-(N-hydroxycarbamyl)phenoxy)cyclohexyl)carboxylate 1m (0.50 g, 1.30 mmol), triethylamine (0.16 g, 1.56 mmol) and acetic anhydride (0.16 g, 1.56 mmol) in 1,4-dioxane solution (6.0 mL) and react at 105°C for 16 hours. The reaction solution was cooled to room temperature and concentrated. The resulting residue was purified by silica gel column chromatography (V EA / V PE =1 / 3) to afford 27a as a colorless oil (0.15 g, 27.58% yield).

[0687] Step 2: Synthesis of (1r,4r)-4-(3-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)cyclohexanol-1-amine hydrochloride 27b

[0688] Tert-butyl ((1r,4r)-4-(3-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)carboxylate 27a (0.38 g, 0.93 mmol) was dissolved in 1,4-dioxane (2.6 mL). 1,4-dioxane hydrochloric acid (2.6 mL, 4 M) was added and reacted at room temperature for 4 hours. The solvent was removed by direct concentration under reduced pressure to afford 27b as a white solid (0.27 g, 84.19% yield).

[0689] Step 3: Synthesis of N-((1r,4r)-4-(3-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 27

[0690] 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 1j (0.24 g, 0.41 mmol) was dissolved in N,N-dimethylformamide (3.2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (0.32 g, 0.83 mmol) was stirred for 10 minutes, and then (1r, 4r)-4-(3-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)cyclohexanol-1-amine hydrochloride 27b (0.14 g, 0.39 mmol) and N,N-diisopropylethylamine (0.16 mL, 1.27 mmol) were added and reacted at room temperature for 12 hours. Water (20 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with DCM (30 mL). The organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL). The organic phase was concentrated and the resulting residue was purified by silica gel column chromatography (V DCM / V MeOH =50 / 1) to give a yellow solid 27 (29.0 mg, 8.06% yield) with a purity of 92.04%.

[0691] MS (ESI, pos.ion) m / z: 869.3 [M+H] + ;

[0692] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.30 (s, 1H), 8.00 (d, J = 9.4Hz, 1H), 7.89 (dd, J = 31.4, 7.7Hz, 2H), 7.50 (d, J = 10.5Hz, 1H), 7.41 (d,J=5.6Hz,1H),7.08(s,1H),6.96(dd,J=48.0,8.3Hz,2H),4.96(d,J=7.3Hz,1H),4.54(d,J=10.6Hz,2H),4.34(s,1H),4.0 9(s,1H),3.31(s,3H),3.07(t,J=11.5Hz,2H),2.93(d,J=16.0Hz,1H),2.87-2.73(m,2H),2.67(d,J=21.4Hz,5H),2.32(d,J= 4.9Hz,2H),2.29-2.14(m,5H),2.10(s,1H),2.01-1.89(m,3H),1.77-1.64(m,2H),1.54-1.41(m,2H),1.29(d,J=15.9Hz,4H).

[0693] Example A In cell western blot

[0694] 1. Cell lines and cell culture

[0695] Human prostate cancer cells (LNCaP) (ATCC source). LNCaP cells were cultured in 1640 medium supplemented with 15% fetal bovine serum. They exhibited adherent growth with a weak doubling time of 72 hours. Cells were tightly adherent and required digestion with 0.05% trypsin containing 0.025% EDTA. Cells were passaged twice weekly. Cells were maintained at 37°C in an incubator with a constant temperature, 0.05% CO2, and saturated humidity.

[0696] 2. Cell Plating

[0697] When LNCaP cells were in the exponential growth phase, they were digested and plated onto black, transparent-bottomed 96-well cell culture plates coated with poly-lysine (Biyuntian, catalog number #C0321). Except for the edge wells, 90 μl of culture medium (1.5×104 cells) was added to each well and the cells were allowed to adhere and grow for 24 h.

