Heterocyclic compound of bifunctional chimera for targeted degradation of androgen receptor and application of heterocyclic compound

Abstract

The invention belongs to the field of medicines, relates to a heterocyclic compound of a bifunctional chimera for targeted degradation of an androgen receptor and application of the heterocyclic compound, and particularly provides a compound as shown in a formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound, and their use in the treatment of diseases associated with androgen receptors. The compound provided by the invention can degrade androgen receptors in prostate cancer cells in a targeted manner and inhibit proliferation of the prostate cancer cells, and also shows good metabolic stability and pharmacokinetic properties. # imgabs0 #

Description

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, and the use of such compounds as androgen receptor (AR) degraders. Background Art

[0002] Androgen receptor (AR) is a hormone nuclear receptor, which can be divided into N-terminal activation domain (NTD), DNA binding domain (DBD) and ligand binding domain (LTD) in structure. It can regulate the gene expression that induces prostate cancer. Therefore, inhibiting androgen receptor is an effective method for treating prostate cancer. Currently available androgen receptor inhibitors such as enzalutamide and bicalutamide mainly exert their inhibitory effects by acting on the ligand binding domain (LTD) of androgen receptor, but some patients will develop drug resistance due to androgen receptor splice variants (AR-Vs) with missing LTD fragments during treatment. Preclinical studies have shown that androgen receptor splice mutants can accelerate the progression of enzalutamide-resistant prostate cancer, and how to solve its drug resistance problem has become a focus of clinical medicine. In addition, more and more studies have shown that androgen receptor also plays an important role in hormone-related diseases such as hair loss, acne, and benign prostatic hyperplasia.

[0003] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to targeted proteins and E3 ubiquitin ligases. Such compounds can be recognized by the cell's proteasome, causing the degradation of targeted proteins, and can effectively reduce the content of targeted proteins in cells. By introducing ligands that can bind to different targeted proteins into PROTAC molecules, it is possible to apply PROTAC technology 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. 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, about 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 it difficult to use again. Therefore, it is necessary to develop new targeted androgen receptor degraders for the treatment of androgen receptor-mediated diseases. Summary of the invention

[0005] The present invention provides a novel structure, good efficacy, high bioavailability, safer compound capable of inhibiting and degrading androgen receptors, for treating diseases mediated by androgen receptors such as cancer, inflammatory diseases or autoimmune diseases. The compound of the present invention has good activity of inhibiting and / or degrading androgen receptors, good pharmacokinetic properties and bioavailability, oral properties and good safety. Therefore, the compound of the present invention has good 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]

[0008] in:

[0009] 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;

[0010] The ARB is

[0011] 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, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6substituted by a haloalkoxy substituent;

[0012] 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, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent;

[0013] R 1a , R 1b , R 1c , R 1d and R 1e Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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 Halogenated alkoxy, 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, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 is substituted with a haloalkoxy substituent; or

[0014] R 1a , R 1b and the carbon atoms to which they are attached, or R 1e , R1d 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, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent;

[0015] 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, -NO 2 , -CN, -OH, -NH 2 , 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;

[0016] 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 -;

[0017] Ra and R b each independently is H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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;

[0018] R c is H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;

[0019] U is selected from

[0020] wherein the dashed line represents a single bond or a double bond;

[0021] R 2 and R 3 each independently is H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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;

[0022] R 4a and R 4b each independently is H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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;

[0023] R 5a , R 5b and R 5cEach independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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 Halogenated alkoxy, 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, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent;

[0024] R 6 , R 7 , R 8 and R 9 Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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;

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

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

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

[0028] t is 1, 2, 3, 4, or 5;

[0029] u is 1, 2, 3, 4, or 5;

[0030] Wherein, the compound represented by the formula (I) does not include the following compounds:

[0031]

[0032] In some embodiments, 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, -NO 2 , -CN, -OH, -NH 2 , 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.

[0033] 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, oxetanyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl radicals are selected from the group consisting of: Pentyl, 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 by 1, 2, 3, 4 or 5 moieties selected from D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 、-CHFCH 2 F, -CF 2 CHF 2 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 and-OCF 3 substituted by a substituent;

[0034] 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 by 1, 2, 3, 4 or 5 moieties selected from D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 、-CHFCH 2 F, -CF 2 CHF 2 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 and-OCF 3 substituted by a substituent.

[0035] In some embodiments, R 1a , R 1b , R 1c , R 1d and R 1e Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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 Halogenated alkoxy, 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, -NO 2 , -CN, -OH, -NH 2 , C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 substituted by a haloalkoxy substituent;

[0036] 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 carbocyclyl, 3-6-atom heterocyclyl and 5-6-atom heteroaryl 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, -NO 2 , -CN, -OH, -NH 2 , 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.

[0037] In some embodiments, R 4a and R 4b Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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;

[0038] R 5a , R 5b and R 5c Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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 Halogenated alkoxy, C 3-6 Cycloalkyl or a heterocyclic group consisting of 3 to 6 atoms, wherein the C1-4 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, -NO 2 , -CN, -OH, -NH 2 , 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.

[0039] In some embodiments, R 2 and R 3 Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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;

[0040] R 6 , R 7 , R 8 and R 9 Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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.

[0041] In some embodiments, R 1a , R 1b , R 1c , R 1d and R 1e Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF 2, -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 、-OCF 3 , 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, 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, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally substituted by 1, 2, 3, 4 or 5 moieties selected from D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 and-OCF 3 substituted by a substituent;

[0042] R 1a , R 1b and the carbon atoms to which they are attached, or R 1e , R 1dand 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. , cyclobutene, cyclopentene, cyclohexene, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl optionally contain 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur or nitrogen, and are optionally replaced by 1, 2, 3 or 4 heteroatoms independently selected from D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 and-OCF 3 substituted by a substituent.

[0043] In some embodiments, R 4a and R 4b Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 or -OCF 3 ;

[0044] R 5a , R 5b and R 5c Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF 2 , -CF3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 、-OCF 3 , 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 by 1, 2, 3, 4 or 5 moieties selected from D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 and-OCF 3 substituted by a substituent.

[0045] In some embodiments, R 2 and R 3 Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 or -OCF 3 ;

[0046] R 6 , R 7 , R 8 and R 9 Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF 2 , -CF 3 、-CH2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 or -OCF 3 .

[0047] In some embodiments, the present invention relates to a compound, which is 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).

[0048]

[0049]

[0050] 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.

[0051] 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) or (XIII) disclosed in the present invention.

[0052] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

[0053] In another aspect, the present invention relates to use of a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII) or a pharmaceutical composition thereof disclosed in the present invention in the preparation of a medicament for preventing, treating or alleviating a disease mediated by an androgen receptor.

[0054] In some embodiments, the androgen receptor-mediated disease is cancer, acne, hirsutism, sebaceous gland enlargement, alopecia, or Kennedy's disease.

[0055] 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.

[0056] On the other hand, the present invention relates to methods for preparing, separating and purifying compounds represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII).

[0057] 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 features in other embodiments, as long as they do not conflict.

[0058] The foregoing content only summarizes certain aspects of the present invention, but is not limited to these aspects. The content of these aspects and other aspects will be described in more detail and completely below. All references in this specification are hereby incorporated by reference in their entirety. When there is a difference between the disclosure of this specification and the cited documents, the disclosure of this specification shall prevail.

[0059] Detailed description of the invention

[0060] Definitions and general terms

[0061] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formula and chemical formula. The present invention is intended to cover all substitutions, modifications and equivalent technical solutions, which are all included in the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described in the present invention can be used to practice the present invention. The present invention is by no means limited to the methods and materials described in the present invention. In the event that one or more of the combined documents, patents and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0062] It should be further appreciated that certain features of the invention, which for clarity are described in the context of multiple 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 sub-combination.

[0063] Unless otherwise indicated, the following definitions used in the present invention shall apply. For purposes of the present invention, chemical elements are consistent 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 can 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.

[0064] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

[0065] 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, conformational isomers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0066] The term "chiral molecule" is a molecule that has the property of being non-superimposable on its mirror image; whereas "achiral molecule" refers to a molecule that is superimposable on its mirror image.

[0067] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0068] The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers, which mixture lacks optical activity.

[0069] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Diastereomer mixtures can be separated by high-resolution analytical operations such as electrophoresis and chromatography, e.g., HPLC.

[0070] The stereochemical definitions and rules used in this invention generally follow S.P. 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. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are used to specify the sign of the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. A specific type of stereoisomer is an enantiomer, and a mixture of such isomers is called a racemic mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0071] Any asymmetric atoms (e.g., carbon, etc.) of the compounds disclosed in this invention can exist in racemic or enantiomerically enriched forms, e.g., in the (R)-, (S)-, or (R,S)- configurational forms. 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.

[0072] Depending on the choice of starting materials and methods, the compounds of this invention can exist in one or a mixture of their possible isomers, e.g., racemates and diastereomer mixtures (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 substituents of the cycloalkyl group may have cis or trans configurations.

[0073] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0074] Any racemate of the resulting final product or intermediate can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of 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 NotreDame Press, Notre Dame, IN 1972); Chiral Separation Techniques: APractical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0075] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of 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.

[0076] "Pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with patient tissues 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.

[0077] The term "optionally substituted by..." can be used interchangeably with the term "unsubstituted or substituted by...", i.e., the structure is unsubstituted or substituted by one or more substituents described in the present invention, including, but not limited to, D, F, Cl, Br, I, N 3 、-CN、-NO 2 、-NH 2 、-OH、-SH、-COOH、-CONH 2 、-C(=O)NHCH 3 、-C(=O)N(CH 3 ) 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, etc.

[0078] In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced by a specific substituent. Unless otherwise indicated, a substituent can be substituted at each reasonable position of the group. When more than one position in the given structural formula can be substituted by one or more specific substituents selected, the substituent can be substituted at each reasonable position in the structural formula in the same or different manner.

[0079] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which 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.

[0080] The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0081] 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.

[0082] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0083] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1 -C 6 "Alkyl" refers specifically to methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 alkyl.

[0084] 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 as 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 an alkylene group or an arylene group, respectively, that is linked.

[0085] The term "D" refers to a single deuterium atom.

[0086] The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0087] The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state of N, S and P; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a substituted hydrogen on a nitrogen atom in a heterocyclic ring, 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).

[0088] The term "alkyl" or "alkyl group" as used herein refers to a saturated straight 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, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ),etc.

[0089] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms and having at least one site of unsaturation, i.e., a carbon-carbon sp 2 Double bond, wherein the alkenyl group may 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, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), 1-propenyl (i.e., propenyl, -CH=CH-CH 3 ),etc.

[0090] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., a carbon-carbon sp triple bond, 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 (-CH 2 C≡CH), 1-propynyl (i.e., propynyl, -C≡C-CH 3 ),etc.

[0091] The term "alkoxy" means an alkyl group attached to the rest of the molecule via 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; in yet other embodiments, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

[0092] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy(i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy(s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy(t-BuO, t-butoxy, -OC(CH 3 ) 3 ),etc.

[0093] The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, -CHF 2 , -CF 3 、-CHFCH 2 F, -CF 2 CHF 2 、-CH 2 CF 3 、-CHFCH 3 、-CH 2 CH 2 F, -CF 2 CH 3 、-CH 2 CF 2 CHF 2 In some embodiments, C 1 -C 6 The haloalkyl group contains a fluorine-substituted C 1 -C 6 In other embodiments, C 1 -C 4 The haloalkyl group contains a fluorine-substituted C 1 -C 4 In some other embodiments, C 1 -C 2 The haloalkyl group contains a fluorine-substituted C 1 -C 2 alkyl.

[0094] 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, -OCHF 2 、-OCF 3 、-OCHFCH 2 F, -OCF 2 CHF 2 、-OCH 2 CF 3 、-OCHFCH 3 、-OCH 2 CH 2 F, -OCF 2 CH 3 、-OCH 2 CF 2 CHF 2 In some embodiments, C 1 -C 6 The haloalkoxy group contains a fluorine-substituted C 1 -C 6Alkoxy; in other embodiments, C 1 -C 4 The haloalkoxy group contains a fluorine-substituted C 1 -C 4 Alkoxy; in some other embodiments, C 1 -C 2 The haloalkoxy group contains a fluorine-substituted C 1 -C 2 Alkoxy.

[0095] 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 between the two. 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, and pyridinyl is a 6-atom heteroaryl group or a 6-membered heteroaryl group.

[0096] 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 C 3- C 10 In other embodiments, the cycloalkyl group contains 3-8 carbon atoms, such as C 3- C 8 In some other embodiments, the cycloalkyl group contains 3-6 carbon atoms, such as C 3- C 6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. 3- C 8 Cycloalkyl includes C 3- C 6 Cycloalkyl; the C 3- C 6Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group is optionally substituted with one or more substituents described herein.

[0097] The term "carbocyclyl" or "carbocycle" refers to a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic system containing 3-12 carbon atoms. Carbobicyclic groups include spirocarbobicyclic groups, fused carbobicyclic groups and bridged carbobicyclic groups, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. 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.

[0098] 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 3-12 ring atoms, wherein the bicyclic or tricyclic ring system may include fused rings, bridged rings and spiro rings. One or more atoms in the ring are independently replaced by heteroatoms, and the heteroatoms have the meanings as described herein. In some embodiments, the heterocyclyl is a monocyclic heterocyclic group consisting of 3-8 ring atoms (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by one or more oxygen atoms to give SO, SO 2 ,PO,PO 2 In some other embodiments, the heterocyclic group is a monocyclic heterocyclic group consisting of 3-6 ring atoms (2-5 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give SO, SO 2 ,PO,PO 2 In other embodiments, the heterocyclic group is a bicyclic heterocyclic group consisting of 7-12 ring atoms (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give SO, SO 2 ,PO,PO 2 The heterocyclyl group is optionally substituted with one or more substituents described herein.

[0099] The ring atoms of the heterocyclic group can be carbon groups or heteroatoms. 2-group 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-oxide. Examples of heterocyclic groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 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 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, etc. In the heterocyclic group -CH 2 Examples of -groups substituted with -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.

[0100] The term "aryl" refers to a monocyclic, bicyclic and tricyclic carbon ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, and wherein each ring system contains a ring consisting of 3-7 atoms. The aryl group is usually, but not necessarily, connected to the parent molecule through 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 by one or more substituents described in the present invention.

[0101] The term "heteroaryl" refers to a monocyclic, bicyclic and tricyclic ring system 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, connected to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described in the present invention. In some embodiments, the heteroaryl group consisting of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

[0102] Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, 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, 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 includes the following bicyclic rings, but is 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.

[0103] As described in the present invention, there are two connection sites on the substructure of the group L 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 linking part L is When, the general formula (I) of the present invention represents that the mm connecting end on L is connected to the androgen receptor recognition / binding part ARB, and the other nn connecting end is connected to the ubiquitin protease recognition / binding part U, as shown in formula a; or represents that the mm connecting end on X is connected to the ubiquitin protease recognition / binding part U, and the other nn connecting end is connected to the androgen receptor recognition / binding part ARB, as shown in formula b.

[0104]

[0105] The term "protecting group" or "PG" refers to a substituent that reacts with other functional groups, usually to block or protect a particular functionality. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the 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 of the hydroxy group used to block or protect the functionality of the hydroxy group. Suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. A "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 -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, etc. 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.

[0106] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII) in vivo. Such conversion is affected by the prodrug being hydrolyzed in the blood or being converted into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. 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 contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent.

[0107] "Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0108] The "pharmaceutically acceptable salt" used in the present invention refers to organic salts and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. 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 1-4 alkyl)4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a group of N. Water-soluble or oil-soluble or dispersible 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 ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1 -C 8 Sulfonates and aromatic sulfonates. Non-toxic physiologically acceptable salts are preferred, although other salts may be useful, for example, in isolating or purifying the product.

[0109] The salts may be formed by conventional means, for example by reacting the free base form of the product with an equivalent of one or more appropriate acids 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.

[0110] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. The solvent forming the solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or a mixture thereof. The term "hydrate" refers to an association formed by the solvent molecule being water.

[0111] 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 combined with one water molecule, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate; in still other embodiments, one molecule of the compound of the present invention may be combined 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.

[0112] The term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing 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 perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0113] 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 exposed or predisposed to the disease but does not yet experience or display symptoms of the disease).

[0114] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are embraced within the scope of the present invention.

[0115] In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the present invention and are included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of the structure are thus unambiguous and defined.

[0116] "Nitrogen oxides" of the compounds of the invention are also included within the scope of the invention. Nitrogen oxides of the compounds of the invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) at elevated temperatures in the presence of an acid such as acetic acid, 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.

[0117] 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 of 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).

[0118] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic part by conventional chemical methods. In general, 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 usually carried out in water or an organic solvent or a mixture of the two. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "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) can be found in a list of other suitable salts.

[0119] Any structural formula given herein is also intended to represent non-isotopically enriched forms of these compounds as well as isotopically enriched forms. 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 introduced into the compounds of the 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.

