阅读说明：本技术 凋亡蛋白抑制剂的二价拮抗剂 (Bivalent antagonists of inhibitor of apoptosis proteins ) 是由 徐晓东 于 2020-04-01 设计创作，主要内容包括：本发明技术涉及与治疗由IAP介导的癌症和病毒感染相关的化合物、组合物和方法,例如,式I(包含式IA、IB、IC、ID、IE、IF和IG)的化合物、其立体异构体或所述化合物或所述化合物的所述立体异构体的药学上可接受的盐。具体地,本发明化合物和组合物可以用于治疗IAP介导的卵巢癌和乙型肝炎感染。(The present technology relates to compounds, compositions and methods related to the treatment of cancers and viral infections mediated by IAPs, for example, compounds of formula I (including formulae IA, IB, IC, ID, IE, IF and IG), stereoisomers thereof or pharmaceutically acceptable salts of said compounds or of said stereoisomers of said compounds. In particular, the compounds and compositions of the invention may be used to treat IAP mediated ovarian cancer and hepatitis B infections.)

1. A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or the stereoisomer of the compound:

wherein

X is O, NR⁶Or CH₂；

q is 0, 1 or 2;

R¹and R²Independently at each occurrence, is selected from substituted or unsubstituted C_1-6Alkyl radical, C_3-6Cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl groups;

R³and R⁴Independently at each occurrence, H, an amino protecting group, or substituted or unsubstituted C_1-6An alkyl group;

R⁵h, F, NH independently at each occurrence₂OH, NH- (amino protecting group) or O- (hydroxyl protecting group);

R⁶independently at each occurrence, H, substituted or unsubstituted C_1-6Alkyl radical, C_3-6A cycloalkyl or amino protecting group; and is

The linker is a divalent moiety selected from a bond, an oxy moiety, or an optionally substituted moiety selected from the group consisting of: amino, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, cycloalkylheteroalkylene, arylene, aralkylene, arylheteroalkylene, heterocyclylene, heterocyclylalkylene, heteroarylene, heteroarylalkylene, and heteroarylheteroalkylene.

2. The compound of claim 1, wherein linker is selected from the group consisting of: heteroalkylene, arylene, aralkylene, arylheteroalkylene, heterocyclylalkylene, and heterocyclylalkylene groups.

3. The compound of claim 1 or claim 2, wherein linker is selected from the group consisting of: c₂-C₁₂Polyalkylene oxides, phenylalkylenes, phenylheteroalkylenes, piperazinylalkylenes, and piperazinylalkylenes.

4. The compound of claim 1, wherein linker is selected from the group consisting of: a bond,

Wherein

m is 0, 1,2,3,4, 5 or 6; and is

n is 1,2,3,4, 5, 6.

5. The compound of claim 4, wherein n is 1,2, or 3, and m is 0, 1,2,3, or 4.

6. The compound of any one of claims 1 to 5, wherein linker isAnd n is 2 or 3.

7. The compound of any one of claims 1 to 5, wherein linker is a bond, -NH-, or-C (O) NH-.

8. The compound of claim 1, wherein linker is

9. The compound of claim 8, wherein m is 1,2,3, or 4.

10. The compound of claim 1, wherein linker is

11. The compound of claim 10, wherein n is 2 or 3.

12. The compound of claim 1, wherein linker is

And wherein

m is 0 or 1.

13. The compound according to any one of claims 1 to 12, wherein R¹And R²Independently selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.

14. The compound according to any one of claims 1 to 13, wherein R³Is methyl,Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

15. The compound according to any one of claims 1 to 14, wherein R⁴Is an amino protecting group.

16. The compound according to any one of claims 1 to 14, wherein R⁴Is H.

17. The compound according to any one of claims 1 to 16, wherein R⁵Is H.

18. The compound of any one of claims 1-17, wherein X is CH₂Or O.

19. The compound of any one of claims 1 to 18, wherein q is 0 or 1.

20. The compound of any one of claims 1 to 17, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or of the stereoisomer of the compound, the compound having the structure of formula IA:

21. the compound of claim 20, wherein R²Is methyl.

22. The compound of claim 20 or 21, wherein R¹Cyclohexyl or isopropyl.

23. The compound of any one of claims 20-22, wherein R³Is methyl.

24The compound of any one of claims 20-23, wherein R⁴Is H.

25. The compound of any one of claims 20-24, wherein R⁵Is H.

26. The compound of claim 1, wherein the compound is selected from any compound of table I.

27. A composition comprising a compound according to any one of claims 1 to 26 and a pharmaceutically acceptable carrier.

28. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 26 for treating a cancer or viral infection mediated by IAP.

29. The pharmaceutical composition of claim 28, wherein the cancer or viral infection mediated by IAP is selected from the group consisting of: ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis B infection.

30. A method of treatment comprising administering to a subject having a cancer or viral infection mediated by IAP an effective amount of a compound of any one of claims 1 to 26, or a pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 26.

31. The method of claim 30, wherein the cancer or viral infection is selected from the group consisting of: ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis B infection.

Technical Field

The present technology relates to compounds, compositions and methods relating to Inhibitors of Apoptosis Proteins (IAPs), including host cell IAPs (ciaps). In particular, the compounds and compositions of the present invention may be used to treat a variety of cancers, including, for example, ovarian cancer and chronic hepatitis B infection.

Background

Apoptosis, also known as programmed cell death, is a key and highly regulated cellular process that occurs in multicellular organisms and apoptotic dysfunction is a hallmark of human cancer. Inhibitors of Apoptosis Proteins (IAPs), such as cytostatics of apoptosis proteins 1 and 2 (cIAP1 and cIAP2) and X-linked inhibitor of apoptosis proteins (XIAP), have been identified as attractive targets for new types of cancer therapies.

In 2015, Pellegrinia et al (PNAS, 2015,112(18), 5803-. Thus, cIAP antagonists may also be effective in treating chronic HBV infection and may promote viral elimination.

Disclosure of Invention

In one aspect, the present technology provides a compound according to formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or of the stereoisomer of the compound:

wherein

X is O, NR⁶Or CH₂；

q is 0, 1 or 2;

R¹and R²Independently at each occurrence is selected from the group consisting ofSubstituted or unsubstituted C_1-6Alkyl radical, C_3-6Cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl groups;

R³and R⁴Independently at each occurrence, H, an amino protecting group, or substituted or unsubstituted C_1-6An alkyl group;

R⁵h, F, NH independently at each occurrence₂OH, NH- (amino protecting group) or O- (hydroxyl protecting group);

R⁶independently at each occurrence, H, substituted or unsubstituted C_1-6Alkyl radical, C_3-6A cycloalkyl or amino protecting group; and is

The linker is a divalent moiety selected from a bond, an oxy moiety, or an optionally substituted moiety selected from the group consisting of: amino, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, cycloalkylheteroalkylene, arylene, aralkylene, arylheteroalkylene, heterocyclylene, heterocyclylalkylene, heteroarylene, heteroarylalkylene, and heteroarylheteroalkylene.

