CN113735845A

CN113735845A - Androgen receptor degradation agent and application thereof

Info

Publication number: CN113735845A
Application number: CN202010462626.XA
Authority: CN
Inventors: 梅德盛; 何宝坤
Original assignee: 梅德盛; 何宝坤
Current assignee: SUZHOU GUOKUANG PHARMTECH Co.,Ltd.
Priority date: 2020-05-27
Filing date: 2020-05-27
Publication date: 2021-12-03

Abstract

Hair brushThe androgen receptor degrading agent is a compound with a structure shown in a formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic marker thereof:

Description

Androgen receptor degradation agent and application thereof

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a novel androgen receptor degrading agent with high bioactivity, a preparation method thereof, a pharmaceutical composition and application in medicine.

Background

Prostate Cancer (PC) is highly prevalent in male malignancies with the first and second mortality rates. Only in china, 150 million patients with prostate cancer currently exist, and the annual growth rate is 8.92%. Meanwhile, epidemiological studies in China show that the incidence of prostate cancer is closely related to the economic development level, and the region with the highest incidence in China is Shanghai city. This cancer is a rapidly progressing malignancy, with an average survival of only 3-5 years from the onset of symptoms if no early diagnosis is available. Early PC can be effectively controlled by surgery or chemotherapy. However, for advanced stage PC, the general therapeutic strategy is an anti-androgen therapy based on androgen and its receptor (AR), i.e. surgical castration therapy (such as bilateral orchiectomy, etc.) and anti-androgen drug therapy. However, most patients treated with this therapy experience a worsening of disease and castration-resistant prostate cancer (CRPC) at 18-24 weeks. At this time, the existing main anti-androgen drugs used clinically, such as enzalutamide, bicalutamide and the like, no longer have an inhibitory effect on CRPC, but have an agonistic effect on CRPC and promote tumor growth. After the appearance of CRPC, 90% of patients die within 2 years. Further studies have shown that androgen and its bound ligand are essential for the growth of CRPC, suggesting that androgen receptor remains an important target for this disease. However, due to the increase of AR expression, AR mutation, AR fragmentation and the like, the existing anti-prostate cancer drugs have drug resistance and even have agonistic activity. CRPC is a huge clinical problem that is urgently needed to be solved.

Protein degradation targeting chimera (PROTAC) technology derived from the nobel prize is an emerging protein degradation technology that utilizes the naturally occurring protein degradation pathways within the cell to eliminate specific proteins that need to be degraded: by means of PROTAC molecule, target protein to be degraded is connected with E3 ubiquitination ligase, and ubiquitin label is transferred to the target protein, resulting in degradation of the target protein. The technology can selectively degrade target protein, is a treatment strategy for removing pathogenic protein like 'weed removal root', and is particularly suitable for pathogenic protein with increased expression or mutation to solve the problem of drug resistance. Meanwhile, the PROTAC technology can target targets which are difficult to be used in the traditional medicine technology, and a potential new treatment method is brought for serious diseases. ProTAC drugs are likely to go beyond the two most important areas of drug development since history: protein kinase inhibitors and monoclonal antibodies, which belong to the technical field of great revolutionary drug development.

AR degrading agent ARV-110 (chemical structure is not disclosed at present) developed by Arvinas based on PROTAC technology has obvious inhibition effect on drug-resistant prostate cancer in preclinical models, phase I clinical research is started in 2019, FDA grants rapid channel qualification in the same year, and good development prospect is shown. However, the molecular weight of the PROTAC drug is about 1000 generally, and the structure is complex, so that various problems (Comput. struct. Biotec, 2019,17: 160-one 176.) exist in vivo and in vitro activity, pharmacokinetic properties and purification, so the PROTAC technology is still in an early development stage. The technology needs to carry out a great deal of research on diversity and difference so as to promote mutation from the technology to clinical drugs, cure CRPC and the like and ensure human health.

The PROTAC drug molecules are all composed of three dumbbell-shaped parts: 1) one end is a structural part specifically combined with target protein to be degraded, and is an important missile guiding head for targeting pathogenic protein, and the missile guiding head is typically a traditional small molecule targeted drug; 2) the other end is a structural part combined with E3 ubiquitination ligase (E3 ligase); 3) middle is a link subsection (journal of chinese pharmaceutical chemistry, 2019,29 (3): 234-240.). High-activity AR degradation agent (DC) based on PROTAC technology at present₅₀<1.0 μ M), the binding moiety to E3 ubiquitination ligase (E3 ligase) is currently typically Von Hippel-lindau (vhl) E3 ubiquitin ligand (CN 201680014250.8; Comput.struct.Biotec 2019,17: 160-176; med. chem.,2019,62(24): 11218-; med, chem, 2019,62 (2): 941 + 964.); the intermediate link is in the form of a chainAnd (5) linking the son. Therefore, the research of the PTOTAC technology AR degradation agent takes the research of a target AR structural part as a core to carry out an integral development strategy of molecular integration evaluation.

One of the large series of compounds reported by Arvinas in CN201680014250.8, AR antagonist compound 26 developed by fevered (j.med.chem., 2011, 54: 7693-7704, compound No. is numbered in literature) is the AR specific binding moiety of the PROTAC technology, and the structure of the compound is as follows:

compd.26 (Peveri literature compound number)

IC₅₀(LNCaP cell)＝59nM

(J.Med.Chem.，2011，54：7693-7704)。

The compound has good biological properties, such as compound 174 (the compound is numbered in patent CN 201680014250.8) and the like, has AR degradation activity of DC50 less than or equal to 50nM on VCaP cells, and compound 469 (the compound is numbered in patent CN 201680014250.8) and the like, and has good pharmacokinetic properties. However, the degradation activity of the compound in patent CN201680014250.8 on VCaP cells is yet to be further improved; meanwhile, the applicant has found that the compound in the patent contains impurities which are difficult to remove, and like the compound 174 and the compound 469 in the patent contain impurities with the molecular weight of M-14, the impurities are difficult to separate by adopting conventional purification technologies such as column chromatography and the like and even by adopting preparative thin layer chromatography, so that the difficulty of production and quality control is greatly increased.

Disclosure of Invention

Problems to be solved by the invention

In order to solve the above technical problems, the present invention provides a novel androgen receptor degrading agent having higher activity for degrading VCaP cells and containing no impurities difficult to remove in the compound.

Means for solving the problems

In order to solve the technical problems, the invention provides the following technical scheme:

a compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof:

wherein the content of the first and second substances,

R₁selected from-CN, -NO₂and-NH₂；

R₂、R₃Each independently selected from hydrogen, deuterium, halogen, C unsubstituted or substituted by halogen_1-6An alkyl group;

R₄、R₅、R₆and R₇Each independently selected from hydrogen, deuterium, C unsubstituted or substituted by halogen_1-6Alkyl, unsubstituted or halogen-substituted C_2-6Alkenyl, C unsubstituted or substituted by halogen_2-6Alkynyl, or R₄And R₅And/or R₆And R₇And the carbon atoms to which they are attached are linked to form a ring;

x, Y are each independently selected from CH and N;

R₈selected from hydrogen, deuterium and unsubstituted or selected from halogen, -OH, -CN, -NH₂And C_1-6C substituted by substituents of alkoxy_1-6Alkyl, or R₈And W₁Connecting to form a ring;

R₉selected from hydrogen, deuterium and unsubstituted or selected from halogen, -OH, -CN, -NH₂And C_1-6C substituted by substituents of alkoxy_1-6An alkyl group;

R₈and R₉Can also be connected into a ring;

a is selected from carbonyl,

The following substituted or unsubstituted groups: c₆-C₁₀Arylene and 5-10 membered heteroarylene, wherein R₁₀、R₁₁Each independently selected from hydrogen, deuterium, unsubstituted or selected from halogen, -OH, -CN, -NH₂And C_1-6C substituted by substituents of alkoxy_1-6Alkyl, C unsubstituted or substituted by a member selected from halogen_2-6Alkenyl, C unsubstituted or substituted by halogen_2-6Alkynyl, or R₁₀And R₁₁And the attached carbon atoms are linked to form a ring;

W₁selected from substituted or unsubstituted C_6-10Arylene, 5-10 membered heteroarylene, C_3-12Cycloalkylene and 3-12 membered heterocycloalkylene;

l is a linker;

VHL is E3 ubiquitin ligase binding fragment.

Preferably, the VHL is a fragment having the structure:

wherein the content of the first and second substances,

R₁₂and R₁₄Each independently selected from hydrogen and substituted or unsubstituted C_1-6Alkyl, said substitution being by a group selected from halogen, -OH, -CN, -NH₂And C_1-6Substituted by a substituent of alkoxy;

R₁₃selected from hydrogen and-OR₁₈Said R is₁₈Selected from hydrogen, R₁₉C (═ O) -, substituted or unsubstituted amino acid residues, or substituted or unsubstituted oligomeric amino acid residues;

R₁₅、R₁₆、R₁₇、R₁₉each independently selected from H, halogen, substituted or unsubstituted: c_1-30Alkyl radical, C_1-30Deuterated alkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_4-8Cycloalkenyl, 3-8 membered heterocyclyl, 3-8 membered heteroalkenyl, 3-8 membered heteroalkynyl, C_4-8Heterocycloalkenyl, C_4-8Heterocycloalkynyl, C_6-10Aryl radical, C_5-10Heteroaryl, alkenylaryl, alkenylheteroaryl, alkynylaryl, alkynylheteroaryl,Amino, alkylamino, alkenylamino, alkynylamino, alkylsulfide, adjacent R₁₅And R₁₆May also be linked to form a ring, said substitution being selected from the group consisting of halogen, -OH, -CN, -NH₂Acetamido and C_1-6Alkoxy radical, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group;

W₂selected from the group consisting of substituted or unsubstituted: c_6-10Aryl radical, C_5-10Heteroaryl group, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, said substitution being by a group selected from halogen, -OH, -CN, -NH₂、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group; w₃Selected from H, halogen, C_1-10Alkyl, -CN and the following substituted or unsubstituted groups: c_6-10Arylene radical, C_5-10Heteroarylene group, C_3-8Cycloalkylene, 3-8 membered heterocyclylene, said substitution being by a group selected from halogen, -OH, -CN, -NH₂And C_1-6Alkoxy radical, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group;

W₄selected from the group consisting of substituted or unsubstituted: c_6-10Aryl radical, C_5-10Heteroaryl group, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, said substitution being by a group selected from halogen, -OH, -CN, -NH₂、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by the substituent of the amino group.

The invention also provides a pharmaceutical composition comprising a compound as described in any of the above, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, and a pharmaceutically acceptable excipient.

Preferably, the pharmaceutical composition is in the form of any one of aqueous dispersion, liquid, gel, syrup, elixir, syrup, suspension, aerosol, controlled-release agent, quick-dissolving agent, effervescent agent, lyophilized agent, tablet, powder, pill, sugar-coated, capsule, delayed release agent, extended release agent, pulsatile controlled release agent, multiparticulate, or immediate release agent.

The invention also provides the application of any one of the compounds or pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotopic labels thereof, or the pharmaceutical composition in preparing medicaments for treating diseases related to androgen receptors.

Preferably, the androgen receptor associated disease is prostate cancer, breast cancer, prostatic hyperplasia, kennedy's disease, hirsutism, acne, alopecia, baldness, muscle failure, gonadal failure, osteoporosis, hypercholesterolemia, male infertility, male sexual dysfunction, anemia obesity, hyposexuality, or depression.

Preferably, the androgen receptor associated disease is castration-resistant prostate cancer.

ADVANTAGEOUS EFFECTS OF INVENTION

1. The theoretical AR specific binding part of the compound is malonamide derivative (A compound), urea derivative (B compound) and phenylenediamine derivative (C compound), but the three compounds are not reported in the documents of AR antagonists at present;

the three derivatives of the patent

Further, applicants have examined the activity of a typical class B compound and surprisingly found that it has little inhibitory effect on AR (IC)₅₀>5.0μM)。

Unexpectedly, recently, class B compounds have been reported in the literature as agonists of eIF2a kinase Heme Regulatory Inhibitors (HRIs) for the treatment of iron deficiency anemia, thalassemia and other anemic diseases, etc. (European Journal of Medicinal Chemistry,2020,187, art.no.11197.DOI:10.1016/j.ejmech.2019.111973.), as reported herein as the following:

HRI agonists reported in the EJMC literature

(Compound No. is a Compound No. in the literature)

2. The compound of the invention has good degradation activity on AR, such as compound 10 and the like on VCaP cells, DC₅₀≦2nM；

3. The applicant also found in their studies that CN201680014250.8 compound has impurities that are difficult to remove. Thus, both of compound 174 and compound 469 (both of the compound numbers are those in CN 201680014250.8) had impurities with a molecular weight of M-14. The impurities are difficult to control within the limits of the original drug impurities in the legislation by conventional purification techniques such as column chromatography and the like, even by preparative thin layer chromatography. The applicant adopts preparative HPLC technology to separate and purify the M-14 impurity of the compound 469, and combines nuclear magnetic and mass spectrum research to confirm that the M-14 is a structural high analog of the compound 469. The existence of the M-14 impurity brings great difficulty to the production and quality control of the raw material medicine, and simultaneously, the cost is obviously increased.

Among the compounds of this patent, compounds such as compound 17 and the like also carry a by-product of M-14 impurity in the preparation reaction system. But is significantly different in that this by-product can be simply removed by conventional techniques such as silica gel column chromatography and the like; meanwhile, in the drug substance of the compound 17, the impurity of M-14 was not detected.

Detailed Description

In order to more clearly describe the context of the present invention, all terms referred to are now defined as follows:

the term "substituted" as used herein, unless otherwise defined, is substituted with the following substituents: alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino wherein 2 amino substituents are selected from alkyl, aryl or arylalkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido such as-SO₂NH₂Substituted sulfonamido, nitro, cyano, carboxy, carbamoyl, e.g. -CONH₂Substituted carbamoyl such as-CONH alkyl, -CONH aryl, -CONH arylalkyl or in the case of two substituents on the nitrogen selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like and substituted heterocyclyl.

The term "alkyl" or "alkylene" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C_1-6Alkyl "means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).

The term "alkenyl" denotes a straight or branched chain hydrocarbon group containing one or more double bonds and typically 2 to 20 carbon atoms in length. For example, "C_2-6Alkenyl "contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, hexenyl, and the like.

The term "alkynyl" denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. For example, "C_2-6Alkynyl "contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, pentynyl, hexynyl, and the like.

The term "heteroalkenyl" means an "alkenyl" as defined above wherein one or more carbon atoms are replaced by a heteroatom selected from N, O, S, or by a group containing a heteroatom selected from N, O, S.

The term "heteroalkynyl" means that one or more of the carbon atoms in "alkynyl" as defined above is replaced by a heteroatom selected from N, O, S, or by a group containing a heteroatom selected from N, O, S.

The term "alkoxy" or "alkyloxy" refers to an-O-alkyl group. "C_1-6Alkoxy "(or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above with the specified number of carbon atoms attached via a sulfur bridge; such as methyl-S-and ethyl-S-.

The term "carbonyl" refers to an organic functional group (C ═ O) formed by double bonding of two atoms, carbon and oxygen.

The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl means C_3-8Including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Bicyclic cyclic alkyl groups include bridged, spiro or fused cyclic cycloalkyl groups.

The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group. Monocyclic ringThe term "cycloalkylene" means C_3-8Including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl. Branched cycloalkenyls such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyl includes bridged, spiro or fused cyclic alkenyl.

"halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "haloalkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with 1 or more halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2, 2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" groups intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with 1 or more fluorine atoms.

"haloalkoxy" or "haloalkyloxy" represents a haloalkyl group as defined above attached via an oxygen bridge having the specified number of carbon atoms. For example, "C_1-6Haloalkoxy "is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2, 2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached via a sulfur bridge; such as trifluoromethyl-S-and pentafluoroethyl-S-.

The term "aryl"/"arylene", alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 6 to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring. For example, the arrowed lines drawn from the ring system indicate that the bond may be attached to any suitable ring atom.

The term "heteroaryl"/"heteroarylene," "heteroaryl ring group," or "heteroaryl ring group" means a stable 3-, 4-, 5-, or 7-membered aromatic monocyclic or aromatic bicyclic ring or a 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered aromatic polycyclic heterocyclic ring that is fully unsaturated, partially unsaturated, and that contains carbon atoms and 1,2,3, or 4 heteroatoms independently selected from N, O and S; and includes any polycyclic group wherein any of the heterocyclic rings defined above are fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic groups described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is no more than 1. Examples of aromatic heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5, 2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, pseudoindazolyl 25 indolyl (indolynyl), indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl (isononyl), Isobenzofuranyl, isochromanyl, isoindolyl, isoindolinyl, isoindolyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, perimidine, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiin, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyranyl, and the like, Pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl and xanthenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3, 4-tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 5,6,7, 8-tetrahydro-quinolinyl, 2, 3-dihydro-benzofuranyl, chromanyl, 1,2,3, 4-tetrahydro-quinoxalinyl and 1,2,3, 4-tetrahydro-quinazolinyl. The present invention also includes fused ring and spiro compounds containing, for example, the above-described heterocycles.

The term "cycloheteroalkyl," as used herein, refers to a monocyclic cycloheteroalkyl system, or to a bicyclic cycloheteroalkyl system. Monocyclic cycloheteroalkyl refers to a 3-to 8-membered cyclic alkyl system containing at least one saturated or unsaturated but not aromatic group selected from O, N, S, P. Bicyclic heteroalkyl systems refer to a cycloheteroalkyl fused to a phenyl, or a cycloalkyl, or a cycloalkenyl, or a cycloheteroalkyl, or a heteroaryl.

The term "bridged cyclic hydrocarbon" as used herein refers to a polycyclic compound that shares two or more carbon atoms. Can be divided into bicyclic bridged cyclic hydrocarbons and polycyclic bridged cyclic hydrocarbons. The former is composed of two alicyclic rings sharing two or more carbon atoms; the latter are bridged ring hydrocarbons consisting of more than three rings.

The term "spirocyclic hydrocarbon" as used herein refers to a polycyclic hydrocarbon in which the single rings share a common carbon atom (referred to as the spiro atom).

The term "substituted" as used herein means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that the normal valency is maintained and that the substitution results in a stable compound. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C ═ C, C ═ N or N ═ N).

In the case of nitrogen atoms (e.g., amines) present on the compounds of the invention, these nitrogen atoms may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxide) to obtain other compounds of the invention. Thus, the nitrogen atoms shown and claimed are considered to encompass both the nitrogen shown and its N-oxide (N → O) derivatives.

When any variable occurs more than one time in any constituent or formula of a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown substituted with 0-3R, the group may be optionally substituted with up to three R groups, and R is independently selected at each occurrence from the definition of R. Furthermore, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When the bond to a substituent is shown as crossing the bond connecting two atoms in a ring, then the substituent may be bonded to any atom on that ring. When a substituent is listed without specifying the atom in that substituent that is bonded to the remainder of the compound having a given formula, then the above substituent may be bonded via any atom in that substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "amino"/"amino group"Representing primary amino groups (-NH), either alone or in combination₂) A secondary amino group (-NH-) or a tertiary amino group

The term "C_1-6Alkylamino "alone or in combination denotes an amine group as defined above, wherein the hydrogen atom of the amine group is substituted by at least one C_1-6Alkyl, wherein "alkyl" denotes as defined above, correspondingly "C_1-6Alkylamino "includes methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino, 3-methyl-2-pentylamino, 4-methyl-2-pentylamino, 3-methyl-3-pentylamino, 2-methyl-3-pentylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino, 2-pentylamino, 3-methyl-1-butylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino, 3-methyl-3-pentylamino, 4-methyl-2-methyl-pentylamino, 2-methyl-3-pentylamino, 2-methyl-pentylamino, 2-methyl-hexylamino, 2-pentylamino, 2-hexylamino, 2-pentylamino, or a, 2, 3-dimethyl-2-butylamino, 3-dimethyl-2-butylamino and the like. In particular "C_1-6Alkylamino "is methylamino, ethylamino, isopropylamino, tert-butylamino, and the like.