[0120] On the other hand, the present invention relates to intermediates for preparing compounds represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XIII).

[0121] On the other hand, 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 a liquid, solid, semi-solid, gel or spray formulation.

[0122] Description of the compounds of the present invention

[0123] 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 treating diseases mediated by androgen receptors such as cancer, inflammatory diseases or autoimmune diseases. The compound of the present invention has good activity of inhibiting and / or degrading androgen receptors, good pharmacokinetic properties and bioavailability, oral performance and good safety.

[0124] 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),

[0125]

[0126] in,

[0127] The ARB is

[0128] L is

[0129] U is selected from

[0130] Its dotted lines represent single or double bonds;

[0131] 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:

[0132]

[0133]

[0134] 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),

[0135]

[0136] Among them, 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;

[0137] The ARB is

[0138] L is

[0139] U is selected from Its dotted lines represent single or double bonds;

[0140] 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;

[0141] The compound represented by the formula (I) does not include the following compounds:

[0142]

[0143] In some embodiments, Ring A is C 3-8Cycloalkyl, 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, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The alkylene group is substituted with a haloalkoxy substituent.

[0144] In some embodiments, Ring A is 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 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, -NO 2 , -CN, -OH, -NH 2 , 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.

[0145] 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 and pyridazinyl are each independently optionally substituted by 1, 2, 3, 4 or 5 moieties selected from D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3、-CHFCH 2 F, -CF 2 CHF 2 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 and-OCF 3 substituted by a substituent.

[0146] In some embodiments, 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, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The alkylene group is substituted with a haloalkoxy substituent.

[0147] 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 to 10 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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.

[0148] 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 are each independently optionally substituted by 1, 2, 3, 4 or 5 moieties selected from D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 、-CHFCH 2 F, -CF 2CHF 2 、 -CH 2 CF 3 、 methoxy, ethoxy, n - propyloxy, isopropyloxy, -OCHF 2 and -OCF 3 substituted by substituents.

[0149] In some embodiments, ring C is a heterocyclic group composed of 3 - 8 atoms, C 6-10 aryl or a heteroaryl composed of 5 - 12 atoms, and the heterocyclic group composed of 3 - 8 atoms, C 6-10 aryl and the heteroaryl composed of 5 - 12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO 2 、 -CN, -OH, -NH 2 、 C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy substituents.

[0150] In some embodiments, ring D is a heterocyclic group composed of 3 - 8 atoms, C 6-10 aryl or a heteroaryl composed of 5 - 12 atoms, and the heterocyclic group composed of 3 - 8 atoms, C 6-10 aryl and the heteroaryl composed of 5 - 12 atoms are each independently optionally substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, -NO 2 、 -CN, -OH, -NH 2 、 C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy substituents.

[0151] In some embodiments, D does not exist.

[0152] In some embodiments, 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 aR b ) n -or-(CR a R b ) n -NR c -; where each R a , R b , R c and n have the meanings as defined in the present invention.

[0153] In some embodiments, R a and R b Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy.

[0154] In some embodiments, R a and R b Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 or -OCF 3 .

[0155] 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.

[0156] In some embodiments, R c H, D, methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0157] In some embodiments, 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, -NO 2 , -CN, -OH, -NH 2 , 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.

[0158] In some embodiments, R 1a , R 1b , R 1c , R 1d and R 1e Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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 Halogenated alkoxy, 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, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent;

[0159] In some embodiments, R 1a , R 1b , R 1c , R 1d and R 1eEach independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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 Halogenated alkoxy, 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, -NO 2 , -CN, -OH, -NH 2 , 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.

[0160] In other embodiments, R 1a , R 1b , R 1c , R 1d and R 1e Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 、-OCF 3, 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 methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, methoxy, ethoxy, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, methoxy, ethoxy, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, methoxy, ethoxy, n-propyl, isopropyl, allyl, propenyl, propenyl, propenyl, methoxy, ethoxy, n-propyl, isopropyl, all ... 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 by 1, 2, 3, 4 or 5 moieties selected from D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 and-OCF 3 substituted by a substituent.

[0161] 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 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, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The alkylene group is substituted with a haloalkoxy substituent.

[0162] In some 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 C 3-6 carbocyclic group, a heterocyclic group composed of 3 to 6 atoms, or a heteroaryl group composed of 5 to 6 atoms, wherein the C 3-6 carbocyclic group, the heterocyclic group composed of 3 to 6 atoms, and the heteroaryl group composed of 5 to 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 substituents independently selected from D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy substituents.

[0163] In some other embodiments, R 1a , R 1b and, together with the carbon atom to which they are attached, or R 1e , R 1d and, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropene, cyclobutene, cyclopentene, cyclohexene, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridyl, 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, thiophenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl optionally contain 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and are optionally substituted by 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 , -CH 2 CF 3 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 and -OCF 3 substituents.

[0164] In some embodiments, R 2 and R 3For H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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

[0165] In some embodiments, R 2 and R 3 Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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.

[0166] In other embodiments, R 2 and R 3 Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 or -OCF 3 .

[0167] In some embodiments, R 4a and R 4b Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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 Halogenated alkoxy.

[0168] In some embodiments, R 4a and R 4b Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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.

[0169] In other embodiments, R 4a and R 4b Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 or -OCF 3 .

[0170] In some embodiments, R 5a , R 5b and R 5c Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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 Halogenated alkoxy, 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, -NO 2 , -CN, -OH, -NH 2 , C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The alkylene group is substituted with a haloalkoxy substituent.

[0171] In some embodiments, R 5a , R 5b and R 5c Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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 Halogenated alkoxy, 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, -NO 2 , -CN, -OH, -NH 2 , 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.

[0172] In other embodiments, R 5a , R 5b and R 5c Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 、-OCF 3, 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 by 1, 2, 3, 4 or 5 moieties selected from D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 and-OCF 3 substituted by a substituent.

[0173] In some embodiments, R 6 , R 7 , R 8 and R 9 Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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

[0174] In some embodiments, R 6 , R 7 , R 8 and R 9 Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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.

[0175] In other embodiments, R6 , R 7 , R 8 and R 9 Each independently represents H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, deuterated methyl, -CHF 2 , -CF 3 、-CH 2 CF 3 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 or -OCF 3 .

[0176] In some embodiments, n is 1, 2, 3, 4, or 5.

[0177] In some embodiments, p is 1, 2, 3, 4, or 5.

[0178] In some embodiments, q is 1, 2, 3, 4, or 5.

[0179] In some embodiments, t is 1, 2, 3, 4, or 5.

[0180] In some embodiments, u is 1, 2, 3, 4, or 5.

[0181] 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).

[0182]

[0183] 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.

[0184] 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),

[0185]

[0186] 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.

[0187] 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).

[0188]

[0189] 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.

[0190] 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),

[0191]

[0192] 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.

[0193] 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),

[0194]

[0195] 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.

[0196] 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).

[0197]

[0198] 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.

[0199] 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).

[0200]

[0201] 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.

[0202] 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),

[0203]

[0204] Among them, R 1c , R1d , 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.

[0205] 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).

[0206]

[0207] 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.

[0208] 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).

[0209]

[0210] Among them, R x For H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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;

[0211] 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.

[0212] 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).

[0213]

[0214] Among them, R x For H, D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , 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;

[0215] 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.

[0216] 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).

[0217]

[0218] 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 in the present invention.

[0219] 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:

[0220]

[0221]

[0222] 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.

[0223] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

[0224] 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) or a pharmaceutical composition thereof disclosed in the present invention in the preparation of a medicament for preventing, treating or alleviating a disease mediated by an androgen receptor.

[0225] In some embodiments, the androgen receptor-mediated disease is cancer, acne, hirsutism, sebaceous gland enlargement, alopecia, or Kennedy's disease.

[0226] 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.

[0227] On the other hand, the present invention relates to methods for preparing, separating and purifying compounds represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII).

[0228] Pharmaceutical compositions, preparations and administration of the compounds of the present invention

[0229] 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 preventive ingredients.

[0230] 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.

[0231] Preparations suitable for oral, sublingual, intranasal or injection administration are prepared according to methods known in the pharmaceutical field and contain at least one active compound. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES (16th ed. 1980).

[0232] 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)), usually mixed with an excipient, diluted by an excipient or enclosed in a carrier which may be in the form of a capsule, sachet, paper or other container. When the excipient acts as a diluent, it may be a solid, semisolid or liquid material which acts as an excipient, carrier or medium for the active ingredient. Thus, the formulation may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (either solid or in a liquid medium), ointment 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.

[0233] In the preparation of the formulation, it may be necessary to grind the active compound before mixing with the other components to provide a suitable particle size. If the active compound is substantially insoluble, it is generally ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, its particle size is adjusted by grinding to have a uniform particle size distribution in the formulation, for example, about 40 mesh. In one embodiment of the invention, the particle size is about 0.1-100 μm.

[0234] Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in 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.

[0235] As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or solvent that is relevant to the consistency of the dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would significantly reduce the efficacy of the disclosed compounds when administered to a patient and / or interactions that would result in a pharmaceutical composition that is not pharmaceutically acceptable. In addition, each excipient must be pharmaceutically acceptable, for example, have a sufficiently high purity.

[0236] 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 functions in the composition. For example, certain pharmaceutically acceptable excipients may be selected that can help produce a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected that can help produce a stable dosage form. Certain pharmaceutically acceptable excipients may be selected that help carry or transport the compounds 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.

[0237] 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. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function and may 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 may be formulated using methods known in the art so as to provide rapid, sustained or delayed release of the active ingredient after administration to a patient.

[0238] The skilled person has the knowledge and skill in the art 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).

[0239] In order to prepare pharmaceutical compositions with the compounds described herein, pharmaceutically acceptable carriers may be solid or liquid carriers. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may contain from about 5% to about 95% of the active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules may be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing various compositions may be found in: A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th ed., 1990, Mack Publishing Company Co., Easton, Pennsylvania.

[0240] In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, various carriers for configuring pharmaceutically acceptable compositions, and known techniques for their preparation are disclosed, and the respective contents of these documents are incorporated by reference into the present invention. Except any commonly used carriers such as due to any undesirable biological effects, or in a harmful manner interacting with any other component in the pharmaceutically acceptable compositions and being incompatible with the compounds of the present invention, the application of the relevant carriers belongs to the scope of the present invention.

[0241] The pharmaceutical compositions disclosed in the present invention are prepared using techniques and methods known to those skilled in the art. Some common methods described in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0242] Therefore, 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 a combination thereof, the process comprising mixing the various ingredients. The pharmaceutical composition comprising a compound disclosed herein can be prepared by mixing at, for example, ambient temperature and atmospheric pressure.

[0243] 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.

[0244] It should also be recognized that certain compounds of the present invention may be used in free form for treatment, 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 these esters, or any other adducts or derivatives that can directly or indirectly provide the compounds of the present invention or their metabolites or residues when administered to a patient in need thereof.

[0245] 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.

[0246] The pharmaceutical composition provided by the present invention can be provided in the form of compressed tablets, tablets, chewable lozenges, instant tablets, composite compressed tablets, or enteric-coated tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that is resistant to gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting 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 can help mask unpleasant tastes or odors and prevent 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 are endowed with the same general characteristics as sugar coatings. Composite compressed tablets are compressed tablets prepared over more than one compression cycle, including multilayer tablets, and compression coatings or dry coating tablets.

[0247] Tablet dosage forms can be prepared from active ingredients 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.

[0248] The pharmaceutical composition provided by the present invention can be provided in a soft capsule or a hard capsule, which can be prepared by gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also referred to as a dry-filled capsule (DFC), consists of two sections, one section is inserted into the other section, and thus the active ingredient is completely encapsulated. 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 shell can contain a preservative to prevent microbial growth. Suitable preservatives are those as described in the present invention, including methylparaben and propylparaben, and sorbic acid. Liquid, semisolid and solid dosage forms provided by the present invention can be encapsulated in a capsule. 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.

[0249] The pharmaceutical compositions provided by the present invention 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 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 transparent, sweet-tasting aqueous alcoholic solutions. Syrups are concentrated sugars such as sucrose in water, and can also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with sufficient pharmaceutically acceptable liquid carriers such as water for accurate and convenient administration.

[0250] The pharmaceutical composition provided by the present invention can be formulated into any dosage form suitable for inhalation administration to patients, such as dry powder, aerosol, suspension or solution composition. In some embodiments, the pharmaceutical composition disclosed in the present invention can be formulated into a dosage form suitable for inhalation administration to patients with dry powder. In some other embodiments, the pharmaceutical composition disclosed in the present invention can be formulated into a dosage form suitable for inhalation administration to patients through a nebulizer. The dry powder composition delivered to the lungs by inhalation generally comprises a fine powder of the compound disclosed in the present invention and one or more fine powder of pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art, including lactose, starch, mannitol, and mono-, di- and polysaccharides. Fine powders can be prepared, for example, by micronization and grinding. In general, size-reduced (such as micronized) compounds can be prepared by about 1 to 10 microns of D 50 values ​​(measured, for example, by laser diffraction).

[0251] 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, active ingredients can be delivered from the patch by ion permeation, as generally described in Pharmaceutical Research, 3(6), 318(1986).

[0252] 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 be configured with water or oil base, and applicable thickener and / or gel and / or solvent.Such matrix can include, water, and / or oil such as liquid paraffin and vegetable oil (such as peanut oil or castor oil), or solvent such as polyethylene glycol.Thickener and gel used according to matrix properties include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxyvinyl polyol and cellulose derivative, and / or glyceryl monostearate and / or nonionic emulsifier.

[0253] The compounds of the present invention can also be combined with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or the polyoxyethylene 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 realizing the controlled release of drugs, for example, crosslinked or amphiphilic block copolymers of polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

[0254] 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.

[0255] Pharmaceutical composition provided by the invention can be formulated into any dosage form suitable for parenteral administration, including solution, suspension, emulsion, micelle, liposome, microsphere, nano system and the solid form suitable for making solution or suspension in liquid before injection. Such dosage form can be prepared according to the conventional method known to the technicians in the field of pharmaceutical science (referring to Remington:The Science and Practice of Pharmacy, the same).

[0256] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solution enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestrants or chelating agents, antifreeze agents, cryoprotectants, thickeners, pH adjusters and inert gases.

[0257] The pharmaceutical composition provided by the present invention can be administered via rectal suppositories, by mixing the drug with a suitable non-irritating excipient (such as cocoa butter, glyceride synthesized from polyethylene glycol), which is solid at room temperature, and then liquefying or dissolving in the rectal cavity to release the drug. Due to individual differences, the severity of symptoms will vary greatly, and each drug has its own unique therapeutic properties. Therefore, the precise administration method, dosage form and treatment plan for each individual should be determined by a practicing physician.

[0258] The pharmaceutical compositions provided by the present invention can be formulated into immediate or modified release dosage forms, including delayed, sustained-pulse-controlled, targeted and programmed release forms.

[0259] Although the compounds of the present invention can be administered directly without any formulation, the compounds of the present invention are usually administered in the form of pharmaceutical formulations containing pharmaceutically acceptable excipients and at least one active ingredient. These formulations can be administered by various 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 injections and oral compositions.

[0260] 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, pulsating or on-demand release drug.

[0261] The compound shown in formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) or a pharmaceutically acceptable salt thereof is usually administered via oral route in the form of a pharmaceutical preparation comprising an 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.

[0262] 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, specifically in the form of tablets or capsules, and particularly relate to a technology aimed at providing drug release targeted to the colon (Patel, MM Expert Opin. Drug Deliv. [Expert Opinion on Drug Delivery] 2011, 8 (10), 1247-1258).

[0263] The pharmaceutical preparations of the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) described above may conveniently be 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 unit 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.

[0264] Pharmaceutical preparations suitable for oral administration may include one or more physiologically compatible carriers and / or excipients, and may be in the form of solid or liquid. Tablets and capsules may be prepared with fillers, binders, lubricants and / or surfactants (such as sodium lauryl sulfate). Liquid compositions may contain conventional additives, such as emulsifiers, suspending agents and / or preservatives. Liquid compositions may 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 may 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.

[0265] 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. Liquid fill materials include solid drugs that have been dissolved, solubilized or dispersed (using suspending agents such as polyethylene glycol 4000, hydrogenated castor oil or beeswax) or liquid drugs in a combination of one or more vehicles (such as glycols, polyols, vegetable oils, mineral oils, triglycerides and surface active agents).

[0266] As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to show a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or alleviate the symptoms of a disease when administered or brought into balance 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 used, the method of administration, the clearance rate of the specific drug, the duration of treatment, combined medication, age, weight, sex, diet and health of the patient, etc. A description of other factors that need to be considered in the art regarding the "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.

[0267] 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 of active compound in the range of 0.1 mg to 1000 mg.