[0698] 3. Preparation and addition of compound solution

[0699] Weigh 1-2 mg of each compound and add appropriate amount of DMSO to dissolve it so that the concentration of the mother solution is 1 mmol / L. Dilution process (final concentration dilution: 1000, 300, 100, 30, 10, 3, 1, 0.3 nmol / L): Take 9 1.5 mL centrifuge tubes, numbered 10000, 1000, 300, 100, 30, 10, 3, 1, 0.3 respectively, add 90 μl complete medium to tube 10000, take 10 μl from the mother solution and add it to tube 10000, mix well; add 90 μl complete medium to tube 1000, take 10 μl from 10000 and add it to tube 1000, mix well; add 70 μl complete medium containing 1% DMSO to tube 300, take 30 μl from 1000 and add it to tube 300, mix well; add 90 μl complete medium containing 1% DMSO to tube 100 For complete DMSO-containing medium, pipette 10 μl from tube 1000 and add it to tube 100. Mix thoroughly. Repeat this process to obtain samples 30, 10, 3, 1, and 0.3, yielding compound solutions of varying concentrations. Pipette 10 μl from each tube and add it to the corresponding 96-well plate after cells have been grown for 24 hours to obtain the desired concentrations (1000, 300, 100, 30, 10, 3, 1, and 0.3 nmol / L). Continue culturing for 48 hours after drug addition.

[0700] 4. In cell western blot test the effect of compounds on cell AR expression

[0701] 1) Fixation: After drug treatment, the culture medium was aspirated and 100 μl of PBS was added to each well to wash the cells. Then, 100 μl of 4% paraformaldehyde (Biyuntian, catalog number #P0099) was added to fix the cells for 30 min.

[0702] 2) Perforation: Pour out the fixative solution, tap thoroughly, add 100 μl PBS (containing 0.1% Triton) to each well and wash three times, each time for 5 minutes (shaking on a shaker).

[0703] 3) Blocking: Empty the washing solution, tap thoroughly, add 100 μl of blocking solution (LI-COR, catalog number #927-60001) to each well, and block for 30 minutes (shaking on a shaker).

[0704] 4) Incubation with primary antibody: Recover the blocking solution and add 50 μl of Androgen Receptor Rabbit mAb (Cell Signaling Technology, Catalog #5153, dilution ratio 1:1200) to each well. Incubate at 4°C overnight. The next day, incubate at room temperature (on a shaker) for 30 minutes and return to room temperature.

[0705] 5) Incubation with secondary antibody: Recover the primary antibody and add 100 μl of TBST (Solarbio, Catalog #T1082) to each well and wash three times for 10 min each time (on a shaker). Then, add 50 μl of fluorescently labeled secondary antibody (LI-COR, Catalog #926-32211, dilution ratio 1:10,000) to each well and incubate at room temperature for 1 h (protect from light and shake on a shaker).

[0706] 6) DNA staining: Recover the secondary antibody, add 100 μl of TBST to each well and wash three times for 10 min each time (protect from light, shake on a rocker), then add 50 μl of DRAQ5 dye (Thermo Fisher Scientific, catalog #62254, dilution ratio 1:10000) to each well and incubate at room temperature for 5 min (protect from light, shake on a rocker).

[0707] 7) Development: Absorb the DNA stain, pat dry, and use CLX dual-color infrared laser imaging system development.

[0708] 8) Analysis of results: The Androgen Receptor fluorescence signal reading for the compound-treated group was ARS, and the DNA fluorescence signal reading was DNAS. The culture medium group without cells was the blank group, and the Androgen Receptor fluorescence signal reading was ARB, and the DNA fluorescence signal reading was DNAB. The cell group with only DMSO but no compound was the control group, and the Androgen Receptor fluorescence signal reading was ARC, and the DNA fluorescence signal reading was DNAC. ΔARS = ARS-ARB; ΔARC = ARC-ARB; ΔDNAS = DNAS-DNAB; ΔDNAC = DNAC-DNAB.

[0709] Inhibition rate: Inhibiton% = [1-(ΔARS / ΔDNAS) / (ΔARC / ΔDNAC)]*100%. The experimental results are shown in Table 1.