Term "(C)_1-6Alkyl radical)₂Amino "alone or in combination means an amino group as defined above wherein the hydrogen atom of the amino group is replaced by two C_1-6Alkyl, wherein "alkyl" represents as defined above, correspondingly, "(C)_1-6Alkyl radical)₂The amino group "includes dimethylamino group, diethylamino group, methylethylamino group and the like.

The term "amino acid residue" as used herein refers to an amino acid in which a carboxyl group or an amine group at the carbon terminal of the amino acid participates in bond formation to lose one molecule of water, and this amino acid unit is referred to as an amino acid residue.

The term "oligomeric amino acid residue" as used herein refers to a residue consisting of 2-10 amino acid residuesOne carbon-terminal carboxyl group or amine group in the formed polypeptide chain participates in the formation of a bond to lose one molecule of water, and the oligomeric amino acid unit is called oligomeric amino acid residue. For example amino acids

The amino acid residue of (A) is

The term "[ Cu ] as used herein]"in this context means a copper (Cu) alloy containing monovalent copper⁺) Or divalent copper (Cu)²⁺) Reagents, e.g. CuI, CuBr, CuCl, CuI₂、CuBr₂、CuCl₂And the like.

The term "isomer" encompasses all isomeric forms including enantiomers, diastereomers, tautomers and geometric isomers (including cis-trans isomers). Thus, individual stereochemical isomers of the contemplated compounds of the present invention or mixtures of enantiomers, diastereomers, tautomers or geometric isomers (or cis-trans isomers) thereof are intended to be within the scope of the present invention.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compounds of the present invention wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups (such as amines); and alkali metal or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, the above conventional non-toxic salts include those derived from inorganic acids such as: hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids; and salts prepared from, for example, the following organic acids: acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, benzenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, the salts described above can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two; generally, a nonaqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred. A list of suitable salts can be found in Remington, The Science and Practice of Pharmacy,22nd Edition,25Allen, L.V.Jr., ed.; pharmaceutical Press, London, UK (2012), the disclosure of which is incorporated herein by reference.

The term "solvate" means a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In certain instances, the solvate will be able to be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular and/or disordered arrangement. Solvates may comprise stoichiometric or non-stoichiometric amounts of solvent molecules. "solvate" encompasses solution phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

The term "ester" is used to denote organic esters, including monoesters, diesters, triesters, and more generally polyesters.

The term "isotopic derivative" means an isotopic derivative in which a hydrogen atom in the general formula (I) is substituted by 1 to 6 deuterium atoms (D), or an isotopic derivative in which a carbon atom in the general formula (I) is substituted by 1 to 3 carbon 14 atoms (14C).

The term "treating" as used herein includes any effect that results in an improvement in the condition, disease, disorder, etc., such as a reduction, modulation, amelioration or elimination, or amelioration of a symptom thereof.

The term "pharmaceutical composition" as used herein refers to a combination of an active agent and an inert or active carrier, such that the composition is particularly suitable for use in vivo or ex vivo diagnosis or treatment. Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and the like. For therapeutic use, salts of the compounds of the present invention are for therapeutic use, and salts of the compounds of the present invention are expected to be pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

Specific pharmaceutical and medical terms

The term "cancer", as used herein, refers to an uncontrolled abnormal growth of cells and under certain conditions is capable of metastasizing (spreading). This type of cancer includes, but is not limited to, solid tumors (e.g., bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (e.g., thyroid), prostate, skin (melanoma), or hematologic tumors (e.g., non-leukemias).

Pharmaceutical compositions and dosages

The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of formula (I) formulated with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally one or more other therapeutic agents as described above. The compounds of the invention can be administered for any of the above uses by any suitable means, for example, orally, such as tablets, capsules (each including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; under the tongue; taking orally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or nonaqueous solutions or suspensions); nasally, including administration to nasal membranes, such as by inhalation spray; topical, such as in cream or ointment form; or rectally, such as in the form of suppositories. They may be administered alone, but are generally administered using a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

Pharmaceutical carriers are formulated according to a number of factors within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent formulated; a subject to whom a composition comprising an active agent is to be administered; the intended route of administration of the composition; and targeted therapeutic indications. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media and various solid and semi-solid dosage forms.

The carrier may include many different ingredients and additives in addition to the active agent, such other ingredients being included in the formulation for various reasons well known to those skilled in the art, e.g., to stabilize the active agent, binders, etc. A description of suitable Pharmaceutical carriers and The factors involved in The selection of carriers can be found in a number of readily available sources, such as Allen, L.V.Jr.et.al.Remington: The Science and Practice of Pharmacy (2Volumes),22nd Edition (2012), Pharmaceutical Press.

Of course, the dosage regimen for the compounds of the present invention will vary depending upon known factors, such as the pharmacodynamic properties of the particular agent and its mode and route of administration; species, age, sex, health condition, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient and the desired effect. According to general guidelines, when used for a given effect, the daily oral dose of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably from about 0.1 mg/day to about 250 mg/day. During constant rate infusion, the most preferred intravenous dose should be from about 0.01 mg/kg/min to about 10 mg/kg/min. The compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.

The compounds are generally formulated in a manner appropriate to the intended form of administration (e.g., oral tablets, capsules, elixirs and syrups)

Are administered in the form of a mixture of suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) selected and in accordance with conventional pharmaceutical practice.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1mg to about 2000 mg of active ingredient per dosage unit. In such pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1 to 95 weight percent, based on the total weight of the composition.

A typical capsule for oral administration contains at least one compound of the invention (250mg), lactose (75mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into size 1 gelatin capsules.

A typical injectable formulation can be prepared as follows: at least one compound of the invention (250mg) was aseptically placed in a vial, lyophilized aseptically and sealed. For use, the vial contents were mixed with 2mL of normal saline to produce an injectable formulation.

The scope of the present invention includes (alone or in combination with a pharmaceutical carrier) pharmaceutical compositions comprising as an active ingredient a therapeutically effective amount of at least one compound of the present invention. Optionally, the compounds of the present invention may be used alone, in combination with other compounds of the present invention

Or in combination with one or more other therapeutic agents, such as an anti-cancer agent or other pharmaceutically active substance.

Regardless of the route of administration chosen, the compounds of the invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response, composition and mode of administration for a particular patient without being toxic to the patient.

The selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention or ester, salt or amide thereof employed; a route of administration; the time of administration; the rate of excretion of the particular compound used; rate and extent of absorption; the duration of the treatment; other drugs, compounds and/or substances used in combination with the particular compound used; age, sex, weight, condition, general health, and prior medical history of the patient being treated are factors well known in the medical arts.

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, to achieve a desired therapeutic effect, the physician or veterinarian can start a relatively large amount of a compound of the invention to be used in a pharmaceutical composition at a level below that required and gradually increase the dosage until the desired effect is achieved. In general, an appropriate daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors recited above. Typically, oral, intravenous, intracerebroventricular, and subcutaneous doses of a compound of the invention are in the range of about 0.01 to about 50mg/kg body weight/day in a patient. If desired, an effective daily dose of the active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, the administration is once daily.

Although the compound of the present invention can be administered alone, it is preferable to administer the compound in the form of a pharmaceutical preparation (composition).

The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.

In a first aspect, the present invention provides a compound having the structure of formula i or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof:

wherein the content of the first and second substances,

R₁selected from-CN, -NO₂and-NH₂；

x, Y are each independently selected from CH and N;

R₈and R₉Can also be connected into a ring;

a is selected from carbonyl,

l is a linker;

VHL is E3 ubiquitin ligase binding fragment.

In a preferred embodiment, the VHL is a fragment having the structure:

wherein the content of the first and second substances,

R₁₅、R₁₆、R₁₇、R₁₉each independently selected from H, halogen, substituted or unsubstituted: c_1-30Alkyl radical, C_1-30Deuterated alkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_4-8Cycloalkenyl, 3-8 membered heterocyclyl, 3-8 membered heteroalkenyl, 3-8 membered heteroalkynyl, C_4-8Heterocycloalkenyl, C_4-8Heterocycloalkynyl, C_6-10Aryl radical, C_5-10Heteroaryl, alkenylaryl, alkenylheteroaryl, alkynylaryl, alkynylheteroaryl, amino, alkylamino, alkenylamino, alkynylamino, alkyl sulfide, adjacent R₁₅And R₁₆May also be linked to form a ring, said substitution being selected from the group consisting of halogen, -OH, -CN, -NH₂Acetamido and C_1-6Alkoxy radical, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group;

W₂selected from the group consisting of substituted or unsubstituted: c_6-10Aryl radical, C_5-10Heteroaryl group, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, said substitution being by a group selected from halogen, -OH, -CN, -NH₂、C_1-6Alkoxy radical, C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group;

W₃selected from H, halogen, C_1-6Alkyl, -CN and the following substituted or unsubstituted groups: c_6-10Arylene radical, C_5-10Heteroarylene group, C_3-8Cycloalkylene, 3-8 membered heterocyclylene, said substitution being by a group selected from halogen, -OH, -CN, -NH₂And C_1-6Alkoxy radical, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group;

In a preferred embodiment, L is W₁And a linker of VHL, W₁And VHL are separated by 2-20 chemical bonds.

In a more preferred embodiment, W₁And VHL are separated by 5-15 chemical bonds, preferably 8-12 chemical bonds.

In a preferred embodiment, L is a divalent moiety containing one or more moieties selected from NR^Y1、O、S、SO、SO₂Sulfonamide, carbonyl, amide, ester, substituted or unsubstituted: alkenylene, alkynylene, alkylene, isoindolinone, C_6-10Arylene radical, C_5-10Heteroarylene group, C_3-8Cycloalkylene, 3-15 membered heterocyclylene, C_4-10Sulfosacylidene, 4-to 10-membered hetero-spirocyclic ringBase, C_5-10The substituents being selected from the group consisting of halogen, -OH, -CN, -NH, and 5-10 membered heterobridged ring groups₂、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group, wherein R^Y1Selected from hydrogen, deuterium, C unsubstituted or substituted by halogen_1-6Alkyl, unsubstituted or halogen-substituted C_2-6Alkenyl, C unsubstituted or substituted by halogen_2-6Alkynyl.

In a preferred embodiment, L is a direct bond, CR^L1R^L2、O、S、SO、SO2、NR^L3、SO₂NR^L3、SONR^L3、CONR^L3、NR^L3CONR^L4、NR^L3SO₂NR^L4、CO、CR^L1＝CR^L2Alkynyl, SiR^L1 R^L2、P(O)R^L1、P(O)OR^L1、NR^L3C(＝NCN)NR^L4、NR^L3C(＝NCN)、NR^L3C(＝CNO₂)NR^L4Optionally substituted with 0-6R^L1And/or R^L2Radical substituted C_3-11Cycloalkyl optionally substituted by 0-6R^L1And/or R^L2Radical substituted C_3-11Heterocyclyl, optionally substituted with 0-6R^L1And/or R^L2Aryl substituted by radicals, optionally substituted by 0-6R^L1And/or R^L2A radical-substituted heteroaryl radical, in which R is^L1Or R^L2Each independently may be attached to other groups to form cycloalkyl and/or heterocyclyl moieties, which moieties may be further substituted with 0-4R^L5And (4) substituting the group. Wherein r is^L1、r^L2、r^L3、r^L4And r^L5Each independently selected from H, halo, C_l-8Alkyl, OC_l-8Alkyl, SC_l-8Alkyl, NHC_1-8Alkyl, N (C)_l-8Alkyl radical)₂、C_3-11Cycloalkyl, aryl, heteroaryl, C_3-11Heterocyclic group, OC_1-8Cycloalkyl, SC_1-8Cycloalkyl, NHC_1-8Cycloalkyl, N (C)_1-8Cycloalkyl radicals₂、N(C_1-8Cycloalkyl) (C)_1-8Alkyl), OH, NH₂、SH、SO₂C_1-8Alkyl, P (O) (OC)_1-8Alkyl) (C_l-8Alkyl), P (O) (OC)_1-8Alkyl radical)₂、CC-C_1-8Alkyl, CCH, CH ═ CH (C)_l-8Alkyl group), C (C)_l-8Alkyl) ═ CH (C)_l-8Alkyl group), Si (OH)₃、Si(C_l-8Alkyl radical)₃、Si(OH)(C_l-8Alkyl radical)₂、COC_l-8Alkyl, CO₂H. Halogen, CN, CF₃、CHF₂、CH₂F、NO₂、SF₅、SO₂NHC_1-8Alkyl, SO₂N(C_1-8Alkyl radical)₂、SONH(C_1-8Alkyl), SON (C)_1-8Alkyl radical)₂、CONHC_1-8Alkyl, CON (C)_1-8Alkyl radical)₂、N(C_1-8Alkyl) CONH (C)_1-8Alkyl group), N (C)_1-8Alkyl) CON (C)_1-8Alkyl radical)₂、NHCONH(C_1-8Alkyl), NHCON (C)_1-8Alkyl radical)₂、NHCONH₂、N(C_1-8Alkyl) SO₂NH(C_1-8Alkyl group), N (C)_1-8Alkyl) SO₂N(C_1-8Alkyl radical)₂、NHSO₂NH(C_1-8Alkyl), NHSO₂N(C_1-8Alkyl radical)₂And NHSO₂NH₂。

In a preferred embodiment, L is:

in a preferred embodiment, R₁is-CN.

In a preferred embodiment, R₂Is Cl, Br, I or-CF₃。

In a preferred embodiment, R₃Is H or F.

In a preferred embodiment, R₄、R₅、R₆And R₇Each independently is methyl.

In a preferred embodiment, R₈Selected from hydrogen, deuterium and C_1-6Alkyl, or R₈And W₁To form a 5-or 6-membered ring.

In a preferred embodiment, R₉Selected from hydrogen, deuterium and C_1-6An alkyl group.

In a preferred embodiment R₁₀、R₁₁Each independently selected from C_1-6Alkyl or R₁₀And R₁₁Are connected into a ring-shaped cyclopropyl.

In a preferred embodiment, R₁₂And R₁₄Are each independently selected from hydrogen and C_1-6An alkyl group.

In a preferred embodiment, R₁₃Selected from hydrogen and-OR₁₈Said R is₁₈Selected from hydrogen, R₁₉C (═ O) -, substituted or unsubstituted amino acid residues or substituted or unsubstituted oligomeric amino acid residues, R₁₉Selected from H, substituted or unsubstituted: c_1-30Alkyl, deuterated C_1-30Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl, alkenylaryl, alkenylheteroaryl, amino, alkylamino, alkylsulfide, said substitution being by 1-2 substituents selected from halogen, -OH, -CN, -NH₂Acetamido and C_1-6Alkoxy radical, C_1-6Substituted by alkyl substituents, amino, alkylThe substituent in the amino group may also form a ring with N.

In a preferred embodiment, R₁₅、R₁₆And R₁₇Each independently selected from H, halogen, substituted or unsubstituted C_1-6Alkyl, adjacent R₁₅And R₁₆May also be linked to form a ring, said substitution being selected from the group consisting of halogen, -OH, -CN, -NH₂And C_1-6Alkoxy, 3-6 membered heterocyclic group, C_1-6Alkylamino and (C)_1-6Alkyl radical)₂Substituted by a substituent of the amino group.

In a preferred embodiment, A is selected from the group consisting of carbonyl,

C₆-C₁₀Arylene and 5-10 membered heteroarylene, wherein R₁₀、R₁₁Each independently selected from hydrogen, deuterium, C_1-6Alkyl, or R₁₀And R₁₁And the attached carbon atoms are joined to form a 3-6 membered ring; said C is₆-C₁₀Arylene is selected from phenylene and naphthylene, heteroaryl in said 5-to 10-membered heteroarylene is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl and indazolyl, preferably, C₆-C₁₀Arylene is phenylene and 5-10 membered heteroarylene is pyridylene.

In a preferred embodiment, W₁Selected from substituted or unsubstituted C_6-10Arylene, 5-to 10-membered heteroarylene, said C₆-C₁₀The arylene group is selected from phenylene and naphthylene, and the heteroaryl group in the 5-to 10-membered heteroarylene group is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazoleA group selected from the group consisting of a thiadiazolyl group, an oxadiazolyl group, a benzothiophenyl group, an indolyl group, a benzimidazolyl group, a benzothiazolyl group, a benzofuranyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group and an indazolyl group, said substitution being by a group selected from the group consisting of halogen, -OH, -CN, -NH₂、C_1-6Alkoxy and C_1-6Substituted by alkyl substituents, preferably, W₁Selected from unsubstituted or selected from halogen, -OH, -CN, -NH₂、C_1-6Alkoxy and C_1-6Phenylene, pyridylene, quinolylene, benzopyrylene and isoindolinone substituted by alkyl substituent.

In a preferred embodiment, W₂Selected from the group consisting of substituted or unsubstituted: c_6-10Arylene radical, C_5-10Heteroarylene, preferably, C_6-10Arylene is phenylene, C_5-10Heteroarylene is thiazolyl, thienyl, imidazolyl, pyridothienyl, oxazolylene, benzopyrazolylene;

said substitution being by a group selected from halogen, -OH, -CN, -NH₂、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group;

W₃selected from the group consisting of H, halogen, -CN, and substituted or unsubstituted: c_6-10Aryl radical, C_1-6Alkyl radical, C_5-10Heteroaryl, said substitution being by a group selected from halogen, -OH, -CN, -NH₂And C_1-6Alkoxy radical, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group; w₄Selected from the group consisting of substituted or unsubstituted: c_6-10Aryl radical, C_5-10Heteroaryl group, C_3-8Cycloalkyl, 3-to 8-membered heterocyclyl, preferably phenyl, isoxazolyl, isoindolinone, cyclopropyl, said substitution being selected from halogen, -OH, -CN, -NH₂、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_1-6Alkylamino and (C)_1-6Alkyl radical)₂The substituent of the amino is taken.

In a preferred embodiment, the compounds of formula I are selected from:

。

In a preferred embodiment, the above pharmaceutical composition is in the form of any one of aqueous dispersion, liquid, gel, syrup, elixir, syrup, suspension, aerosol, controlled release agent, quick-dissolving agent, effervescent agent, lyophilized agent, tablet, powder, pill, coated, capsule, delayed release agent, extended release agent, pulsatile controlled release agent, multiparticulate or immediate release agent.

The invention also provides the compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic marker thereof, or the application of the pharmaceutical composition in preparing drugs for treating androgen receptor related diseases.

In a preferred embodiment, the androgen receptor associated disease is prostate cancer, breast cancer, prostate hyperplasia, kennedy's disease, hirsutism, acne, alopecia, muscle failure, gonadal failure, osteoporosis, hypercholesterolemia, male infertility, male sexual dysfunction, anemic obesity, low sexual desire, or depression.

In a preferred embodiment, the androgen receptor associated disease is castration-resistant prostate cancer.

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

The weight volume percentage units in the present invention are well known to those skilled in the art and refer to, for example, the weight of solute in a 100ml solution.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

These examples are for illustrative purposes only and do not limit the scope of the claims provided herein.

Overview.¹H-NMR spectrum Bruker-400 or OxFORD-AS500 nuclear magnetic resonance apparatus, the chemical shift unit is one millionth, the internal standard is tetramethylsilane. The coupling constant (J) is close to 0.1 Hz. The abbreviations used are as follows: s, single multiplet; d, doublet; t, triplet; q, quartet; qu, quintet; m, multiplet; br, broad peak. Mass Spectrometry A Quattro MicroTM API triple quadrupole mass spectrometer was used.

Example 1 preparation of N- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutan-2-yl) amino) -2-oxyethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide (compound 1).