In any embodiment of the compound of formula (I):

R¹and R²Independently selected from substituted or unsubstituted C_1-6Alkyl radical, C_3-6Cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl groups;

R³and R⁴Independently H, an amino protecting group or substituted or unsubstituted C_1-6An alkyl group;

R⁵is H, F, NH₂OH, NH- (amino protecting group) or O- (hydroxyl protecting group);

R⁶is H, substituted or unsubstituted C_1-6Alkyl radical, C_3-6A cycloalkyl or amino protecting group; and is

The linker is divalent and is selected from the group consisting of: a bond, amino, oxy, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, cycloalkylheteroalkylene, arylene, aralkylene, arylheteroalkylene, heterocyclylene, heterocyclylalkylene, heteroarylene, heteroarylalkylene, and heteroarylheteroalkylene.

In a related aspect, there is provided a composition comprising a compound of any one of the embodiments described herein and a pharmaceutically acceptable carrier.

In another aspect, there is provided a pharmaceutical composition comprising an effective amount of a compound of any one of the embodiments described herein for use in treating an IAP-mediated disorder or condition, such as various cancers (e.g., ovarian cancer, fallopian tube cancer, peritoneal cancer) or viral infections (e.g., chronic hepatitis b infection).

In another aspect, a method is provided that includes administering to a subject having a cIAP-mediated disorder condition an effective amount of a compound of any one of the embodiments described herein, or administering a pharmaceutical composition including an effective amount of a compound of any one of the embodiments described herein.

Detailed Description

In various aspects, the present technology provides compounds and methods for antagonizing the effects of cIAP and treating cIAP-mediated disorders and conditions. The compounds provided herein can be formulated into pharmaceutical compositions and medicaments for use in the disclosed methods. Also provided is the use of the compounds in the preparation of pharmaceutical formulations and medicaments.

As defined below, the following terms are used throughout.

As used herein and in the appended claims, singular articles such as "a," "an," and "the" and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate embodiments and does not pose a limitation on the scope of the claims unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential.

As used herein, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If a term is used that is not clear to one of ordinary skill in the art, then "about" will mean up to plus or minus 10% of the particular term, taking into account the context in which it is used.

In general, reference to an element such as hydrogen or H is meant to include all isotopes of that element. For example, if the R group is defined to contain hydrogen or H, it also contains deuterium and tritium. Thus, radioactive isotopes such as tritium, C are included¹⁴、P³²And S³⁵Are within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those of skill in the art based on the disclosure herein.

Typically, "substituted" refers to an organic group (e.g., alkyl) as defined below in which one or more bonds to the hydrogen atoms contained therein are replaced with a bond to a non-hydrogen or non-carbon atom. Substituted groups also include groups in which one or more bonds of a carbon or hydrogen atom are replaced with one or more bonds of a heteroatom that includes a double or triple bond. Thus, unless otherwise specified, a substituted group is substituted with one or more substituents. In any embodiment, a substituted group is substituted with 1,2,3,4, 5, or 6 substituents. Examples of the substituent include: halogen (i.e., F, Cl, Br, and I); a hydroxyl group; alkoxy, alkenyloxy, aryloxy, arylalkoxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy; oxygen radicals, such as carbon radicals; a carboxylic acid ester; an ester; a carbamate; an oxime; a hydroxylamine; an alkoxyamine; an arylalkoxyamine; a thiol; a sulfide; a sulfoxide; a sulfone; sulfonyl, sulfonamide; an amine; an N-oxide; hydrazine; a hydrazide; hydrazone; an azide; an amide; urea; amidines; guanidine; an enamine; an imide; an isocyanate; an isothiocyanate; a cyanate ester; a thiocyanate; an imine; a nitro group; nitriles (i.e., CN); and so on.

Substituted cyclic groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl also include rings and ring systems in which the bond to a hydrogen atom is replaced by a bond to a carbon atom of an acyclic group. Thus, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl and alkynyl groups as defined below.

Alkyl groups include straight and branched chain alkyl groups having from 1 to 12 carbon atoms and typically from 1 to 10 carbons or, in any embodiment, from 1 to 8, from 1 to 6, or from 1 to 4 carbon atoms. Examples of straight chain alkyl groups include groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isoamyl, and 2, 2-dimethylpropyl. Representative substituted alkyl groups can be substituted one or more times with substituents such as those listed above and include, but are not limited to, haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, sulfanyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.

Cycloalkyl includes monocyclic, bicyclic, or tricyclic alkyl groups having 3 to 12 carbon atoms in the ring or, in any embodiment, 3 to 10, 3 to 8, or 3 to 4,5, or 6 carbon atoms. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In any embodiment, cycloalkyl has 3 to 8 ring members, while in other embodiments the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Bicyclic and tricyclic ring systems contain both bridged cycloalkyl and fused rings, such as but not limited to bicyclo [2.1.1] hexane, adamantyl, decahydronaphthyl, and the like. The substituted cycloalkyl group may be substituted one or more times by non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also comprise rings substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or more than once substituted, such as but not limited to 2,2-, 2,3-, 2,4-, 2,5-, or 2, 6-disubstituted cyclohexyl, which may be substituted with substituents such as those listed above.

Cycloalkylalkyl is an alkyl group as defined above, wherein a hydrogen or carbon bond of the alkyl group is replaced by a bond to a cycloalkyl group as defined above. In any embodiment, cycloalkylalkyl has 4 to 16 carbon atoms, 4 to 12 carbon atoms, and typically 4 to 10 carbon atoms. Substituted cycloalkylalkyl groups may be substituted at the alkyl, cycloalkyl, or both the alkyl and cycloalkyl portions of the group. Representative substituted cycloalkylalkyl groups may be mono-substituted or substituted more than once, such as but not limited to mono-, di-or tri-substituted with substituents such as those listed above.