[0268] In treating 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 should be understood that the amount of compound actually administered will be determined by the attending physician based on the relevant circumstances, including the disease being treated, the selected route of administration, the actual one or more compounds to be taken, the age, body weight and response of the specific patient and the severity of the patient's symptoms, and therefore, the above dosage range should not limit the scope of the invention in any way. In some cases, dosage levels below the lower limit of the above dosage range may be more appropriate, while in other cases, higher doses that do not produce any side effects can be used, provided that this larger dose is first divided into several smaller doses for administration throughout the day.

[0269] The term "administration" refers to providing a therapeutically effective amount of a drug to an individual, and the administration methods include oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, etc. The dosage forms include ointments, lotions, tablets, capsules, pills, flying powders, granules, suppositories, pills, lozenges, injections, sterile solutions or non-aqueous solutions, suspensions, emulsions, patches, etc. The active ingredient is compounded with a non-toxic pharmaceutically acceptable carrier (such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).

[0270] The preferred route of administration will vary with clinical characteristics, and the change in dosage must depend on the condition of the patient being treated. The doctor will determine the appropriate dosage based on the individual patient. The therapeutically effective amount per unit dose depends on body weight, physiological function and the selected vaccination regimen. The compound per unit dose refers to the weight of the compound at each administration, excluding the weight of the carrier (the drug contains a carrier).

[0271] The pharmaceutical composition provided by the present invention can be formulated into single dose or multiple dose administration. The single dose preparation is packaged in an ampoule, a vial or a syringe. The multiple dose parenteral preparation must contain an antimicrobial agent at a bacteriostatic or antifungal concentration. All parenteral preparations must be sterile, as known and practiced in the art.

[0272] 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.

[0273] In some embodiments, the treatment methods of the present invention include 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. Each embodiment of the present invention includes treating the diseases mentioned in the present invention 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.

[0274] 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 administration. 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 embodiments, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be intranasal administration.

[0275] In some embodiments, the compound of the present invention or a pharmaceutical composition comprising the compound 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, once, twice, three times or four times a day. In some embodiments, it is administered once a day. In some other embodiments, it is administered twice a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. The appropriate dosing regimen of the compound of the present invention or a pharmaceutical composition comprising the compound 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 of the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention, including the duration of the 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, etc., within the knowledge and experience of the technician. Such a technician should also understand that for individual patients' responses to the dosing regimen, or when individual patients need to change over time, it may be required to adjust the appropriate dosing regimen.

[0276] The compounds of the present invention can be administered simultaneously with one or more other therapeutic agents, or before or after them. The compounds of the present invention can be administered separately with other therapeutic agents by the same or different routes of administration, or 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, this combination product uses the compounds of the present invention (within the dosage range described herein) and other pharmaceutically active agents (within its dosage range).

[0277] Accordingly, in one aspect, the present invention includes 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.

[0278] In addition, the compounds of the present invention can be administered in the form of prodrugs. In the present invention, the "prodrug" of the compounds of the present invention is a functional derivative that can ultimately release the compounds of the present invention in vivo when administered to a patient. When administering the compounds of the present invention in the form of prodrugs, those skilled in the art may implement one or more of the following methods: (a) changing the in vivo onset time of the compound; (b) changing the in vivo duration of action of the compound; (c) changing the in vivo transport or distribution of the compound; (d) changing the in vivo solubility of the compound; 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 the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

[0279] Uses of the compounds and pharmaceutical compositions of the present invention

[0280] The compounds and pharmaceutical compositions provided by the present invention can be used to prepare drugs for degrading androgen receptor (AR), and can also be used to prepare drugs for preventing, treating or alleviating diseases mediated by androgen receptor, especially cancer.

[0281] 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).

[0282] The compounds of the present invention can be applied to, but are not limited to, the use of the compounds of the present invention or the effective amount of the pharmaceutical composition administered to patients to prevent, treat or alleviate androgen receptor-mediated diseases. The androgen receptor-mediated diseases further include, but are not limited to, cancer, acne, hirsutism, sebaceous gland enlargement, alopecia or Kennedy's disease.

[0283] The compounds of the present invention can be applied to, but are not limited to, the use of an effective amount of the compounds or pharmaceutical compositions of the present invention to administer to a patient to prevent, treat or alleviate cancer, acne, hirsutism, sebaceous gland enlargement, hair loss or Kennedy's disease. The cancer further includes, but is 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.

[0284] The compounds and pharmaceutical compositions of the present invention are useful for human treatment and can also be used in veterinary treatment of pets, introduced species of animals and mammals in farm animals. Other examples of animals include horses, dogs and cats. Here, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

[0285] General synthetic steps

[0286] To describe 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.

[0287] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown 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.

[0288] Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of the non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art by modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

[0289] 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 were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0290] Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal. Anhydrous dichloromethane and chloroform were obtained by drying under reflux with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0291] The following reactions were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.

[0292] The chromatographic column used was a silica gel column, and the silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0293] 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1 H NMR spectrum of CDC1 3 DMSO-d 6 , CD 3 OD or acetone-d 6is the solvent (in ppm), using TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. 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 doublet of doublets), dt (doublet of triplets), td (triplet of doublets), tt (triplet of triplets). The coupling constant, J, is expressed in Hertz (Hz).

[0294] The low-resolution mass spectrometry (MS) data were measured under the following conditions: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL / min. Mobile phase: 5%-95% (CH 3 CN) in (H 2 O) using electrospray ionization (ESI) at 210 nm / 254 nm with UV detection.

[0295] The 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.

[0296] The following abbreviations are used throughout this invention:

[0297] CH 2 Cl 2 、DCM dichloromethane mg mg

[0298] CDC1 3 Deuterated chloroform g grams

[0299] DMSO dimethyl sulfoxide mL, ml milliliter

[0300] DMSO-d 6 Deuterated dimethyl sulfoxide μL, μl microliter

[0301] EtOAc, EA Ethyl acetate nL, nl Nanoliter

[0302] CH 3 OH, MeOH methanol min minutes

[0303] CD 3 OD deuterated methanol h hour

[0304] nM nanomolar PE petroleum ether (60-90℃)

[0305] μM micromolar RT, rt, rt room temperature

[0306] mmol, mM millimole EDTA ethylenediaminetetraacetic acid

[0307] M mole per liter Boc, BOC tert-butyloxycarbonyl

[0308] ng nanogram DMF N,N-dimethylformamide

[0309] μg microgram HCl hydrochloric acid

[0310] CDI N,N'-CarbonyldiimidazoleTHF Tetrahydrofuran

[0311] ACN Acetonitrile TFA Trifluoroacetic acid

[0312] DIPEA N,N-diisopropylethylamine wt mass fraction

[0313] HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0314] The following synthetic schemes describe procedures for preparing compounds disclosed herein.

[0315] Synthesis Scheme 1

[0316]

[0317] Compound (I) can be synthesized by referring to the method of Synthesis Scheme 1; wherein R x and R y Each independently is D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 1a , R 1b , R 1d , R 1eand R 9 It has the definition as described in the present invention. Compound (Ia) reacts with 3-aminopiperidine-2,6-dione under appropriate conditions (such as triethylamine, 120°C) to obtain compound (Ib); compound (Ib) reacts with tert-butyl piperazine-1-carboxylate under appropriate conditions (such as N,N-diisopropylethylamine, 90°C) to obtain compound (Ic); compound (Ic) reacts under acidic conditions (such as hydrogen chloride) to obtain compound (Id); compound (Ie) reacts with di-tert-butyl dicarbonic acid under appropriate conditions (such as 50°C) to obtain compound (If); compound (If) reacts with 4-hydroxymethylpiperidine under appropriate conditions (such as potassium carbonate and tetrabutylammonium iodide) to obtain compound (Ig); compound (Ig) reacts under appropriate conditions (under sulfur trioxide pyridine) to obtain compound (Ih); compound (Ih) reacts with compound (Id) under appropriate 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).

[0318] Synthesis Scheme 2

[0319]

[0320] Compound (II) can be synthesized by referring to the method of Synthesis Scheme 2; wherein R x and R y Each independently is D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 1c , R 1d , R 1e and R 9It has the definition as described in the present invention. Compound (II-a) reacts with iodomethane under appropriate conditions (such as potassium carbonate) to obtain compound (II-b); compound (II-b) reacts with tert-butyl (4-hydroxycyclohexyl)carbamate under appropriate conditions (such as sodium hydride) to obtain compound (II-c); compound (II-c) reacts under acidic conditions (such as hydrogen chloride) to obtain compound (II-d). Compound (II-d) reacts with compound (Ij) under appropriate conditions (such as 1-propylphosphoric anhydride, diisopropylethylamine) to obtain compound (II).

[0321] Synthesis Scheme 3

[0322]

[0323] Compound (III) can be synthesized by referring to the method of Synthesis Scheme 3; wherein R x and R y Each independently is D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 1c , R 1d , R 1e and R 9 It has the definition as described in the present invention. Compound (III-a) reacts with iodomethane under appropriate conditions (such as potassium carbonate) to obtain compound (III-b); compound (III-b) reacts with tert-butyl (4-hydroxycyclohexyl)carbamate under appropriate conditions (such as sodium hydride) to obtain compound (III-c); compound (III-c) reacts under acidic conditions (such as hydrogen chloride) to obtain compound (III-d). Compound (III-d) reacts with compound (Ij) under appropriate conditions (such as 1-propylphosphoric anhydride, diisopropylethylamine) to obtain compound (III).

[0324] Synthesis Scheme 4

[0325]

[0326] Compound (IV) can be synthesized by referring to the method of Synthesis Scheme 4; wherein R x , R y and R z Each independently is D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 1a , R 1b , R 1d , R 1e and R 9 The compound (Im) is reacted with the compound (IV-a) under suitable conditions (such as 60°C) to obtain the compound (IV-b); the compound (IV-b) is reacted with the compound (IV-c) under acidic conditions (such as under the action of hydrogen chloride); the compound (IV-c) is reacted with the compound (Ij) under suitable conditions (such as under the action of HATU or DIPEA) to obtain the compound (IV).

[0327] The compounds, pharmaceutical compositions and applications of the present invention are further described below in conjunction with the examples. Example

[0328] 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

[0329]

[0330] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione 1b

[0331] 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, and then cooled to room temperature for 1 hour. The solid was precipitated and filtered. The filter cake was washed with water (100 mL), and the filter cake was slurried with water (300 mL), filtered, and vacuum dried to obtain a purple-gray solid 1b (21.67 g, yield 60.62%).

[0332] MS (ESI, pos.ion) m / z: 295.1 [M+H] + .

[0333] Step 2: Synthesis of 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin- Oxazine-1-carbamic acid tert-butyl ester 1c

[0334] 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), and tert-butyl piperazine-1-carboxylate (6.96 g, 37.39 mmol) and N,N-diisopropylethylamine (10.98 g, 84.98 mmol) were added under 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), and the organic phase was washed with saturated sodium chloride solution (200 mL), concentrated, and the residue was slurried with ethyl acetate (30 mL), filtered, and the filter cake was vacuum dried at 45°C to obtain a yellow solid 1c (9.65 g, yield 61.66%).

[0335] MS (ESI, neg.ion) m / z: 459.3 [MH] - .

[0336] Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione Hydrochloride 1d

[0337] 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 4M hydrogen chloride in 1,4-dioxane solution (36 mL). Stir overnight at room temperature, and concentrate the reaction solution to dryness to obtain a light yellow solid 1d (8.31 g, yield 99.92%).

[0338] MS (ESI, pos.ion) m / z: 361.1 [M+H] + .

[0339] Step 4: Synthesis of tert-butyl 6-chloropyridazine-3-carboxylate 1f

[0340] 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 completed, the mixture was heated to 50°C and reacted overnight. The reaction system was concentrated under reduced pressure, ethyl acetate (200 mL) was added to dissolve the mixture, and the mixture was washed with water (200 mL×2). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (V EA / V PE =1 / 10) to give a white solid 1f (17.00 g, yield 62.78%).

[0341] Step 5: Synthesis of tert-butyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate 1 g

[0342] 6-Chloropyridazine-3-carboxylic acid tert-butyl ester 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, concentrated under reduced pressure, and dichloromethane (120 mL) and water (120 mL) were added, stirred, separated, and the organic phase was concentrated to dryness, slurried with dichloromethane (15 mL) and petroleum ether (30 mL), and the solid was collected by filtration and dried under vacuum to obtain 1g of a white solid (20.58 g, yield 88.58%).

[0343] MS (ESI, pos.ion) m / z: 294.1 [M+H] + .

[0344] Step 6: Synthesis of tert-butyl 6-(4-(formyl)piperidin-1-yl)pyridazine-3-carboxylate 1h

[0345] 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, add sulfur trioxide pyridine (16.28 g, 102.27 mmol), and react at 0°C for 0.5 hours. Add water (250 mL), extract with ethyl acetate (100 mL), wash the organic phase with water (250 mL×5), concentrate, and the residue is purified by 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%).

[0346] MS (ESI, pos.ion) m / z: 292.2 [M+H] + .

[0347] Step 7: Synthesis of 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline- tert-butyl 5-(5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylate 1i

[0348] 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-(piperazine-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 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%).

[0349] MS (ESI, pos.ion) m / z: 636.2 [M+H] + .

[0350] Step 8: Synthesis of 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline- 5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 1j

[0351] 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 solution (6 mL). Stir for 2 h, and concentrate the reaction solution to dryness to obtain a yellow solid 1j (0.18 g, yield 98.71%).

[0352] MS (ESI, pos.ion) m / z: 580.5 [M+H] + .

[0353] Step 9: Synthesis of tert-butyl ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamate 1l

[0354] 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, concentrate, and the 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%).

[0355] Step 10: Synthesis of ((1r,4r)-4-(3-chloro-4-(N-hydroxycarbamoyl)phenoxy)cyclohexyl)carbamoyl Tert-butyl ester 1m

[0356] Dissolve tert-butyl ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamate 1l (0.50 g, 1.43 mmol) in methanol solution (5.0 mL), add hydroxylamine hydrochloride (0.30 g, 4.32 mmol) while stirring, and finally add triethylamine (0.46 g, 4.55 mmol) dropwise. After the addition is completed, heat to 75°C and reflux for 13 hours. After the reaction of the raw material is completed by TLC monitoring, the reaction solution is directly concentrated under reduced pressure to obtain a white solid 1m (0.53 g, yield 96.88%).

[0357] Step 11: Synthesis of (1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)amino Tert-butyl ester 1n

[0358] 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 completed, water (10 mL) is added for quenching, and the mixture is purified by silica gel column chromatography (V EA / V PE =1 / 5) to obtain a white solid 1n (0.15 g, yield 27.58%).

[0359] Step 12: Synthesis of (1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexane-1-amino salt Acid 1o

[0360] Dissolve tert-butyl (1r,4r)-4-(3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)carbamate 1n (0.15 g, 0.38 mmol) in 1,4-dioxane solution (1.0 mL), add 4M 1,4-dioxane hydrochloric acid solution (1.0 mL) dropwise with stirring, and continue to stir at room temperature for 3 hours under nitrogen protection. After TLC monitoring shows that the raw material has reacted completely, the mixture is directly concentrated under reduced pressure to remove the solvent to obtain a white solid 1o (0.10 g, yield 79.52%). 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

[0361] 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, 0.34 mmol) was added while stirring. , 0.69mmol), after stirring for 30 minutes, add (1r,4r)-4-3-chloro-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexane-1-amino hydrochloride 1o (0.10g, 0.30mmol), and finally add N,N-diisopropylethylamine (0.20mL) dropwise. After the dropwise addition, continue to stir at room temperature for 12 hours under nitrogen protection. TLC monitors that the raw material has reacted completely, and water (6mL) is added to the reaction solution to quench. Solid precipitates, stir for 10 minutes, filter, collect the filter cake, dry in vacuum, and chromatograph by silica gel column (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%).

[0362] MS (ESI, pos.ion) m / z: 856.3 [M+H] + .

[0363] 1 H NMR (400 MHz, DMSO-d 6)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).

[0364] 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

[0365]

[0366] Step 1: Synthesis of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride 1p

[0367] 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 solution in 1,4-dioxane (2 mL). Stir overnight, and concentrate the reaction solution to dryness to obtain a white solid 1p (2.11 g, yield 100%).

[0368] MS (ESI, pos.ion) m / z: 251.1 [M+H] + .

[0369] Step 2: Synthesis of 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylic acid 1q

[0370] Dissolve tert-butyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate 1g (2.00g, 6.82mmol) in 1,4-dioxane (5mL), add 4M hydrogen chloride solution in 1,4-dioxane (2mL), stir for 16h, and concentrate the reaction solution to dryness to obtain a light yellow solid 1q (1.62g, yield 100%).

[0371] MS (ESI, pos.ion) m / z: 238.2 [M+H] + .

[0372] Step 3: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin- 1-yl)pyridazine-3-carboxamide 1r

[0373] 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), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (5.19 g, 13.66 mmol) was added, and 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 reaction was carried out 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%).

[0374] MS (ESI, pos.ion) m / z: 470.1 [M+H] + .