Tert-butyl ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamate

Tert-butyl ((1r,3r) -3-hydroxy-2, 2,4, 4-tetramethylcyclobutyl) carbamate (1.0g,4.1mmoL) was charged into a 100mL single-neck flask, THF (30mL) was added, and NaH (329mg, 8.2mmoL) was added after cooling to below 10 ℃. After stirring for 30 minutes, 2-chloro-4-fluorobenzonitrile (767mg, 4.92mmoL) was added, after the addition was complete, the temperature was raised to 70 ℃ and the reaction was monitored by TLC for completion. The solvent was distilled off under reduced pressure, and methylene chloride and water were added to the residue to separate the solution. The organic phase is decompressed and the solvent is removed, the residue is separated by flash column chromatography, the eluent w is ethyl acetate and petroleum ether which are 1:5, 1.44g of the product is obtained, and the yield is 92%.¹H NMR(400MHz,DMSO-d₆)δ7.56(d,J＝7.4Hz,1H),7.47(d,J＝2.1Hz,1H),7.06(dd,J＝7.5,2.0Hz,1H),6.03(s,1H),2.84(s,1H),1.58(s,2H),0.92(s,6H),0.87(s,6H)。

4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzonitrile

Tert-butyl ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamate (1.44g,3.8mmoL) was added to a 100mL single-neck flask, and then hydrochloric acid/1.4-dioxane solution (4M, 10mL) was added thereto, followed by stirring at room temperature and completion of the reaction monitored by TLC. The solvent was evaporated under reduced pressure and the residue was used in the next reaction without purification.

1- ((4- ((tert-butoxycarbonyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid

Cyclopropane-1, 1-dicarboxylic acid (1.45g, 11.5mmoL) was dissolved in THF (40mL), TEA (1.4mL, 11.5mmoL) was added under ice bath, and SOCl was added dropwise₂(0.8mL, 11.5 mmoL). After the completion of the addition, the reaction was carried out for 1 hour in an ice bath. After this time (4-aminophenyl) carbamic acid tert-butyl ester (2.1g, 10mmoL) was added and the reaction was monitored by TLC for completion. The reaction was quenched by addition of water (20 mL). Extract with DCM (30 mL). The organic phase was evaporated under reduced pressure to remove the solvent, and the residue was subjected to flash column chromatography using methanol with dichloromethane ratio of 1:50 to 1:20 to give 1.43g of the desired product in 44.7% yield.

1- ((4-aminophenyl) carbamoyl) cyclopropane-1-carboxylic acid

1- ((4- ((tert-butoxycarbonyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid (1.43g, 6.5mmoL) was added to a 100mL single-necked flask, and then hydrochloric acid/1, 4-dioxane solution (4M, 20mL) was added thereto and stirred at room temperature, and the reaction was monitored by TLC for completion, and the solvent was distilled off under reduced pressure, and the residue was used in the next reaction without purification.

1- ((4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid

1- ((4-aminophenyl) carbamoyl) cyclopropane-1-carboxylic acid (860mg, 2.41mmoL) was added to methanol (10mL), followed by addition of 2-methylpyridine-N-borane (0.28g, 2.65mmoL) and tert-butyl 2- ((5-oxopentyl) oxy) acetate (575mg, 2.65mmoL), stirring at room temperature, and TLC to monitor completion of the reaction. Adding water to quench the reaction, evaporating the solvent under reduced pressure, adding ethyl acetate and water to the residue, extracting, and separating. The organic phase was evaporated under reduced pressure and the residue was separated by flash column chromatography eluting with methanol and dichloromethane at 1:30 to give 481mg of the desired product in 47.4% yield.¹H NMR(400MHz,CDCl₃)δ7.40-7.32(m,2H),6.62-6.54(m,2H),4.33(s,2H),3.49(t,J＝7.5Hz,2H),3.11(t,J＝7.6Hz,2H),1.67(m,4H),1.43(s,9H),1.37–1.24(m,2H),1.16(m,2H),1.20–1.12(m,4H)。

Tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate

1- ((4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid (481mg, 1.15mmoL) was dissolved in DMF (30mL) and 4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzonitrile (300mg, 0.95mmoL) was added, followed by DIPEA (0.76mL) and HATU (522.3mg, 1.34mmoL) in that order, stirring at room temperature, TLC monitoring completion of the reaction, spotting completion of the reaction, evaporation of DMF under reduced pressure, addition of water to the residue and extraction with DCM. Separating, distilling off solvent under reduced pressure from organic phase, separating residue by flash column chromatography, eluting with ethyl acetate and petroleum ether at a ratio of 1:5-1:1 to obtain target product 470mg with a yield of 72.5%.¹H NMR(400MHz,CDCl₃)δ9.50(s,1H),7.63(d,J＝7.4Hz,1H),7.39-7.27(m,3H),7.08(dd,J＝7.5,2.0Hz,1H),6.77(s,1H),6.62–6.54(m,2H),4.61(s,1H),4.33(s,2H),3.92(s,1H),3.53–3.44(m,3H),3.11(t,J＝7.5Hz,2H),1.80-1.69(m,2H),1.65-1.60(m,4H),1.64–1.49(m,2H),1.43(s,9H),1.37–1.24(m,2H),1.23(s,6H),1.12(s,6H)。

2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid

Mixing 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetic acidTert-butyl ester (470mg, 0.79mmoL) was dissolved in DCM (4mL), TFA (4mL) was added and stirred at room temperature, TLC monitored for completion of reaction, spin-dried TEA was extracted with DCM and water, organic layer was spin-dried and flash column chromatography was used to isolate 395mg of the desired product in 92% yield.¹H NMR(400MHz,CD₃OD)δ7.70(d,J＝8.7Hz,1H),7.17(d,J＝8.8Hz,2H),7.11(d,J＝2.4Hz,1H),6.96(dd,J＝8.8,2.4Hz,1H),6.62(d,J＝8.9Hz,2H),4.56(s,2H),4.23(s,1H),4.10(q,J＝7.1Hz,1H),3.96(s,2H),3.90(s,1H),3.52(t,J＝6.4Hz,2H),3.08(t,J＝7.0Hz,2H),2.01(s,2H),1.64(dt,J＝13.9,7.0Hz,4H),1.52(d,J＝12,4H),1.24(s,H),1.22(s,6H),1.15(s,6H)。

N- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy)

-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutan-2-yl) amino) -2-oxyethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide

Compound 2- ((5- ((4- (1- (((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid (395mg, 0.63mmoL) was added to DMF (10mL) followed by EDCI (242mg, 1.26mmoL), HOBT (171.0mg, 1.26mmoL), DIPEA (0.33mL,1.89mmoL) and after stirring for 5 minutes (2S,4R) -1- ((S) -2- (l 2-azepinyl) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxy-carboxylic acid Amide (304.2mg, 0.63mmoL, prepared according to CN 201680014250.8). After the addition was complete, stirring was continued at room temperature and the reaction was monitored by TLC. DMF was evaporated under reduced pressure and water was added to the residue which was extracted with DCM. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography using methanol with dichloromethane at 1:50-1:10 to give the desired product 480mg in 72.5% yield.¹H NMR(400MHz,CD₃OD)δ8.87(s,1H),8.57(d,J＝8.0Hz,1H),7.70(d,J＝8.0Hz,1H),7.56(d,J＝8.0Hz,1H),7.45-7.37(m,4H),7.21-7.18(m,2H),7.10(d,J＝4.0Hz,1H),6.95(dd,J＝4.0,4.0Hz,1H),6.66-6.62(m,1H),5.01-4.97(m,1H),4.70(d,J＝8.0Hz,1H),4.60-4.56(m,1H),4.44(s,1H),4.21(s,1H),3.99-3.95(m,2H),3.92-3.83(m,2H),3.77-3.73(m,1H),3.61-3.56(m,2H),3.12(t,J＝8.0Hz,2H),2.47(s,3H),2.24-2.17(m,1H),1.98-1.92(m,1H),1.71-1.63(m,4H),1.60-1.51(m,5H),1.47(d,J＝8.0Hz,3H),1.21(s,6H),1.14(s,6H),1.04(s,9H)。MS-ESI:1051.4[M+H]⁺。

Example 2N- (((1r,3r) -3- (3-bromo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- ((5- (2- (((S) -1- ((2S, preparation of 4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide (compound 2).

4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-bromobenzylnitrile hydrochloride

This compound was prepared as in example 1 except that 4-fluoro-2-bromoxynil was used in place of 2-chloro-4-fluorobenzonitrile, and 4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzonitrile was used. The yield thereof was found to be 82%.¹H NMR(400MHz,DMSO-d₆)δ7.56(d,J＝7.4Hz,1H),7.47(d,J＝2.1Hz,1H),7.06(dd,J＝7.5,2.0Hz,1H),6.03(s,1H),2.84(s,1H),1.58(s,2H),0.92(s,6H),0.87(s,6H)。

Tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-bromo-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate

This compound was prepared as in example 1 except that 4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-bromobenzylnitrile hydrochloride was used in place of 4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzonitrile, and tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate. The yield thereof was found to be 43%.¹H NMR(400MHz,CDCl₃)δ9.50(s,1H),7.63(d,J＝7.4Hz,1H),7.39-7.27(m,3H),7.08(dd,J＝7.5,2.0Hz,1H),6.77(s,1H),6.62-6.54(m,2H),4.61(s,1H),4.33(s,2H),3.92(s,1H),3.53-3.44(m,3H),3.11(t,J＝7.5Hz,2H),1.80(m,2H),1.67(m,4H),1.64-1.49(m,2H),1.43(s,9H),1.37-1.24(m,2H),1.23(s,6H),1.12(s,6H)。

2- ((5- ((4- (1- (((1r,3r) -3- (3-bromo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetic acid

The preparation of this compound was the same as that of tert-butyl 2- ((5- ((4- (1- (((1r,3r) -3- (3-bromo-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate in example 1 except that tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate was replaced with tert-butyl 2- ((4- (1- ((((1r, preparation of 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid. The product was used in the next reaction without purification.

N- (((1R,3R) -3- (3-bromo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutan-2-yl) amino) -2-oxyethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide

The preparation of the compound was the same as that of N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2 in example 1 except that 2- ((5- ((4- (1- ((((1r,3r) -3- (3-bromo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetic acid was used in place of 2- ((5- ((4- (1- ((((((1 r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid, preparation of 2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 40%.¹H NMR(400MHz,CD₃OD)δ8.87(s,1H),7.68(d,J＝8.0Hz,1H),7.45-7.37(m,4H),7.25(d,J＝4.0Hz,1H),7.20(d,J＝8.0Hz,2H),6.99(dd,J＝4.0,4.0Hz,1H),6.64(d,J＝8.0Hz,2H),5.06-4.96(m,1H),4.70(d,J＝4.0Hz,1H),4.58(q,J＝4.0Hz,1H),4.45(s,1H),4.19(s,1H),3.99(q,J＝12.0Hz,2H),3.92-3.84(m,2H),3.77-3.73(m,1H),3.60-3.57(m,2H),3.11(t,J＝4.0Hz,2H),2.25-2.20(m,1H),1.98-1.91(m,1H),1.73-1.64(m,4H),1.55-1.50(m,5H),1.47(d,J＝8.0Hz,3H),1.21(s,6H),1.14(s,6H),1.04(s,9H)。MS-ESI:1097.3[M+H]⁺。

Example 3N- ((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- ((5- (2- ((S) -1- ((3r, preparation of 4S) -3-hydroxy-4- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxyethyl) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide (compound 3).

((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamic acid tert-butyl ester

This compound was prepared as in example 1 except that 4-fluoro-2-iodobenzonitrile was used in place of 4-fluoro-2-chlorobenzene, and tert-butyl ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamate was prepared. The yield thereof was found to be 75%,¹H NMR(400MHz,CDCl₃)δ7.48(d,J＝8.7Hz,1H),7.35(d,J＝2.4Hz,1H),6.83(dd,J＝8.7,2.3Hz,1H),4.66(d,J＝8.1Hz,1H),3.93(s,1H),3.67(d,J＝8.5Hz,1H),1.45(s,9H),1.17(s,6H),1.13(s,6H)。ESI-MS:371.2[M-Boc+H]⁺。

4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-iodobenzonitrile hydrochloride

This compound was prepared as in 4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzonitrile in example 1, except that tert-butyl ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamate in example 1 was used in place of tert-butyl ((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamate. The yield thereof was found to be 92%.

Tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (4-cyano-3-iodophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate

The compound was prepared as in example 1 except that 4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-iodobenzonitrile hydrochloride was used in place of 4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzonitrileOxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) tert-butyl acetate. The yield thereof was found to be 52%. MS-ESI 773.3[ M + H ]]⁺。

2-5- ((4- (1- ((((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid

The present compound was prepared as in example 1 except that tert-butyl 2- ((5- ((4- (1- (((1r,3r) -3- (4-cyano-3-iodophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate was replaced with tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate, preparation of 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid. The yield thereof was found to be 95%.

N- (((1R,3R) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- ((5- (2- (((S) -1- ((3R,4S) -3-hydroxy-4- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide

In addition to the replacement of 2- ((5- ((4- (1- (((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid with 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid, the present compoundsWas prepared as described for N- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutan-2-yl) amino) -2-oxyethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide in example 1. The yield thereof was found to be 38%.¹H NMR(400MHz,CD₃OD)δ8.87(s,1H),8.60(d,J＝4.0Hz,1H),7.58(d,J＝8.0Hz,1H),7.48-7.39(m,5H),7.21-7.18(m,2H),7.00(dd,J＝4.0,4.0Hz,1H),6.65(d,J＝4.0Hz,2H),5.01-4.99(m,1H),4.70(d,J＝12.0Hz,1H),4.61-4.56(m,1H),4.45(s,1H),4.17(s,1H),3.98(q,J＝12.0Hz,2H),3.91-3.82(m,2H),3.77-3.73(m,1H),3.60-3.56(m,2H),3.12(t,J＝8.0Hz,2H),2.47(s,3H),2.25-2.20(m,1H),1.98-1.94(m,1H),1.72-1.65(m,4H),1.57-1.52(m,5H),1.47(d,J＝8.0Hz,3H),1.21(s,6H),1.14(s,6H),1.04(s,9H)。ESI-MS:1143.1[M+H]⁺。

Example 4N- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- (6- (2- ((((S) -1- (((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutan-2-yl) amino) -2-oxoethoxy) hex-1-yl) phenyl) cyclopropane-1, preparation of 1-dicarboxamide (Compound 4)

1- (4-iodo-phenylcarbamoyl) -cyclopropanecarboxylic acid methyl ester

Methyl cyclopropane-1, 1-dicarboxylate (1.51g, 10.5mmoL) was dissolved in anhydrous THF (20mL), triethylamine (1.5mL, 10.5mmoL) was added and the temperature was lowered to-10 ℃ and thionyl chloride (0.76mL,10.5mmoL) was slowly added thereto, and the temperature was controlled to-8 ℃ during the addition and the reaction was carried out for 1 hour while maintaining the temperature. P-iodoaniline (2g,9.1mmoL) in anhydrous tetrahydrofuran THF (5mL) was added to the reaction systemThe reaction was carried out at room temperature for 2h and monitored by TLC for completion. The reaction was quenched with water and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography eluting with ethyl acetate and petroleum ether at 1:4-1:1 to give 2.5g, 69.4% yield.¹H NMR(400MHz,CDCl₃)δ7.65(d,J＝8Hz,2H),7.41(d,J＝8Hz,2H),3.77(s,3H),1.89-1.80(m,2H),1.77-1.67(m,2H)。MS-ESI:346.0[M+H]⁺。

1- (4- (6-tert-Butoxycarbonylmethoxy-hexyl-1-ynyl) -phenylcarbamoyl) -cyclopropanecarboxylic acid methyl ester

Methyl 1- (4-iodo-phenylcarbamoyl) -cyclopropanecarboxylate (1.0g,2.9mmoL), tert-butyl hexyl-5-ethoxyacetate (680mg,3.2mmoL), cuprous iodide (110mg,0.58mmoL), PdCl₂(PPh₃)₂(127mg,0.29mmoL) was added to a 100mL three-necked flask, DMF (20mL), TEA (1.2mL, 8.7mmoL) was added, and the mixture was replaced with nitrogen 3 times, and then the mixture was heated to 60 ℃ overnight and the reaction was monitored by TLC for completion. The reaction solution was quenched with water and extracted with DCM. The solvent is evaporated under reduced pressure, and the residue is subjected to flash column chromatography, wherein the eluent is ethyl acetate and petroleum ether in a ratio of 1:5-1: 1. 1.0g was obtained, yield 83.3%.¹H NMR(400MHz,Chloroform-d)δ＝10.98(s,1H),7.61–7.58(d,J＝12Hz,2H),7.43–7.41(d,J＝9Hz,2H),4.04(d,J＝0.8Hz,2H),3.82(s,3H),3.65(t,J＝6.2Hz,2H),2.52(t,J＝6.8Hz,2H),2.13(t,J＝1.2Hz,1H),1.95–1.71(m,5H),1.69(t,J＝1.2Hz,1H),1.56(s,9H)。MS-ESI:430.3[M+H]⁺。

1- (4- (6-tert-Butoxycarbonylmethoxy-hex-1-ynyl) -phenylcarbamoyl) -cyclopropanecarboxylic acid

Methyl 1- (4- (6-tert-butoxycarbonylmethoxy-hex-1-ynyl) -phenylcarbamoyl) -cyclopropanecarboxylate (1g,2.3mmoL) was dissolved in a mixed solution of methanol (10mL) and water (10mL), and sodium hydroxide (373mg,9.2mmoL) was added thereto and stirred at room temperature overnight. TLC monitored the reaction complete. The pH value of the reaction solution is adjusted to be neutral by using 0.2M dilute hydrochloric acid, the solvent is distilled off under reduced pressure, and the reaction solution is dried under high vacuum and is directly used for the next reaction without purification.

Tert-butyl 2- ((6- (4- (1- ((((((1 r, r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) hexyl-5-alkynyl-1-yloxy) acetate

Except that 1- ((4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid was replaced by 1- (4- (6-tert-butoxycarbonylmethoxy-hex-1-ynyl) -phenylcarbamoyl) -cyclopropanecarboxylic acid, in addition to replacing HATU with EDCI/HOBt, this compound was prepared as in example 1 for tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate. The yield thereof was found to be 71.4%.¹H NMR(400MHz,CDCl₃)δ8.07(s,1H),7.62(dd,J＝8.7,2.5Hz,1H),7.52(d,J＝8.6Hz,1H),7.44–7.36(m,1H),7.03–6.90(m,2H),6.84(dd,J＝8.7,2.4Hz,1H),4.02(s,2H),3.62(t,J＝6.2Hz,2H),2.50(t,J＝6.8Hz,2H),2.11(s,1H),1.75(s,2H),1.82–1.67(m,2H),1.66(s,2H),1.54(s,9H),1.31(s,3H),1.30–1.15(m,12H)。MS-ESI:676.2[M+H]⁺。

1- ((6- (4- (1- ((((((1 r,3) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido)) phenyl) hexyl-5-alkynyl-1-yloxy) acetic acid

This compound was prepared as in example 1 except that tert-butyl 2- ((6- (4- (1- (((((1r, r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) hexyl-5-alkynyl-1-yloxy) acetate was used in place of tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate (1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid.

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- (6- (2- (((((S) -1- ((((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) hex-1-yl) phenyl) cyclopropane-1, 1-dicarboxamide.

The preparation of the present compound was the same as that of N- ((1 r) in example 1 except that 2- ((6- (4- (1- (((((1r,3) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido)) phenyl) hexyl-5-alkynyl-1-yloxy) acetic acid was used in place of 2- ((5- ((4- (1- (((((1r, 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid, preparation of 3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxetan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 72.8%.¹H NMR(400MHz,CD₃OD)δ8.87(s,1H),7.71(d,J＝8.0Hz,1H),7.51-7.47(m,2H),7.45-7.39(m,4H),7.35-7.32(m,2H),7.11(d,J＝4.0Hz,1H),6.96(dd,J＝4.0,4.0Hz,1H),5.00-4.97(m,1H),4.71-4.68(m,1H),4.58(t,J＝8.0Hz,2H),4.44(s,1H),4.22(s,1H),4.0(d,J＝4.0Hz,2H),3.91(s,1H),3.87-3.84(m,1H),3.76-3.73(m,1H),3.64(t,J＝8Hz,2H),2.47(s,3H),2.21-2.19(m,1H),1.98-1.94(m,1H),1.85-1.82(m,2H),1.77-1.71(m,2H),1.58-1.56(m,4H),1.50(d,J＝8.0Hz,3H),1.22(s,6H),1.15(s,6H),1.04(s,9H)。MS-ESI:1046.0[M+H]⁺。

Example 5N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- (6- (2- ((((S) -1- (((2S, preparation of 4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) hexanoyl) phenyl) cyclopropane-1, 1-dicarboxamide (compound 5).

N- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- (6- (2- ((((S) -1- ((((((2S, 4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutan-2-yl) amino) -2-oxoethoxy) hex-1-yl) phenyl) cyclopropane-1, 1-dicarboxamide (100mg, 0.095mmoL) was added to water (2mL), and a small amount of zeolite was added thereto, followed by reflux reaction overnight. The reaction was monitored by LC-MS for completion. Cooling to room temperature, extracting with dichloromethane, evaporating the solvent under reduced pressure, separating the residue by flash column chromatography, eluting with methanol and dichloromethane of 1:50-1:10, and obtaining the yield of 62.3%.¹H NMR(400MHz,CD₃OD)δ8.87(s,1H),8.00(d,J＝8.0Hz,2H),7.74-7.69(m,3H),7.44-7.35(m,4H),7.11(d,J＝4.0Hz,1H),6.96(dd,J＝4.0,4.0Hz,1H),5.01-4.97(m,1H),4.70-4.68(m,1H),4.60-4.54(m,1H),4.44(s,1H),4.23(s,1H),3.99-3.91(m,3H),3.86-3.83(m,1H),3.76-3.72(m,1H),3.58(t,J＝8Hz,2H),3.05(t,J＝8Hz,2H),2.47(s,3H),2.24-2.17(m,1H),1.98-1.91(m,1H),1.80-1.67(m,4H),1.60-1.57(m,5H),1.48(d,J＝4.0Hz,3H),1.22(s,6H),1.15(s,6H),1.04(s,9H)。MS-ESI:1064.3[M+H]⁺。

Example 6N- (((1r,3r) -3- (4-cyano-3-chlorophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- ((1- (2- (3- ((S) -1- (((2S, preparation of 4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxetan-2-yl) ureido) ethylpiperidin-4-ylethynyl) phenyl) cyclopropane-1, 1-dicarboxamide (compound 6).

4- ((4-aminophenyl) ethynyl) piperidine-1-carboxylic acid tert-butyl ester

4-Iodoaniline (1.0g,4.57mmoL) and 4-ethynylpiperidine-1-carboxylic acid tert-butyl ester (1.15g,5.48mmoL) were added to a 100mL three-necked flask, followed by DMF (20mL), CuI (0.18g,0.91mmoL) and PdCl₂(PPh₃)₂(0.2g,0.457 mmoL). Nitrogen was replaced three times, triethylamine (1.9mL,13.71mmoL) was injected, the reaction was allowed to warm to 60 ℃ for 3h, and the completion of the reaction was monitored by TLC. Adding ethyl acetate and water, separating liquid, distilling off the solvent by organic phase under reduced pressure, separating the residue by flash column chromatography, and obtaining 1.2g of product with the yield of 88.2% by using ethyl acetate and petroleum ether as eluent in a ratio of 1:10-1: 1.¹H NMR(400MHz,DMSO-d₆)δ7.14-6.96(m,2H),6.48(d,J＝8.2Hz,2H),5.38(s,2H),3.62(ddd,J＝13.3,6.1,3.9Hz,2H),3.10(s,2H),2.76(tt,J＝8.4,3.9Hz,1H),1.77(ddt,J＝13.2,6.7,3.6Hz,2H),1.45(ddd,J＝12.9,8.6,3.7Hz,2H),1.39(s,9H)。

4- (piperidin-4-ylethynyl) aniline

Tert-butyl 4- ((4-aminophenyl) ethynyl) piperidine-1-carboxylate (1.2g,4mmoL) was added to a 50mL single-neck flask, dichloromethane (10mL), trifluoroacetic acid (5mL) was added, stirring was carried out at room temperature for 2h, TLC monitored for completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was used in the next reaction without purification.

(tert-butyl 2- (4- (((4-aminophenyl) ethynyl) piperidin-1-yl) ethyl) carbamate

4- (piperidin-4-ylethynyl) aniline (0.1g,0.33mmoL) was added to a 25mL single-necked flask, DMF (5mL), cesium carbonate (0.54g,1.66mmoL), Boc-bromoethylamine (98mg,0.43mmoL) was added, stirred overnight at room temperature, and the reaction was monitored by TLC for completion. Adding organic solvent ethyl acetate and water, separating, distilling off solvent under reduced pressure, separating residue by flash column chromatography, and eluting with methanol and dichloromethane at ratio of 1:50-1:20 to obtain product 78mg with yield of 62.4%.¹H NMR(400MHz,DMSO-d6)δ7.08-6.94(m,2H),6.64(t,J＝5.8Hz,1H),6.55-6.40(m,2H),5.36(s,2H),3.01(q,J＝6.6Hz,2H),2.67(s,2H),2.29(t,J＝7.0Hz,2H),2.11(s,2H),1.79(d,J＝12.0Hz,2H),1.53(tq,J＝9.4,6.2,4.7Hz,2H),1.36(s,9H)。MS-ESI:344.4[M+H]⁺。

1- ((4- ((1- (2- ((tert-butoxycarbonyl) amino) ethyl) piperidin-4-ylethynyl) phenyl) carbamoyl) cyclopropane-1-carboxylic acid

This compound was prepared as in example 1 for 2- ((4- ((tert-butoxycarbonyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid, except that tert-butyl 2- (4- (((4-aminophenyl) ethynyl) piperidin-1-yl) ethyl) carbamate was used instead of tert-butyl (4-aminophenyl) carbamate. The yield thereof was found to be 27.8%.¹H NMR(400MHz,DMSO-d₆)δ9.87(s,1H),7.59(d,J＝8.6Hz,2H),7.35(d,J＝8.2Hz,2H),7.11(t,J＝5.8Hz,1H),4.42(s,1H),3.02-3.18(m,6H),2.48(t,J＝7.0Hz,2H),2.09(d,J＝15.7Hz,2H),1.89(t,J＝7.2Hz,2H),1.37(m,9H)。MS-ESI:356.3[M+H]⁺。

Tert-butyl (2- (4- ((4- (1- (((((1r, 3r) -3- (4-cyano-3-chlorophenoxy))) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) ethynyl) piperidin-1-yl) ethyl) carbamate

This compound was prepared as in example 1 for tert-butyl 2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) oxy) acetate, except that 1- ((4- ((1- (2- ((tert-butoxycarbonyl) amino) ethyl) piperidin-4-ylethynyl) phenyl) carbamoyl) cyclopropane-1-carboxylic acid was used instead of 1- ((4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) carbamoyl) cyclopropane-1-carboxylic acid and the condensing agent was changed from HATU to EDCI/HOBT And (4) preparing. The yield thereof was found to be 87.5%.¹H NMR(400MHz,CDCl₃)δ7.56(d,J＝8.7Hz,1H),7.52(d,J＝8.5Hz,2H),7.38-7.33(m,2H),6.94(d,J＝2.4Hz,1H),6.78(dd,J＝8.7,2.4Hz,1H),6.55(s,1H),6.14(s,1H),4.01(s,1H),3.93(d,J＝7.8Hz,1H),3.58(d,J＝6.0Hz,2H),3.25(s,2H),3.12(s,2H),2.39(s,2H),2.02(d,J＝9.9Hz,2H),1.73(q,J＝4.9Hz,2H),1.42(q,J＝4.9Hz,2H),1.37(s,9H),1.19(d,J＝6.5Hz,12H)。MS-ESI:716.3[M+H]⁺。

N- (4- ((1- (2-aminoethyl) piperidin-4-yl) ethynyl) phenyl) -N- ((1r,3r) -3- (4-cyano-3-chlorophenoxy) -2,2,4, 4-tetramethylcyclobutyl) cyclopropane-1, 1-dicarboxamide

This compound was prepared as in example 1 except that tert-butyl (2- (4- ((4- (1- (((((1r, 3r) -3- (4-cyano-3-chlorophenoxy))) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) ethynyl) piperidin-1-yl) ethyl) carbamate was used in place of tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate Preparation of (1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid. The product was used in the next reaction without purification.

4-Nitrophenyl (2- (4- ((4- (1- (((1r,3r) -3- (4-cyano-3-chlorophenoxy))) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) ethynyl) piperidin-1-yl) ethyl) carbamate

The compound N- (4- ((1- (2-aminoethyl) piperidin-4-yl) ethynyl) phenyl) -N- ((1r,3r) -3- (4-cyano-3-chlorophenoxy) -2,2,4, 4-tetramethylcyclobutyl) cyclopropane-1, 1-dicarboxamide (0.49mmoL) was added to a 25mL one-neck flask, DCM (15mL), TEA (0.2mL,1.47mmoL) and finally 4-nitrophenylcarbonyl chloride (128mg,0.63mmoL) were added and the reaction stirred at room temperature for 2h, TLC monitored for completion and the next reaction was carried out directly.

N- (((1R,3R) -3- (4-cyano-3-chlorophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- ((1- (2- (3- ((S) -1- (((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutan-2-yl) ureido) ethylpiperidin-4-ylethynyl) phenyl) cyclopropane-1, 1-dicarboxamide

TEA (0.2mL,1.47mmoL) was added directly to the reaction solution in the above step, followed by (0.35g,0.73mmoL) of (2S,4R) -1- ((S) -2- (l 2-azanyl) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide, stirred overnight at room temperature, TLC monitored for completion of the reaction, added organic solvents dichloromethane and water for extraction, separated, evaporated the solvent under reduced pressure, and the residue was separated by flash column chromatography using methanol as eluent, dichloromethane ═ 1:50-1:10, to give 150mg of the product in 26.3% yield.¹H NMR(400MHz,CD₃OD)δ8.88(s,1H),7.72(d,J＝8.0Hz,1H),7.54(d,J＝8.0Hz,2H),7.45-7.34(m,6H),7.12(d,J＝4.0Hz,1H),6.96(dd,J＝4.0,4.0Hz,1H),5.03-4.97(m,1H),4.63(s,3H),4.58(t,J＝4.0Hz,1H),4.45(s,1H),4.42(s,1H),4.24(s,1H),4.00-3.89(m,2H),3.75-3.72(m,1H),3.61-3.56(m,1H),3.40-3.34(m,2H),3.20-2.99(m,4H),2.47(s,3H),2.25-2.16(m,3H),1.99-1.92(m,5H),1.61-1.57(m,4H),1.52(d,J＝8.0Hz,3H),1.22(s,6H),1.16(s,6H),1.03(s,9H)。MS-ESI:1086.3[M+H]⁺。

Example 7N- (((1r,3r) -3- (4-cyano-3-chlorophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- ((1- (2- (((S) -1- ((2S), preparation of 4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) piperidin-4-yl) ethynyl) phenyl) cyclopropane-1, 1-dicarboxamide (compound 7).

2- (4- (((4-aminophenyl) ethynyl) piperidin-1-yl) acetic acid tert-butyl ester

This compound was prepared as described for tert-butyl 2- (4- (((4-aminophenyl) ethynyl) piperidin-1-yl) ethyl) carbamate in example 6, except that tert-butyl 2-bromoacetate was used in place of Boc-bromoethylamine. The yield thereof was found to be 76.9%.¹H NMR(400MHz,CDCl₃)δ7.22-7.15(m,2H),6.62-6.54(m,2H),3.72(s,3H),3.23(s,2H),2.81(q,J＝8.6,6.2Hz,2H),2.61(s,1H),2.42(d,J＝10.3Hz,2H),2.01-1.88(m,2H),1.80(qd,J＝8.9,4.6Hz,2H)。MS-ESI:315.3[M+H]⁺。

1- ((4- ((1- (2- (tert-butoxy) -2-oxyethyl) piperidin-4-yl) ethynyl) phenyl) carbamoyl) cyclopropane-1-carboxylic acid

The preparation of this compound was carried out in the same manner as described above, except that tert-butyl 2- (4- (((4-aminophenyl) ethynyl) piperidin-1-yl) acetate was used instead of tert-butyl (4-aminophenyl) carbamatePreparation of 2- ((4- ((tert-butoxycarbonyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid in example 1. The yield thereof was found to be 27.8%.¹H NMR(400MHz,CDCl₃)δ11.36(s,1H),7.54(d,J＝8.4Hz,2H),7.34(d,J＝8.3Hz,2H),3.81(d,J＝6.4Hz,5H),3.62(s,2H),3.29(s,2H),2.99(s,1H),2.38(s,2H),2.05(d,J＝38.0Hz,2H),1.75(s,2H),1.69(s,2H)。MS-ESI:427.4[M+H]⁺。

Tert-butyl 2- (4- ((4- (1- ((((1r,3r) -3- (4-cyano-3-chlorophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) ethynyl) piperidin-1-yl) acetate

This compound was prepared as described for tert-butyl 2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) oxy) acetate in example 1, except that 1- ((4- ((1- (2- (tert-butoxy) -2-oxyethyl) piperidin-4-yl) ethynyl) phenyl) carbamoyl) cyclopropane-1-carboxylic acid was used instead of 1- ((4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) carbamoyl) cyclopropane-1-carboxylic acid, and the condensing agent was changed from HATU to EDCI, HOBT And (4) preparation. The yield thereof was found to be 50%.¹H NMR(400MHz,CDCl₃)δ9.67(s,1H),7.56(dd,J＝8.7,1.8Hz,1H),7.50-7.43(m,2H),7.40-7.32(m,2H),6.94(d,J＝2.3Hz,1H),6.78(dt,J＝8.8,2.2Hz,2H),4.00(s,1H),3.92(d,J＝7.7Hz,1H),3.14(s,2H),2.89-2.79(m,2H),2.63(s,1H),2.44(s,2H),1.89-1.74(m,6H),1.68(q,J＝5.1Hz,2H),1.49-1.42(m,9H),1.18(dd,J＝8.3,1.8Hz,12H)。MS-ESI:687.2[M+H]⁺。

2- (4- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) ethynyl) piperidin-1-yl) acetic acid

The present compound was prepared as in example 1 except that tert-butyl 2- (4- ((4- (1- ((((1r,3r) -3- (4-cyano-3-chlorophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) ethynyl) piperidin-1-yl) acetate was used in place of tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate, preparation of 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid. The product was used in the next reaction without purification.

N- (((1r,3r) -3- (4-cyano-3-chlorophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -N- (4- ((1- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) piperidin-4-yl) ethynyl) phenyl) cyclopropane-1, 1-dicarboxamide.

In addition to the substitution of 2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid with 2- (4- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid, this compound was prepared as in example 1 with N- ((1r, preparation of 3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxetan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 27%.¹H NMR(400MHz,CD₃OD)δ8.88(s,1H),7.72(d,J＝8.0Hz,1H),7.52-7.50(m,2H),7.46-7.41(m,4H),7.37-7.34(m,2H),7.12(d,J＝4.0Hz,1H),6.96(dd,J＝4.0,4.0Hz,1H),5.02-4.98(m,1H),4.67(s,7H),4.58(t,J＝8.0Hz,1H),4.44(s,1H),4.25(s,1H),3.93(s,1H),3.88-3.85(m,1H),3.75(dd,J＝4.0,4.0Hz,1H),3.08(s,2H),2.86-2.84(m,1H),2.48(s,3H),2.21-2.18(m,1H),2.04-1.95(m,4H),1.85-1.82(m,1H),1.60-1.58(m,5H),1.53(d,J＝4.0Hz,3H),1.23(s,6H),1.17(s,6H),1.04(s,9H)。MS-ESI:1057.4[M+H]⁺。

Example 8 preparation of (3S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetamide) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4-methylthiazol-5-yl) benzyl) pyrrolidine-3-carboxamide (Compound 8)

Tert-butyl (4- (4-methylthiazol-5-yl) benzyl) carbamate

Tert-butyl (4-bromophenyl) carbamate (7.23g, 25.28mmoL), 4-methylthiazole (5g, 50.5mmoL), palladium acetate (57mg, 0.25mmoL) and potassium acetate (4.95g, 50.50mmoL) were added to N, N-dimethylacetamide (100mL), replaced with nitrogen three times, stirred at 80 ℃ for 18h, and the reaction was monitored by TLC for completion. Cool to room temperature and filter the reaction mixture. To the filtrate was added (150mL), and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was filtered. The solid was collected by filtration and dried in an oven at 50 ℃ to give 3.48g of a grey solid in 82% yield.¹H NMR(400MHz,DMSO-d6)δ8.95(s,1H),7.42(dd,J₁＝11.6Hz，J₂＝7.2Hz,2H),7.29(d,J＝8.1Hz,2H),4.12(d,J＝6.2Hz,2H),2.41(s,3H),1.36(s,9H)。

(4- (4-methylthiazol-5-yl) phenyl) carboxamide hydrochloride

Tert-butyl (4- (4-methylthiazol-5-yl) benzyl) carbamate (502mg, 1.65mmoL) was dissolved in methanol (3mL), followed by addition of hydrochloric acid/1, 4 dioxane (4.0M,8mL), stirring at room temperature, and completion of the reaction monitored by TLC. The solvent was evaporated under reduced pressure and dried under high vacuum, and the residue was used in the next reaction without purification to obtain 440mg of a solid.

Tert-butyl (2S,4R) -4-hydroxy-2- (((1S) -1- (4- (4-methyl-1, 3-thiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-carboxylate

(2S,4R) -l- ((tert-butoxy) carbonyl) -4-hydroxypyrrolidine-2-carboxylic acid (480mg, 2.08mmoL) was added to a mixed solution of dichloromethane (10mL) and DIPEA (894mg, 6.925mmoL), and HOBT (790mg, 2.08mmoL), HATU (790mg, 2.08mmoL), and (lS) -l- (4- (4-methyl-l, 3-thiazol-5-yl) phenyl) ethan-l-amine (440mg, 1.385mmoL) were added. After the addition was complete, the mixture was stirred at room temperature for 12 hours. TLC monitored the reaction complete. Water (5 mL. times.2) was added to separate the layers. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography with methanol to dichloromethane to 1: 50. 510mg of yellow product are obtained with a yield of 58.8%.¹H NMR(400MHz,CDCl₃)δ8.68(s,1H),7.36(dd,J＝22.3,7.8Hz,4H),4.48(m,2H),3.77-3.60(m,1H),3.52(dd,J＝11.2,4.6Hz,1H),2.51(s,3H),2.01-2.11(m,1H),1.66-1.73(m,2H),1.56-1.48(m,2H),1.43(d,J＝6.6Hz,9H)。MS-ESI:432.1[M+H]⁺。

(2S,4R) -4-hydroxy-N- ((S) -l- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide hydrochloride

Tert-butyl (2S,4R) -4-hydroxy-2- (((1S) -1- (4- (4-methyl-1, 3-thiazol-5-yl) phenyl) ethyl) carbamoyl ] pyrrolidine-1-carboxylate (510mg, 11.59mmoL) was dissolved in methanol (3mL), hydrochloric acid/1, 4 dioxane (4.0M,5mL) was added, the mixture was stirred at room temperature for 30 minutes, TLC monitored for completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was dried under high vacuum and used in the next reaction without further purification to give 405mg of a solid.