Alkenyl groups comprise straight and branched chain alkyl groups as defined above, except that at least one double bond is present between two carbon atoms. Alkenyl groups have 2 to 12 carbon atoms and typically 2 to 10 carbons or, in any embodiment, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In any embodiment, an alkenyl group has one, two, or three carbon-carbon double bonds. Examples include, but are not limited to, vinyl, allyl, -CH ═ CH (CH)₃)、-CH＝C(CH₃)₂、-C(CH₃)＝CH₂、-C(CH₃)＝CH(CH₃)、-C(CH₂CH₃)＝CH₂And the like. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as but not limited to mono-, di-, or tri-substituted with substituents such as those listed above.

Cycloalkenyl comprises cycloalkyl as defined above, with at least one double bond between two carbon atoms. In some embodiments, cycloalkenyl groups can have one, two, or three double bonds, but do not include aromatic compounds. Cycloalkenyl groups have from 4 to 14 carbon atoms, or in some embodiments, from 5 to 14 carbon atoms, from 5 to 10 carbon atoms, or even 5,6,7, or 8 carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl.

Cycloalkenylalkyl is an alkyl group as defined above wherein the hydrogen bond or carbon bond of the alkyl group is replaced by a bond to the cycloalkenyl group as defined above. Substituted cycloalkenylalkyl groups may be substituted at the alkyl, cycloalkenyl, or both the alkyl and cycloalkenyl portions of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those enumerated above.

Alkynyl groups comprise straight and branched chain alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Alkynyl groups have 2 to 12 carbon atoms and typically 2 to 10 carbons or in any embodiment 2 to 8, 2 to 6 or 2 to 4 carbon atoms. In any embodiment, the alkynyl group has one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to, -C ≡ CH, -C ≡ CCH₃、-CH₂C≡CCH₃、-C≡CCH₂CH(CH₂CH₃)₂And so on. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as but not limited to mono-, di-or tri-substituted with substituents such as those listed above.

Aryl is a cyclic aromatic hydrocarbon containing no heteroatoms. Aryl herein includes monocyclic, bicyclic and tricyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl. In any embodiment, the aryl group contains 6 to 14 carbons in the ring portion of the group, and in other embodiments 6 to 12 or even 6 to 10 carbon atoms. In any embodiment, aryl is phenyl or naphthyl. Although the phrase "aryl" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups having other groups, such as alkyl or halo, bonded to one ring member. In practice, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups may be mono-substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.

An aralkyl group is an alkyl group as defined above, wherein a hydrogen bond or a carbon bond of the alkyl group is replaced by a bond to the aryl group as defined above. In any embodiment, an aralkyl group contains 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. Substituted aralkyl groups may be substituted at the alkyl, aryl, or both the alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl, and fused (cycloalkylaryl) alkyl groups, such as 4-indanylethyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.

Heteroalkyl is alkyl wherein at least one carbon is substituted with a heteroatom selected from N, O or S. Thus, heteroalkyl groups may comprise straight and branched chain heteroalkyl groups having from 1 to 11 carbon atoms, and typically from 1 to 10 carbons, or in any embodiment, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. In any embodiment, the heteroalkyl group may have 1,2,3,4, or 5 heteroatoms selected from N, O or S. In any embodiment, the heteroalkyl group may contain 1 or two heteroatoms, such as 1 or 2 oxygen atoms, 1 or 2 nitrogen atoms, one or two sulfur atoms, oxygen and nitrogen atoms, oxygen and sulfur atoms, or nitrogen and sulfur atoms. Heteroalkyl groups include, for example, methoxy, ethoxy, methoxyethyl, methylthio, methylthiopropyl, ethoxymethyl, and methylaminobutyl. The heteroalkyl group may be substituted one or more times as if the alkyl group were substituted with substituents such as those listed above. In any embodiment, the heteroalkyl can be substituted with an oxo group to form a ketone, amide, sulfone, sulfoxide, or sulfonamide.

Heterocyclyl includes aromatic (also referred to as heteroaryl) and non-aromatic ring compounds containing 3 or more ring members, one or more of which is a heteroatom such as, but not limited to N, O and S. In any embodiment, heterocyclyl contains 1,2,3, or 4 heteroatoms. In any embodiment, heterocyclyl includes monocyclic, bicyclic, and tricyclic rings having 3 to 16 ring members each, while other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclyl encompasses aromatic, partially unsaturated and saturated ring systems, such as imidazolyl, imidazolinyl, imidazolidinyl. The phrase "heterocyclyl" includes fused ring materials, including those that include fused aromatic and non-aromatic groups, such as benzotriazolyl, 2, 3-dihydrobenzo [1,4] dioxinyl, and benzo [1,3] dioxolyl. The phrase also encompasses bridged polycyclic ring systems containing heteroatoms, such as, but not limited to quinuclidinyl. However, the phrase does not include heterocyclyl groups having other groups such as alkyl, oxo, or halo attached to one of the ring members. In practice, these groups are referred to as "substituted heterocyclyl". Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolanyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, dihydroimidazolyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathianyl, dioxacyclohexyl, dithianyl, pyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridinyl, dihydrodithiazinyl, dihydrodisulfinyl, homopiperazinyl, quinuclidinyl, indolyl, indolinyl, isoindolyl, tetrahydrofuranyl, dioxolanyl, pyrazinyl, triazinyl, thianyl, thiazolyl, isothiazolyl, thiadiazolyl, and the like, Azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxadiazolyl, benzoxazinyl, benzodithiazinyl, benzoxazinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [1,3] dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridinyl, isoxazolopyridinyl, purinyl, xanthine, adenine, guanine, quinolyl, isoquinolyl, quinolizinyl, quinolinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, indolinyl, dihydrobenzodioxinyl, tetrahydroindolyl, and benzothiazolyl, Tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridinyl, tetrahydrotriazolopyridinyl and tetrahydroquinolinyl. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as but not limited to pyridyl or morpholinyl, which is 2-, 3-, 4-, 5-or 6-substituted or disubstituted with various substituents as listed above.

Heteroaryl is an aromatic ring compound containing 5 or more ring members, one or more of which is a heteroatom such as, but not limited to N, O and S. Heteroaryl groups include, but are not limited to, the following groups: pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, benzothienyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzothiazolyl, benzothiadiazole, imidazopyridinyl, isoxazolopyridinyl, thienyl, heptyl, xanthine, adenine, ornitrogen, quinolyl, isoquinolyl, tetrahydroquinolyl, quinoxalyl and quinazolinyl. Heteroaryl groups include fused ring compounds in which all rings are aromatic, such as indolyl, and fused ring compounds in which only one ring is aromatic, such as 2, 3-indolinyl. Although the phrase "heteroaryl" includes fused ring compounds, the phrase does not include heteroaryl groups having other groups, such as alkyl, bound to one of the ring members. In contrast, heteroaryl groups having such substitutions are referred to as "substituted heteroaryl groups". Representative substituted heteroaryl groups can be substituted one or more times with various substituents such as those listed above.