[0710] Table 1 Degradation rate of androgen receptor (AR) by the compounds of the present invention at different concentrations

[0711] Conclusion: The compounds of the present invention showed good activity in degrading androgen receptor.

[0712] Example B ELISA test

[0713] 1. Cell lines and cell culture

[0714] Human prostate cancer cells (LNCaP) (ATCC source). LNCaP cells were cultured in 1640 medium supplemented with 15% fetal bovine serum. They exhibited adherent growth with a weak doubling time of 72 hours. Cells were tightly adherent and required digestion with 0.05% trypsin containing 0.025% EDTA. Cells were passaged twice weekly. Cells were maintained at 37°C in an incubator with a constant temperature, 0.05% CO2, and saturated humidity.

[0715] 2. Cell Plating

[0716] When LNCaP cells were in the exponential growth phase, the cells were digested and plated into 48-well plates. 450 μl of culture medium (5×10 4 cells) was added to each well, and the cells were allowed to adhere and grow for 24 h.

[0717] 3. Preparation and addition of compound solution

[0718] Weigh 1-2 mg of each compound and add appropriate amount of DMSO to dissolve it so that the concentration of the mother solution is 1 mmol / L. Dilution process (final concentrations: 1000, 200, 40, 8, 1.6, 0.32, 0.064 nmol / L): Take 8 1.5 mL centrifuge tubes, numbered 10000, 1000, 200, 40, 8, 1.6, 0.32, 0.064, add 90 μl complete medium to tube 10000, take 10 μl from the mother solution and add it to tube 10000, mix well; add 450 μl complete medium to tube 1000, take 50 μl from tube 10000 and add it to tube 1000, mix well; add 400 μl complete medium containing 1% DMSO to tube 200, take 100 μl from tube 1000 and add it to tube 200, mix well; add 400 μl complete medium containing 1% DMSO to tube 40 For complete DMSO-containing medium, pipette 100 μl from tube 200 and add it to tube 40. Mix thoroughly. Repeat this process to obtain samples 8, 1.6, 0.32, and 0.064, yielding compound solutions of varying concentrations. Pipette 50 μl from each tube and add it to the corresponding 48 wells of cells grown for 24 hours after attachment to obtain the desired concentrations (1000, 200, 40, 8, 1.6, 0.32, and 0.064 nmol / L). Continue culturing for 48 hours after drug addition.

[0719] 4. ELISA test of the effect of compounds on cell AR expression

[0720] After 48 hours of drug exposure, aspirate the culture medium, rinse once with 500 μl of PBS, and lyse the cells in 50 μl of cell lysis buffer on ice for 15 minutes, gently tapping occasionally to promote lysis. Transfer the lysate to a 1.5 ml EP tube and centrifuge at 14,000 rpm at 4°C for 15 minutes. Remove the supernatant for later use. Assay the protein concentration of the lysate using the BCA assay. Adjust the protein concentration to 0.1 mg / ml using the sample diluent in the ELISA kit (Cell Signaling Technology, catalog #12850C).

[0721] 1) Remove the strips required for the test from the sealed bag that has been equilibrated to room temperature, put the unused strips and desiccant back into the aluminum foil bag, seal the bag, and return it to 4°C.

[0722] 2) Add 100 μl of diluted cell lysate to appropriate wells, seal the wells with sealing tape, and incubate at 4°C overnight.

[0723] 3) Gently remove the sealing tape, discard the liquid in the wells, add 200 μl 1X Wash Buffer to each well, and wash 4 times.

[0724] 4) Add 100 μl of detection antibody to each well. Seal the wells with adhesive tape and incubate at 37°C for 60 min.

[0725] 5) Repeat the cleaning procedure (step 3).

[0726] 6) Add 100 μl of HRP-labeled secondary antibody to each well. Seal the wells with adhesive tape and incubate at 37°C for 30 min.

[0727] 7) Repeat the cleaning procedure (step 3).

[0728] 8) Add 100 μl of TMB substrate to each well, seal with adhesive tape, and incubate the plate at 37°C for 10 min.