[0375] Step 4: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)- 1-(2-(2-yl)pyridazine-3-carboxamide 1s

[0376] 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) under 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 turn, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and the residue is purified by silica gel column chromatography (V EA / V PE =1 / 1) to obtain an off-white solid 1s (1.15 g, yield 57.69%). MS (ESI, pos.ion) m / z: 468.4 [M+H] + .

[0377] Step 5: Synthesis of ethyl 2-(3-(2,6-dioxopiperidin-3-yl)ureido)-4-methylthiophene-3-carboxylate 2b

[0378] Dissolve 2-amino-4-methylthiophene-3-carboxylic acid ethyl ester 2a (5.0 g, 26.99 mmol) and triethylamine (10.92 g, 107.96 mmol) in dichloromethane (37.88 mL), add CDI (8.75 g, 53.98 mmol), stir for 3 hours, add 3-aminopiperidine-2,6-dione hydrochloride (4.89 g, 29.69 mmol), continue stirring for 12 hours, filter, wash the filter cake with water (300 mL) and ethyl acetate (150 mL) in turn, collect the filter cake and dry it to obtain an off-white solid 2b (6.8 g, yield 74.23%).

[0379] MS (ESI, pos.ion) m / z: 340.3 [M+H] + .

[0380] Step 6: Synthesis of ethyl 5-bromo-2-(3-(2,6-dioxopiperidin-3-yl)ureido)-4-methylthiophene-3-carboxylate 2c

[0381] Dissolve ethyl 2-(3-(2,6-dioxopiperidin-3-yl)ureido)-4-methylthiophene-3-carboxylate 2b (1.0 g, 2.95 mmol) in DMF (5 mL), cool to 0°C, add N-bromosuccinimide (0.58 g, 3.25 mmol), and stir for 2 hours. Add water (20 mL), extract with ethyl acetate (30 mL), wash the organic phase with water (20 mL × 2), collect the organic phase, and concentrate to dryness to obtain a brown oil 2c (1.2 g, 97.37%).

[0382] Step 7: Synthesis of 6-bromo-3-(2,6-dioxopiperidin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4 (1H,3H)-dione 2d

[0383] 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 and stirred for 4 h. The reaction solution was poured into water (100 mL), the pH was adjusted to 1 with 2 M HCl, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with water (50 mL × 2), and the organic phase was collected and concentrated to obtain 2d (0.42 g, yield 39.33%).

[0384] MS (ESI, pos. ion) m / z: 372.2 [M+H] + .

[0385] Step 8: Synthesis of 4-(3-(2,6-dioxypiperidin-3-yl)-5-methyl-2,4-dioxy-1,2,3,4-tetrahydrothiophene tert-Butyl (2,3-d)pyrimidin-6-yl)piperazine-1-carboxylate 2e

[0386] 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), tert-butyl piperazine-1-carboxylate (2.00 g, 10.74 mmol) and N,N-diisopropylethylamine (2.08 g, 16.11 mmol) were added, and the mixture was reacted at 90 °C for 25 h. 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 obtained residue was purified by silica gel column chromatography (V EA / V PE = 1 / 1) to obtain a brown oil 2e (1.5 g, yield 58.46%).

[0387] 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

[0388] tert-Butyl 4-(3-(2,6-dioxopiperidin-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 1,4-dioxane solution of 4 M hydrogen chloride (5 mL), and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated to obtain a brown solid 2f (1.0 g, yield 96.15%).

[0389] MS (ESI, pos. ion) m / z: 478.5 [M+H]+ .

[0390] Step 10: Synthesis of N-(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(3-(2,6-di oxopiperidin-3-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)piperazin-1-yl) 2-Methyl)piperidin-1-yl)pyridazine-3-carboxamide

[0391] 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), stirred at room temperature for 2.5 h, sodium triacetoxyborohydride (0.27 g, 1.29 mmol) was added, and the stirring reaction was continued 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 obtain an off-white solid 2 (44 mg, yield 12.41%, purity 90.97%).

[0392] MS(ESI,pos.ion)m / z:829.30[M+H] + ;

[0393] 1 H NMR (400 MHz, CDCl 3 )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),2.17(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).

[0394] 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

[0395]

[0396] Step 1: Synthesis of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide 1t

[0397] 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)urea hexafluorophosphate (0.27 g, 0.71 mmol) was added, and then 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 added, and 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 with water (30 mL×2) and saturated sodium chloride solution (30 mL) in sequence, and concentrated to obtain a white solid 1t (0.13 g, yield 95.42%).

[0398] MS (ESI, pos.ion) m / z: 391.2 [M+H] + .

[0399] Step 2: Synthesis of 4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridinium tert-Butyl (1H-1,2,4-triazole-3-carbonyl)piperazine-1-carboxylate 3a

[0400] 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, the temperature was raised to 65°C, and the reaction was stirred for 8 h. Saturated sodium chloride aqueous solution (5 mL) was added to the reaction solution, stirred for 0.5 h, filtered, the filter cake was rinsed with water (1 mL), and the filter cake was dried to obtain a yellow solid 3a (0.30 g, yield 94.13%).

[0401] MS (ESI, neg.ion) m / z: 634.45 [MH] - .

[0402] 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

[0403] 4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-1H-1,2,4-triazole-3-carbonyl)piperazine-1-carboxylic acid tert-butyl ester 3a (298 mg, 0.47 mmol) was dissolved in dichloromethane (3 mL), replaced with nitrogen protection, and trifluoroacetic acid (0.5 mL, 6.73 mmol) was added under stirring, and the reaction was continued for 16 h. The reaction solution was concentrated under reduced pressure, and ethanol (15 mL) was added to the residue to dissolve, and the solvent was concentrated under reduced pressure to obtain a yellow solid 3b (304 mg, yield 100%).

[0404] 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-triazole-1- 3-(2-(2-pyridazine)-3-carboxamide

[0405] 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, and the mixture was filtered after stirring for 0.5 h. The filter cake was washed with water (2 mL), and the filter cake was collected and dried. The 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%).

[0406] MS(ESI,pos.ion)m / z:810.60[M+H] + ;

[0407] 1 H NMR (400 MHz, DMSO-d 6) δ (ppm) 11.12 (s, 1H), 9.79 (s, 1H), 9.17 (d, J = 8.1 Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 8.37 (d, J = 9.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 11.2 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.56 (tt, J = 10.0, 4.2 Hz, 1H), 3.96 (dd, J = 7.6, 3.7 Hz, 1H), 3.90 (d, J = 9.5 Hz, 4H), 3.44 - 3.37 (m, 2H), 3.34 (s, 2H), 2.90 (ddd, J = 16.7, 13.8, 5.4 Hz, 1H), 2.65 - 2.53 (m, 2H), 2.18 - 2.10 (m, 2H), 2.05 (dd, J = 10.9, 5.6 Hz, 1H), 2.00 - 1.91 (m, 2H), 1.72 (dd, J = 17.6, 7.5 Hz, 2H), 1.55 (td, J = 13.2, 6.7 Hz, 2H).

[0408] 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

[0409]

[0410] Step 1: Synthesis of tert-butyl 6-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyridazine-3-carboxylate 4a

[0411] Dissolve tert - butyl 6 - chloropyridazine - 3 - carboxylate 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) in 1,4 - dioxane (20 mL), and react at 100 °C for 8 h. Filter the reaction solution to remove potassium carbonate, concentrate the filtrate, and purify the obtained residue by silica gel column chromatography (V PE / V EA = 2 / 1) to obtain a white solid 4a (1.10 g, yield 64.79%).

[0412] MS (ESI, pos. ion) m / z: 365.8 [M + H] + .

[0413] Step 2: Synthesis of 6-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyridazine-3-carboxylic acid 4b

[0414] Dissolve tert-butyl 6-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyridazine-3-carboxylate 4a (0.50 g, 1.37 mmol) in methanol (10 mL) and water (2 mL), add lithium hydroxide monohydrate (0.23 g, 5.48 mmol), and react at room temperature for 15 h. The reaction solution was concentrated, water (10 mL) was added, and the pH was adjusted to 6 with 1M hydrochloric acid. Solids precipitated and were filtered. The filter cake was rinsed with water (10 mL), and the filter cake was collected and dried to obtain white solid 4b (0.36 g, yield 85.10%).

[0415] MS (ESI, pos.ion) m / z: 309.2 [M+H] + .

[0416] Step 3: Synthesis of 4-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazine- 3-Methyl)piperazine-1-carboxylic acid tert-butyl ester 4c

[0417] 6-(4-(tert-butyloxycarbonyl)piperazine-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), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (0.89 g, 2.34 mmol) was added. The mixture was stirred at room temperature for 10 min, and then 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride 1p (0.34 g, 1.17 mmol) was added. The mixture was reacted at room temperature for 4 hours. Water (100 mL) was added, and solids precipitated. The solids were 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 give a white solid 4c (0.40 g, yield 63.32%).

[0418] MS (ESI, pos.ion) m / z: 541.2 [M+H] + .

[0419] Step 4: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(piperidin-1-yl)pyridazine- 3-Formamide hydrochloride 4d

[0420] 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 4M hydrogen chloride in 1,4-dioxane solution (4 mL) and stirred at room temperature for 15 h. The reaction solution was concentrated to give a white solid 4d (0.35 g, yield 99.17%).

[0421] MS (ESI, pos.ion) m / z: 441.3 [M+H] + .

[0422] Step 5: Compositing (S)-2-((4-(6-(((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazin-1-yl)methyl)morpholine -4-tert-Butyl formate 4e

[0423] 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) were dissolved in dichloromethane (10 mL), stirred at room temperature for 1 h, and then sodium triacetoxyborohydride (0.46 g, 2.19 mmol) was added and reacted at room temperature for 3 hours. Water (10 mL) was added, and the mixture was extracted with DCM (50 mL×3). The organic phases were combined and concentrated, and the residue was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give a light yellow solid 4e (0.23 g, yield 49.00%).

[0424] MS (ESI, pos.ion) m / z: 640.4 [M+H] + .

[0425] Step 6: Compositing N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((R)-morpholin-2-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide Hydrochloride 4f

[0426] (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 (0.24 g, 0.37 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane solution (4 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated to give a yellow solid 4f (0.20 g, yield 92.53%).

[0427] MS (ESI, pos.ion) m / z: 540.4 [M+H] + .

[0428] Step 7: Compositing N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((2S)-4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxopiperidin-3-yl)- (5-(2-( ... Pyridazine-3-carboxamide 4

[0429] 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, and a solid precipitated. The solid was filtered and the filter cake was dried. The solid 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%).

[0430] MS (ESI, pos.ion) m / z: 814.1 [M+H] + ;

[0431] 1 H NMR (400 MHz, DMSO-d 6)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=11.5Hz,1H),3.91-3.81(m,2H),3.71(s,4H),3.59(d,J=11.9Hz,1H),3.4 7 (d, J = 11.8 Hz, 1H), 3.00 (t, J = 11.1 Hz, 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, 10.8 Hz, 2H), 1.52 (q, J = 10.5 Hz, 2H). Example 5 N-((1r, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 5

[0432]

[0433]

[0434] Step 1: Synthesis of tert-butyl 4-(1-benzylpiperidin-4-yl)piperazine-1-carboxylate 5b

[0435] Dissolve tert-butyl piperazine-1-carboxylate (5.1 g, 26.95 mmol) in tetrahydrofuran (50 mL), add 1-benzylpiperidin-4-one 5a (5.07 g, 27.22 mmol), adjust pH to 6 with acetic acid (15 mL), stir for 0.5 h, cool to 0 ° C, slowly add sodium triacetoxyborohydride (3.08 g, 14.55 mmol), move to room temperature and react for 4 h. Add sodium bicarbonate solution to the reaction solution to quench, adjust the pH value to 9-10, extract with ethyl acetate (250 mL × 3), wash the combined organic phase with saturated sodium chloride solution (50 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a yellow liquid 5b (9.6 g, yield 99.09%).

[0436] Step 2: Synthesis of tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate 5c

[0437] 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 with hydrogen 3 times (hydrogen balloon), continue stirring at room temperature for 4 hours. TLC detected that the raw material reacted completely, directly filtered, collected the filtrate, and concentrated under reduced pressure to obtain a yellow oil 5c (2.20 g, yield 97.83%).

[0438] Step 3: Synthesis of tert-butyl 4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidine-1-carboxylate 5d

[0439] Dissolve tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate 5c (0.70 g, 2.60 mmol) in N,N-dimethylformamide (8 mL), add 1,2-difluoro-4-nitrobenzene (0.42 g, 2.65 mmol) and triethylamine (0.53 g, 5.2 mmol), and react at room temperature for 14 h. Pour the reaction solution into water (30 mL) to quench, extract with ethyl acetate (60 mL × 2), wash the combined organic phase with saturated sodium chloride solution (20 mL × 3), dry over anhydrous sodium sulfate, filter, collect the filtrate and concentrate, and the residue is purified by silica gel column chromatography (V PE / V EA =10 / 1) to give a yellow solid 5d (0.38 g, yield 35.8%).

[0440] Step 4: Synthesis of 2-fluoro-4-nitrophenyl-4-piperidin-4-piperazine 5e

[0441] 4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidine-1-carboxylic acid tert-butyl ester 5d (0.38 g, 0.93 mmol) was dissolved in ethyl acetate (3.0 mL), and 4 M hydrogen chloride ethyl acetate solution (0.70 mL, 2.79 mmol) was added under stirring, and the mixture was reacted at room temperature for 6 h. The reaction solution was concentrated to obtain a yellow solid 5e (0.32 g, yield 99.76%).

[0442] Step 5: Compositing N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3- Formamide 5f

[0443] 2-Fluoro-4-nitrophenyl-4-piperidin-4-piperazine 5e (0.32 g, 0.93 mmol) was dissolved in N,N-dimethylformamide (4 mL), 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, and the mixture was reacted at 100°C for 16 h. The reaction solution was cooled to room temperature, quenched with water (20 mL), extracted with dichloromethane (35 mL×2), the organic phases were combined and concentrated, and the residue was purified by silica gel column chromatography (100% EtOAc) to obtain a yellow solid 5f (0.20 g, yield 32.50%).

[0444] Step 6: Compositing 6-(4-(4-(4-amino-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-yl Formamide 5g

[0445] 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) solution, iron powder (48.59 mg, 0.87 mmol) and ammonium chloride (77.56 mg, 1.45 mmol) in water (1 mL) were added, and the mixture was refluxed at 85°C for 3 h. The reaction solution was cooled to room temperature, diluted with ethanol (20 mL), filtered with diatomaceous earth pad, the filtrate was collected, concentrated, the obtained solid was slurried with water (30 mL), filtered, the filter cake was collected and dried to obtain 5 g (0.17 g, yield 93.71%) of yellow solid. Step 7: Compositing N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-3-yl) Oxazine-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 5

[0446] Dissolve 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 in N,N-dimethylformamide (3 mL), add 3-bromopiperidine-2,6-dione (0.10 g, 0.54 mmol) and sodium bicarbonate (0.068 g, 0.81 mmol), protect with nitrogen, and react at 70°C for 15 h. The reaction solution was cooled to room temperature, and water (20 mL) was added to the reaction solution to quench. Solid precipitated, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried, and then purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give an off-white solid 5 (20 mg, yield 10.01%).

[0447] MS (ESI, pos.ion) m / z: 744.7 [M+H] + ;

[0448] 1 H NMR (400 MHz, DMSO-d 6 )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=7.7Hz,1H),4.5 4(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,3H),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).

[0449] 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

[0450]

[0451] Step 1: Synthesis of 1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazine- 3-yl)piperidine-4-carboxylic acid 1u

[0452] 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, and the mixture was reacted at room temperature for 6 h. Saturated sodium bicarbonate solution and saturated sodium thiosulfate solution (V / V=1 / 1, 25 mL) were added to the reaction solution to quench the mixture, and the mixture was stirred for 30 min, extracted with DCM (50 mL×2), and the combined organic phases were washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated to obtain a yellow solid 1u (0.50 g, yield 48.55%).

[0453] Step 2: Synthesis of methyl 4-bromo-3-fluorobenzoate 6b

[0454] 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, and the mixture was reacted at 70°C for 16 h. The reaction solution was cooled to room temperature, concentrated, and the obtained white solid was slurried with a saturated sodium bicarbonate solution (10 mL), filtered, and the filter cake was collected and dried to obtain a white solid 6b (1.6 g, yield 75.18%).

[0455] Step 3: Synthesis of tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate 6c

[0456] Dissolve methyl 4-bromo-3-fluorobenzoate 6b (0.50 g, 2.15 mmol) in toluene (5.0 mL), add tert-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) in sequence at 10°C, replace with nitrogen protection, and reflux 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 give a yellow solid 6c (0.50 g, yield 68.6%).