Heterocyclylalkyl is an alkyl group as defined above in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to the heterocyclyl group as defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, heterocyclyl, or both the alkyl and heterocyclyl portions of the group. Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above.

A heteroaralkyl is an alkyl group as defined above, wherein a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined above. Substituted heteroaralkyl groups may be substituted at the alkyl, heteroaryl, or both the alkyl and heteroaryl portions of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those enumerated above.

Carbon-containing groups described herein having two or more points of attachment (i.e., divalent, trivalent, or multivalent) within the compounds of the present technology are designated by the use of the suffix "ene". For example, a divalent alkyl group is an alkylene group, a divalent heteroalkyl group is a heteroalkylene group, a divalent aryl group is an arylene group, a divalent heteroaryl group is a divalent heteroarylene group, and the like. Such divalent groups may also be substituted with one or more substituents, for example with one or two substituents. In any embodiment, the substituent is an oxo group and may, for example, provide a divalent group having one or two ketones, esters, or amides, depending on whether the carbon adjacent to the heteroatom is substituted with an oxo group. The heteroatoms may also have chemically permissible substituents. For example, the sulfur atom may be substituted with one or two oxo groups to form a sulfoxide or sulfone. However, substituted groups having a single point of attachment to the compounds of the present technology are not referred to using the "ene" name. Thus, for example, chloroethyl is not referred to herein as chloroethylene. Cyclic groups such as aralkylene, arylheteroalkylene, heterocyclylalkylene, and the like, which also have an acyclic (i.e., straight or branched) portion, can have a point of attachment on only the acyclic portion or on both the cyclic and acyclic portions. For example, divalent heterocyclylheteroalkylene groups, such as the following:

there may be a point of attachment at each heteroalkylene moiety of the group, or there may be one point of attachment on the heteroalkylene moiety and another point of attachment on the heterocyclic moiety. Divalent cyclic groups substituted with acyclic groups but having two points of attachment on the ring system are substituted cycloalkenes. For example, the 2-methylphenyl radical with the attachment points at positions 1 and 4 is an arylene radical, rather than an aralkylene radical.

An alkoxy group is a hydroxyl group (-OH) in which the bond to a hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.

As used herein, the terms "alkanoyl" and "alkanoyloxy" can refer to-c (O) -alkyl and-O-c (O) -alkyl, respectively, each containing 2 to 5 carbon atoms. Similarly, "aroyl" and "aroyloxy" refer to-C (O) -aryl and-O-C (O) -aryl.

As used herein, the term "protecting group" refers to a chemical group that exhibits the following properties: 1) selectively reacting with the desired function in good yield to give a protected substrate that is stable to the intended reaction for which protection is desired; 2) can be selectively removed from the protective substrate to produce the desired function; and 3) can be removed in good yield by a reagent compatible with another functional group present or generated in such an intended reaction. Examples of suitable protecting Groups can be found in Greene et al, (1991) Protective Groups in Organic Synthesis, 3 rd edition (John Wiley & Sons, Inc.) which is hereby incorporated by reference in its entirety for any and all purposes as if fully set forth herein. The hydroxyl protecting group includes ethers, esters, carbonates, and the like. Hydroxyl protecting groups include, but are not limited to: methoxymethyl ether (MOM), Methoxyethoxymethyl Ether (MEM), benzyloxymethyl ether (BOM), tetrahydropyranyl ether (THP), benzyl ether (Bn), p-methoxybenzyl ether, trimethylsilyl ether (TMS), Triethylsilyl Ether (TES), triisopropylsilyl ether (TIPS), tert-butyldimethylsilyl ether (TBDMS), tert-butyldiphenylsilyl ether (TBDPS), o-nitrobenzyl ether, p-nitrobenzyl ether, trityl ether, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, benzoate (Bz), allyl carbonate (alloc), Dimethylthiocarbamate (DMTC), benzyl carbonate (Cbz), tert-butyl carbonate (Boc), and 9- (fluorenylmethyl) carbonate (Fmoc). Amino protecting groups include, but are not limited to, carbamate, sulfonyl, silyl, and the like. For example, amino protecting groups include mesitylenesulfonyl chloride (Mts), benzyloxycarbonyl (Cbz or Z), tert-butoxycarbonyl (Boc), tert-butyldimethylsilyl (TBS or TBDMS), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), tosyl, phenylsulfonyl, 2-pyridylsulfonyl or suitable photolabile protecting groups such as 6-nitrovaleryloxycarbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, α -dimethyldimethoxybenzyloxycarbonyl (DDZ), 5-bromo-7-nitroindolinyl, and the like. Amino protecting groups susceptible to acid-mediated removal include, but are not limited to, Boc and TBDMS. Amino protecting groups that are resistant to acid-mediated removal and sensitive to hydrogen-mediated removal include, but are not limited to, Alloc, Cbz, nitro, and 2-chlorobenzyloxycarbonyl. The amino group that is sensitive to base-mediated removal but resistant to acid-mediated removal comprises Fmoc.

The terms "aryloxy" and "arylalkoxy" refer to a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to an oxygen atom at an alkyl group, respectively. Examples include, but are not limited to, phenoxy, naphthoxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.

As used herein, the term "carboxylate" refers to the-COOH group.

As used herein, the term "ester" refers to-COOR⁷⁰and-C (O) O-G groups. R⁷⁰Is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. G is a carboxylate protecting group. Carboxylate protecting groups are well known to those of ordinary skill in the art. An exhaustive list of protecting groups for carboxylate functional groups can be found in protective groups in organic synthesis, Greene, t.w.; wuts, p.g.m., john willi publishing company, new york, (3 rd edition, 1999), which may be added or removed using the procedures set forth therein.

The term "amide" (or "amide group") comprises C-and N-amide groups, i.e., -C (O) NR, respectively⁷¹R⁷²and-NR⁷¹C(O)R⁷²A group. R⁷¹And R⁷²Independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Thus, amide groups include, but are not limited to, carbamoyl (-C (O) NH)₂) And a carboxamide group (-NHC (O) H). In any embodiment, the amide is-NR⁷¹C(O)-(C_1-5Alkyl) and the group is referred to as "carbonylamino", and in other embodiments, the amide is-nhc (o) -alkyl and the group is referred to as "alkanoylamino".