Tert-butyl ((S) -l- ((2S,4R) -4-hydroxy-2- ((S) -l- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-l-yl) -3, 3-dimethyl-l-oxobutan-2-yl) carbamate

(2S) -2- ((tert-butoxy) carbonyl) amino-3, 3-dimethylbutanoic acid (424mg, 1.83mmoL) was added to dichloromethane (10mL), followed by DIPEA (237mg, 6.35mmoL), HATU (698mg, 1.91mmoL), HOBt (248mg,1.91mmoL), (2S,4R) -4-hydroxy-N- ((lS) -l- (4- (4-methyl-l, 3-thiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide hydrochloride (405mg, 1.27 mmoL). After the addition was complete, stirring was continued at room temperature for 12 hours. TLC monitored the reaction complete. Adding water, and separating. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography eluting with methanol and dichloromethane at 1:30 to give 550mg of a pale yellow solid in 81% yield.¹H NMR(400MHz,CDCl₃)δ8.68(s,1H),7.44(m,1H),7.40-7.29(m,4H),5.18(d,J＝9.0Hz,1H),4.76(t,J＝8.0Hz,1H),4.64-4.45(m,2H),4.31(dd,J＝14.9,5.1Hz,1H),4.12(dd,J＝20.3,10.3Hz,2H),2.62-2.53(m,1H),2.51(s,3H),2.12(dd,J＝13.4,8.2Hz,1H),1.52-1.42(m,2H),1.40(s,9H),0.90(s,9H)。MS-ESI:545.3[M+H]⁺。

(3S,4R) -1- ((S) -2-amino-3, 3-dimethylbutanol) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-3-carboxamide

Tert-butyl ((S) -1- ((3R,4S) -3-hydroxy-4- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamate (80mg,0.15mmoL) was added to methanol (2mL) and hydrochloric acid/1, 4 dioxane (4.0M,4mL) was added. After the addition was complete, the reaction was stirred at room temperature and monitored by TLC for completion. The solvent was evaporated under reduced pressure and the residue was dried under high vacuum and used directly in the next reaction without purification.

Tert-butyl (4-nitrophenyl) 1, 4-phenylamino dicarbonate

The compound tert-butyl (4-aminophenyl) carbamate (1.0g,4.8mmoL), TEA (1.46g,14.4mmoL) were added to DCM (15mL), and p-nitrophenyl chloroformate (1.25g,6.24mmoL) was added. After the addition was complete, the reaction was carried out at room temperature for 2h and monitored by TLC for completion. The product was used in the next reaction without purification.

Tert-butyl (4- (3- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenylcarbamate

TEA (6mL), 4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzylnitrile hydrochloride (1.5g,6.24mmoL) were added to the reaction solution in the previous step. After the addition was complete, the reaction was carried out at room temperature for 2h and monitored by TLC for completion. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography eluting with ethyl acetate and petroleum ether at 1:5-1:1 to give 1.2g of product in 49% yield.¹H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.46(s,1H),7.88(d,J＝8.7Hz,1H),7.34-7.20(m,5H),7.01(dd,J＝8.7,1.9Hz,1H),6.19(d,J＝8.8Hz,1H),4.26(s,1H),3.71(d,J＝8.8Hz,1H),1.45(s,9H),1.13(d,J＝10.6Hz,6H),1.03(d,J＝12.6Hz,6H)。

1- (4-aminophenyl) -3- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) urea

Tert-butyl (4- (3- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenylcarbamate (600mg) was dissolved in DCM (2mL), hydrochloric acid/1, 4 dioxane (4.0M,8.0mL) was added, the reaction was stirred at room temperature for 40 minutes, TLC monitored for completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was dried under high vacuum and used in the next reaction without purification.

Tert-butyl 2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetate)

This compound was prepared as in example 1 for 1- ((4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid except that 1- (4-aminophenyl) -3- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) urea was used in place of 1- ((4-aminophenyl) carbamoyl) cyclopropane-1-carboxylic acid. The yield thereof was found to be 51%.¹H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.88(d,J＝8.8Hz,1H),7.22(d,J＝2.3Hz,1H),7.07(d,J＝8.6Hz,2H),7.01(dd,J＝8.8,2.3Hz,1H),6.46(d,J＝8.5Hz,2H),6.03(d,J＝8.8Hz,1H),4.25(s,1H),3.93(s,2H),3.70(d,J＝8.8Hz,1H),3.43(t,J＝6.3Hz,2H),2.93(t,J＝6.5Hz,2H),1.59-1.46(m,4H),1.42(s,9H),1.14(s,6H),1.04(s,6H)。

2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetic acid

This compound was prepared as in example 1 except that tert-butyl 2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetate was used in place of tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate, preparation of 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid.

Preparation of (3S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetamide) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4-methylthiazol-5-yl) benzyl) pyrrolidine-3-carboxamide

In addition to the replacement of 2- ((5- ((4- (1- (((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetic acid for 2- ((5- ((4- (1- ((((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid, HATU for EDCI and (3S,4R) -1- ((S) -2-amino-3, 3-dimethylbutanol) -4-hydroxy-N- (4- (4-methylbutanoic acid) were used Isothiazol-5-yl) benzyl) pyrrolidine-3-carboxamide instead of (2S,4R) -1- ((S) -2- (l 2-azanyl) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide this compound was prepared as in N- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S, preparation of 4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 67%.¹H NMR(400MHz,CD₃OD)δ8.88(s,1H),7.72(d,J＝8.0Hz,1H),7.56(d,J＝8.0Hz,1H),7.47-7.44(m,4H),7.42-7.40(m,2H),7.20-7.09(m,3H),6.96(dd,J＝4.0,4.0Hz,1H),6.30(d,J＝8.0Hz,1H),4.71-4.68(m,1H),4.53-4.47(m,2H),4.38-4.34(m,1H),4.20(s,1H),3.96(q,J＝16.0Hz,2H),3.89-3.78(m,3H),3.76-3.61(m,2H),3.55-3.50(m,2H),2.47(s,3H),2.27-2.17(m,1H),2.12-1.99(m,1H),1.67-1.60(m,2H),1.57-1.50(m,2H),1.47-1.40(m,2H),1.23(s,6H),1.13(s,6H),1.04(s,9H)。MS-ESI:969.4[M+H]⁺。

Example 9 preparation of (2S,4R) -1- ((S) -2- (2- ((5- (4- (3- ((1R,3R) -3-) (3-chloro-4-cyanophenol)) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenoxy) pentyl) oxy) acetamide) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) pyrrolidine-2-carboxamide (Compound 9)

(5- (4-Nitro-phenoxy) -pentyloxy) -acetic acid tert-butyl ester

P-nitrophenol (323mg,2.32mmoL), (5-hydroxy-pentyloxy) -acetic acid tert-butyl ester (506mg,2.32mmoL), triphenylphosphine (913mg,3.48mmoL) were put into a 25mL one-neck flask, anhydrous THF (10.0mL) was added, and DEAD (606mg,3.48mmoL) was slowly added dropwise while cooling on ice. After the addition was complete, the reaction was allowed to proceed overnight at room temperature and monitored by TLC for completion. The reaction was quenched with water and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography eluting with ethyl acetate and petroleum ether at 1:5-1: 1. 656mg are obtained, yield 83.4%.¹H NMR(400MHz,CDCl₃)δ8.30-8.15(m,2H),7.06-6.87(m,2H),4.10(d,J＝4.3Hz,2H),4.10(s,2H),3.59(dd,J＝15.1,8.8Hz,2H),2.01-1.82(m,2H),1.79–1.58(m,2H),1.51(s,9H)。MS-ESI:362.0[M+Na]⁺。

(5- (4-amino-phenoxy) pentyloxy) -acetic acid tert-butyl ester

(5- (4-Nitro-phenoxy) -pentyloxy) -acetic acid tert-butyl ester (362mg,1.16mmoL), absolute ethanol (10mL) were added to a one-necked flask (25mL), zinc powder (754mg,11.6mmoL) and acetic acid (3mL) were added. The reaction was carried out at room temperature for 1h and monitored by TLC for completion. Filtering with diatomite, evaporating the solvent under reduced pressure, and separating the residue by flash column chromatography, wherein the eluent is ethyl acetate and petroleum ether in a ratio of 1:5-1: 1. 158mg of product are obtained with a yield of 44.1%.

Tert-butyl 2- ((5- (4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenoxy) pentyl) acetate)

4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzylnitrile hydrochloride (177mg,0.56mmoL) and triethylamine (170mg,1.68mmoL) were added to DCM (2.0 mL). In an ice bath and N₂Triphosgene (55mg, 0.18mmoL) was added under protection. The reaction was continued for 1 hour, followed by addition of (5- (4-amino-phenoxy) pentyloxy) -acetic acid tert-butyl ester (158mg, 0.51 mmoL). After the addition was complete, the mixture was stirred at room temperature overnight. TLC monitored the reaction complete. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography eluting with ethyl acetate and petroleum ether at 1:5-1: 1. 115mg of product are obtained with a yield of 33.5%.¹H NMR(400MHz,CDCl₃)δ7.58(d,J＝6.6,2H),7.26-7.19(m,4H),6.99-6.89(m,4H),6.80(dd,J＝8.7,2.4Hz,2H),4.13(s,2H),4.12(m,1H),4.02(m,1H),4.10-3.89(m,2H),3.63(m,2H),1.91-1.72(m,4H),1.54(s,9H),1.29-1.17(m,2H),1.19(s,6H)1.13(s,6H)。

2- ((5- (4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenoxy) pentyl) oxy) acetic acid

This compound was prepared as in example 1 except that tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) oxy) acetate was replaced with tert-butyl 2- ((5- (4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) oxy) acetate, 2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid. The product was used in the next reaction without purification.

(2S,4R) -1- ((S) -2- (2- ((5- (4- (3- ((1R,3R) -3-) (3-chloro-4-cyanophenol)) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenoxy) pentyl) oxy) acetamide) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) pyrrolidine-2-carboxamide

The preparation of the present compound was the same as that of N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2 in example 1 except that 2- ((5- (4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenoxy) pentyl) oxy) acetic acid was used in place of 2- ((5- (1- (((((1r, 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid, 2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 64.5%.¹H NMR(400MHz,CD₃OD)δ8.88(s,1H),7.70(d,J＝8.0Hz,1H),7.57-7.53(m,1H),7.45-7.37(m,4H),7.23(d,J＝8.0Hz,2H),7.15-7.11(m,1H),6.96(dd,J＝4.0,4.0Hz,1H),6.87-6.83(m,2H),5.01-4.94(m,1H),4.70(d,J＝8.0Hz,1H),4.59-4.54(m,1H),4.44(s,1H),4.18(s,1H),4.03-3.94(m,4H),3.76-3.69(m,1H),3.65-3.54(m,2H),3.26-3.20(m,1H),2.47(s,3H),2.24-2.19(m,1H),1.98-1.87(m,1H),1.83-1.80(m,2H),1.76-1.69(m,2H),1.65-1.56(m,2H),1.50(d,J＝8.0Hz,3H),1.23(s,6H),1.14(s,6H),1.04(s,9H)。MS-ESI:984.1[M+Na]⁺。

Example 10 preparation of (3S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((R) -1- (4- (thiazol-5-yl)) phenyl) ethyl) pyrrolidine-3-carboxamide (Compound 10)

The preparation of the present compound was the same as that of 2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetic acid in example 1 except that 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid was used instead of 2- ((5- (1- (((((1r, 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid. The yield thereof was found to be 53%.¹H NMR(400MHz,CD₃OD)δ8.97(s,1H),8.14(s,1H),7.70(d,J＝8.0Hz,1H),7.63-7.61(m,2H),7.38-7.36(m,2H),7.15-7.10(m,3H),6.96(dd,J＝4.0,4.0Hz,1H),6.71-6.69(m,2H),4.99-4.93(m,1H),4.70(d,J＝8.0Hz,1H),4.59-4.53(m,1H),4.43(s,1H),4.17(s,1H),4.00(q,J＝16.0Hz,2H),3.85-3.83(m,2H),3.76-3.72(m,1H),3.60-3.56(m,2H),3.11(t,J＝8.0Hz,2H),2.21-2.17(m,1H),1.96-1.89(m,1H),1.73-1.68(m,4H),1.62-1.50(m,2H),1.45(d,J＝4.0Hz,3H),1.22(s,6H),1.14(s,6H),1.04(s,9H)。ESI-MS:969.2[M+H]⁺。

Example 11 preparation of (2S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-bromo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5) -yl) phenyl) ethyl) pyrrolidine-2-carboxamide (Compound 11)

1- ((1r,3r) -3- (3-bromo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -3- (4-nitrophenyl) urea

4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-bromoxynil hydrochloride (400mg, 1.12mmoL and triethylamine (136mg,1.34mmoL) were added to DCM (15mL) and stirred for 15 minutes and then completely dissolved, 1-isocyanate-4-nitrobenzene (166mg,1.01mmoL) was added thereto, the reaction was stirred at room temperature, TLC was used to monitor completion of the reaction, the solvent was distilled off under reduced pressure, the residue was separated by flash column chromatography, ethyl acetate, petroleum ether ═ 1:6-1:1 was used as an eluent, and 500mg of the product was obtained in 92% yield.¹H NMR(400MHz,DMSO-d6):δ9.37(s,1H),8.15(d,J＝9.3Hz,2H),7.86(d,J＝8.7Hz,1H),7.61(d,J＝9.3Hz,2H),7.36(d,J＝2.3Hz,1H),7.04(dt,J＝10.4,5.2Hz,1H),6.55(d,J＝8.6Hz,1H),4.29(s,1H),3.72(d,J＝8.5Hz,1H),1.16(s,6H),1.06(s,6H)。

1- (4-aminophenyl) -3- ((1r,3r) -3- (3-bromo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) urea

1- ((1r,3r) -3- (3-bromo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -3- (4-nitrophenyl) urea (450mg,0.93mmoL) was added to methanol (10mL), ammonium chloride (494mg,9.26mmoL) and iron powder (259mg,4.63mmoL) were further added, the reaction was carried out at 80 ℃ and the completion of the reaction was monitored by TLC. Filter and wash the residue with dichloromethane/methanol 10/1. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography eluting with ethyl acetate and petroleum ether at 1:6-1: 1. 106mg of a white solid was obtained in a yield of 25%.¹H NMR (400MHz, DMSO-d6): δ 8.09(s,1H),7.86(d, J ═ 7.2Hz,1H),7.35(s,1H),7.01(d, J ═ 8.4Hz,3H),6.46(d, J ═ 7.2Hz,2H),6.04(d, J ═ 7.4Hz,1H),4.68(s,2H),4.24(s,1H),3.69(d, J ═ 7.7Hz,1H),1.08(d, J ═ 38.2Hz, 12H). A significant amount of debrominated byproducts were found in this reaction.

Tert-butyl 2- (5- (4- (3- ((1r,3r)3- (3-bromo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxo) acetate

This compound was prepared as in example 1 for 1- ((4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid except that 1- (4-aminophenyl) -3- ((1r,3r) -3- (3-bromo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) urea was used in place of 1- ((4-aminophenyl) carbamoyl) cyclopropane-1-carboxylic acid. The yield thereof was found to be 82%.¹H NMR(400MHz,CDCl₃)：δ7.53(dd,J＝10.9,4.9Hz,1H),7.11-7.02(m,3H),6.83-6.75(m,1H),6.59(dd,J＝8.6,4.4Hz,2H),5.98(s,1H),4.75(d,J＝8.7Hz,1H),3.96(d,J＝4.7Hz,2H),3.88(d,J＝8.5Hz,2H),3.67-3.47(m,2H),3.13(dd,J＝15.0,8.0Hz,2H),1.79-1.72(m,1H),1.71-1.64(m,2H),1.54(td,J＝8.6,4.2Hz,1H),1.49(S,9H),1.13(s,6H),1.04(s,6H)。

2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxo) acetic acid

This compound was prepared as in example 1 except that tert-butyl 2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetate was replaced with tert-butyl 2- (5- (4- (3- ((1r,3r) -3- (3-bromo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate, 2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid.

(3S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-bromo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) -phenyl) amino) pentyl) oxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethylpyrrolidine-3-carboxamide

The preparation of the present compound was the same as that of N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2 in example 1, except that 2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxo) acetic acid was used in place of 2- ((5- ((4- (1- (((((1r, 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid, preparation of 2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 73%.¹H NMR(400MHz,CD₃OD)：δ8.88(s,1H),7.70(d,J＝8.0Hz,1H),7.48-7.37(m,5H),7.26(d,J＝4.0Hz,1H),7.10(d,J＝8.0Hz,2H),7.00(dd,J＝4.0,4.0Hz,1H),6.67(d,J＝8.0Hz,2H),5.00-4.97(m,1H),4.70(d,J＝4.0Hz,1H),4.60-4.54(m,1H),4.44(s,1H),4.16(s,1H),4.03-3.92(m,1H),3.86-3.83(m,2H),3.76-3.73(m,1H),3.60-3.56(m,2H),3.15-3.05(m,2H),2.47(s,3H),2.25-2.19(m,1H),1.97-1.91(m,1H),1.73-1.65(m,4H),1.58-1.54(m,2H),1.47(d,J＝4.0Hz,3H),1.22(s,6H),1.14(s,6H),1.04(s,9H)。MS-ESI:1027.1[M+H]⁺。

Example 12 preparation of (2S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-iodo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5) -yl) phenyl) ethyl) pyrrolidine-2-carboxamide (Compound 12)

(4- (3- (((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) carbamic acid tert-butyl ester

4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-iodobenzonitrile hydrochloride (410mg,1.0mmoL) and triethylamine (0.42mL,3mmoL) were added to DCM (15.0mL), and triphosgene (100mg,0.36mmoL) was added slowly while cooling on ice. After the addition, the reaction was continued for 1.5h in an ice bath. To this mixture was added tert-butyl (4-aminophenyl) carbamate (230mg,1.1 mmoL). After the addition was complete, the mixture was stirred at room temperature overnight and the reaction was monitored by TLC for completion. Filtration, cake washing with DCM and drying gave product 200m g, 34.0% yield. 1H NMR (400MHz, DMSO-d6) δ 9.14(s,1H),8.48(s,1H),7.75(d, J ═ 12.0Hz,1H),7.49(d, J ═ 4.0Hz,1H),7.23-7.30(m,4H),7.03(dd, J ═ 4.0Hz,1H),6.20(d, J ═ 12Hz,1H),4.21(s,1H),3.70(d, J ═ 8.0Hz,1H),1.46(s,9H),1.14(s,6H),1.04(s, 6H).

MS-ESI:605.0[M+H]⁺。

1- (4-aminophenyl) -3- ((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) urea

The preparation of the compound was the same as that of 2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetic acid tert-butyl ester in example 1 except that tert-butyl (4- (3- (((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) carbamate was used in place of tert-butyl 2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid.

Tert-butyl 2- ((5- ((4- (3- (((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxo) acetate

Except using 1- (4-aminophenyl) -In addition to 3- ((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) urea instead of 1- ((4-aminophenyl) carbamoyl) cyclopropane-1-carboxylic acid, 2- ((5- ((4- (3- (((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxo) tert-butyl acetate tert-butyl ester was prepared as in example 1 for 1- ((4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid in 54.3% yield.¹H NMR(400MHz,CDCl₃)δ7.48(d,J＝8Hz,1H),7.32(s,1H),7.06-7.08(m,2H),6.81(d,J＝12Hz,1H),6.60-6.67(m,2H),5.98(s,1H),4.75(d,J＝8.0Hz,1H),3.94-3.98(m,2H),3.86-3.89(m,2H),3.50-3.58(m,2H),3.11-3.18(m,2H),1.63-1.70(m,4H),1.47(s,9H),1.12(s,6H),1.04(s,6H)。MS-ESI:705.1[M+H]⁺。

2- ((5- ((4- (3- (((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxyacetic acid

This compound was prepared as in example 1 except that tert-butyl 2- ((5- ((4- (1- (((1r,3r) -3- (4-cyano-3-iodophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxo) acetate was used in place of tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate, preparation of 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid.