[0729] 9) Add 100 μl of STOP solution to each well and shake gently for a few seconds to terminate the reaction.

[0730] 10) Read the absorbance at 450 nm within 30 minutes after adding the STOP solution

[0731] 11) Result analysis: The data obtained from the compound-treated group is ODSample, and the cell group treated with only DMSO without compound is the blank control group ODControl.

[0732] Inhibition rate Inhibiton% = (1-ODSample / ODControl) * 100%. The experimental results are shown in Table 2.

[0733] Table 2 Degradation rate of androgen receptor (AR) by the compounds of the present invention at different concentrations

[0734] Conclusion: The compounds of the present invention showed good activity in degrading androgen receptor.

[0735] Example C In cell western blot

[0736] 1. Cell lines and cell culture

[0737] Human prostate cancer cells (LNCaP) (ATCC source). LNCaP cells were cultured in 1640 medium supplemented with 10% fetal bovine serum. They exhibited weak adherent growth, with a doubling time of 72 hours. Cells were tightly adherent and required digestion with 0.05% trypsin containing 0.025% EDTA. Cells were passaged twice weekly. Cells were maintained at 37°C in an incubator with a constant CO2 concentration of 0.05% and saturated humidity.

[0738] 2. Cell Plating

[0739] LNCaP cells were digested and diluted to an appropriate concentration. Only cells with viability above 90% were used for subsequent experiments. Cells were plated into poly-lysine-coated, black, clear-bottomed 384-well cell culture plates (BD, catalog #356663), excluding the edge wells, and allowed to adhere and grow for 24 hours.

[0740] 3. Preparation and addition of compound solution

[0741] Weigh 1-2 mg of each compound and dissolve in DMSO to a stock solution concentration of 10 mmol / L. Dilute the solution to various concentrations in culture medium and add it to cells, achieving final concentrations of 3000, 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, and 0.15 nmol / L, respectively. Continue culturing for 24 hours after treatment.

[0742] 4. In cell western blot test the effect of compounds on cell AR expression

[0743] 1) Fixation: After drug treatment, the culture medium was removed, 100 μl of PBS was added to each well to wash the cells, and then 40 μl of 4% paraformaldehyde (Biyuntian, catalog number #P0099) was added to fix the cells for 30 min.

[0744] 2) Perforation: Empty the fixative solution, add 50 μl PBS to each well (wash twice), add 50 μl Triton-X 100 (0.1%) to each well, and incubate at room temperature for 30 min.

[0745] 3) Blocking: Empty the washing solution, tap thoroughly, add 30 μl of blocking solution (LI-COR, catalog number #927-70001) to each well, and block for 60 minutes.

[0746] 4) Incubation with primary antibody: Recover the blocking solution and add 30 μl of Androgen Receptor Rabbit mAb (Cell Signaling Technology, Catalog #5153, dilution ratio 1:1200) to each well. Incubate at room temperature for 90 min.

[0747] 5) Incubation with secondary antibody: Recover the primary antibody and wash four times with 50 μl of TBST (Solarbio, Catalog #T1082) per well for 10 min each wash. Then, add 30 μl of fluorescently labeled secondary antibody (Invitrogen, Catalog #R8727, dilution ratio 1:10,000) and DNA dye Hoechst 33342 (Invitrogen, Catalog #H3570, dilution ratio 1:10,000) to each well and incubate at room temperature for 1 h.

[0748] 6) Development: Recover the secondary antibody and wash three times with 50 μl of PBST per well. Then, wash twice with 50 μl of PBS per well. After removing the PBS, invert the plate and centrifuge at 1000 rpm for 1 min. Develop the cells using a PE Operetta CLS high-content cell imager.

[0749] 7) Data Analysis

[0750] Inhibition rate calculation: %inhibition=(Signalcmpd-SignalAve_VC) / (SignalAve_PC-SignalAve_VC)×100. Ave_PC :average luminescence value of positive control. Signal Ave_VC :average luminescence value of negative control.