As used herein, the term "nitrile" or "cyano" refers to a-CN group.

The carbamate groups comprise N-and O-carbamate groups, i.e., -NR, respectively⁷³C(O)OR⁷⁴and-OC (O) NR⁷³R⁷⁴A group. R⁷³And R⁷⁴Independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. R⁷³Or may be H.

As used herein, the term "amine" (or "amino") refers to-NR⁷⁵R⁷⁶Group, wherein R⁷⁵And R⁷⁶Independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. In any embodiment, the amine is alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH₂Methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino or benzylamino.

The term "sulfonamide" encompasses S-and N-sulfonamide groups, i.e., -SO₂NR⁷⁸R⁷⁹and-NR⁷⁸SO₂R⁷⁹A group. R⁷⁸And R⁷⁹Independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Thus, sulfonamide groups include, but are not limited to, sulfamoyl (-SO)₂NH₂). In any of the embodiments herein, the sulfonamide group is-NHSO₂-alkyl and is known as "alkylsulfonylamino".

The term "thiol" refers to the-SH group, while "sulfide" comprises the-SR⁸⁰The group "sulfoxide" comprises-S (O) R⁸¹The group "sulfone" contains-SO₂R⁸²And sulfonyl contains-SO₂OR⁸³。R⁸⁰、R⁸¹、R⁸²And R⁸³Each independently is substituted as defined hereinOr unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl groups. In any embodiment, the sulfide is alkylthio, -S-alkyl.

The term "urea" refers to-NR⁸⁴-C(O)-NR⁸⁵R⁸⁶A group. R⁸⁴、R⁸⁵And R⁸⁶The groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

The term "amidine" refers to-C (NR)⁸⁷)NR⁸⁸R⁸⁹and-NR⁸⁷C(NR⁸⁸)R⁸⁹Wherein R is⁸⁷、R⁸⁸And R⁸⁹Each independently is hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

The term "guanidine" refers to-NR⁹⁰C(NR⁹¹)NR⁹²R⁹³Wherein R is⁹⁰、R⁹¹、R⁹²And R⁹³Each independently is hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

The term "enamine" refers to-C (R)⁹⁴)＝C(R⁹⁵)NR⁹⁶R⁹⁷and-NR⁹⁴C(R⁹⁵)＝C(R⁹⁶)R⁹⁷Wherein R is⁹⁴、R⁹⁵、R⁹⁶And R⁹⁷Each independently is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl as defined herein.

As used herein, the term "halogen" or "halo" refers to bromine, chlorine, fluorine, or iodine. In any embodiment, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.

As used herein, the term "hydroxy" may refer to-OH or its ionized form-O^-. "hydroxyalkyl" is an alkyl group substituted with a hydroxyl group,such as HO-CH₂-。

The term "imide" refers to-C (O) NR⁹⁸C(O)R⁹⁹Wherein R is⁹⁸And R⁹⁹Each independently is hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

The term "imine" means-CR¹⁰⁰(NR¹⁰¹) and-N (CR)¹⁰⁰R¹⁰¹) Group, wherein R¹⁰⁰And R¹⁰¹Each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R is¹⁰⁰And R¹⁰¹Not both hydrogen.

As used herein, the term "nitro" refers to-NO₂A group.

As used herein, the term "trifluoromethyl" refers to-CF₃。

As used herein, the term "trifluoromethoxy" refers to-OCF₃。

The term "azido" refers to-N₃。

The term "trialkylammonium" refers to-N (alkyl)₃A group. Trialkylammonium groups are positively charged and therefore typically have an associated anion, such as a halide anion.

The term "isocyano" refers to — NC.

The term "isothiocyanato" refers to-NCS.

Pharmaceutically acceptable salts of the compounds described herein are within the skill of the present invention and include acid or base addition salts that retain the desired pharmacological activity and are not biologically undesirable (e.g., the salts are not unduly toxic, allergic, or irritant, and are bioavailable). When the compounds of the present technology have a basic group such as an amino group, pharmaceutically acceptable salts can be formed from inorganic acids (e.g., hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginic acid, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid)Tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compounds of the present technology have an acidic group such as a carboxylic acid group, they can be reacted with metals such as basic and alkaline earth metals (e.g., Na)⁺、Li⁺、K⁺、Ca²⁺、Mg²⁺、Zn²⁺) Ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine, and ornithine). Such salts may be prepared in situ during isolation and purification of the compounds or by reacting a purified compound in free base or free acid form, respectively, with a suitable acid or base, respectively, and isolating the salt thus formed.

Those skilled in the art will appreciate that compounds of the present technology may exhibit tautomeric, conformational isomeric, geometric, and/or stereoisomeric phenomena. Since the formula diagrams within the specification and claims may represent only one possible tautomeric, conformational isomeric, stereochemical or geometric isomeric form, it is to be understood that the present technology encompasses any tautomeric, conformational isomeric, stereochemical and/or geometric isomeric form of the compound, as well as mixtures of these various forms, having one or more of the utilities described herein.

"tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The presence and concentration of isomeric forms will depend on the environment in which the compound is placed and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, guanidine can assume the following isomeric forms, also called tautomers of each other, in protic organic solutions:

since the representative compounds are limited by the structural formulae, it is understood that all chemical formulae of the compounds described herein represent all tautomeric forms of the compounds and are within the technical scope of the invention.

Unless a particular stereochemistry is explicitly indicated, stereoisomers (also referred to as optical isomers) of compounds encompass all chiral, diastereomeric and racemic forms of the structure. Thus, the compounds used in the present technology comprise enriched or resolved optical isomers at any or all asymmetric atoms, as may be apparent from the figures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers, may be separated or synthesized so as to be substantially free of their enantiomeric or diastereomeric counterparts, and such stereoisomers are within the scope of the present technology.

In one aspect, the present technology provides a compound of formula I as described above. In any embodiment, the compound of formula I is a compound of formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or of said stereoisomer of said compound:

variable joints X, q, R¹、R²、R³、R⁴And R⁵Can be defined as having any of the values disclosed herein.