(2S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-iodo-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5) -yl) phenyl) ethyl) pyrrolidine-2-carboxamide

The preparation of the present compound was the same as that of N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2 in example 1 except that 2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxyacetic acid was used in place of 2- ((5- ((4- (1- (((((1r, 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid, 2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 52.6%.¹H NMR(400MHz,CD₃OD)δ8.88(s,1H),8.64(d,J＝4.0Hz,1H),7.66-7.64(m,1H),7.60-7.55(m,1H),7.47-7.34(m,5H),7.13(d,J＝4.0Hz,1H),7.02-6.98(m,1H),6.66(d,J＝4.0Hz,1H),6.17-6.06(m,1H),4.97-5.02(m,1H),4.70(d,J＝4.0Hz,1H),4.58(q,J＝4.0Hz,1H),4.45-4.40(m,1H),4.13(s,1H),4.00(q,J＝4.0Hz,2H),3.86-3.82(m,1H),3.78-3.72(m,1H),3.63-3.54(m,2H),3.12-3.08(m,1H),2.47(s,3H),2.25-2.20(m,1H),1.97-1.91(m,1H),1.73-1.63(m,3H),1.59-1.51(m,2H),1.47(d,J＝4.0Hz,3H),1.22-1.20(m,6H),1.13-1.12(m,6H),1.04(s,9H)。MS-ESI:1075.3[M+H]⁺。

Example 13 preparation of (2S,4R) -1- ((S) -2- (2- ((6- (4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) hexyl-5-yn-1-yl) oxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethylpyrrolidine-2-carboxamide (Compound 13)

1- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -3- (4-iodophenyl) urea

4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzylnitrile hydrochloride (1.2g,3.83mmoL) was dissolved in DCM (40mL) and cooled to 0 ℃. N is a radical of₂Triphosgene (372mg,1.25mmoL) was added under protection and reacted for 1 h. Followed by 4-iodoaniline (762mg,3.48mmol) and stirred at room temperature overnight. TLC monitored the reaction complete. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography eluting with ethyl acetate and petroleum ether at 1:5-1: 1. 1.0g of product is obtained with a yield of 49.9%.¹H NMR(400MHz,DMSO-d6)δ8.74(s,1H),7.92(d,J＝8.8Hz,1H),7.56(d,J＝8.8Hz,2H),7.34-7.23(m,3H),7.04(dd,J＝8.8Hz,2.4Hz,1H),6.33(d,J＝8.7Hz,1H),4.31(s,1H),3.73(d,J＝8.7Hz,1H),1.18(s,6H),1.09(s,6H)。MS-ESI:524.0[M+H]⁺。

Tert-butyl 2- ((6- (4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) hexyl-5-yn-1-yl) oxy) acetate

A mixture of 1- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -3- (4-iodophenyl) urea (200mg,0.38mmoL), tert-butyl 2- (hex-5-yn-1-yloxy) acetate (89mg,0.42mmoL), cuprous iodide (15mg,0.08mmoL), PdCl₂(PPh₃)₂(17mg,0.04mmoL) was added to a 25mL three-necked flask, DMF (5mL) and TEA (0.16mL,1.2mmoL) were added, displaced 3 times with nitrogen, warmed to 60 ℃ overnight, and monitored by TLC for completion. Water was added to quench the reaction and DCM was used for extraction. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography eluting with ethyl acetate and petroleum ether at 1:5-1: 1. 147mg were obtained, yield 63.9%.¹H NMR(400MHz,CDCl₃)δ7.60(d,J＝8.7,1H),7.38-7.29(m,4H),6.98(d,J＝2.4Hz,1H),6.82(dd,J＝8.7Hz,2.4Hz,1H),4.01(s,2H),4.00(s,1H),3.95(d,J＝8.7Hz,1H),3.61(t,J＝6.3Hz,2H),2.48(t,J＝6.9Hz,2H),1.88-1.79(m,2H),1.78-1.70(m,2H),1.54(s,9H),1.21(d,J＝5.9Hz,12H)。

2- ((6- (4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) hexyl-5-yn-1-yl) oxy) acetic acid

This compound was prepared as in example 1 except that tert-butyl 2- ((6- (4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) hexyl-5-yn-1-yl) oxy) acetate was used in place of tert-butyl 2- ((5- ((4- (1- (((((1r, 3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate, preparation of 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid.

(2S,4R) -1- ((S) -2- (2- ((6- (4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) hexyl-5-yn-1-yl) oxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethylpyrrolidine-2-carboxamide

The preparation of the present compound was the same as that of N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2 in example 1 except that 2- ((6- (4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) hexyl-5-yn-1-yl) oxy) acetic acid was used in place of 2- ((5- ((4- (1- ((((((((1 r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid, preparation of 2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 55.5%.¹H NMR(400MHz,CD₃OD)δ8.88(s,1H),7.95(d,J＝8.0Hz,2H),7.73(d,J＝8.0Hz,1H),7.56-7.48(m,2H),7.45-7.37(m,4H),7.12(d,J＝4.0Hz,1H),6.97(dd,J＝4.0Hz,4.0Hz,1H),6.40(d,J＝8.0Hz,1H),5.00-4.93(m,1H),4.70-4.66(m,1H),4.60-4.54(m,1H),4.44(s,1H),4.21(s,1H),3.98(q,J＝8.0Hz,2H),3.88-3.83(m,1H),3.76-3.72(m,1H),3.63-3.54(m,4H),3.04-3.00(m,2H),2.47(s,3H),2.24-2.17(m,1H),1.97-1.91(m,1H),1.79-1.67(m,4H),1.58-1.52(m,2H),1.49(d,J＝8.0Hz,3H),1.25(s,6H),1.16(s,6H),1.04(s,9H)。MS-ESI:977.2[M+H]⁺。

Example 14 preparation of (3S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) -2-fluorophenyl) amino) pentyl) oxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethylpyrrolidine-3-carboxamide (Compound 14)

Tert-butyl 2- (((5- ((2-fluoro-4-nitrophenyl) amino) pentyl) oxy) acetate

This compound was prepared as in example 1 for 1- ((4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid, except that 2-fluoro-4-nitroaniline was used instead of 1- ((4-aminophenyl) carbamoyl) cyclopropane-1-carboxylic acid. The yield thereof was found to be 65.0%.¹H NMR(400MHz,DMSO-d6)δ6.54-6.42(m,1H),6.33(dd,J＝13.8,2.4Hz,1H),6.25(dd,J＝8.4,2.1Hz,1H),4.25(s,1H),3.93(d,J＝2.3Hz,2H),3.42(t,J＝6.5Hz,2H),2.92(s,2H),1.59-1.46(m,4H),1.45-1.39(m,9H),1.39-1.31(m,2H)。

Tert-butyl 2- (((5- ((4-amino-2-fluorophenyl) amino) pentyl) oxy) acetate

Tert-butyl 2- (((5- ((2-fluoro-4-nitrophenyl) amino) pentyl) oxy) acetate (3.8g,10.7mmoL) was dissolved in methanol (40mL), and Pd/C (50 wt%) (800mg) was added to replace H3 times₂Stirred at room temperature overnight. TLC monitored the reaction complete. It was filtered through Celite and the filter cake was washed with methanol (5 mL. times.3). The solvent was evaporated under reduced pressure and the residue was used in the next reaction without purification. 3.2g was obtained, yield 92.0%.¹H NMR(400MHz,DMSO-d6)δ6.51-6.43(m,1H),6.33(dd,J＝13.8,2.4Hz,1H),6.25(dd,J＝8.4,2.1Hz,1H),4.52(s,2H),4.25(s,1H),3.93(d,J＝2.3Hz,2H),3.42(t,J＝6.5Hz,2H),2.92(s,2H),1.62-1.46(m,4H),1.41(d,J＝5.4Hz,9H),1.39-1.31(m,2H)。

3-2- (((5- ((2-fluoro-4- (((4-nitrophenoxy) carbonyl) amino) phenyl) amino) pentyl) oxy) acetic acid tert-butyl ester

Tert-butyl (((5- ((4-amino-2-fluorophenyl) amino) pentyl) oxy) acetate (200mg, 0.613mmoL) and triethylamine (186mg, 1.842mmoL) were dissolved in dichloromethane (5.0mL), and 4-nitrophenylcarbonyl chloride (160mg, 0.796mmoL) was added thereto, followed by reaction at room temperature for 2 hours and completion of the reaction as monitored by TLC, which was directly used for the next reaction.

Tert-butyl 2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) -2-fluorophenyl) amino) pentyl) oxy) acetate)

4- (((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzonitrile (192mg, 0.613mmoL) basified with triethylamine was added to the reaction solution of the previous step, the reaction was carried out overnight at room temperature, TLC was monitored to be complete, water was added, the solution was separated, the solvent was distilled off under reduced pressure, the residue was separated by flash column chromatography, and an eluent, ethyl acetate: petroleum ether ═ 1:5-1:1, gave 102mg of the product in a yield of 26%.¹H NMR(400MHz,CDCl₃)δ7.54(d,J＝8.7Hz,1H),6.98(dd,J＝12.2,2.0Hz,1H),6.91(t,J＝6.9Hz,2H),6.76(dd,J＝8.7,2.4Hz,1H),6.64(t,J＝8.9Hz,1H),6.18(s,1H),4.80(d,J＝8.6Hz,1H),3.96(d,J＝4.7Hz,2H),,3.54(t,J＝6.3Hz,2H),3.14(t,J＝7.0Hz,2H),1.74-1.50(m,6H),1.47(d,J＝5.0Hz,9H),1.14(s,6H),1.09(s,6H)。

2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) -2-fluorophenyl) amino) pentyl) oxy) acetic acid)

This compound was prepared as in example 1 except that tert-butyl 2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) -2-fluorophenyl) amino) pentyl) oxy) acetate was used in place of tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate, preparation of 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid.

(3S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) -2-fluorophenyl) amino) pentyl) oxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethylpyrrolidine-3-carboxamide

The compound was prepared as in example 1 except that 2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) -2-fluorophenyl) amino) pentyl) oxy) acetic acid was used in place of 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid.Preparation of phenylphenoxy) -2,2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 26%.¹H NMR(400MHz,CD₃OD)δ8.88(s,1H),7.72(d,J＝8.0Hz,1H),7.45-7.37(m,4H),7.20-7.16(m,1H),7.11(d,J＝4.0Hz,1H),6.97(dd,J＝4.0,4.0Hz,1H),6.86-6.84(m,1H),6.73-6.69(m,1H),5.01-4.98(m,1H),4.69-4.68(m,1H),4.60-4.54(m,1H),4.44(s,1H),4.18(s,1H),4.03-3.92(m,2H),3.85-3.83(m,2H),3.76-3.72(m,1H),3.59-3.53(m,2H),3.15(t,J＝8.0Hz,2H),2.48(s,3H),2.24-2.19(m,1H),1.98-1.93(m,1H),1.75-1.64(m,4H),1.58-1.54(m,2H),1.49(d,J＝8.0Hz,3H),1.23(s,6H),1.15(s,6H),1.03(s,9H)。ESI-MS:1001.3[M+H]⁺。

Example 15 preparation of (2S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2),2,4, 4-tetramethylcyclobutyl) ureido) -3-fluorophenyl) amino) pentyl) oxy) acetamido) -3, 3-dimethylbutyryl) -4-methyl-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethylpyrrolidine-2-carboxamide (Compound 15)

2- (((5- ((3-fluoro-4-nitrophenyl) amino) pentyl) oxy) acetic acid tert-butyl ester

This compound was prepared as in example 1 for 1- ((4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid, except that 2-fluoro-4-nitroaniline was used instead of 1- ((4-aminophenyl) carbamoyl) cyclopropane-1-carboxylic acid. The yield thereof was found to be 84%.¹H NMR(400MHz,CDCl₃)δ7.94(t,J＝9.0Hz,2H),6.34(ddd,J＝13.3,9.2,2.5Hz,1H),5.24-5.17(m,2H),3.99-3.88(s,2H),3.53(dt,J＝15.7,5.9Hz,2H),3.27-3.12(m,2H),1.86-1.69(m,2H),1.56-1.51(m,2H),1.51-1.39(m,9H)。

Synthesis of tert-butyl 2- (((5- ((4-amino-3-fluorophenyl) amino) pentyl) oxy) acetate

This compound was prepared as in example 13 except for substituting tert-butyl 2- (((5- ((3-fluoro-4-nitrophenyl) amino) pentyl) oxy) acetate with tert-butyl 2- (((5- ((2-fluoro-4-nitrophenyl) amino) pentyl) oxy) acetate for tert-butyl 2- (((5- ((4-amino-2-fluorophenyl) amino) pentyl) oxy) acetate in 90% yield.¹H NMR(400MHz,DMSO-d6)δ6.51-6.43(m,1H),6.33(dd,J＝13.8,2.4Hz,1H),6.25(dd,J＝8.4,2.1Hz,1H),4.52(s,2H),4.25(s,1H),3.93(d,J＝2.3Hz,2H),3.42(t,J＝6.5Hz,2H),2.92(s,2H),1.62-1.46(m,4H),1.41(d,J＝5.4Hz,9H),1.39-1.31(m,2H)。

Tert-butyl 2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) -3-fluorophenyl) amino) pentyl) oxy) acetate)

The compound 4- (((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzylnitrile hydrochloride (188mg, 0.6mmoL) and triethylamine (182mg, 1.8mmoL) were added to methylene chloride (10.0mL), triphosgene (59.4mg, 0.2mmoL) is added into the system under the ice-water bath, and the reaction is carried out for 3 hours at room temperature after the addition is finished, tert-butyl 2- (((5- ((4-amino-3-fluorophenyl) amino) pentyl) oxy) acetate (215mg, 0.66mmoL) was added and reacted at room temperature overnight, TLC monitored completion of reaction, water was added, liquid was separated, the solvent was evaporated under reduced pressure, the residue was separated by flash column chromatography, and the eluent was ethyl acetate: petroleum ether 1:5-1:1, 200mg of the product was obtained, yield 52.9%.¹H NMR(400MHz,CDCl₃)δ7.52(d,J＝8.7Hz,1H),6.95-6.78(m,4H),6.72(dd,J＝8.7,2.4Hz,1H),4.36(dd,J＝8.4,4.6Hz,1H),3.91(s,3H),3.85-3.75(m,2H),3.65-3.54(m,2H),3.47(t,J＝6.6Hz,2H),1.63-1.57(m,2H),1.54-1.47(m,2H),1.46(s,9H),1.40-1.23(m,2H),1.10(s,6H),0.92(s,6H)。

2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) -3-fluorophenyl) amino) pentyl) oxy) acetic acid)

This compound was prepared as in example 1 except that tert-butyl 2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) -3-fluorophenyl) amino) pentyl) oxy) acetate was used in place of tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate, preparation of 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid. The product was used in the next reaction without purification.

(2S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2),2,4, 4-tetramethylcyclobutyl) ureido) -3-fluorophenyl) amino) pentyl) oxy) acetamido) -3, 3-dimethylbutyryl) -4-methyl-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethylpyrrolidine-2-carboxamide

The preparation of this compound was the same as that of N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2 in example 1, except that 2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) -3-fluorophenyl) amino) pentyl) oxy) acetic acid was used in place of 2- ((5- ((4- (1- (((((1r, 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid, 2,4, 4-Tetramethylcycloyl) -N- (4- ((5- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- (((S) -1-)Preparation of (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 57.7%.¹H NMR(400MHz,CD₃OD)δ8.88(s,1H),7.69-7.66(m,1H),7.46-7.37(m,4H),7.06(d,J＝4.0Hz,1H),7.00(d,J＝4.0Hz,1H),6.93-6.89(m,3H),5.01-4.98(m,1H),4.68-4.54(m,3H),4.44(s,1H),4.08(s,1H),3.97(q,J＝8.0Hz,2H),3.76-3.71(m,2H),3.67-3.58(m,2H),3.52-3.35(m,2H),2.48(s,3H),2.24-2.19(m,1H),1.98-1.94(m,1H),1.67-1.62(m,2H),1.58-1.52(m,2H),1.50(d,J＝8.0Hz,3H),1.47-1.43(m,2H),1.11(s,6H),1.03(s,9H),0.96(s,6H)。ESI-MS:1001.3[M+H]⁺。

EXAMPLE 16 preparation of (2S) -1- (((S) -2- (2- (4- (4'- (3- ((1r,3r)) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) - [1,1' -biphenyl ] -4-yl) butoxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethylpyrrolidine-2-carboxamide (Compound 16)

2- (but-3-yn-1-yloxy) acetic acid tert-butyl ester

Compound 3-butyn-1-ol (2.5g,35.71mmoL) was added to a 250mL single-neck flask, toluene (50mL) and water (50mL) were added, followed by tetrabutylammonium bisulfate (2.43g,7.14 mmoL). After the addition was complete, the mixture was stirred at room temperature for 1 hour, and tert-butyl 2-bromoacetate (8.31g,42.85mmoL) was added to the mixture to react overnight. And (3) detecting by TLC (thin layer chromatography), completely reacting, directly adding ethyl acetate and water into the reaction solution, separating, evaporating the solvent by organic phase under reduced pressure, and separating the residue by using flash column chromatography, wherein an eluent is ethyl acetate and petroleum ether in a ratio of 1:50-1:10 to obtain 4.2g of a product, and the yield is 64%.¹H NMR(400MHz,CDCl₃)δ3.99(s,2H),3.65(t,J＝7.0Hz,2H),2.51(td,J＝7.0,2.7Hz,2H),1.98(t,J＝2.7Hz,1H),1.46(s,9H)。

Tert-butyl 2- ((4- (4 '-nitro- [1,1' -biphenyl ] -4-yl) but-3-yn-1-yl) oxy) acetate

The compound 4-iodo-4 '-nitro-1, 1' -biphenyl (2.5g,7.69mmoL) was added to a 100mL single-necked flask, followed by DMF (15mL), tert-butyl 2- (but-3-yn-1-yloxy) acetate (2.12g,11.53mmoL), CuI (0.3g, 1.54mmoL), TEA (2.33g, 23.07mmoL), and PdCl₂(PPh₃)₂(0.34g, 0.769 mmoL). And then N₂The mixture was heated to 60 ℃ under a gas atmosphere and stirred overnight. TLC detection shows that the reaction is complete, and ethyl acetate and water are added directly into the reaction solution. Separating, distilling off solvent under reduced pressure by organic phase, separating residue by flash column chromatography, and eluting with ethyl acetate and petroleum ether at a ratio of 1:30-1:10 to obtain 2.3g of product with yield of 78.5%.¹H NMR(400MHz,CDCl₃)δ8.34-8.25(m,2H),7.77-7.68(m,2H),7.54(q,J＝8.5Hz,4H),4.05(s,2H),3.77(t,J＝7.1Hz,2H),2.79(t,J＝7.1Hz,2H),1.49(s,9H)。

2- (4- (4 '-amino- [1,1' -biphenyl ] -4-yl) butoxy) acetic acid tert-butyl ester

2- ((4- (4 '-nitro- [1,1' -biphenyl)]-4-yl) but-3-yn-1-yl) oxy) tert-butyl acetate (1g,2.62mmoL) was added to a 100mL one-neck flask, MeOH (20mL), PtO was added₂(0.1g, 10%/w/w), replacement of H₂Three times, stirred at room temperature overnight. TLC detection reaction is complete, filtration is carried out, the filtrate is decompressed and the solvent is evaporated, the residue is separated by flash column chromatography, the eluent is ethyl acetate and petroleum ether which are 1:10-1:1, 0.585g of product is obtained, and the yield is 63%.¹H NMR(400MHz,DMSO-d₆)δ7.47-7.38(m,2H),7.36-7.27(m,2H),7.23-7.14(m,2H),6.72-6.52(m,2H),5.18(s,2H),3.92(s,2H),3.44(t,J＝6.3Hz,2H),2.57(t,J＝7.5Hz,2H),1.70-1.57(m,2H),1.55-1.46(m,2H),1.41(s,9H)。

Tert-butyl 2- (4- (4'- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) - (1,1' -biphenyl) -4-yl) butoxy) acetate

The compound 4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzonitrile hydrochloride (157mg, 0.5mmoL) was added to a 50mL one-necked flask, DCM (5mL) was added, and TEA (303mg,3.0mmoL) and triphosgene (49mg,0.165mmoL) were slowly added while cooling on ice. After the addition, the reaction was continued for 3 hours in an ice bath. Tert-butyl 2- (4- (4 '-amino- (1,1' -biphenyl) -4-yl) butoxy) acetate (213mg,0.6mmoL) was further added thereto, and the reaction was stirred at room temperature overnight. TLC check reaction complete, to the reaction liquid add ethyl acetate and water. Separating, distilling off solvent under reduced pressure from organic phase, separating residue by flash column chromatography, eluting with ethyl acetate and petroleum ether at a ratio of 1:5-1:1 to obtain 130mg of product with a yield of 40%.¹H NMR(400MHz,DMSO-d₆)δ8.72(s,1H),7.90(d,J＝8.8Hz,1H),7.62-7.40(m,6H),7.30-7.17(m,3H),7.02(dd,J＝8.8,2.4Hz,1H),6.33(d,J＝8.8Hz,1H),4.29(s,1H),3.93(s,2H),3.73(d,J＝8.7Hz,1H),3.45(t,J＝6.2Hz,2H),2.61(t,J＝7.4Hz,2H),1.63(p,J＝7.4Hz,2H),1.52(p,J＝6.3Hz,2H),1.41(s,9H),1.27-1.20(m,2H),1.17(s,6H),1.07(s,6H)。

2- (4- (4'- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) - (1,1' -biphenyl) -4-yl) butoxy) acetic acid

This compound was prepared as in example 1 except that tert-butyl 2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) - (1,1' -biphenyl) -4-yl) butoxy) acetate was used in place of tert-butyl 2- ((5- ((4- (1- ((((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) acetate, preparation of 3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid. The product was used in the next reaction without purification.