[0751] Calculating DC 50 And draw the effect dose curve: Y=Bottom+(Top-Bottom) / (1+10^((LogDC 50 -X)*HillSlope))

[0752] X: log of compound concentration; Y: % Inhibition. The experimental results are shown in Table 3. The results show that most of the compounds of the present invention degrade active DC 50 <1000nM, preferably DC 50 <500nM, more preferably DC 50 <100nM.

[0753] Table 3 Degradation activity of the compounds of the present invention on androgen receptor (AR) DC 50

[0754] Conclusion: The compounds of the present invention have good degradation activity on androgen receptor (AR).

[0755] Hair regeneration effect of the compound of Example D on the C57 mouse androgenic alopecia model

[0756] 1. Purpose of the experiment

[0757] The purpose of this study is to compare the hair regeneration effect of the compounds prepared by the present invention as AR protein degraders in the androgenic alopecia model in C57BL / 6J mice through the transdermal administration route, so as to provide data support for subsequent clinical trials.

[0758] 2. Test Principle

[0759] After shaving mice with an electric shaver, intraperitoneal injection of a dose of testosterone propionate (TP) solution can delay hair regrowth in mice, simulating an AR-mediated androgenic alopecia model. The compound of the present invention, as an AR protein degrader, promotes hair growth in this AR-mediated androgenic alopecia model, which can, to a certain extent, reflect its therapeutic efficacy.

[0760] 3. Test compound

[0761] The name of the test compound I is testosterone propionate TP; the name of the test compound II is Example 1 of the compound of the present invention; the name of the test compound III is minoxidil; the name of the test compound IV is ARV110.

[0762] 4. Experimental Animals

[0763] Strain: C57BL / 6N mice; Age: 6-7 weeks; Gender: male; Number of animals: 45 (9 in reserve); Housing environment: Specific pathogen Free (SPF).

[0764] 5. Experimental Design

[0765] 36 mice were deeply anesthetized and their back hair was shaved using an animal shaver.

[0766] 6. Grouping

[0767] This experiment was divided into 6 groups. The TP was started on the day of hair removal. The administration time of Example 1 was the second day after hair removal, which was counted as Day 1 (the day of hair removal was counted as Day 0). 36 mice in good condition were randomly selected and divided into the following groups:

[0768] Mouse grouping and drug administration regimen

[0769] 7. Preparation of test compounds

[0770] The drug preparation method and storage conditions are shown in the following table;

[0771] In this experiment, 5% minoxidil tincture was a commercial product (Mandy).

[0772] 8. Observe and detect indicators

[0773] Hair regrowth (anagen) score (0 points: no darkening of skin color in all areas; 1 point: darkening of gray skin color areas; 2 points: visible short hairs; 3 points: sparse hairs; 4 points: dense hairs; 5 points: complete hair growth).

[0774] All mice were photographed on day 0 after shaving, and then the mice were photographed and scored 3 times per week until the end of the experiment.

[0775] At the end of the experiment, skin and blood samples were taken as needed.

[0776] 9. Drug withdrawal and experiment termination criteria

[0777] Animal experiments will be terminated if the animal's health deteriorates, the animal continues to suffer, is unable to eat or drink, or if the animal becomes emaciated and loses more than 20% of its body weight. Animals will be euthanized before death or coma.

[0778] 10. Statistical Analysis

[0779] All data are expressed as mean ± standard error (MEAN ± SEM). Single-factor multilevel analysis of variance was used for statistics. Stundent's t or rank sum test was used to compare each drug group with the model group. The p value was calculated. p < 0.05 indicated a significant difference between the two groups, and p < 0.01 indicated an extremely significant difference between the two groups.