In any embodiment of the compounds of formula I or IA, X may be O. In any other embodiment, X may be CH₂. In still other embodiments, X may be NR⁶. In any embodiment, q may be 2. In any embodiment, q can be 1. In any embodiment, q may be 0. In any embodiment, the compound has the structure of any one of formulas IB, IC, ID, IE, IF, or IG, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or a stereoisomer of the compound:

as noted above, in any embodiment of compounds of formula I (including but not limited to compounds of formula IA, IB, IC, ID, IE, IF, or IG), the linker is a divalent moiety selected from a bond, an oxy moiety, or an optionally substituted moiety selected from the group consisting of: amino, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, cycloalkylheteroalkylene, arylene, aralkylene, arylheteroalkylene, heterocyclylene, heterocyclylalkylene, heteroarylene, heteroarylalkylene, and heteroarylheteroalkylene. In any embodiment, the linker is an optionally substituted moiety selected from the group consisting of: amino, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, cycloalkylheteroalkylene, arylene, aralkylene, arylheteroalkylene, heterocyclylene, heterocyclylalkylene. In any embodiment, the linker is an optionally substituted heterocyclylheteroalkylene, heteroarylene, heteroarylalkylene, or heteroarylheteroalkylene. In any embodiment, the linker is optionally substituted with one, two, three, or four oxo groups. In any embodiment, the linker is optionally substituted on carbon or sulfur and includes one or two carbonyl groups or one or two sulfonyl groups.

In any embodiment, the linker may be selected from the group consisting of: heteroalkylene, arylene, aralkylene, arylheteroalkylene, heterocyclylalkylene, and heterocyclylalkylene groups. In any embodiment herein, the linker may be selected from a bond, an amino group, or an optionally substituted heteroalkylene group. In any embodiment herein, the linker may be selected from the group consisting of: c₂-C₁₂Polyalkylene oxides, phenylalkylenes, phenylheteroalkylenes, piperazinylalkylenes, and piperazinylalkylenes. For example, the linker may be selected from the group consisting of: a bond,

Wherein

m is 0, 1,2,3,4, 5 or 6; and is

n is 1,2,3,4, 5, 6.

Further, in any embodiment that includes such a linker, n can also be 1,2, or 3 and/or m can be 0, 1,2,3, or 4. In any embodiment, m may be 0 and/or n may be 1. In any embodiment, the linker can be a bond, -NH-or-C (O) NH-.

In any embodiment, the joint may beWherein n is 1,2,3,4, 5, 6. For example, n may be 2 or may be 3.

In any embodiment, the joint may beAnd m may be 0, 1,2,3,4, 5 or 6. For example, m may be 1,2,3 or 4.

In any embodiment, the joint may beWherein n is 1,2,3,4, 5, 6. For example, n may be 2 or 3.

In any embodiment, the joint may beOrAnd wherein m may be 0, 1,2,3,4, 5 or 6. In any such embodiment, m may be 0 or 1.

Any of the embodiments of the compounds of formula I (including but not limited to compounds of formula IA, IB, IC, ID, IE, IF or IG)In the examples, R¹And R²And may be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl or cyclopentyl. In any embodiment, R³And may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In any embodiment, R⁴May be H. In any embodiment, R⁴Can be an amino protecting group as defined herein, for example, a carbamate such as, but not limited to, benzyloxycarbonyl, t-butoxycarbonyl, fluorenyloxycarbonyl, or allyloxycarbonyl. In any embodiment herein, R⁶May be H. In any embodiment, R⁶Can be an amino protecting group as defined herein, for example, a carbamate such as, but not limited to, benzyloxycarbonyl, t-butoxycarbonyl, fluorenyloxycarbonyl, or allyloxycarbonyl. In any embodiment of compounds of formula I (including but not limited to compounds of formula IA, IB, IC, ID, IE, IF or IG), R²And may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In any embodiment, R¹May be cyclohexyl or isopropyl, and/or R²May be methyl, and/or R³May be methyl, and/or R⁴May be H, and/or R⁵May be H. In any embodiment, R¹May be the same or different at each occurrence of R²May be the same or different at each occurrence of R³May be the same or different at each occurrence of R⁴May be the same or different at each occurrence of R⁵May be the same or different at each occurrence of, and/or R⁶May be the same or different at each occurrence.

In one aspect of the present technology, there is provided a composition comprising aspects and embodiments of a compound of formula I (including but not limited to compounds of formula IA, IB, IC, ID, IE, IF, or IG) in any one of its aspects and embodiments, and a pharmaceutically acceptable carrier. In a related aspect, there is provided a pharmaceutical composition comprising an effective amount of a compound of the aspects and embodiments of the compound of formula I (and without limitation a compound of formula IA, IB, IC, ID, IE, IF or IG) for use in the treatment of a cancer or viral infection mediated by IAPs, such as cIAP. The cancer or viral infection mediated by IAP can be ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis b infection.

In another aspect, a method is provided comprising administering to a subject having a cancer or viral infection mediated by IAPs, e.g., cIAP, an effective amount of a compound of any of the aspects and embodiments of a compound of formula I (including but not limited to compounds of formula IA, IB, IC, ID, IE, IF, or IG) or administering a pharmaceutical composition comprising an effective amount of a compound of any of the aspects and embodiments of a compound of formula I. The cancer or viral infection mediated by IAP can be ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis b infection.

An "effective amount" refers to the amount of a compound or composition required to produce the desired effect. One example of an effective amount comprises an amount or dose that results in an acceptable degree of toxicity and bioavailability for therapeutic (pharmaceutical) use, including but not limited to treatment of IAP-mediated cancer or viral infection. The cancer or viral infection mediated by IAP can be ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis b infection. Another example of an effective amount comprises an amount or dose capable of reducing symptoms associated with a viral infection, such as viral titer. As used herein, a "subject" or "patient" is a mammal, such as a cat, dog, rodent, or primate. Typically, the subject is a human, and preferably a human having or suspected of having a cancer or viral infection mediated by IAP, such as, but not limited to, ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis b infection. The terms "subject" and "patient" are used interchangeably.

Accordingly, the present technology provides pharmaceutical compositions and medicaments that include any of the compounds disclosed herein (e.g., a compound of formula I, including but not limited to compounds of formula IA, IB, IC, ID, IE, IF, or IG), and a pharmaceutically acceptable carrier or one or more excipients or fillers. The compositions may be used in the methods and treatments described herein. Such compositions and medicaments comprise a therapeutically effective amount of any compound as described herein, including but not limited to compounds of formula I (or formula IA, IB, IC, ID, IE, IF, or IG). The pharmaceutical compositions may be packaged in unit dosage form.