(2S) -1- (((S) -2- (2- (4- (4'- (3- ((1r,3r)) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) - (1,1' -biphenyl) -4-yl) butoxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethylpyrrolidine-2-carboxamide

This compound was prepared as in 2- ((5- ((4- (1- (((1r,3r) -3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) carbamoyl) cyclopropane-1-carboxylic acid in example 1 except that 2- (4- (4'- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) - (1,1' -biphenyl) -4-yl) butoxy) acetic acid was used in place of 1- ((4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) phenyl) carbamoyl) cyclopropane-1-carboxylic acid, preparation of 2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamido) phenyl) amino) pentyl) oxy) tert-butyl acetate. The yield thereof was found to be 59.0%.¹H NMR(400MHz,CD₃OD)δ8.87(s,1H),7.72(d,J＝8.0Hz,1H),7.53-7.49(m,4H),7.45-7.37(m,6H),7.28(d,J＝8.0Hz,2H),7.12(t,J＝4.0Hz,1H),6.96(d,J＝4.0Hz,1H),4.99-4.94(m,1H),4.68(s,1H),4.59-4.55(m,1H),4.43(s,1H),4.19(s,1H),3.96(d,J＝4.0Hz,2H),3.88-3.83(m,2H),3.76-3.73(m,1H),3.58(t,J＝8.0Hz,2H),2.70(t,J＝8.0Hz,2H),2.47(s,3H),2.25-2.18(m,1H),1.97-1.92(m,1H),1.79-1.77(m,2H),1.71-1.67(m,2H),1.48(d,J＝8.0Hz,3H),1.25(s,6H),1.16(s,6H),1.03(s,9H)。ESI-MS:1030.1[M+H]⁺。

EXAMPLE 17 preparation of (3R,5S) -1- (S) -2- (2- (5- (4- (3- (1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetamide) -3, 3-dimethylbutyryl) -5- (((((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-3-ylacetate (Compound 17)

(S) - (1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamate tert-butyl

Tert-butyl (S) - (1- (4-bromophenyl) ethyl) carbamate (30.0g, 100mmoL), 4-methylthiazole (19.8g, 200mmoL), palladium acetate (226mg, 1.0mmoL) and potassium acetate (19.6g, 20mmoL) were charged into a 500mL three-necked flask, N-dimethylacetamide (200mL) was added thereto, nitrogen was replaced three times, and the reaction was carried out at 120 ℃ for 5 hours. TLC monitored the reaction was complete, cooled to room temperature, and filtered. To the filtrate was added ethyl acetate (800mL), washed three times with water (500mL), separated, the solvent was evaporated by organic phase under reduced pressure, and the residue was separated by flash column chromatography using ethyl acetate and petroleum ether (1: 5) as eluent to give 22.6g of the product with a yield of 71.1%.¹H NMR(400MHz,DMSO-d6):δ8.67(s,1H),7.41(d,J＝8.2Hz,2H),7.36(d,J＝8.3Hz,3H),4.86-4.80(m,1H),2.53(s,3H)。

(S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethan-1-amine hydrochloride

This compound was prepared as in example 1 except that tert-butyl ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamate was replaced with (S) - (1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamate tert-butyl group for the preparation of 4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzonitrile.

(2S,4R) -4-acetoxy-1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid

Boc-L-hydroxyproline (2.0g,8.65mmoL) was added to a 100mL single vial, pyridine (20mL) was added, and acetic anhydride (8.2mL,86.5mmoL) was added last, stirred at room temperature for 3h, and TLC monitored for completion of the reaction. The solvent was evaporated under reduced pressure and the residue was used in the next reaction without purification.

(2S,4R) -4-acetoxy-2- ((((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester

(2S,4R) -4-acetoxy-1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (214mg,0.82mmoL) was added to a 50mL single-necked flask, followed by the addition of dichloromethane (10mL), DIPEA (0.33mL,1.89mmoL), HOBT (106mg,0.82mmoL) and (S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethan-1-amine hydrochloride (0.63mmoL), HATU (300mg,0.82mmoL) was finally added, the reaction was monitored for completion by stirring at room temperature for 1 h.TLC, water (5 mL. times.2) was added, the solution was separated, the organic phase was evaporated off under reduced pressure, and the residue was separated by flash column chromatography using methanol as eluent, dichloromethane ═ 1:50, yielding 180mg of 60.3%.¹H NMR(400MHz,CDCl₃):δ8.73(s,1H),7.40-4.45(m,4H),5.31-5.00(m,2H),4.65-4.23(m,1H),3.75(td,J＝6.7,4.0Hz,2H),3.23(dd,J＝7.5,4.2Hz,2H),2.55(s,3H),2.08(s,3H),1.53-1.48(m,12H)。

(3R,5S) -5- (((((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-3-acetoxy ester

This compound was prepared as in example 1 except that tert-butyl ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamate was replaced with tert-butyl (2S,4R) -4-acetoxy-2- ((((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-carboxylate.

(3R,5S) -1- ((S) -2- ((tert-Butoxycarbonyl) amino) -3, 3-dimethylbutyryl) -5- (((S-1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-3-ylacetate

Boc-L-tert-leucine (189mg,0.82mmoL) was added to a 25mL single vial, dichloromethane (10mL), DIPEA (0.33mL, 1.88mmoL), HOBt (110mg,0.82mmoL), (3R,5S) -5- ((((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-3-acetate (0.38mmoL) was added, HATU (300mg,0.82mmoL) was added last, stirred at room temperature for 2 hours, TLC was monitored for reaction completion, water (5mL x 2) was added, the solvent was evaporated under reduced pressure, the residue was separated by flash column chromatography using ethyl acetate, petroleum ether ═ 1:5 as eluent, to give 130mg of product in 58.3% yield.¹H NMR(400MHz,CDCl₃):δ8.69(s,1H),7.38(q,J＝8.3Hz,4H),5.32(s,1H),5.19(d,J＝9.5Hz,1H),5.07(t,J＝7.2Hz,1H),4.76(t,J＝7.6Hz,1H),4.22(d,J＝9.5Hz,1H),4.10-4.03(m,1H),3.71(dd,J＝11.8,4.3Hz,1H),2.82-2.73(m,2H),2.52(s,3H),2.13(dd,J＝13.5,9.3Hz,1H),2.04(s,3H),1.46(d,J＝6.9Hz,3H),1.42(s,9H),1.01(s,9H)。

(3R,5S) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -5- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-3-acetate

This compound was prepared as in example 1 for 4- ((1R,3R) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzonitrile except that (3R,5S) -1- ((S) -2- ((t-butoxycarbonyl) amino) -3, 3-dimethylbutyryl) -5- (((S-1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-3-ylacetate was used in place of t-butyl ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamate, which was not purified, directly used for the next reaction.

(3R,5S) -1- (S) -2- (2- (5- (4- (3- (1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetamide) -3, 3-dimethylbutyryl) -5- ((((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-3-ylacetate

In addition to the replacement of 2- ((5- ((4- (1- (((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetic acid with 2- ((5- ((4- (1- ((((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid, and (3R,5S) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -5- (((S) -1- (4- (4-methylthio) amino) pentyl) oxy) acetic acid Instead of (2S,4R) -1- ((S) -2- (l 2-azanyl) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide, oxazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-3-acetate was prepared the same as N- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S, preparation of 4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 53.2%.¹H NMR(400MHz,CD₃OD)δ8.87(s,1H),7.71(d,J＝8.0Hz,1H),7.45-7.37(m,4H),7.11-7.07(m,3H),6.96(dd,J＝4.0,4.0Hz,1H),6.63(d,J＝8.0Hz,2H),6.04(d,J＝12.0Hz,1H),5.33-5.32(m,1H),5.02-4.96(m,1H),4.60-4.55(m,2H),4.17(s,1H),4.12(d,J＝12.0Hz,1H),3.99(q,J＝8.0Hz,2H),3.89-3.83(m,2H),3.60-3.56(m,2H),3.09(t,J＝8.0Hz,2H),2.47(s,3H),2.41-2.35(m,1H),2.14-2.07(m,1H),2.03(s,3H),1.71-1.63(m,4H),1.59-1.53(m,2H),1.48(d,J＝4.0Hz,3H),1.21(s,6H),1.14(s,6H),1.03(s,9H)。MS-ESI:1025.5[M+H]⁺。

Example 18(3R,5S) -1- ((S) -2- (2- (4- ((4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) butoxy) acetyl) -3, 3-dimethylbutanoyl) -5- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-3-ylacetate (Compound 18)

In the final step of the preparation of compound 17, an impurity was isolated by flash column chromatography and was structurally identified as compound 18.¹H NMR(400MHz,DMSO-d6)δ8.87(s,1H),7.71(d,J＝8.0Hz,1H),7.46-7.37(m,4H),7.11-7.06(m,3H),6.96(dd,J＝4.0,4.0Hz,1H),6.65(d,J＝8.0Hz,2H),5.36-5.32(m,1H),5.03-4.98(m,1H),4.60-4.55(m,3H),4.17(s,1H),4.12(d,J＝12.0Hz,1H),3.99(q,J＝8.0Hz,2H),3.89-3.83(m,2H),3.61-3.59(m,2H),3.12(t,J＝8.0Hz,2H),2.48(s,3H),2.41-2.36(m,1H),2.14-2.07(m,1H),2.02(s,3H),1.78-1.72(m,4H),1.50(d,J＝8.0Hz,3H),1.22(s,6H),1.14(s,6H),1.04(s,9H)。MS-ESI:1011.5[M+H]⁺。

Example 19 preparation of (2S,4R) -1- ((2S) -2- (2- ((5- ((4- (3- (3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N-methyl-N- ((S) -1- (4- (4-methylthiazol-5-yl)) phenyl) ethyl) pyrrolidine-2-carboxamide (Compound 19)

(S) - (1- (4-bromophenyl) ethyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl (S) - (1- (4-bromophenyl) ethyl) carbamate (5.0g, 16.7mmoL) was added to DMF (10 mL). Sodium hydride (801.5mg, 20.1mmoL) was added slowly in an ice bathThe reaction was allowed to proceed to room temperature for 30 minutes, and iodomethane (2.85g, 20.1mmoL) was added thereto to allow the reaction to proceed at room temperature for 2 hours, followed by completion of the reaction by TLC. The reaction solution was quenched with a saturated ammonium chloride solution, ethyl acetate and water were added, and the solution was separated. The organic phase was distilled under reduced pressure, and the residue was separated by flash column chromatography to give 5.1g of the desired product, eluent PE: EA ═ 10:1, yield 97.5%.¹H NMR(400MHz,CDCl₃)δ7.50(dd,J＝8.8,2.2Hz,2H),7.19(d,J＝8.3Hz,2H),5.52–5.34(m,1H),2.61(s,3H),1.51(s,9H)。MS-ESI:314.3[M+H]⁺。

(S) -methyl (1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamate tert-butyl

Tert-butyl (S) - (1- (4-bromophenyl) ethyl) (methyl) carbamate (3.0g, 9.58mmoL), 4-methylthiazole (1.9g, 19.2mmoL), palladium acetate (21.3mg, 0.095mmoL) and potassium acetate (1.9g, 19.2mmoL) were added to DMF (20mL), replaced with nitrogen three times, warmed to 90 ℃ and stirred overnight. After cooling to room temperature, the mixture was filtered, and ethyl acetate and water were added to separate the layers. The organic phase was distilled under reduced pressure, and the residue was separated by flash column chromatography to give 1.4g of the desired product, eluent PE: EA ═ 5:1, yield 45.2%.¹H NMR(400MHz,CDCl₃)δ8.72(s,1H),7.45(d,J＝8.3Hz,2H),7.37(d,J＝8.2Hz,2H),2.67(s,3H),2.58(s,3H),1.57(d,J＝7.1Hz,3H),1.54(s,9H)。MS-ESI:333.3[M+H]⁺。

(S) -N-methyl-1- (4- (4-methylthiazol-5-yl) phenyl) -1-amine hydrochloride

(S) -methyl (1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamate tert-butyl (1.4g, 4.2mmoL) was added to HCl/1, 4-dioxane (4M, 12mL), stirred at room temperature for 2h, TLC checked for completion, and the reaction was distilled under reduced pressure and used directly in the next reaction.

(2S,4R) -4-hydroxy-2- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester

((S) -N-methyl-1- (4- (4-methylthiazol-5-yl) phenyl) -1-amine hydrochloride (1.13g, 4.2mmoL) was added to dichloromethane (30mL), and DIPEA (2.2mL, 12.6mmoL), HOBT (850mg, 6.3mmoL), (2S,4R) -1- (tert-butoxycarbonyl) -4-hydroxypyrrolidine-2-carboxylic acid (971mg, 4.2mmoL), and HATU (2.4g, 6.3mmoL) were sequentially added thereto, stirred at room temperature overnight, TLC monitored for completion of the reaction, the solvent was distilled off under reduced pressure, DCM and water were added to the residue, the solution was separated, the solvent was distilled under reduced pressure, the residue was separated by flash column chromatography, the eluent was DCM: MeOH ═ 30:1, to give the target product 1.7g, with a yield of 91.4%.¹H NMR(400MHz,CDCl₃)；δ8.73(s,1H),7.49-7.44(m,2H),7.35-7.31(m,2H),6.13-6.06(m,1H),4.66-4.62(m,1H),3.83-3.79(m,2H)，3.57-3.53(m,1H)，2.84(s,3H),2.34-2.24(m,2H),1.60(d,J＝7.1Hz,3H),1.50(s,9H)。MS-ESI:446.3[M+H]⁺。

(2S,4R) -4-hydroxy-N-methyl-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide hydrochloride

Tert-butyl (2S,4R) -4-hydroxy-2- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-carboxylate (1.7g, 3.82mmoL) was added to 1.4-dioxane (10mL), HCl/1, 4-dioxane (4.0M, 15mL) was added, stirred at room temperature for 2h, TLC checked for completion of the reaction, and the reaction was directly used for the next reaction by distillation under reduced pressure.

Tert-butyl ((S) -1- ((2S,4R) -4-hydroxy-2- (methyl ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutynin-2-yl) carbamate

(2S,4R) -4-hydroxy-N-methyl-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide hydrochloride (300mg, 0.79mmoL) was added to dichloromethane (5mL), followed by DIPEA (0.41mL, 2.36mmoL), HOBt (160mg,1.18mmoL), (S) -2- (((tert-butoxycarbonyl) amino) -3, 3-dimethylbutyric acid (182mg, 0.79mmoL), and finally HATU (448mg, 1.18mmoL) was added, stirring was carried out overnight at room temperature, the reaction was checked for completion by TLC, the reaction solution was distilled under reduced pressure to remove DMF, the residue was added with DCM and water, the organic phase was distilled under reduced pressure, the residue was separated with flash column chromatography, eluent DCM: MeOH ═ 30:1, 155mg of the target product was obtained with a yield of 35.2%.¹H NMR(400MHz,CDCl₃):δ8.73(s,1H),7.45(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),6.07-6.03(m,1H),5.39-5.30(m,2H),5.06(t,J＝10.0Hz,2H),4.63(s,1H),4.29-4.24(m,2H),3.89-.86(m,1H),2.91(s,3H),2.60(s,3H),2.16-2.06(m,2H),1.59(d,J＝10.0Hz,3H),1.46(s,9H),1.11(s,9H)。MS-ESI:559.3[M+H]⁺。

(2S,4R) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -4-hydroxy-N-methyl-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide hydrochloride

Tert-butyl ((S) -1- ((2S,4R) -4-hydroxy-2- (methyl ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxybutynin-2-yl) carbamate (150mg 0.27mmoL) was added to a 100mL one-neck flask, 1, 4-dioxane (3mL) was added, HCl/1, 4-dioxane (4M, 3mL) was added and reacted for 1 h. TLC detection reaction is complete, the solvent is evaporated under reduced pressure, high vacuum drying is carried out, and the residue is directly used for the next reaction without purification.

(2S,4R) -1- ((2S) -2- (2- ((5- ((4- (3- (3- (3-chloro-4-cyanophenoxy)) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N-methyl-N- ((S) -1- (4- (4-methylthiazol-5-yl)) phenyl) ethyl) pyrrolidine-2-carboxamide

Except that 2- ((5- ((4- (1- (((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid was replaced by 2- ((5- ((4- (3- (3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) amino) pentyl) oxy) acetic acid and ((2S,4R) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -4-hydroxy-N-methyl-N- ((S) -1- (4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid was used -methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide hydrochloride instead of (2S,4R) -1- ((S) -2- (l 2-azanyl) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide this compound was prepared as described for N- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S, preparation of 4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 61.1%.¹H NMR(400MHz,CD₃OD)δ8.89(s,1H),7.72-7.67(m,2H),7.51-7.47(m,2H),7.39-7.36(m,1H),7.10-7.03(m,3H),6.96(d,J＝8.0Hz,1H),6.62(d,J＝8.0Hz,2H),4.97-4.91(m,1H),4.76(d,J＝16.0Hz,1H),4.60(d,J＝24.0Hz,2H),4.16(s,1H),4.05-3.90(m,3H),3.85-3.83(m,2H),3.66-3.54(m,2H),3.13-3.07(m,2H),2.49(s,3H),2.33-2.27(m,1H),2.08-2.00(m,1H),1.90(s,3H),1.74-1.62(m,5H),1.56(d,J＝8.0Hz,3H),1.21(s,6H),1.13(s,6H),1.07(s,9H)。MS-ESI:997.5[M+H]⁺。

EXAMPLE 20 preparation of (3R,5S) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3- -4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) oxy) pentyl) oxy) acetamido) -3, 3-dimethylbutanoyl) -5- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-3-ylacetate (Compound 20)

Except that 2- ((5- ((4- (1- (((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) ureido) phenyl) oxy) pentyl) oxy) acetic acid was substituted with 2- ((5- ((4- (3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid and (3R,5S) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -5- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) oxy) acetic acid was substituted with (3R,5S) -1- ((S) -2-amino-3, 3-dimethylbutyryl) ) Ethyl) carbamoyl) pyrrolidine-3-acetate instead of (2S,4R) -1- ((S) -2- (l 2-azanyl) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide this compound was prepared as in N- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S, preparation of 4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 73%.¹H NMR(400MHz,CD₃OD)δ8.88(s,1H),7.71(d,J＝8.7Hz,1H),7.48-7.35(m,4H),7.26-7.23(m,2H),7.11(d,J＝2.3Hz,1H),6.96(d,J＝8.8Hz,1H),6.88-6.83(m,2H),5.33-5.31(m,1H),5.01(q,J＝7.1Hz,1H),4.60-4.55(m,2H),4.18(s,1H),4.12(d,J＝12.0Hz,1H),4.01-3.94(m,4H),3.94-3.86(m,2H),3.69-3.56(m,2H),2.48(s,3H),2.41-2.36(m,1H),2.15-2.08(m,1H),2.04(s,3H),1.91-1.80(m,2H),1.77-1.70(m,1H),1.67-1.55(m,2H),1.50(d,J＝6.7Hz,3H),1.24(s,6H),1.15(s,6H),1.06(s,9H)。MS-ESI:1026.2[M+H]⁺。