[0457] Step 4: Synthesis of 4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid 6d

[0458] 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 6c (0.20 g, 0.77 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.15 g, 0.59 mmol) were dissolved in tetrahydrofuran (2.0 mL), 1M sodium hydroxide solution (1.18 mL, 1.18 mmol) was added, nitrogen was replaced for protection, and the reaction was carried out at 60°C for 6 h. The reaction solution was cooled to room temperature, and the pH of the reaction solution was adjusted to 5 with 1N hydrochloric acid solution, and then water (15 mL) was added to precipitate a solid, which was filtered and the filter cake was collected and dried to obtain a white solid 6d (0.16 g, yield 83.46%).

[0459] Step 5: Synthesis of (S)-4-(4-(2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperidin-1-yl Tert-Butyl Formate 6e

[0460] 4-(4-(tert-Butyloxycarbonyl)piperazine-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 the mixture was 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 added, and nitrogen was replaced for protection, and the mixture was reacted at room temperature for 12 h. Water (15 mL) was added to the reaction solution, and the mixture was filtered, and the filter cake was collected and dried to obtain a white solid 6e (0.19 g, yield 88.65%).

[0461] Step 6: Synthesis of (S)-N-(2,6-dioxopiperidin-3-yl)-3-fluoro-4-(piperidin-1-yl)benzamide hydrochloride Salt 6f

[0462] Dissolve (S)-tert-butyl 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 4M hydrogen chloride ethyl acetate solution (0.33 mL, 1.32 mmol), and react at room temperature for 4 h. The reaction solution was concentrated to obtain a white foamy solid 6f (0.16 g, yield 98.67%).

[0463] Step 7: Compositing N-(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(4-(S)-2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluoro Phenylpiperazine-1-carbonyl)piperidin-1-yl)pyridazine-3-carboxamide 6

[0464] 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 reaction was carried out at room temperature for 6 h under nitrogen protection. 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 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%).

[0465] MS (ESI, Pos.ion) m / z: 801.3 [M+H] + ;

[0466] 1 H NMR (400 MHz, DMSO-d 6 )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),3.09(s,4 H),2.11(s,4H),1.99-1.88(m,4H),1.77(d,J=12.8Hz,2H),1.67-1.48(m,8H).

[0467] 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

[0468]

[0469] Step 1: Synthesis of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate 7b

[0470] 1-(4-bromophenyl)piperazine 7a (1.50 g, 6.22 mmol), triethylamine (1.57 g, 15.55 mmol), 4-dimethylamine pyridine (76 mg, 0.62 mmol) were dissolved in acetonitrile (30 mL), and Boc anhydride (1.49 g, 6.84 mmol) was added and reacted at room temperature for 3 h. The reaction solution was poured into water (200 mL) and stirred for crystallization, 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, yield 82.44%). MS (ESI, pos.ion) m / z: 341.25 [M+H] + .

[0471] Step 2: Synthesis of tert-butyl 4-(4-(2,4-dimethoxypyrimidin-5-yl)phenyl)piperazine-1-carboxylate 7c

[0472] 4-(4-bromophenyl)piperazine-1-carboxylic acid tert-butyl ester 7b (0.50 g, 1.47 mmol), (2,4-dimethoxypyrimidin-5-yl)boric 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 h. The reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (V PE / V EA =9 / 1) to give an off-white solid 7c (0.32 g, yield 54.53%).

[0473] MS (ESI, pos.ion) m / z: 401.3 [M+H] + .

[0474] Step 3: Synthesis of 5-(4-(piperazin-1-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione hydrochloride 7d

[0475] 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 solution (4.0 mL, 2.5 mmol) was added, and the mixture was reacted at 100°C for 8 h. The reaction solution was cooled to room temperature, methanol (10 mL) was added, and the mixture was stirred for crystallization for 2 h, filtered, and the filter cake was rinsed with methanol (5.0 mL), and the filter cake was collected and dried to obtain an off-white solid 7d (0.20 g, yield 81.06%).

[0476] MS (ESI, pos.ion) m / z: 273.3 [M+H] + .

[0477] Step 4: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2,4-diphenyl)- 1,2,3,4-tetrahydropyrimidin-5-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 7

[0478] 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 reacted at room temperature for 12 h. Pour water (20 mL) into the reaction solution and stir for 30 min. Solid precipitates and is filtered. The filter cake is rinsed with water (20 mL). The filter cake is collected and dried. The obtained off-white solid is purified by HPLC [eluent: 37% ACN / 63% water (0.01% TFA)] to obtain an off-white solid 9 (20 mg, yield 43.07%). MS (ESI, pos.ion) m / z: 724.6 [M+H] + ;

[0479] 1 H NMR (400 MHz, CDCl 3 )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=14.7H z,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=11.7Hz,2 H),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).

[0480] 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

[0481]

[0482] Step 1: Synthesis of tert-butyl 4-(4-(2,6-dimethoxypyrimidin-4-yl)phenyl)piperazine-1-carboxylate 8b

[0483] 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 residue was purified by silica gel column chromatography (V PE / V EA =9 / 1) to give an off-white solid 8b (0.46 g, yield 50.32%).

[0484] MS (ESI, pos.ion) m / z: 401.3 [M+H] + .

[0485] Step 2: Synthesis of 6-(4-(piperazin-1-yl)phenyl)-pyrimidine-2,4(1H,3H)-dione hydrochloride 8c

[0486] 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 solution (4.0 mL, 2.5 mmol) was added, and the mixture was reacted at 100°C for 18 h. The reaction solution was cooled to room temperature, and the pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution. The mixture was stirred for crystallization for 2 h, filtered, and the filter cake was collected and dried to obtain an off-white solid 8c (0.20 g, yield 81.71%).

[0487] MS (ESI, pos.ion) m / z: 273.3 [M+H] + .

[0488] Step 3: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2,6-diphenyl)- oxo-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)

[0489] Piperazine-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 8

[0490] Dissolve 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) in methanol (3.0 mL). After stirring for 10 min, add sodium cyanoborohydride (27.3 mg, 0.13 mmol) and react at room temperature for 18 h. Add water (30 mL) to the reaction solution, stir for 30 min, precipitate a solid, filter, wash the filter cake with water (20 mL), collect the filter cake and dry it. The obtained solid is purified by HPLC preparation [eluent: 37% ACN / 63% water (0.01% TFA)] to obtain an off-white solid 8 (34 mg, yield 43.94%).

[0491] MS(ESI,pos.ion)m / z:724.6[M+H] + ;

[0492] 1 H NMR(400MHz,DMSO-d 6 )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).

[0493] 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

[0494]

[0495] Step 1: Synthesis of tert-6-(4-(4-(3-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylic acid Butyl ester 9a

[0496] 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 obtained residue was purified by slurrying with water (20 mL), filtered, and the filter cake was treated with a mixed solution 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%).

[0497] MS (ESI, pos.ion) m / z: 487.5 [M+H] + .

[0498] Step 2: Synthesis of tert-6-(4-(4-(4-amino-3-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylic acid Butyl ester 9b

[0499] 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 carbon (0.39 g, 3.65 mmol) were dissolved in methanol (10 mL) and stirred at room temperature for 24 hours for hydrogenation reaction. The filtrate was filtered and concentrated to obtain a light yellow solid 9b (0.45 g, yield 94.05%).

[0500] MS (ESI, pos.ion) m / z: 457.4 [M+H] + .

[0501] Step 3: Synthesis of 6-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl) Piperidin-1-yl)pyridazine-3-carboxylic acid tert-butyl ester 9c

[0502] Dissolve tert-butyl 6-(4-(4-(4-amino-3-fluorophenyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylate 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) in N,N-dimethylformamide (5 mL), heat to 70 ° C and stir for 25 hours. Add water (10 mL) and dichloromethane (10 mL) to extract the liquid, concentrate the organic phase, and separate and purify the residue by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give a yellow solid 9c (0.39 g, yield 69.71%).

[0503] MS (ESI, pos.ion) m / z: 568.7 [M+H]+ .

[0504] 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

[0505] Tert-butyl 6-(4-(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 (4M, 4 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain a yellow solid 9d (0.39 g, yield 98.36%).

[0506] MS (ESI, pos.ion) m / z: 512.5 [M+H] + .

[0507] 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-carboxylate Amine 9

[0508] (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-(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-propylphosphoric 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, and the liquid was extracted and concentrated. The organic phase was purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give an off-white solid 9 (16.0 mg, yield 13.42%) with a purity of 89.46%.

[0509] MS (ESI, pos.ion) m / z: 787.3 [M+H] + ;

[0510] 1H 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).

[0511] 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

[0512]

[0513] Step 1: Synthesis of tert-butyl ((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)carbamate 10b

[0514] Trans-4-Boc-aminocyclohexanol (1.00 g, 4.64 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydride (0.28 g, 6.96 mmol, wt 60%) was added under stirring at 0°C, followed by 4-fluoro-2-methoxybenzonitrile 10a (0.84 g, 5.57 mmol), and the mixture was reacted for 6 hours. Water (200 mL) was added to the reaction solution to quench the reaction, and solids precipitated. The filter cake was rinsed with water (50 mL) and dried to obtain a white solid 10b (0.95 g, yield 59.04%).

[0515] Step 2: Synthesis of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-methoxybenzonitrile hydrochloride 10c

[0516] Dissolve tert-butyl ((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)carbamate 10b (0.20 g, 0.58 mmol) in 1,4-dioxane hydrochloric acid solution (4M, 4 mL) and stir at room temperature for 6 hours. Concentrate the reaction solution to obtain a light yellow solid 10c (0.16 g, yield 98.01%). MS (ESI, pos.ion) m / z: 247.2 [M+H] + .

[0517] Step 3: Synthesis of 6-chloro-N-((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)pyridazine-3-carboxylate Amine 10d

[0518] 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-propylphosphoric 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 spin-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%).

[0519] 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)

[0520] Pyridazine-3-carboxamide 10e

[0521] 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 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%).

[0522] MS (ESI, pos.ion) m / z: 659.4 [M+H] + .

[0523] 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

[0524] 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) were added to water (2 mL), and the mixture was refluxed at 85°C for 7 hours. The mixture was filtered and the filtrate was concentrated. The residue was slurried with water (20 mL), filtered and the filter cake was dried under vacuum to obtain an off-white solid 10f (0.3 g, yield 59.30%).

[0525] MS (ESI, pos.ion) m / z: 629.4 [M+H] + .

[0526] 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)

[0527] Piperazine-1-yl)piperidin-1-yl)pyridazine-3-carboxamide 10

[0528] 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), heated to 70 ° C and stirred for 21 hours. Water (10 mL) was added to the reaction solution to quench, solid precipitated, filtered, the filter cake was rinsed with water (10 mL), 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%.

[0529] MS (ESI, pos.ion) m / z: 740.4 [M+H] + ;

[0530] 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).

[0531] 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

[0532]

[0533] Step 1: Synthesis of (1-(4-nitrophenyl)piperidin-4-yl)methanol 11b

[0534] 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, poured into ice water (160 mL) for quenching, stirred for 1 hour, filtered, and the solid was collected and dried to obtain a yellow solid 11b (16.74 g, yield 99.97%).

[0535] Step 2: Synthesis of 1-(4-nitrophenyl)piperidine-4-carboxaldehyde 11c

[0536] (1-(4-nitrophenyl)piperidin-4-yl)methanol 11b (3.00 g, 12.70 mmol), dimethyl sulfoxide (0.93 g, 12.7 mmol), N,N-diisopropylethylamine (11.49 g, 88.90 mmol) were dissolved in dichloromethane (30 mL), sulfur trioxide pyridine (12.13 g, 76.20 mmol) was added at 0°C, and the mixture was reacted for 2 hours. Water (30 mL) was added, the liquids were separated, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oil 11c (2.90 g, yield 97.50%).

[0537] Step 3: Synthesis of tert-butyl 4-((1-(4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate 11d

[0538] 1-(4-nitrophenyl)piperidine-4-carboxaldehyde 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 hours, then cooled to 0°C, sodium triacetoxyborohydride (5.25 g, 24.76 mmol) was added, and the reaction was naturally restored to room temperature for 16 hours. Saturated sodium bicarbonate solution (50 mL) was added to the reaction solution, stirred for 0.5 hours, filtered, the filter cake was rinsed with water (30 mL), and the filter cake was collected and dried to obtain a yellow solid 11d (3.15 g, yield 62.90%).

[0539] MS(ESI,pos.ion)m / z:405.30[M+H] + .

[0540] Step 4: Synthesis of tert-butyl 4-((1-(4-aminophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate 11e

[0541] 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), and water (5 mL), iron powder (3.05 g, 54.53 mmol) and ammonium chloride (1.25 g, 23.37 mmol) were added, and the mixture was reacted at 65°C for 2 hours. The reaction solution was cooled to room temperature, ethyl acetate (80 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with ethyl acetate (30 mL). The filtrate was collected, saturated sodium bicarbonate solution (20 mL) was added, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain an off-white solid 11e (2.92 g, yield 100%).

[0542] MS (ESI, pos.ion) m / z: 375.3 [M+H] + .

[0543] Step 5: Synthesis of (Z)-4-((1-(4-(2-(1-cyano-2-((ethoxycarbonyl)amino)-2-oxoethylidene) tert-Butyl (4-(2-( ...

[0544] Dissolve tert-butyl 4-((1-(4-aminophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate 11e (2.4 g, 6.41 mmol) in water (5 mL) and acetic acid (15 mL), add sodium nitrite (0.53 g, 7.69 mmol) at 0°C, stir and react for 0.5 hours, add 18-crown ether-6 (0.85 g, 3.21 mmol) and N-cyanoacetylurethane (1.20 g, 7.69 mmol), and react at room temperature for 2 hours. Adjust the solution pH to 8 with saturated sodium bicarbonate solution, add ethyl acetate (100 mL), separate the liquids, collect the organic phase, dry it with anhydrous sodium sulfate, filter and concentrate to obtain black solid 11f (3.47 g, yield 99.97%).

[0545] Step 6: Synthesis of 4-((1-(4-(6-cyano-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl)piperidine- tert-Butyl 4-(4-yl)methyl)piperazine-1-carboxylate 11g

[0546] (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 residue was separated and purified by silica gel column chromatography (V DCM / V MeOH =30 / 1) to give 11 g (1.45 g, yield 45.67%) of brown solid.

[0547] MS (ESI, pos.ion) m / z: 496.0 [M+H] + .

[0548] 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

[0549] Dissolve 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 11 g (0.20 g, 0.40 mmol) in dichloromethane (3 mL), add hydrochloric acid ethyl acetate solution (0.10 g, 2.80 mmol, 4 mol / L), react at room temperature, filter with suction, collect the filter cake and spin dry to give a brown solid 11h (0.15 g, yield 93.99%).

[0550] 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-triazine-2-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin Oxazine-3-carboxamide 11

[0551] 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), 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 and stirred for 1 hour, filtered, the filter cake was collected and dried, and then subjected to 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%.

[0552] MS (ESI, pos.ion) m / z: 750.0 [M+H] + .

[0553] 1 H NMR (400 MHz, DMSO-d 6 )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),7.2 5(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).

[0554] 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

[0555]

[0556] Step 1: Synthesis of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate 12b

[0557] 1-(4-bromophenyl)piperazine 12a (1.50 g, 6.22 mmol), triethylamine (1.57 g, 15.55 mmol), 4-dimethylamine pyridine (76 mg, 0.62 mmol) were dissolved in acetonitrile (30 mL), and Boc anhydride (1.49 g, 6.84 mmol) was added and reacted at room temperature for 3 hours. The reaction solution was poured into water (200 mL) and stirred for crystallization for 30 minutes, filtered, and the filter cake was rinsed with water (20 mL), and the filter cake was collected and dried to obtain an off-white solid 12b (1.75 g, yield 82.44%).

[0558] MS(ESI,pos.ion)m / z:341.25[M+H] + .

[0559] Step 2: Synthesis of tert-butyl 4-(4-(2,4-dimethoxypyrimidin-5-yl)phenyl)piperazine-1-carboxylate 12c

[0560] 4-(4-bromophenyl)piperazine-1-carboxylic acid tert-butyl ester 12b (0.50 g, 1.47 mmol), (2,4-dimethoxypyrimidin-5-yl)boric 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), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (V PE / V EA =9 / 1) to afford an off-white solid 12c (0.32 g, yield 54.53%).

[0561] MS (ESI, pos.ion) m / z: 401.3 [M+H] + .

[0562] Step 3: Synthesis of 5-(4-(piperazin-1-yl)phenyl)-pyrimidine-2,4(1H,3H)-dione hydrochloride 12d

[0563] Dissolve tert-butyl 4-(4-(2,4-dimethoxypyrimidin-5-yl)phenyl)piperazine-1-carboxylate 12c (0.10 g, 0.25 mmol) in acetic acid (5.0 mL), add 2M aqueous hydrochloric acid solution (4.0 mL, 2.5 mmol), and react at 100°C for 8 hours. The reaction solution was cooled to room temperature, methanol (10 mL) was added, stirred for crystallization for 2 hours, 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, yield 81.06%). MS (ESI, pos.ion) m / z: 273.3 [M+H] + .