Pharmaceutical compositions and medicaments may be prepared by mixing one or more compounds of the present technology, stereoisomers thereof and/or pharmaceutically acceptable salts thereof with pharmaceutically acceptable carriers, excipients, binders, diluents and the like, for use in the prevention and treatment of conditions associated with the effects of increased plasma and/or hepatic lipid content. The compounds and compositions described herein may be used in the preparation of formulations and medicaments for the prevention or treatment of cancer or viral infections associated with or mediated by IAPs, including but not limited to those described herein. Such compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions. The compositions of the present invention may be formulated for a variety of routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or by an implantable reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injections. The following dosage forms are given by way of example and should not be construed as limiting the technology of the present invention.

For oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, caplets and sachets are acceptable as solid dosage forms. These dosage forms may be prepared, for example, by mixing one or more compounds of the present technology, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as starch or other additives. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, polydextrose, starch, agar, alginate, chitin, chitosan, pectin, tragacanth, acacia (gum arabic), gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, the oral dosage form may contain other ingredients to aid administration, such as non-reactive diluents, or lubricating agents (e.g., magnesium stearate), or preservatives (e.g., parabens or sorbic acid), or antioxidants (e.g., ascorbic acid, tocopherol or cysteine), disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents, or flavoring agents. The tablets and pills may be further treated with suitable coating materials known in the art.

Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions and solutions, which may contain non-reactive diluents such as water. The drug formulations and medicaments can be prepared as liquid suspensions or solutions using sterile liquids such as, but not limited to, oils, water, alcohols, and combinations of these liquids. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents may be added for oral or parenteral administration.

As mentioned above, the suspension may comprise an oil. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. The suspension formulation may also contain fatty acid esters such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. The suspension formulation may include alcohols such as, but not limited to, ethanol, isopropanol, cetyl alcohol, glycerol, and propylene glycol. Ethers (such as, but not limited to, poly (ethylene glycol)), petroleum hydrocarbons (such as mineral oil and petrolatum), and water may also be used in the suspension formulation.

Injectable dosage forms generally comprise aqueous or oily suspensions, which may be prepared using suitable dispersing or wetting agents and suspending agents. Injectable dosage forms may be in the form of a solution phase or a suspension, prepared with a solvent or diluent. Acceptable solvents or vehicles include sterile water, Ringer's solution, or isotonic aqueous saline solution. Alternatively, sterile oils may be employed as a solvent or suspending agent. Typically, the oil or fatty acid is non-volatile and comprises natural or synthetic oils, fatty acids, mono-, di-or triglycerides.

For injection, the pharmaceutical formulation and/or the medicament may be a powder suitable for reconstitution with a suitable solution as described above. Examples of such powders include, but are not limited to, freeze-dried powders, spin-dried powders or spray-dried powders, amorphous powders, granules, precipitates or microparticles. For injection, the formulation may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations of these.

The compounds of the present technology can be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders or aerosols containing any suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobials, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The carrier and stabilizer vary with the requirements of the particular compound, but typically comprise a non-ionic surfactant (Tweens, Pluronics or polyethylene glycol), harmless proteinaceous serum albumin, sorbitan esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars or sugar alcohols. The compounds of the present technology are typically delivered by inhalation using both aqueous and non-aqueous (e.g. in fluorocarbon propellants) aerosols.

Dosage forms for topical (including buccal and sublingual) or transdermal administration of the compounds of the present technology include powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and with any preservatives or buffers that may be required. Powders and sprays can be prepared, for example, with excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Ointments, pastes, creams and gels may also contain excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Absorption enhancers may also be used to increase the flux of the compounds of the present technology across the skin. The rate of such flow can be controlled by providing a rate controlling membrane (e.g., as part of a transdermal patch) or dispersing the compound in a polymer matrix or gel.

In addition to the above representative dosage forms, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore encompassed by the present technology. Such excipients and carriers are described, for example, "Remingtons Pharmaceutical Sciences," mark publishing company, inc (Mack pub. co.), n.j. incorporated herein by reference.

As described below, the formulations of the present technology can be designed in short-acting, rapid-release, long-acting, and sustained-release forms. Thus, the drug formulation may also be formulated for controlled release or slow release.

The compositions of the invention may also include, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a long term storage and/or delivery effect. Thus, the drug formulation and drug may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously in the form of a depot injection or implant (e.g., a stent). Such implants may use known inert materials such as silicones and biodegradable polymers.

The specific dose can be adjusted according to the disease condition, age, body weight, general health, sex and diet, administration interval, administration route, secretion rate and drug combination of the subject. It is well within the limits of routine experimentation to contain an effective amount of any of the above dosage forms and, therefore, is well within the scope of the present technology.

The effective amount can be readily determined by one skilled in the art by simply administering the compound of the present technology to the patient in an increased amount until, for example, a desired therapeutic response is observed. The compounds of the present technology may be administered to a patient at a dosage in the range of about 0.1 to about 1,000mg per day. For a normal adult human having a body weight of about 70kg, a dosage in the range of about 0.01 to about 100mg per kg body weight per day is sufficient. However, the particular dosage employed may be varied or adjusted as desired by one of ordinary skill in the art. For example, the dosage may depend on a variety of factors, including patient need, severity of the condition being treated, and the pharmacological activity of the compound used. Determination of the optimal dose for a particular patient is well known to those skilled in the art.

The therapeutic effectiveness of a treatment according to the present technology can be readily determined using a variety of assay and model systems.

The effectiveness of the compositions and methods of the present technology can also be demonstrated by a reduction in the symptoms of hyperlipidemia, such as a reduction in triglycerides in the bloodstream. The effectiveness of the compositions and methods of the present technology can also be evidenced by a reduction in the signs and symptoms of chronic liver disease, hypercholesterolemia, obesity, metabolic syndrome, cardiovascular disease, gastrointestinal disease, atherosclerosis, renal disease, colorectal cancer, and stroke.

For each of the specified conditions described herein, the test subject will exhibit a 10%, 20%, 30%, 50% or greater reduction, up to 75-90%, or 95% or greater reduction, in one or more symptoms caused by or associated with the disorder in the subject, as compared to a placebo-treated or other suitable control subject.

In one aspect, a compound of the present technology is administered to a patient in an amount or dosage suitable for therapeutic use. In general, the unit dosage of a compound comprising the techniques of the present invention will vary depending upon patient considerations. Such considerations include, for example, age, regimen, condition, gender, extent of disease, contraindications, concomitant therapy, and the like. Exemplary unit dosages based on such considerations may also be adjusted or modified by the practitioner of ordinary skill in the art. For example, a unit dose for a patient comprising a compound of the technology may be 1X 10^-4g/kg to 1g/kg, preferably 1X 10^-3g/kg to 1.0 g/kg. The dose of the compounds of the present technology may also vary from 0.01mg/kg to 100mg/kg, or preferably from 0.1mg/kg to 10 mg/kg.