Example 21 preparation of (2S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1-methylureido) phenyl) amino) pentyl) oxy) acetamide) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((S) -1- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (Compound 21)

3- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1-methyl-1- (4-nitrophenyl) urea

1- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -3- (4-nitrophenyl) urea (256mg, 0.58mmoL) was charged to a 25mL single vial, DMF (3mL) was added and the temperature was reduced to 0 ℃. 60% sodium hydride (28mg, 0.69mmoL) was added thereto, and the reaction was maintained at 0 ℃ for 30 minutes. Finally, iodomethane (99mg, 0.69mmoL) was added and the reaction was maintained at 0 ℃ for 2 hours, and the reaction was complete by TLC. Quenching the reaction by using a saturated ammonium chloride solution, adding EA and water for extraction and liquid separation, carrying out reduced pressure distillation on an organic phase, and separating residues by using flash column chromatography to obtain a target product 130mg and an eluent PE: EA (2: 1) with the yield of 49.2%. 1H NMR (400MHz, CDCl3) δ 8.37-8.33(m,2H),7.59(d, J ═ 8.7Hz,1H),7.53-7.50(m,2H),6.96(d, J ═ 2.4Hz,1H),6.80(dd, J ═ 8.7Hz 2.4Hz,1H),4.72(d, J ═ 7.9Hz,1H),3.94-3.92(m,1H),3.42(s,3H),1.20(s,6H),1.10(s, 6H). MS-ESI 457.2[ M + H ]]⁺。

1- (4-aminophenyl) -3- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1-methylurea

3- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1-methyl-1- (4-nitrophenyl) urea (130mg, 0.28mmoL) was charged into a 25mL three-necked flask, methanol (5mL), Pd/C (39mg, 30% wt) was added, hydrogen was replaced three times, and the mixture was stirred at room temperature for 3 hours to complete the reaction by TLC. The reaction mixture was filtered through celite, and the filtrate was distilled under reduced pressure to give 120mg of the desired product in 99.1% yield. MS-ESI 427.3[ M + H ]]⁺。

Tert-butyl 2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1-methylureido) phenyl) amino) pentyl) oxy) acetate

1- (4-aminophenyl) -3- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1-methylurea (120mg, 0.28mmoL) was charged into a 25mL one-necked flask, methanol (3mL) was added, followed by the addition of 2-methylpyridine-N-borane (67.3mg, 0.31mmoL) and tert-butyl 2- ((5-oxypentyl) oxy) acetate (67.3mg, 0.31mmoL) in that order, stirred at room temperature for 3 hours and the reaction was checked by TLC to be complete. Quenching the reaction solution by adding water, distilling the reaction solution under reduced pressure, adding EA and water for extraction and liquid separation, distilling the organic phase under reduced pressure, and separating the residue by using flash column chromatography to obtain the target product 139.0mg and the eluent PE: EA (2: 1) with the yield of 78.4%. 1H NMR (400MHz, CDCl)₃)δ7.56(d,J＝8.7Hz,1H),7.11(d,J＝8.6Hz,2H),6.93(d,J＝2.0Hz,1H),6.78(dd,J＝8.7Hz 2.1Hz,1H),6.70(d,J＝8.1Hz,2H),4.54(d,J＝8.6Hz,1H),4.00(s,2H),3.89(s,1H),3.59(t,J＝6.2Hz,2H),3.25(s,3H),3.19(t,J＝6.9Hz,2H),1.74-1.60(m,4H),1.61-1.57(m,2H),1.53(s,9H),1.20(s,6H),1.15(s,6H),0.98(s,6H)。MS-ESI:627.5[M+H]⁺。

2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1-methylureido) phenyl) amino) pentyl) oxy) acetic acid)

Tert-butyl 2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1-methylureido) phenyl) amino) pentyl) oxy) acetate (135mg, 0.22mmoL) was charged into a 25mL single-neck flask, and dichloromethane (2mL) and trifluoroacetic acid (2mL) were added and stirred at room temperature for 2 hours with TLC to check completion of the reaction.

(2S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1-methylureido) phenyl) amino) pentyl) oxo) acetamide) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide

(2S,4R) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -4-hydroxy-N-methyl-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (34.6mg, 0.07mmoL), 2- ((5- ((4- (3- (((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1-methylureido) phenyl) amino) pentyl) oxy) acetic acid (41mg,0.07mmoL), HOBt (39mg,0.28mmoL), DMF (2mL) were added to a 25mL single-necked flask, cooling to-20 deg.C, adding EDCI (55mg,0.28mmoL), reacting overnight, detecting the reaction completion by TLC the next day, adding DCM and water for extraction, separating liquid, distilling organic phase under reduced pressure, separating residue by flash column chromatography to obtain target product 15mg, eluent DCM: MeOH (20: 1), yield 22%.¹H NMR(400MHz,CD₃OD)δ8.87(s,1H),7.66(d,J＝8.0Hz,1H),7.48-7.38(m,4H),7.13-7.06(m,3H),6.88(d,J＝8.8Hz,2.4Hz,1H),6.70(d,J＝8.7Hz,2H),5.06-5.01(m,1H),4.78-4.73(m,2H),4.62-4.59(m,1H),4.49(s,1H),4.08(s,1H),4.02(d,J＝9.8Hz,2H),3.88(m,1H),3.79(m,2H),3.65(m,2H),3.21–3.15(m,4H),2.47(s,3H),2.19(m,1H),1.99–1.96(m,1H),1.74–1.73(m,4H),1.64-1.60(m,3H),1.52(d,J＝7.0Hz,3H),1.09(s,6H),1.03(s,9H),0.94(s,6H)。MS-ESI:997.5[M+H]⁺。

Example 22 preparation of (2S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1, 3-dimethylureido) phenyl) amino) pentyl) oxo) acetamide) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (Compound 22)

3- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1, 3-dimethyl-1- (4-nitrophenyl) urea

1- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -3- (4-nitrophenyl) urea (256mg, 0.58mmoL) was charged to a 25mL single vial, DMF (3mL) was added and the temperature was reduced to 0 ℃. 60% sodium hydride (70.0mg, 1.74mmoL) was added thereto, and the reaction was carried out at 0 ℃ for 30 minutes. Finally, methyl iodide (332.0mg, 0.69mmoL) was added and the reaction was maintained at 0 ℃ for 2 hours, and the reaction was completed by TLC. Quenching the reaction with saturated ammonium chloride solution, adding EA and water, extracting, separating, distilling the organic phase under reduced pressure, separating the residue with flash column chromatography to obtain 201mg of target product, eluting PE: EA (2: 1), and obtaining yield of 74.0%.¹H NMR(400MHz,CDCl₃)δ8.22(d,J＝8.0Hz,2H),7.55(d,J＝8.7Hz,1H),7.34(d,J＝8.0Hz,2H),6.95(d,J＝2.4Hz,1H),6.79(dd,J＝8.0Hz,4.0Hz,1H),4.04(s,1H),3.65(s,1H),3.37(s,3H),2.57(s,3H),1.36(s,6H),1.24(s,6H)。

1- (4-aminophenyl) -3- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1, 3-dimethylurea

3- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1, 3-dimethyl-1- (4-nitrophenyl) urea (180mg, 0.38mmoL) was charged into a 25mL three-necked flask, methanol (5mL), Pd/C (36mg, 20% wt) was added, hydrogen was replaced three times, and the mixture was stirred at room temperature for 3 hours to complete the reaction by TLC. The reaction mixture was filtered through celite, and the filtrate was distilled under reduced pressure to give 150mg of the target product with a yield of 90%. The product was used in the next reaction without purification. MS-ESI 441.5[ M + H ]]⁺。

Tert-butyl 2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1, 3-dimethylureido) phenyl) amino) pentyl) oxy) acetate

1- (4-aminophenyl) -3- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1, 3-dimethylurea (150mg, 0.34mmoL) was charged into a 25mL one-necked flask, methanol (4mL) was added, followed by the sequential addition of 2-methylpyridine-N-borane (82.0mg, 0.38mmoL) and tert-butyl 2- ((5-oxopentyl) oxy) acetate (82.2mg, 0.38mmoL), and the reaction was stirred at room temperature for 3 hours and checked by TLC for completion. Quenching the reaction solution by adding water, distilling the reaction solution under reduced pressure, adding EA and water for extraction and liquid separation, distilling the organic phase under reduced pressure, and separating the residue by using flash column chromatography to obtain a target product of 141.0mg and an eluent PE of EA (2: 1), wherein the yield is 65%. MS-ESI of 641.3[ M + H ]]⁺。

2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1, 3-dimethylureido) phenyl) amino) pentyl) oxy) acetic acid

Tert-butyl 2- ((5- ((4- (3- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1, 3-dimethylureido) phenyl) amino) pentyl) oxy) acetate (130mg, 0.20mmoL) was added to a 25mL single vial, dichloromethane (2mL) and trifluoroacetic acid (2mL) were added, stirred at room temperature for 2 hours, TLC detected reaction was complete, the reaction solution was evaporated under reduced pressure to remove the solvent, and the residue was dried under high vacuum to give 105 mg.

(2S,4R) -1- ((S) -2- (2- ((5- ((4- (3- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1, 3-dimethylureido) phenyl) amino) pentyl) oxy) acetamide) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((S) -1- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide

Except that 2- ((5- ((4- (1- (((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -1, 3-dimethylureido) phenyl) amino) pentyl) oxy) acetic acid was used in place of 2- ((5- (4- (1- (((((1R, 3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carbamoyl) cyclopropane-1-carboxamide) phenyl) amino) pentyl) oxy) acetic acid and (3R,5S) -1- ((S) -2-amino-3, 3-dimethylbutanoyl) -5- (((S) -1- (4-d-yphenoxy) phenyl) amino) pentyl) oxy) acetic acid was used - (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-3-acetate instead of (2S,4R) -1- ((S) -2- (l 2-azanyl) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide, this compound was prepared as in N- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclyl) -N- (4- ((5- (2- (((S) -1- ((2S, preparation of 4R) -4-hydroxy-2- (((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) pentyl) amino) phenyl) cyclopropane-1, 1-dicarboxamide. The yield thereof was found to be 51%.¹H NMR(400MHz,CD₃OD)δ8.87(s,1H),7.66(d,J＝8.0Hz,1H),7.48-7.35(m,4H),7.13-7.00(m,3H),6.88(d,J＝8.8Hz,2.4Hz,1H),6.64(d,J＝8.0Hz,2H),5.06-5.01(m,1H),4.80-4.55(m,4H),4.44(s,1H),4.14(s,1H),3.99(q,J＝8.0Hz,2H),3.80-3.60(m,2H),3.76(m,3H),3.52(s,1H),3.09(t,J＝8.0Hz,2H),2.47(s,3H),2.41(s,3H),2.125-2.15(m,1H),2.10-1.80(m,2H),1.71-1.63(m,4H),1.59-1.53(m,2H),1.47(d,J＝4.0Hz,3H),1.20(s,6H),1.05(s,6H),1.03(s,9H)。MS-ESI:1011.3[M+H]⁺。

EXAMPLE 23 PROTAC Compound Activity assay (Western Blot method)

VCap cells were plated in 12-well plates with a next day cell density of 80% -90% and different compounds were added at final concentrations of 0.03, 0.1, 0.3, 1.0, 3.0, 10.0, 30.0, 100.0, 300.0 and 1000.0nM, respectively. After 24h of dosing, the cell culture medium was removed and the cells were washed with cold PBS, 60 μ L of protein lysate was added per well, the cells were blown off with Tip and the cell lysate was mixed well. Then, the cell lysate is centrifuged at 12000rpm at 4 ℃ for 15min, the supernatant is taken and added with 15 μ L of 5X protein loading buffer solution, and after uniform mixing, water bath at 100 ℃ is carried out for 10 min; taking out and putting on iceAfter cooling, centrifugation was carried out for 1min, and the supernatant was used for western blot detection. After Western blot detection, the detection result is subjected to statistics of the expression level of the androgen receptor by using Image J software, and then DC for degrading the androgen receptor by each compound is calculated according to the expression level of the receptor₅₀。

In this test, Compound DC₅₀The activity is divided into four layers, wherein +++ (DC)₅₀≦2nM)；+++(2<DC₅₀≦10nM)；++(10<DC₅₀≦50nM)；+(DC₅₀>50nM)。

Compound DC of the invention₅₀As shown in the table below.

。

Claims

1. A compound having the structure of formula i or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof:

wherein the content of the first and second substances,

R₁selected from-CN, -NO₂and-NH₂；

x, Y are each independently selected from CH and N;

R₈and R₉Can also be connected into a ring;

a is selected from carbonyl,

l is a linker;

VHL is E3 ubiquitin ligase binding fragment.

2. The compound having the structure of formula i, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof of claim 1, wherein VHL is a fragment having the structure:

wherein the content of the first and second substances,

W₂selected from the group consisting of substituted or unsubstituted: c_6-10Aryl radical, C_5-10Heteroaryl group, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, said substitution being by a group selected from halogen, -OH, -CN, -NH₂、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6AlkylamineA radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group; w₃Selected from H, halogen, C_1-10Alkyl, -CN and the following substituted or unsubstituted groups: c_6-10Arylene radical, C_5-10Heteroarylene group, C_3-8Cycloalkylene, 3-8 membered heterocyclylene, said substitution being by a group selected from halogen, -OH, -CN, -NH₂And C_1-6Alkoxy radical, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group;

3. The compound of claim 1, wherein L is W, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof, wherein L is₁And a linker of VHL, W₁And VHL are separated by 2-20 chemical bonds.

4. The compound of claim 3, wherein L is W, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof, wherein L is₁And a linker of VHL, W₁And VHL are separated by 5-15 chemical bonds, preferably 8-12 chemical bonds.

5. A compound of formula i, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug thereof, according to claim 3Or an isotopic label, wherein L is a divalent moiety comprising one or more moieties selected from NR^Y1、O、S、SO、SO₂Sulfonamide, carbonyl, amide, ester, substituted or unsubstituted: alkenylene, alkynylene, alkylene, isoindolinone, C_6-10Arylene radical, C_5-10Heteroarylene group, C_3-8Cycloalkylene, 3-15 membered heterocyclylene, C_4-10Spirocyclic idene, 4-10 membered heterospirocyclic idene, C_5-10The substituents being selected from the group consisting of halogen, -OH, -CN, -NH, and 5-10 membered heterobridged ring groups₂、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group, wherein R^Y1Selected from hydrogen, deuterium, C unsubstituted or substituted by halogen_1-6Alkyl, unsubstituted or halogen-substituted C_2-6Alkenyl, C unsubstituted or substituted by halogen_2-6Alkynyl.

6. A compound having the structure of formula i or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof according to claim 1, wherein L is selected from the group consisting of:

。

7. a compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof according to claim 1 wherein R is₁is-CN, R₂Is Cl, Br, I or-CF₃。

8. A compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof according to claim 1 wherein R is₃Is H or F.

9. A compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof according to claim 1 wherein R is₄、R₅、R₆And R₇Each independently is methyl.

10. A compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof according to claim 1 wherein R is₈Selected from hydrogen, deuterium and C_1-6Alkyl, or R₈And W₁To form a 5-or 6-membered ring.

11. A compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof according to claim 1 wherein R is₉Selected from hydrogen, deuterium and C_1-6An alkyl group.

12. A compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof according to claim 1 wherein R is₁₀、R₁₁Each independently selected from C_1-6Alkyl or R₁₀And R₁₁Are connected into a ring-shaped cyclopropyl.

13. A compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof according to claim 2 wherein R is₁₂And R₁₄Are each independently selected from hydrogen and C_1-6An alkyl group.

14. A compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof according to claim 2 wherein R is₁₃Selected from hydrogen and-OR₁₈Said R is₁₈Selected from hydrogen, R₁₉C (═ O) -, substituted or unsubstituted amino acid residues or substituted or unsubstituted oligomeric amino acid residues, R₁₉Selected from H, substituted or unsubstituted: c_1-30Alkyl, deuterated C_1-30Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl, alkenylaryl, alkenylheteroaryl, amino, alkylamino, alkylsulfide, said substitution being by 1-2 substituents selected from halogen, -OH, -CN, -NH₂Acetamido and C_1-6Alkoxy radical, C_1-6The substituent of the alkyl is substituted, wherein the substituent of the amino and the alkylamino can also form a ring together with N.

15. A compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof according to claim 2 wherein R is₁₅、R₁₆And R₁₇Each independently selected from H, halogen, substituted or unsubstituted C_1-6Alkyl, adjacent R₁₅And R₁₆May also be linked to form a ring, said substitution being selected from the group consisting of halogen, -OH, -CN, -NH₂And C_1-6Alkoxy, 3-6 membered heterocyclic group, C_1-6Alkylamino and (C)_1-6Alkyl radical)₂Substituted by a substituent of the amino group.

16. The compound of claim 1, wherein A is selected from the group consisting of carbonyl, and pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs, and isotopic labels thereof,

17. The compound of claim 1, wherein W is a compound having the structure of formula i or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein W is a hydrogen atom₁Selected from substituted or unsubstituted C_6-10Arylene, 5-to 10-membered heteroarylene, said C₆-C₁₀The arylene group is selected from phenylene and naphthylene, and the heteroaryl group in the 5-to 10-membered heteroarylene group is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothiadiazolylThienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, and indazolyl, said substitution being selected from the group consisting of halogen, -OH, -CN, -NH₂、C_1-6Alkoxy and C_1-6Substituted by alkyl substituents, preferably, W₁Selected from unsubstituted or selected from halogen, -OH, -CN, -NH₂、C_1-6Alkoxy and C_1-6Phenylene, pyridylene, quinolylene, benzopyrylene and isoindolinone substituted by alkyl substituent.

18. A compound having the structure of formula i or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof according to claim 2 wherein W is₂Selected from the group consisting of substituted or unsubstituted: c_6-10Arylene radical, C_5-10Heteroarylene, preferably, C_6-10Arylene is phenylene, C_5-10Heteroarylene is thiazolyl, thienyl, imidazolyl, pyridothienyl, oxazolylene, benzopyrazolylene;

W₃selected from H, halogen, C_1-6Alkyl, -CN and the following substituted or unsubstituted groups: c_6-10Aryl radical, C_5-10Heteroaryl, said substitution being by a group selected from halogen, -OH, -CN, -NH₂And C_1-6Alkoxy radical, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl radical, C_5-10Heteroaryl group, C_1-6Alkylamino radical and (C)_1-6Alkyl radical)₂Substituted by a substituent of an amino group; w₄Selected from the group consisting of substituted or unsubstituted: c_6-10Aryl radical, C_5-10Heteroaryl group, C_3-8Cycloalkyl, 3-to 8-membered heterocyclic group, preferably phenyl, isoxazolyl, isoindolinone, cyclopropyl, said substitutionIs selected from halogen, -OH, -CN, -NH₂、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_1-6Alkylamino and (C)_1-6Alkyl radical)₂The substituent of the amino is taken.

19. A compound having the structure of formula i, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, according to any one of claims 1-18, wherein the compound of formula i is selected from the group consisting of:

。

20. a pharmaceutical composition comprising a compound of any one of claims 1-19, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof, and a pharmaceutically acceptable excipient.

21. A pharmaceutical composition according to claim 20 in the form of any one of aqueous dispersion, liquid, gel, syrup, elixir, syrup, suspension, aerosol, controlled release formulation, fast dissolving agent, effervescent formulation, lyophilized formulation, tablet, powder, pill, coated, capsule, delayed release formulation, extended release formulation, pulsatile controlled release formulation, multiparticulate formulation or immediate release formulation.

22. Use of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition according to claims 20 to 21 for the manufacture of a medicament for the treatment of an androgen receptor associated disease.

23. The use according to claim 22, wherein the androgen receptor associated disease is prostate cancer, breast cancer, prostate hyperplasia, kennedy's disease, hirsutism, acne, alopecia, baldness, muscle failure, gonadal failure, osteoporosis, hypercholesterolemia, male infertility, male sexual dysfunction, anemic obesity, hypoactive sexual desire, or depression.

24. The use according to claim 22, wherein the androgen receptor associated disease is castration-resistant prostate cancer.