[0780] 11. Experimental Results

[0781] Six groups were included in this experiment: Vehicle, TP (1.25 mg / mouse), TP (1.25 mg / mouse) + 5% minoxidil, TP (1.25 mg / mouse) + 0.3% ARV-110, TP (1.25 mg / mouse) + 0.3% Example 1, and TP (1.25 mg / mouse) + 0.6% Example 1. The results of the hair regeneration effect on the C57 mouse model of androgenic alopecia are shown in Table 4 below:

[0782] Table 4 Hair regeneration effect on C57 mouse androgenic alopecia model

[0783] The results show that the hair development score of the TP (1.25 mg / rat) group was 0.27 after 28 days of administration, indicating almost no hair development, which was significantly lower than that of the Vehicle group, indicating that the model was successfully established.

[0784] The mean score in the TP (1.25 mg / animal) + minoxidil 5% group was 0.22, which was not significantly different from the TP (1.25 mg / animal) model group. The score in the TP (1.25 mg / animal) + ARV-110 0.3% group was significantly higher on Day 28 than in the TP (1.25 mg / animal) model group (p < 0.01).

[0785] The scores for the TP (1.25 mg / mouse) + Example 1 0.3% concentration group and the TP (1.25 mg / mouse) + Example 1 0.6% concentration group on Day 28 were significantly different from those in the TP (1.25 mg / mouse) model group (p < 0.001). The scores for the TP (1.25 mg / mouse) + Example 1 0.3% concentration group and the TP (1.25 mg / mouse) + Example 1 0.6% concentration group on Day 28 were significantly different from those in the TP (1.25 mg / mouse) + minoxidil 5% concentration group (p < 0.001).

[0786] The scores of the TP (1.25 mg / mouse) + Example 1 0.3% group and the TP (1.25 mg / mouse) + Example 1 0.6% group on Day 28 were significantly different from those of the TP (1.25 mg / mouse) + ARV-110 0.3% group (p<0.05).

[0787] Example E Western blotting assay

[0788] 1. Cell lines and cell culture

[0789] Human prostate cancer cells (LNCaP) (ATCC source). LNCaP cells were cultured in 1640 medium supplemented with 15% fetal bovine serum. They exhibited adherent growth with a weak doubling time of 72 hours. Cells were tightly adherent and required digestion with 0.05% trypsin containing 0.025% EDTA. Cells were passaged twice weekly. Cells were maintained at 37°C in an incubator with a constant temperature, 0.05% CO2, and saturated humidity.

[0790] When LNCaP cells were in the exponential growth phase, the cells were digested and plated into 24-well plates at 8 × 10 4 After the cells adhered to the wall for one day, they were cultured with drugs and proteins were extracted 48 hours after drug treatment.

[0791] 2. Cell Protein Extraction

[0792] Remove the culture medium from the cells in the 24-well plate, wash once with PBS, and add 50 μL RIPA lysis buffer (containing 100 μM PMSF) to each well. After thorough mixing, let it stand on ice for 10 minutes, then scrape the cells with a pipette tip and transfer the cell lysate to the corresponding 1.5 mL centrifuge tube. Then, centrifuge at 12000 rpm at 4°C for 15 minutes. The supernatant is used for WB experiments. The samples can be stored at -80°C.

[0793] 3. Protein Concentration Determination

[0794] Use the BCA protein concentration assay kit to prepare the BSA standard assay solution and the sample to be tested according to the instructions (the sample to be tested can be diluted before testing). Use a 96-well plate to load the sample. After filling each well with PBS to 20 μl, add 200 μl of BCA working solution (prepared according to the kit) to each well. After mixing, incubate at 37°C for 20-30 minutes, and then measure the absorbance at 562 nm. Record the readings and draw a standard curve with a standard concentration gradient. Substitute the sample absorbance into the standard curve to calculate the sample protein concentration.

[0795] 4. Western blotting experimental standard process

[0796] 4.1) Protein denaturation: Take the protein lysate, add 5× Loading Buffer, and denature at 100°C for 5 min.

[0797] 4.2) Sample loading and electrophoresis: Using a 10% ExpressCast PAGE color gel rapid kit (New Saimei Biotechnology Co., Ltd., cat. no. P2012) and SDS-PAGE electrophoresis buffer, equal amounts of protein sample and protein marker were loaded into each well, and electrophoresis was performed at 150 V for 40-60 min.