[0564] 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)

[0565] Piperazine-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 12

[0566] 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 reacted at room temperature for 12 hours. Water (20 mL) was poured into the reaction solution and stirred for 30 minutes. 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%.

[0567] MS (ESI, pos.ion) m / z: 725.6 [M+H] + .

[0568] 1 H NMR (400 MHz, CDCl 3 )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=14.7H z,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=11.7Hz,2 H),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).

[0569] 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

[0570]

[0571]

[0572] Step 1: Synthesis of tert-butyl 4-(4-(2,6-dimethoxypyrimidin-4-yl)phenyl)piperazine-1-carboxylate 13b

[0573] 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 residue was purified by silica gel column chromatography (V PE / V EA =9 / 1) to give an off-white solid 13b (0.46 g, yield 50.32%).

[0574] MS (ESI, pos.ion) m / z: 401.3 [M+H] + .

[0575] Step 2: Synthesis of 6-(4-(piperazin-1-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione hydrochloride 13c

[0576] 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 solution (4.0 mL, 2.5 mmol, 2 M) was added, and the mixture was reacted at 100°C for 18 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution. The mixture was stirred for crystallization for 2 hours, filtered, and the filter cake was collected and dried to obtain an off-white solid 13c (0.20 g, yield 81.71%).

[0577] MS (ESI, pos.ion) m / z: 273.3 [M+H] + .

[0578] 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)

[0579] Piperazine-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 13

[0580] 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 reacted 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. 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 a HPLC purity of 97.56%.

[0581] MS (ESI, pos.ion) m / z: 724.6 [M+H] + .

[0582] 1 H NMR (400 MHz, DMSO-d 6 )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),2.40-2.0 5(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).

[0583] 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

[0584]

[0585] Step 1: Synthesis of tert-butyl ((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)carbamate 14b

[0586] 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), and the mixture was reacted at 0°C for 6 hours. Water (200 mL) was added to the reaction solution to quench the reaction, and the solid was precipitated, filtered, and the filter cake was dried to obtain a white solid 14b (0.95 g, yield 59.04%). Step 2: Synthesis of ((1r,4r)-4-(4-(N-hydroxyamino) tert-Butyl imide)-3-methoxyphenoxy)cyclohexyl)carbamate 14c

[0587] Tert-butyl ((1r,4r)-4-(4-cyano-3-methoxyphenoxy)cyclohexyl)carbamate 14b (0.76 g, 2.19 mmol) was dissolved in methanol solution (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 obtain a white solid 14c (0.83 g, yield 99.70%).

[0588] MS (ESI, pos.ion) m / z: 380.5 [M+H] + .

[0589] Step 3: Synthesis of ((1r,4r)-4-(3-methoxy-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl)amine Tert-butyl formate 14d

[0590] 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. The mixture was reacted at 60°C for 8 hours under nitrogen protection. Water (20 mL) and dichloromethane (20 mL) were added to the reaction solution, and the extract was separated. The organic phase was concentrated, and the residue was purified by column chromatography (V PE / V EA =5 / 1) to give a white solid 14d (0.15 mg, yield 17.61%).

[0591] MS(ESI,pos.ion)m / z:412.3[M+Na] + .

[0592] Step 4: Synthesis of (1r,4r)-4-(3-methoxy-4-(1,2,4-oxadiazol-3-yl)phenoxy)cyclohexane-1-amine Hydrochloride 14e

[0593] 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 solution (2 mL, 4 M) and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain a white solid 14e (0.12 g, yield 95.63%).

[0594] Step 5: Synthesis of 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline- 5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(1r,4r)-4-(3-methoxy-4-(1,2,4-oxadiazol-3-yl)benzene Oxy)cyclohexyl)pyridazine-3-carboxamide 14

[0595] (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), 1-propylphosphoric anhydride (0.47 g, 0.74 mmol, 50% EA solution) was added at 0°C, and the reaction 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 obtain yellow solid 14 (30.0 mg, yield 9.57%) with a purity of 98.29%.

[0596] MS (ESI, pos.ion) m / z: 851.6 [M+H] + .

[0597] 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).

[0598] 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

[0599]

[0600] Step 1: Synthesis of 1-(4-nitrophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione 15b

[0601] 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 then the pH was adjusted to 5, filtered, and the filter cake was rinsed with water (50 mL). The filter cake was collected and dried to obtain a light yellow solid 15b (2.59 g, yield 78.36%).

[0602] Step 2: Synthesis of 1-(4-aminophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione 15c

[0603] 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 mixed solvent 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, rinsed with ethanol (5 mL), and the filtrate was concentrated. The residue was added with water (10 mL) and slurried for 20 minutes, filtered with suction, and the filter cake was dried to obtain a white solid 15c (1.56 g, yield 74.59%).

[0604] MS (ESI, pos.ion) m / z: 204.0 [M+H] + .

[0605] Step 3: Synthesis of N-((1r,4r)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((4-(2,4-diphenyl)- Oxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)

[0606] (amino)methyl)piperidin-1-yl)pyridazine-3-carboxamide 15

[0607] 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, followed by the addition of sodium triacetylborohydride (0.16 g, 0.75 mmol) 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 15 (20.0 mg, yield 11.58%) with a purity of 93.37%.

[0608] MS (ESI, pos.ion) m / z: 655.0 [M+H] + .

[0609] 1 H NMR (400 MHz, DMSO-d 6)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),3.0 8-2.87(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).

[0610] 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

[0611]

[0612] Step 1: Synthesis of 5-fluoro-1-(4-nitrophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione 16b

[0613] 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 then the pH was adjusted to 5, filtered, and the filter cake was rinsed with water (50 mL). The filter cake was collected and dried to obtain a light yellow solid 16b (2.48 g, yield 69.66%).

[0614] Step 2: Synthesis of 5-fluoro-1-(4-aminophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione 16c

[0615] 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 mixed solvent of ethanol (5 mL), water (5 mL) and DMF (1 mL), and refluxed at 85°C for 5 hours. The mixture was filtered while hot, rinsed with ethanol (2 mL), and the filtrate was concentrated to obtain a white solid 16c (0.12 g, yield 70.52%).

[0616] MS(ESI,pos.ion)m / z:222.1[M+H] + .

[0617] Step 3: Synthesis of 6-(4-(((4-(5-fluoro-2,4-dioxo-3H-pyrimidin-1-yl)phenyl)amino)methyl)piperidin pyridin-1-yl)-N-((1r,4r)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide 16

[0618] 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 the reaction was carried out at room temperature for 1 hour. Subsequently, sodium triacetoxyborohydride (0.12 g, 0.57 mmol) was added, and the reaction was continued for 4 hours. The reaction solution was concentrated, and the obtained 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] + .

[0619] 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.61(d,J = 8.2Hz,1H),7.86(d,J = 8.8Hz,1H),7.80(d,J = 9.5Hz,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).

[0620] 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

[0621]

[0622]

[0623] Step 1: Synthesis of 4-fluoro-1-methyl-1H-indazole-7-carbonitrile 17b

[0624] 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, the filter cake was collected, and dried, and the obtained solid was separated and purified by column chromatography (V PE / V EA =10 / 1) to give a white solid 17b (0.68 g, yield 69.51%).

[0625] MS (ESI, pos.ion) m / z: 176.1 [M+H] + .

[0626] Step 2: Synthesis of N-((1r,4r)-4-((7-cyano-1-methyl-1H-indazol-4-yl)oxy)cyclohexyl)amino Tert-Butyl Formate 17c

[0627] 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, stir for 10 minutes, filter, collect the filter cake and spin dry, and the obtained solid is separated and purified by column chromatography (V PE / V EA =4 / 1) to give a white solid 17c (0.45 g, yield 38.69%).

[0628] MS(ESI,pos.ion)m / z:393.2[M+Na] + .

[0629] Step 3: 1-Methyl-4-(((1r,4r)-4-aminocyclohexyl)oxy)-1H-indazole-7-carbonitrile hydrochloride 17d

[0630] Weigh tert-butyl N-((1r,4r)-4-((7-cyano-1-methyl-1H-indazol-4-yl)oxy)cyclohexyl)carbamate 17c (0.45 g, 1.21 mmol), add ethyl acetate solution of hydrochloric acid (9.1 mL, 4 M), and react at room temperature for 2 hours. The reaction solution was spin-dried to obtain an off-white solid 17d (0.37 g, yield 99.28%).

[0631] 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)cyclohexane 1-(2-[(2-[(2-yl)pyridazine-3-carboxamide))

[0632] 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, 1-propylphosphoric 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 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%.

[0633] MS (ESI, pos.ion) m / z: 832.3 [M+H] + .

[0634] 1 H NMR (400 MHz, CDCl 3)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,1H),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),2.84-2. 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).

[0635] 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

[0636]

[0637] Step 1: Synthesis of 4-fluoro-1-methyl-1H-indole-7-carbonitrile 18b

[0638] 4-Fluoro-1H-indole-7-carbonitrile 18a (0.40 g, 2.50 mmol) was dissolved in N,N-dimethylformamide (4 mL), potassium carbonate (0.86 g, 6.25 mmol) and iodomethane (0.71 g, 5.00 mmol) were added, and the mixture was reacted at room temperature for 2 hours. Water (12 mL) was added to the reaction solution, stirred for 20 minutes, filtered, and the filter cake was dried in vacuo to obtain a white solid 18b (0.34 g, yield 78.16%).

[0639] Step 2: Synthesis of N-((1r,4r)-4-((7-cyano-1-methyl-1H-indol-4-yl)oxy)cyclohexyl)amino Tert-Butyl Formate 18c

[0640] 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). After stirring for 10 minutes, add 4-fluoro-1-methyl-1H-indole-7-carbonitrile 18b (0.30 g, 1.72 mmol), and allow the reaction to return to room temperature naturally for 2 hours. Quench the reaction by adding water (5 mL) at 0 °C. After stirring for 10 minutes, filter, collect the filter cake and evaporate to dryness. The resulting solid is purified by column chromatography (V PE / V EA = 4 / 1) to obtain a white solid 18c (73.0 mg, yield 11.47%). MS (ESI, pos. ion) m / z: 271.2 [M+H] + .

[0641] Step 3: 1-Methyl-4-(((1r,4r)-4-aminocyclohexyl)oxy)-1H-indole-7-carbonitrile hydrochloride 18d

[0642] Weigh tert-butyl N-((1r,4r)-4-((7-cyano-1-methyl-1H-indol-4-yl)oxy)cyclohexyl)carbamate 18c (70.0 mg, 0.19 mmol), add an ethyl acetate solution of hydrochloric acid (1.4 mL, 4 M), and react at room temperature for 1 hour. Evaporate the reaction solution to dryness to obtain an off-white solid 18d (58.0 mg, yield 100%).

[0643] MS (ESI, pos. ion) m / z: 392.2 [M+Na] + .

[0644] 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)cyclohexane 1-(2-[ ...(pyridazine-3-carboxamide

[0645] Dissolve 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) in N,N-dimethylformamide (4.0 mL). Cool the temperature to 0 °C, and slowly add 1-propylphosphonic anhydride (0.24 g, 0.38 mmol, 50% EA solution). React at room temperature for 4 hours. Quench the reaction by adding water (10 mL), extract with DCM (20 mL×3), collect the organic phase and evaporate to dryness. The resulting residue is purified by silica gel column chromatography (V DCM / VMeOH =20 / 1) to give a yellow solid 18 (20.0 mg, yield 13.28%) with a purity of 95.30%.

[0646] MS (ESI, pos.ion) m / z: 831.4 [M+H] + .

[0647] 1 H NMR (400 MHz, CDCl 3 )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),7.01-6.9 6(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),2.24(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).

[0648] 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

[0649]

[0650] Step 1: Synthesis of (2S,5R)-5-(2,4-dioxo-3H-pyrimidin-1-yl)tetrahydrofuran-2-carbaldehyde 19b

[0651] 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), reacted at 80°C for 2 hours, filtered, the filter cake was washed with acetonitrile (30 mL), and the filtrate was concentrated to obtain a white solid 19b (0.99 g, yield 99.95%).

[0652] Step 2: Synthesis of 4-(((2S,5R)-5-(2,4-dioxo-3H-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl) Piperazine-1-carboxylic acid tert-butyl ester 19c

[0653] (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 reacted at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, stirred for 30 minutes, filtered, and the filter cake was washed with water (10 mL). The filter cake was dried to obtain a yellow solid 19c (1.44 g, yield 99.45%).

[0654] Step 3: Synthesis of 1-((2R,5S)-5-(piperazin-1-ylmethyl)tetrahydrofuran-2-yl)-1,2,3,4-tetrahydropyrimidine Pyridine-2,4-dione hydrochloride 19d

[0655] 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 1,4-oxathiazine in hydrogen chloride (20 mL, 4 M) and reacted at room temperature for 3 hours. The reaction solution was filtered and the filter cake was dried to obtain a yellow solid 19d (1.10 g, yield 91.74%).

[0656] Step 4: N-((1r,4S)-4-((3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(((2S,5R)-5-(2,4- (2H)-1,2-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide 19

[0657] 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 obtain brown solid 19 (18.0 mg, yield 8.98%) with a purity of 96.93%.

[0658] MS (ESI, pos.ion) m / z: 636.3 [M+H] + ;

[0659] 1 H NMR (400 MHz, DMSO-d 6)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).

[0660] 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

[0661]

[0662] Step 1: Synthesis of 1-((2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl)dihydropyrimidine-2,4(1H,3H)-dihydropyrimidine Keto 20a

[0663] 2',3'-dideoxyuridine 19a (1.00 g, 4.71 mmol) and 10% palladium / carbon (0.40 g) were dissolved in methanol (10 mL). The mixture was switched to hydrogen and reacted at room temperature for 23 hours. The reaction solution was filtered and the filtrate was concentrated to obtain a white solid 20a (1.00 g, yield 99.06%).

[0664] Step 2: Synthesis of (2S,5R)-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)tetrahydrofuran-2-carbaldehyde 20b

[0665] 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 solution was filtered, the filter cake was washed with acetonitrile (30 mL), and the filtrate was concentrated to obtain a white solid 20b (0.99 g, yield 99.94%).

[0666] Step 3: Synthesis of 4-(((2S,5R)-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methane tert-Butyl)piperazine-1-carboxylate 20c

[0667] (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 reacted at room temperature for 12 hours. Water (50 mL) and dichloromethane (20 mL) were added to the reaction solution, and the liquid was extracted and separated. The organic phase was concentrated to obtain a yellow oil 20c (1.60 g, yield 88.78%).

[0668] Step 4: Synthesis of 1-((2R,5S)-5-(piperazin-1-ylmethyl)tetrahydrofuran-2-yl)dihydropyrimidine-2,4-(1H, 3H)-dione hydrochloride 20d

[0669] 4-(((2S,5R)-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester 20c (1.60 g, 4.18 mmol) was dissolved in a solution of 1,4-oxathiazine in hydrogen chloride (22 mL, 4 M) and reacted at room temperature for 2 hours. The reaction solution was filtered and the filter cake was dried to obtain a yellow solid 20d (1.10 g, yield 82.48%).

[0670] MS (ESI, pos.ion) m / z: 281.2 [M+H] + .

[0671] 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

[0672] 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, the filter cake was collected and dried, and 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%.

[0673] MS (ESI, pos.ion) m / z: 638.3 [M+H]+ .

[0674] 1 H NMR (400 MHz, CDCl 3 )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,1 H),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),4.1 3-4.04(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).

[0675] 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

[0676]

[0677] Step 1: Synthesis of 2-((3S)-2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione 21b

[0678] (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, and the mixture was reacted at 120°C for 3 hours. The reaction solution was cooled to room temperature and stirred for 1 hour, filtered, and the filter cake was washed with water (10 mL), the filter cake was collected and slurried with water (30 mL), filtered, and the filter cake was collected and dried to obtain a purple-gray solid 21b (2.20 g, yield 61.54%).

[0679] Step 2: Synthesis of (S)-4-(2-(-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl) tert-Butyl)piperazine-1-carboxylate 21c

[0680] 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, and 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, which was filtered by suction. The filter cake was slurried with water (50 mL), filtered by suction, and the filter cake was collected and dried to obtain a yellow solid 21c (2.50 g, yield 72.61%).

[0681] Step 3: Synthesis of (S)-2-(-2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1, 3-Diketone hydrochloride 21d

[0682] (S)-4-(2-(-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylic acid tert-butyl ester 21c (2.50 g, 5.43 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (15 mL, 4 M) and reacted at room temperature for 5 hours. The reaction solution was filtered and the filter cake was dried to obtain a green solid 21d (2.10 g, yield 97.48%).

[0683] Step 4: Synthesis of (S)-6-(4-((4-(2-(-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole tert-Butyl (5-doline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylate 21e

[0684] 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-(piperazine-1-yl)isoindoline-1,3-dione hydrochloride 21d (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. Add water (20 mL) to the reaction solution, separate the liquids, wash the organic phase with saturated sodium bicarbonate solution (20 mL), concentrate, and the resulting residue is purified by silica gel column chromatography (V DCM / V MeOH =20 / 1) to give a light yellow solid 21e (0.54 g, yield 49.50%).