[0798] 4.3) Membrane Transfer: After removing the gel, cut off the excess and transfer to a PVDF membrane via wet transfer (PVDF membrane needs to be activated with methanol for 1 minute before use). 120V, 2h. A large amount of heat is generated during the transfer process, so an ice box is required to cool it down.

[0799] 4.4) Blocking: Place the PVDF membrane after transfer on the QuickBlock TM Block in blocking solution (Biyuntian, catalog number #P0228) at room temperature with shaking for 15 minutes.

[0800] 4.5) Incubation with primary antibodies: Cut the PVDF membrane according to the molecular weight indicated on the marker and incubate with AR and GAPDH primary antibodies, respectively. The antibodies were diluted 1:1000 in Western primary antibody diluent (Biyuntian, catalog number #P0023A-100ml) and blocked overnight at 4°C.

[0801] 4.6) Incubation with secondary antibodies: After incubation with primary antibodies, shake the PVDF membrane on a shaker for 1 hour, return it to room temperature, and then wash it three times with TBST for 5 minutes each time. After washing, place the membrane in the corresponding secondary antibody and incubate it at room temperature for 1 hour on a shaker.

[0802] 4.7) Membrane washing and exposure: After incubation with the secondary antibody, the membrane was washed three times in TBST on a shaker for 5 minutes each time. After washing, the fluorescence on the membrane was excited using the ECL method.

[0803] The experimental results are shown in Table 5, which show that the compounds provided by the present invention have a good degradation effect on LNCaP cell AR protein. The effects of Examples 20 and 21 are comparable to those of Example 1.

[0804] Table 5 Effects of compounds on AR protein degradation in LNCaP cells

[0805] In the description of this specification, the description with reference to the terms "one embodiment", "an implementation", "some embodiments", "example", "specific example" or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment, implementation or example are included in at least one embodiment, implementation or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment, implementation or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments, implementations or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments, implementations or examples described in this specification and the features of different embodiments, implementations or examples without contradiction.

[0806] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I), in, ARB is the androgen receptor recognition / binding part, L is the linking part, and U is the ubiquitin protease recognition / binding part; these three parts are connected by chemical bonds; The ARB is Ring A is C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 12 atoms, wherein the C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5 to 12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent; Ring B is C 6-10 Aryl or heteroaryl consisting of 5 to 12 atoms, wherein the C 6-10 The aryl group and the heteroaryl group consisting of 5 to 12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent; R 1a , R 1b , R 1c , R 1d and R 1e Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 12 atoms, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5 to 12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 is substituted with a haloalkoxy substituent; or R 1a , R 1b and the carbon atoms to which they are attached, or R 1e , R 1d Together with the carbon atom to which they are attached, they form C 3-8 A carbocyclic group, a heterocyclic group consisting of 3 to 8 atoms, or a heteroaryl group consisting of 5 to 10 atoms, wherein the C 3-8 The carbocyclic group, the heterocyclic group consisting of 3-8 atoms and the heteroaryl group consisting of 5-10 atoms optionally contain 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur or nitrogen, and are optionally substituted by 1, 2, 3 or 4 heteroatoms independently selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent; L is wherein ring C and ring D are each independently a heterocyclic group consisting of 3 to 8 atoms, C 6-10 aryl or heteroaryl composed of 5-12 atoms, the heterocyclic group composed of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5 to 12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 is substituted by a haloalkoxy substituent; or D is absent; L 1 is a bond, -O-, -S-, -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, -(CR a R b ) n -, -O-(CR a R b ) n -, -(CR a R b ) n -O-, -NR c -(CR a R b ) n - or -(CR a R b ) n -NR c -; R a and R b Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R c H, D, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl; U is selected from Its dotted lines represent single or double bonds; R 2 and R 3 For H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 4a and R 4b Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 5a , R 5b and R 5c Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl or a heterocyclic group consisting of 3-8 atoms, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl and the heterocyclic group consisting of 3-8 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent; R 6 , R 7 , R 8 and R 9 Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; n is 1, 2, 3, 4 or 5; p is 1, 2, 3, 4 or 5; q is 1, 2, 3, 4, or 5; t is 1, 2, 3, 4, or 5; u is 1, 2, 3, 4, or 5; Wherein, the compound represented by the formula (I) does not include the following compounds:

2. The compound according to claim 1, wherein L is a substructure of one of the following: wherein the substructures are each independently optionally substituted by 1, 2, 3, 4 or 5 selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The left and right connection sites on the substructure of L can be connected to the ARB part or the U part in formula (I) respectively.

3. The compound according to claim 1 or 2, wherein Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3; Ring B is phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3.

4. A compound according to any one of claims 1 to 3, wherein R 1a , R 1b , R 1c , R 1d and R 1e Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl or heteroaryl composed of 5-10 atoms, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5 to 10 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 substituted by a haloalkoxy substituent; R 1a , R 1b and the carbon atoms to which they are attached, or R 1e , R 1d Together with the carbon atom to which they are attached, they form C 3-6 A carbocyclic group, a heterocyclic group consisting of 3 to 6 atoms, or a heteroaryl group consisting of 5 to 6 atoms, wherein the C 3-6 The carbocyclic group, the heterocyclic group consisting of 3-6 atoms and the heteroaryl group consisting of 5-6 atoms optionally contain 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur or nitrogen, and are optionally substituted by 1, 2, 3 or 4 heteroatoms independently selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The alkylene group is substituted with a haloalkoxy substituent.

5. A compound according to any one of claims 1 to 4, wherein R 4a and R 4b Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy; R 5a , R 5b and R 5c Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl or a heterocyclic group consisting of 3 to 6 atoms, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and the heterocyclic group consisting of 3-6 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The alkylene group is substituted with a haloalkoxy substituent.

6. A compound according to any one of claims 1 to 5, wherein R 2 and R 3 Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy; R 6 , R 7 and R 8 Each independently represents H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy.

7. The compound according to any one of claims 1 to 6, wherein R 1a , R 1b , R 1c , R 1d and R 1e Each is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl or aryl radicals are substituted or replaced by 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl radicals ...1,3,4-oxadiazole, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl radicals are substituted or replaced by , propargyl, propynyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, 1,2,4-oxadiazole, 1,3 , 4-oxadiazole, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3; R 1a , R 1b and the carbon atoms to which they are attached, or R 1c , R 1d and together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropene, cyclobutene, cyclopentene, cyclohexene, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropene, cyclobutene, cyclopentene, cyclohexene, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. The alkyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl groups optionally contain 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur or nitrogen, and are optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3.

8. The compound according to any one of claims 1 to 7, wherein R 4a and R 4b Each is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 or -OCF3; R 5a , R 5b and R 5c Each is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl , propargyl, propynyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 and -OCF3.

9. The compound according to any one of claims 1 to 8, wherein R 2 and R 3 Each is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 or -OCF3; R 6 , R 7 , R 8 and R 9 Each is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF2, -CF3, -CH2CF3, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2 or -OCF3.

10. A compound according to any one of claims 1 to 9, which is a compound of formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII), R 1a , R 1b , R 1c , R 1d , R 1e , Ring A, Ring B, Ring C, Ring D, L 1 , R 2 , R 3 , R 4a , R 4b , R 5a , R 5b , R 5c , R 6 , R 7 , R 8 , R 9 , p, q, t and u each independently have the meaning as described in any one of claims 1-9.

11. A compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

12. A pharmaceutical composition comprising the compound of any one of claims 1-11; and the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

13. Use of the compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 in the preparation of a medicament for preventing, treating or alleviating a disease mediated by androgen receptor.

14. The use according to claim 13, wherein the disease mediated by androgen receptor is cancer, acne, hirsutism, sebaceous gland enlargement, alopecia or Kennedy's disease; The cancer is prostate cancer, breast cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer or melanoma.

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