[0685] Step 5: Synthesis of (S)-6-(4-((4-(2-(-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole (doline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 21f

[0686] 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), and a solution of hydrogen chloride in 1,4-dioxane (4 mL, 4 M) was added, and the mixture was reacted at room temperature for 4 hours. The reaction solution was concentrated to obtain a yellow solid 21f (0.49 g, yield 99.53%).

[0687] 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 1-yl)piperidin-1-yl)pyridazine-3-carboxamide 21

[0688] (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-propylphosphoric anhydride (0.29 g, 0.45 mmol, 50% EA solution) was added and reacted 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 obtain a yellow solid 21 (125.0 mg, yield 32.17%) with a purity of 99.60%.

[0689] MS (ESI, pos.ion) m / z: 855.2 [M+H] + .

[0690] 1 H NMR (599 MHz, CDCl 3)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),2.7 9(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).

[0691] 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

[0692]

[0693] Step 1: Synthesis of 2-((3R)-2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione 22b

[0694] (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, and the mixture was reacted at 120°C for 3 hours. The reaction solution was cooled to room temperature and stirred for 1 hour, filtered, and the filter cake was washed with water (10 mL), the filter cake was collected and slurried with water (30 mL), filtered, and the filter cake was collected and dried to obtain a purple-gray solid 22b (2.50 g, yield 69.93%).

[0695] Step 2: Synthesis of 4-(2-((3R)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl) tert-Butyl)piperazine-1-carboxylate 22c

[0696] 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 reaction was carried out at 90 °C for 8 hours. The reaction solution was cooled to room temperature, water (30 mL) was added, and a solid was precipitated. The solid was filtered by suction, the filter cake was slurried with water (50 mL), filtered by suction again, and the filter cake was collected and dried to obtain a yellow solid 22c (3.50 g, yield 89.45%).

[0697] Step 3: Synthesis of 2-((3R)-2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1, 3-Diketone hydrochloride 22d

[0698] 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 a 1,4-dioxane solution of hydrogen chloride (20 mL, 4 M), and the reaction was carried out at room temperature for 5 hours. The reaction solution was filtered by suction, and the filter cake was dried by rotary evaporation to obtain a green solid 22d (3.00 g, yield 97.47%).

[0699] Step 4: Synthesis of 6-(4-((4-(2-((3R)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole tert-Butyl (5-doline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylate 22e

[0700] tert-Butyl 6-(4-formylpiperidin-1-yl)pyridazine-3-carboxylate 1h (0.50 g, 1.72 mmol) was dissolved in dichloromethane (20 mL), and 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) was added with stirring. The reaction was carried out at room temperature for 1 hour, and then sodium triacetoxyborohydride (1.09 g, 5.16 mmol) was added. The reaction was carried out at room temperature for 5 hours. Water (20 mL) was added to the reaction solution, and the layers were separated. The organic layer was washed with a 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 obtain a pale yellow solid 22e (0.60 g, yield 55.00%).

[0701] Step 5: Synthesis of 6-(4-((4-(2-((3R)-2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole (doline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid 22f

[0702] 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), and a solution of hydrogen chloride in 1,4-dioxane (4 mL, 4 M) was added, and the mixture was reacted at room temperature for 4 hours. The reaction solution was concentrated to obtain a yellow solid 22f (0.54 g, yield 98.71%).

[0703] 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

[0704] 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 reacted 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%.

[0705] MS (ESI, pos.ion) m / z: 855.2 [M+H] + ;

[0706] 1 H NMR (599 MHz, CDCl 3)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,2H),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).

[0707] 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

[0708]

[0709] Step 1: Synthesis of 7-fluoro-3-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile 23b

[0710] 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 under stirring at room temperature, and the mixture was reacted for 1 hour. Saturated ammonium chloride solution (10 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and concentrated to obtain a light yellow solid 23b (0.24 g, yield 66.94%).

[0711] Step 2: Synthesis of 7-fluoro-3-methoxy-2,3-dihydro-1H-indene-4-carbonitrile 23c

[0712] 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, and the reaction was continued for 3 hours. Then iodomethane (0.17 g, 1.23 mmol) was added dropwise, and the reaction was stirred at room temperature for 4 hours. Water (12 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (12 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (V PE / V DCM =1 / 3) to give a light yellow oil 23c (83 mg, yield 35.28%).

[0713] Step 3: Synthesis of N-((1r,4r)-4-((7-cyano-1-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)cyclo tert-Butyl hexyl carbamate 23d

[0714] 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 the mixture was 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 mixture was stirred 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 phase was concentrated, and the 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%).

[0715] MS (ESI, pos.ion) m / z: 387.1 [M+H] + .

[0716] Step 4: Synthesis of 3-methoxy-7-(((1r,4r)-4-aminocyclohexyl)oxy)-2,3-dihydro-1H-indene-4-carboxylate Nitrile 23e

[0717] 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 THF solution of hydrogen chloride (1 mL, 4.0 mol / L) and reacted at room temperature for 1 hour. The reaction solution was dried to give a white solid 23e (25.9 mg, yield 99.87%).

[0718] MS(ESI,pos.ion)m / z:287.35[M+H] + .

[0719] Step 5: Synthesis of N-((1r,4r)-4-((7-cyano-1-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)cyclo Hexane)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1- 2-(4-(2-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 23

[0720] 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), 1-propylphosphonic anhydride (110.7 mg, 0.17 mmol, 50% EA solution) was slowly added at 0°C and the reaction was allowed to proceed at room temperature for 12 minutes. Water (10 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with DCM (20 mL × 3). The combined organic phase was spin-dried and the residue was purified by silica gel column chromatography (V DCM / V MeOH =19 / 1) to give a yellow solid 23 (37 mg, yield 49.98%) with a purity of 96.61%.

[0721] MS (ESI, pos.ion) m / z: 848.3 [M+H] + ;

[0722] 1 H NMR (599 MHz, CDCl 3 )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=13.4H z,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,1H),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).

[0723] 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

[0724]

[0725]

[0726] Step 1: Synthesis of 4-fluoro-1-isopropyl-1H-indole-7-carbonitrile 24a

[0727] Sodium hydride (0.19 g, 4.8 mmol, 60% wt) was dissolved in DMF (20 mL) at 0°C, 4-fluoro-1H-indole-7-carbonitrile 18a (0.64 g, 4.0 mmol) was added, and the reaction was continued for 20 minutes, and then 2-iodopropane (0.68 g, 4.0 mmol) was added, and the reaction was continued at 0°C for 12 hours. Saturated ammonium chloride solution (20 mL) was added to the reaction solution to quench, and the mixture was extracted with EA (20 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (V PE / V EA =4 / 1) to afford 24a as a colorless oil (0.34 g, yield 41.45%).

[0728] MS (ESI, pos.ion) m / z: 203.2 [M+H] + .

[0729] Step 2: Synthesis of 1-isopropyl-4-(((1r,4r)-4-aminocyclohexyl)oxy)-1H-indole-7-carbonitrile 24b

[0730] Dissolve tert-butyl N-((1r,4r)-4-hydroxycyclohexyl)carbamate (0.45 g, 2.07 mmol) in N,N-dimethylformamide (5 mL), add sodium hydride (0.095 g, 2.39 mmol, 60% in oil) at 0°C, stir for 1 hour, add 4-fluoro-1-isopropyl-1H-indole-7-carbonitrile 24a (0.32 g, 1.59 mmol) in N,N-dimethylformamide (0.5 mL), and naturally return to room temperature for 12 hours. Add water (5 mL) to the reaction solution to quench, extract with EA (10 mL × 3), wash the combined organic phase with saturated sodium chloride solution (5 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a white solid 24b (0.24 g, yield 50.15%).

[0731] MS(ESI,pos.ion)m / z:297.95[M+H] + .

[0732] 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

[0733] Dissolve 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) in DCM (2.0 mL), cool to 0 °C, and slowly add 1-propylphosphonic anhydride (0.37 g, 0.58 mmol, 50% EA solution). React at room temperature for 5 hours. Quench the reaction by adding water (10 mL), extract with DCM (20 mL × 3), collect the organic phase and evaporate to dryness. The resulting residue is separated and purified by silica gel column chromatography (V DCM / V MeOH = 19 / 1) to obtain a yellow solid 24 (55 mg, yield 22.40%), purity 95.48%.

[0734] MS(ESI,pos.ion)m / z:859.30[M+H] + ;

[0735] 1 H NMR(400MHz,CDCl 3)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),2.2 7-2.17(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).

[0736] 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

[0737]

[0738] Step 1: Synthesis of (S)-morpholin-2-ylmethanol hydrochloride 25b

[0739] (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate 25a (1.00 g, 4.60 mmol) was dissolved in 1,4-dioxane hydrochloride solution (10 mL, 4 M) and reacted at room temperature for 4 hours. The reaction solution was concentrated to obtain a white solid 25b (0.70 g, yield 99.01%).

[0740] Step 2: Synthesis of N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-(hydroxymethyl) (Phenyl)pyridazine-3-carboxamide 25c

[0741] 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 give a yellow solid 25c (1.60 g, yield 88.43%).

[0742] Step 3: Synthesis of N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-formyl)- (Phenyl)pyridazine-3-carboxamide 25d

[0743] 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 obtain a light yellow oil 25d (99.0 mg, yield 99.43%).

[0744] 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- Formamide 25

[0745] N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-formylmorpholine)pyridazine-3-carboxamide 25d (0.10 g, 0.21 mmol), (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), 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, which was filtered, and the collected filter cake was dried and purified by silica gel column chromatography (V DCM / V MeOH =30 / 1) to obtain a white solid 25 (28.0 mg, yield 15.84%) with a purity of 91.38%.

[0746] MS (ESI, pos.ion) m / z: 788.3 [M+H] + ;

[0747] 1H NMR (599 MHz, CDCl 3 )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=13.9,5.4Hz,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=1 5.6Hz,1H),4.83-4.79(m,1H),4.45(d,J=12.8Hz,1H),4.35(d,J=9.6Hz,1 H),4.19(d,J=13.1Hz,1H),4.14(d,J=13.0Hz,1H),4.09(d,J=7.8Hz,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).

[0748] 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

[0749]

[0750] Step 1: Synthesis of (R)-2-hydroxymethylmorpholine hydrochloride 26b

[0751] (R)-tert-Butyl 2-(hydroxymethyl)morpholine-4-carboxylate 26a (1.00 g, 4.60 mmol) was dissolved in 1,4-dioxane hydrochloride solution (7.8 mL, 4 M) and reacted at room temperature for 3 hours. The reaction solution was concentrated to obtain a white solid 26b (0.70 g, yield 99.01%).

[0752] Step 2: Synthesis of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-(hydroxymethyl) (Phenyl)pyridazine-3-carboxamide 26c

[0753] 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 give a white solid 26c (1.20 g, yield 99.48%).

[0754] MS (ESI, pos.ion) m / z: 472.2 [M+H] + .

[0755] Step 3: Synthesis of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-formyl)- (Phenyl)pyridazine-3-carboxamide 26d

[0756] 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 obtain a light yellow oil 26d (0.19 g, yield 91.88%).

[0757] MS (ESI, pos.ion) m / z: 488.2 [M+H] + .

[0758] 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- Formamide 26

[0759] N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((S)-2-formylmorpholine)pyridazine-3-carboxamide 26d (0.19 g, 0.40 mmol), (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), 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. It was filtered by suction. The collected filter cake was dried and then purified by silica gel column chromatography (V DCM / V MeOH=40 / 1) to give a white solid 26 (91.0 mg, yield 27.64%) with a purity of 96.46%.

[0760] MS (ESI, pos.ion) m / z: 788.3 [M+H] + ;

[0761] 1 H NMR (599 MHz, CDCl 3 )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=13.9Hz ,4H),1.97(dt,J=12.7,7.9Hz,1H),1.53-1.47(m,2H),1.29(d,J=22.6Hz,2H).

[0762] 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

[0763]

[0764] Step 1: Synthesis of ((1r,4r)-4-(3-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)cyclohexyl) Tert-Butyl Formate 27a

[0765] Dissolve tert-butyl ((1r,4r)-4-(3-chloro-4-(N-hydroxycarbamide)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 residue was purified by silica gel column chromatography (V EA / V PE =1 / 3) to afford 27a as a colorless oil (0.15 g, yield 27.58%).

[0766] Step 2: Synthesis of (1r,4r)-4-(3-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)cyclohexanol 1-Amine hydrochloride 27b

[0767] 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 solution (2.6 mL), and hydrochloric acid 1,4-dioxane solution (2.6 mL, 4 M) was added, and reacted at room temperature for 4 hours. The solvent was directly concentrated under reduced pressure to obtain a white solid 27b (0.27 g, yield 84.19%).

[0768] Step 3: Synthesis of N-((1r,4r)-4-(3-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)cyclohexane 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

[0769] 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, and it was extracted with DCM (30 mL). The organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL), and the organic phase was concentrated. The residue was purified by silica gel column chromatography (V DCM / V MeOH =50 / 1) to give a yellow solid 27 (29.0 mg, yield 8.06%) with a purity of 92.04%.

[0770] MS (ESI, pos.ion) m / z: 869.3 [M+H] + ;

[0771] 1 H NMR (400 MHz, DMSO-d 6 )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),4.09(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).

[0772] Example A In cell western test

[0773] 1. Cell lines and cell culture

[0774] Human prostate cancer cell LNCaP (ATCC source). LNCaP cells were cultured in 1640 medium containing 15% fetal bovine serum. The cells grew by adhering to the wall, with weak adhesion ability and a doubling time of 72h. The cells were tightly adhered to each other and needed to be digested with 0.05% trypsin containing 0.025% EDTA. The cells were passaged twice a week. The cells were cultured at a constant temperature of 37°C and a volume fraction of 0.05% CO. 2 , in an incubator with saturated humidity.

[0775] 2. Cell Plating

[0776] When LNCaP cells were in the exponential growth phase, the cells were digested and plated into a black transparent bottom 96-well cell culture plate 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 hours.

[0777] 3. Preparation and addition of compound solution

[0778] Weigh 1-2 mg of each compound, 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 is: 1000, 300, 100, 30, 10, 3, 1, 0.3nmol / L): Take 9 1.5mL centrifuge tubes, numbered 10000, 1000, 300, 100, 30, 10, 3, 1, 0.3 respectively, add 90μl complete medium to tube 10000, take 10μl from the mother solution and add it to tube 10000, mix well; add 90μl complete medium to tube 1000, take 10μl from 10000 and add it to tube 1000, mix well; add 70μl complete medium containing 1% DMSO to tube 300, take 30μl from 1000 and add it to tube 300, mix well; add 90μl containing 1% Complete medium of DMSO, take 10μl from 1000 and add it to tube 100, mix well; and so on, get samples 30, 10, 3, 1, 0.3, and get compound solutions of different concentrations. Take 10μl from each of the above tubes and add it to the corresponding 96-well cells after 24h of cell attachment growth to get the corresponding required concentration (1000, 300, 100, 30, 10, 3, 1, 0.3nmol / L). Continue to culture for 48h after drug treatment.

[0779] 4. In cell western blot to test the effect of compounds on cell expression of AR

[0780] 1) Fixation: After drug treatment, the culture medium was removed, 100 μl of PBS was added to each well for washing, and then 100 μl of 4% paraformaldehyde (Biyuntian, catalog number #P0099) was added for fixation for 30 min.

[0781] 2) Perforation: Pour out the fixative, tap clean, add 100 μl PBS (containing 0.1% Triton) to each well and wash 3 times, 5 min each time (shaking on a shaker). 3) Blocking: Pour out the wash solution, tap clean, add 100 μl blocking solution (LI-COR, catalog number #927-60001) to each well and block for 30 min (shaking on a shaker).

[0782] 4) Incubation with primary antibody: Recover the blocking solution, add 50 μl Androgen Receptor Rabbit mAb (Cell Signaling Technology, Catalog #5153, dilution ratio 1:1200) to each well, incubate at 4°C overnight, incubate at room temperature for 30 minutes (shaking on a shaker) the next day, and return to room temperature.

[0783] 5) Incubation with secondary antibody: Recover the primary antibody, add 100 μl TBST (Solarbio, catalog number #T1082) to each well and wash 3 times, each time for 10 min (shaking on a rocker), then add 50 μl fluorescently labeled secondary antibody (LI-COR, catalog number #926-32211, dilution ratio 1:10000) to each well and incubate at room temperature for 1 h (protect from light, shake on a rocker).

[0784] 6) DNA staining: Recover the secondary antibody, add 100 μl TBST to each well and wash three times, each time for 10 min (protect from light, shake on a shaker), then add 50 μl DRAQ5 dye (Thermo Fisher Scientific, catalog number #62254, dilution ratio 1:10000) to each well and incubate at room temperature for 5 min (protect from light, shake on a shaker).

[0785] 7) Development: Absorb the DNA stain, pat dry, and use CLX dual-color infrared laser imaging system development.

[0786] 8) Result analysis: The Androgen Receptor fluorescence signal reading of 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; △ARS=ARS-ARB; △ARC=ARC-ARB; △DNAS=DNAS-DNAB; △DNAC=DNAC-DNAB;

[0787] Inhibition rate Inhibiton% = [1-(△ARS / △DNAS) / (△ARC / △DNAC)]*100%. The experimental results are shown in Table 1.

[0788] Table 1 Degradation rate of androgen receptor (AR) by the compounds of the present invention at different concentrations

[0789]

[0790] Conclusion: The compounds of the present invention show good activity in degrading androgen receptor.

[0791] Example B ELISA test

[0792] 1. Cell lines and cell culture

[0793] Human prostate cancer cell LNCaP (ATCC source). LNCaP cells were cultured in 1640 medium containing 15% fetal bovine serum. The cells grew by adhering to the wall, with weak adhesion ability and a doubling time of 72h. The cells were tightly adhered to each other and needed to be digested with 0.05% trypsin containing 0.025% EDTA. The cells were passaged twice a week. The cells were cultured at a constant temperature of 37°C and a volume fraction of 0.05% CO. 2 , in an incubator with saturated humidity.

[0794] 2. Cell Plating

[0795] 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.

[0796] 3. Preparation and addition of compound solution

[0797] Weigh 1-2 mg of each compound, 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 is: 1000, 200, 40, 8, 1.6, 0.32, 0.064nmol / L): Take 8 1.5mL centrifuge tubes, numbered 10000, 1000, 200, 40, 8, 1.6, 0.32, 0.064 respectively, add 90μl complete medium to tube 10000, take 10μl from the mother solution and add it to tube 10000, mix well; add 450μl complete medium to tube 1000, take 50μl from 10000 and add it to tube 1000, mix well; add 400μl complete medium containing 1% DMSO to tube 200, take 100μl from 1000 and add it to tube 200, mix well; add 400μl containing 1% Complete medium of DMSO, take 100μl from 200 and add it to tube 40, mix well; and so on, get samples 8, 1.6, 0.32, 0.064, and get compound solutions of different concentrations. Take 50μl from each of the above tubes and add it to the corresponding 48 wells after the cells have grown for 24 hours, and you can get the corresponding required concentrations (1000, 200, 40, 8, 1.6, 0.32, 0.064nmol / L). Continue to culture for 48 hours after drug treatment.

[0798] 4. ELISA test of the effect of compounds on cell expression of AR

[0799] After 48 hours of drug action, the culture medium was removed, 500 μl PBS was added for washing, and 50 μl cell lysis solution was added for lysis on ice for 15 minutes, with gentle tapping from time to time to promote lysis. The lysate was transferred to a 1.5 ml EP tube, centrifuged at 14000 rpm, 4 ° C for 15 minutes, and the supernatant was taken for use. The protein concentration of the lysate was detected by the BCA method, and the protein concentration was adjusted to 0.1 mg / ml using the sample diluent in the ELISA kit (CellSignaling Technology, catalog number #12850C).

[0800] 1) Take out 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.

[0801] 2) Add 100 μl of diluted cell lysate to appropriate wells, seal the wells with sealing tape, and incubate at 4°C overnight.

[0802] 3) Gently remove the sealing tape, discard the liquid in the wells, add 200μl 1X Wash Buffer to each well, and wash 4 times.

[0803] 4) Add 100 μl of detection antibody to each well, seal the wells with sealing tape, and incubate at 37°C for 60 min.

[0804] 5) Repeat the cleaning procedure (step 3).

[0805] 6) Add 100 μl of HRP-labeled secondary antibody to each well, seal the wells with sealing tape, and incubate at 37°C for 30 min.

[0806] 7) Repeat the cleaning procedure (step 3).

[0807] 8) Add 100 μl of TMB substrate to each well, seal with sealing tape and incubate the plate at 37°C for 10 min.

[0808] 9) Add 100 μl of STOP solution to each well and shake gently for a few seconds to terminate the reaction.

[0809] 10) Read the absorbance at 450 nm within 30 minutes after adding the STOP solution

[0810] 11) Result analysis: The data obtained from the compound treatment group is ODSample, and the cell group with only DMSO but no compound is the blank control group ODControl.

[0811] Inhibition rate Inhibiton% = (1-ODSample / ODControl) * 100%. The experimental results are shown in Table 2.

[0812] Table 2 Degradation rate of androgen receptor (AR) by the compounds of the present invention at different concentrations

[0813]

[0814] Conclusion: The compounds of the present invention show good activity in degrading androgen receptor.

[0815] Example C In cell western test

[0816] 1. Cell lines and cell culture

[0817] Human prostate cancer cell LNCaP (ATCC source). LNCaP cells were cultured in 1640 medium containing 10% fetal bovine serum. The cells adhered to the wall and grew, with weak adhesion ability and a doubling time of 72h. The cells were tightly adhered and needed to be digested with 0.05% trypsin containing 0.025% EDTA. The cells were passaged twice a week. The cells were cultured at a constant temperature of 37°C and a volume fraction of 0.05% CO. 2 , in an incubator with saturated humidity.

[0818] 2. Cell Plating

[0819] LNCaP cells were digested and diluted to an appropriate concentration, and only when their viability was higher than 90% could they be used for subsequent experiments. The cells were plated into a black transparent bottom 384-well cell culture plate coated with poly-lysine (BD, catalog number #356663), and except for the edge wells, the cells were grown for 24 hours.

[0820] 3. Preparation and addition of compound solution

[0821] Weigh 1-2 mg of each compound, add appropriate amount of DMSO to dissolve, so that the concentration of the mother solution is 10 mmol / L. Then dilute it with culture medium to different concentrations, add it to the cells, so that the final concentration is 3000, 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15 nmol / L. Continue to culture for 24 hours after drug treatment.

[0822] 4. In cell western blot to test the effect of compounds on cell expression of AR

[0823] 1) Fixation: After drug treatment, the culture medium was removed, 100 μl PBS was added to each well to wash once, and then 40 μl 4% paraformaldehyde (Biyuntian, catalog number #P0099) was added to fix for 30 minutes.

[0824] 2) Perforation: Pour out 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

[0825] 30min.

[0826] 3) Blocking: Pour out 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.

[0827] 4) Incubation with primary antibody: Recover the blocking solution, add 30 μl of Androgen Receptor Rabbit mAb (Cell Signaling Technology, catalog #5153, dilution ratio 1:1200) to each well, and incubate at room temperature for 90 minutes.

[0828] 5) Incubation with secondary antibody: Recover the primary antibody, add 50 μl TBST (Solarbio, catalog number #T1082) to each well and wash 4 times, 10 min each time, then add 30 μl fluorescent labeled secondary antibody (Invitrogen, catalog number #R8727, dilution ratio 1:10000) and DNA dye Hoechst 33342 to each well

[0829] (Invitrogen, catalog #H3570, dilution ratio 1:10000) and incubated at room temperature for 1 h.

[0830] 6) Development: Recover the secondary antibody, add 50 μl PBST to each well and wash 3 times, then add 50 μl PBS to each well and wash 2 times. After removing PBS, invert the plate and centrifuge at 1000 rpm for 1 min. Use PE Operetta CLS high-content cell imager for development.

[0831] 7) Data analysis:

[0832] Inhibition rate calculation:

[0833] %inhibition=(Signalcmpd-SignalAve_VC) / (SignalAve_PC-SignalAve_VC)×100.

[0834] Signal Ave_PC :average luminescence value of positive control.

[0835] Signal Ave_VC :average luminescence value of negative control.

[0836] Calculate DC 50 And draw the effect dose curve:

[0837] Y=Bottom+(Top-Bottom) / (1+10^((LogDC 50 -X)*HillSlope))

[0838] 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.

[0839] Table 3 Degradation activity of the compounds of the present invention on androgen receptor (AR) DC 50

[0840] Compound No. <![CDATA[DC 50 (nM)]]> Compound No. <![CDATA[DC 50 (nM)]]> 1 241.9 18 73.1 4 316.7 25 23.81 10 >1000 26 22.49 17 123.5 27 245.20

[0841] Conclusion: The compounds of the present invention have good degradation activity on androgen receptor (AR).

[0842] Example D Effect of Compounds on Hair Regeneration in C57 Mouse Model of Androgenic Alopecia

[0843] 1. Purpose of the experiment

[0844] The purpose of this study is to compare the hair regeneration effect of the compounds prepared by the present invention as AR protein degraders on the androgenic alopecia model in C57BL / 6J mice through the transdermal administration route, so as to provide data support for subsequent clinical experiments.

[0845] 2. Test Principle

[0846] After the mice were shaved with an electric shaver, a certain dose of testosterone propionate (TP) solution was intraperitoneally injected, which can cause delayed hair regeneration in the mice, and is used to simulate the AR-mediated androgenic alopecia model. The compound of the present invention is a degrader of AR protein, and its hair growth-promoting effect on the AR-mediated androgenic alopecia model can reflect its efficacy to a certain extent.

[0847] 3. Test compounds

[0848] The name of the test compound I: testosterone propionate TP; the name of the test compound II: Example 1 of the compound of the present invention; the name of the test compound III: minoxidil; the name of the test compound IV: ARV110.

[0849] 4. Experimental Animals

[0850] Strain: C57BL / 6N mice; Age: 6-7 weeks; Gender: male; Number of animals: 45 (9

[0851] Reserve); Rearing environment: Specific pathogen Free (SPF).

[0852] 5. Experimental Design

[0853] 36 mice were deeply anesthetized and the hair on the back of the mice was shaved with an animal shaver.

[0854] 6. Grouping

[0855] This experiment was divided into 6 groups. The TP start time was 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 grouped as shown in the following table:

[0856] Mouse grouping and drug administration regimen

[0857]

[0858] 7. Preparation method of test compound

[0859] The drug preparation method and storage conditions are shown in the following table;

[0860]

[0861] The 5% minoxidil tincture used in this experiment was a commercially available product (Mandy).

[0862] 8. Observe the test indicators

[0863] Hair regrowth (anagen) score (0: no darkening of skin color in all areas; 1: darkening of gray skin color areas; 2: short hairs visible; 3: sparse hairs; 4: dense hairs; 5: complete hair growth).

[0864] 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.

[0865] At the end of the experiment, skin sampling and blood sampling were performed as needed.

[0866] 9. Drug withdrawal and experiment termination criteria

[0867] Animal experiments will be terminated when the health of the animals continues to deteriorate, the animals continue to suffer, are unable to eat or drink, or when the animals become emaciated and lose more than 20% of their body weight. Animals will be euthanized before death or coma.

[0868] 10. Statistical Analysis

[0869] All data were expressed as mean ± standard error (MEAN ± SEM). Single factor multi-level analysis of variance was used for statistics, and Stundent'st or rank sum test was used to compare each medication group with the model group, and 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.

[0870] 11. Experimental Results

[0871] Six groups were set up in this experiment, namely Vehicle, TP (1.25 mg / mouse) group, TP (1.25 mg / mouse) + minoxidil 5% concentration group, TP (1.25 mg / mouse) + ARV-110 0.3% concentration group, TP (1.25 mg / mouse) + Example 1 0.3% concentration group and TP (1.25 mg / mouse) + Example 1 0.6% concentration group.

[0872] Concentration group. The results of hair regeneration effect on C57 mouse androgenic alopecia model are shown in the following Table 4:

[0873] Table 4 Effects on hair regeneration in C57 mouse androgenic alopecia model

[0874]

[0875] From the results, it can be seen that the hair development score of the TP (1.25 mg / mouse) group was 0.27 after 28 days of administration, with almost no hair development, which was significantly lower than that of the Vehicle group, indicating that the model was successfully established.

[0876] The mean score of the TP (1.25 mg / mouse) group + minoxidil 5% group was 0.22, which was not significantly different from the TP (1.25 mg / mouse) model group. The score of the TP (1.25 mg / mouse) + ARV-110 0.3% group on Day 28 was significantly higher than that of the TP (1.25 mg / mouse) model group (p<0.01).

[0877] The scores of 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 of the TP (1.25 mg / mouse) model group (p<0.001). The scores of 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 of the TP (1.25 mg / mouse) group + minoxidil 5% concentration group (p<0.001).

[0878] 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).

[0879] Example E Western blotting assay

[0880] 1. Cell lines and cell culture

[0881] Human prostate cancer cell LNCaP (ATCC source). LNCaP cells were cultured in 1640 medium containing 15% fetal bovine serum. The cells grew by adhering to the wall, with weak adhesion ability and a doubling time of 72h. The cells were tightly adhered to each other and needed to be digested with 0.05% trypsin containing 0.025% EDTA. The cells were passaged twice a week. The cells were cultured at a constant temperature of 37°C and a volume fraction of 0.05% CO. 2 , in an incubator with saturated humidity.

[0882] When LNCaP cells were in the exponential growth phase, the cells were digested and plated into 24-well plates at 8 × 10 4 After one day of adherent growth, the cells were cultured with drugs and proteins were extracted 48 hours after drug treatment.

[0883] 2. Cell Protein Extraction

[0884] The culture medium was removed from the cells in the 24-well plate, and the cells were washed once with PBS. Then 50 μL of RIPA lysis buffer (containing 100 μM PMSF) was added to each well. After thorough mixing, the cells were placed on ice for 10 min, and then the cells were scraped off with a pipette tip. The cell lysate was transferred to the corresponding 1.5 mL centrifuge tube, and then centrifuged at 12000 rpm at 4°C for 15 min. The supernatant was used for WB experiments. The samples can be stored at -80°C.

[0885] 3. Protein Concentration Determination

[0886] Use the BCA protein concentration assay kit to prepare the BSA standard assay solution and the sample to be tested (the sample to be tested can be diluted before testing) according to the instructions, use a 96-well plate to add the sample, fill each well with PBS to 20 μl, add 200 μl of BCA working solution (prepared according to the kit), mix well, place at 37°C for 20-30 minutes, and then detect the absorbance at 562nm. After recording the readings, make a standard curve with the standard concentration gradient, and substitute the sample absorbance to calculate the sample protein concentration.

[0887] 4. Western blotting experimental standard process

[0888] 4.1) Protein denaturation: Take protein lysis buffer, add 5× Loading Buffer, and denature at 100 °C for 5 min.

[0889] 4.2) Loading and electrophoresis: Use the 10% ExpressCast PAGE Color Gel Fast Kit (New Cellmax Biotechnology Co., Ltd., product number #P2012) and SDS-PAGE electrophoresis solution. After loading the same mass of protein samples and protein marker into each well, perform electrophoresis at 150 V for 40 - 60 min.

[0890] 4.3) Membrane transfer: After removing the gel, cut off the excess part, and transfer it to a PVDF membrane by wet transfer method (the PVDF membrane needs to be activated with methanol for 1 min before use), at 120 V for 2 h. During the membrane transfer process, a large amount of heat is generated, and an ice box is required to cool down.

[0891] 4.4) Blocking: Place the PVDF membrane after membrane transfer in QuickBlock TM Blocking Solution (Beyotime, product number #P0228), and shake at room temperature for 15 min for blocking.

[0892] 4.5) Incubating with primary antibody: Cut the PVDF membrane according to the molecular weight indicated on the marker, and place them in the primary antibodies of AR and GAPDH respectively. The antibodies are diluted at a ratio of 1:1000 with Western Primary Antibody Dilution Solution (Beyotime, product number #P0023A - 100ml), and incubate at 4 °C overnight.

[0893] 4.6) Incubating with secondary antibody: After incubating with the primary antibody, shake the PVDF membrane on a shaker for 1 h to return to room temperature, then wash it 3 times with TBST, 5 min each time. After washing, place the membrane in the corresponding species of secondary antibody respectively, and incubate on a shaker at room temperature for 1 h.

[0894] 4.7) Membrane washing and exposure: After incubating with the secondary antibody, place the membrane in TBST and shake on a shaker for 3 times, 5 min each time. After membrane washing, use the ECL method to excite the fluorescence on the membrane.

[0895] The experimental results obtained are shown in Table 5, which indicates that the compound provided by the present invention has a good degradation effect on AR protein in LNCaP cells, and the effects of Examples 20 and 21 are equivalent to that of Example 1.

[0896] Table 5 Degradation effect of the compound on AR protein in LNCaP cells

[0897] Compound (concentration) Average degradation efficiency% Example 1 (1000 nM) 64.50 Example 20 (1000 nM) 66.90 Example 21 (1000 nM) 70.22

[0898] 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" etc. 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 may be combined in any one or more embodiments, implementations or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments, implementations or examples described in this specification and the features of the different embodiments, implementations or examples, without contradiction.

[0899] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary 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 Halogenated alkoxy, 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 as a key, -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 Halogenated alkoxy, 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 Halogenated alkoxy, 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 Halogenated alkoxy, 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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