The examples herein are provided to illustrate the advantages of the present technology and to further assist those of ordinary skill in the art in making or using the compounds or salts, pharmaceutical compositions, derivatives, solvates, metabolites, prodrugs, racemic mixtures, or tautomeric forms thereof of the present technology. The examples herein are also presented in order to more fully illustrate preferred aspects of the present technology. The examples should in no way be construed as limiting the scope of the present technology as defined by the appended claims. Examples may include or incorporate any of the variations, aspects, or aspects of the present technology described above. The above-described variations, aspects, or aspects may also each further comprise or incorporate variations of any or all of the other variations, aspects, or aspects of the present technology.

Examples of the invention

General Synthesis and analytical details

All reagents and materials were obtained or purchased from commercial suppliers.

Representative general synthetic schemes

The following compounds are prepared or may be prepared using procedures known to those of ordinary skill in the art as indicated in the synthetic schemes below.

List of abbreviations

ACN acetonitrile

AcOH acetic acid

Ad₂PBu butyl di-1-adamantylphosphine

t-Bu tert-butyl

t-BuXPhos 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl

CDI 1,1' -carbonyldiimidazole

DCM dichloromethane

DIAD diisopropyl azodicarboxylate

DMF dimethyl formamide

DMA dimethyl acetamide

DMAP 4-dimethylaminopyridine

DMP tert-2, 2-dimethoxypropane

DMSO dimethyl sulfoxide

EDC 3- (ethyliminomethyleneamino) -N, N-dimethylpropan-1-amine

Et Ethyl group

HATU (1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide hexafluorophosphate)

LAH lithium aluminum hydride

Me methyl group

MeCN acetonitrile

NCS N-chlorosuccinimide

PCC pyridinium chlorochromate

Pd₂(dba)₃Tris (diphenylmethanone acetone) dipalladium

Pd(dppf)Cl₂[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)

PE Petroleum Ether

Ph phenyl

Py pyridine

Ruphos 2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl

STAB sodium triacetoxyborohydride

TEA Triethylamine

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl group

TsCl tosyl chloride

TsOH p-toluenesulfonic acid

Xantphos 4, 5-bis (diphenylphosphino) -9, 9-dimethyldibenzopyran

Example 1: synthesis of Compound I:

(2S) -1- [ (2S) -2- [ [ (benzyloxy) carbonyl]Amino group]-2-Cyclohexylacetyl]Pyrrolidine-2-carboxylic acid tert-butyl ester (compound I-1): to (S) - [ [ (benzyloxy)Carbonyl radical]Amino group](cyclohexyl) acetic acid (10.0g, 34.49mmol) in DMF (120mL) was added (2S) -pyrrolidine-2-carboxylic acid tert-butyl ester (6.6g, 38.8mmol) and DIEA (15.6g, 121 mmol). Then in N₂HATU (29.1g, 76.5mmol) was added to the mixture at 0 ℃. The mixture was stirred at 0 ℃ for 2 hours. After the reaction was complete, the mixture was purified by reverse phase flash column chromatography with CH₃CN/H₂O (1/0, v/v) to give the title compound as a pale yellow oil (16.2g, 100%). LCMS (ESI, M/z) [ M + H ]]⁺＝445.3。

(2S) -1- [ (2S) -2-amino-2-cyclohexylacetyl group]Pyrrolidine-2-carboxylic acid tert-butyl ester (compound I-2): to a solution of compound I-1(16.2g, 36.4mmol) in EtOAc (200mL) and EtOH (150mL) was added Pd/C (8.0g, dry). The mixture is left at room temperature in H₂Stirred for 16 hours. After completion of the reaction, the mixture was filtered. The filtrate was evaporated in vacuo to give the title compound (10.3g, crude product) as a colorless oil. LCMS (ESI, M/z) [ M + H ]]⁺＝311.2。

(2S) -1- [ (2S) -2- [ (2S) -2- [ [ (benzyloxy) carbonyl](methyl) amino group]Propionamido group]-2-Cyclohexylacetyl]Pyrrolidine-2-carboxylic acid tert-butyl ester (compound I-3): to a solution of compound I-2(10.3g, 33.2mmol) in DMF (130mL) was added (2S) -2- [ [ (benzyloxy) carbonyl](methyl) amino group]Propionic acid (8.8g, 37.5mmol) and DIEA (13.6mL, 78.1 mmol). Then in N₂HATU (25.8g, 68.0mmol) was added to the mixture at 0 ℃. The mixture was stirred at 0 ℃ for 2 hours. After the reaction was complete, the mixture was purified by reverse phase flash column chromatography with CH₃CN/H₂O (1/0, v/v) to give the title compound as a pale yellow oil (16.3g, 92%). LCMS (ESI, M/z) [ M + H ]]⁺＝530.3。

(2S) -1- [ (2S) -2- [ (2S) -2- [ [ (benzyloxy) carbonyl](methyl) amino group]Propionamido group]-2-Cyclohexylacetyl]Pyrrolidine-2-carboxylic acid (compound I-4): to a solution of compound I-3(16.3g, 30.8mmol) in DCM (150mL) was added TFA (50 mL). The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was evaporated in vacuo. The residue was purified by reverse phase flash column chromatography over CH₃CN/H₂O(60/40，v/v)Purification to give the title compound as a pale yellow solid (13.2g, 90%). LCMS (ESI, M/z) [ M + H ]]⁺＝474.3。

N- [ (1R) -5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl]T-butyl carbamate (compound I-5): to a solution of (1R) -5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-amine (5.0g, 22.1mmol) in DCM (100mL) was added TEA (5.3g, 52.4mmol) and Boc₂O (6.2g, 28.4 mmol). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was evaporated in vacuo. The residue was purified by flash column chromatography with petroleum ether/EtOAc (4/1, v/v) to give the title compound as a white solid (7.6g, 100%). LCMS (ESI, M/z) [ M + H ]]⁺＝326.1。

N- [ (1R) -5-hydroxy-1, 2,3, 4-tetrahydronaphthalen-1-yl]T-butyl carbamate (compound I-6): mixing compound I-5(5.2g, 15.9mmol), KOH (2.5g, 44.6mmol) and Pd₂(dba)₃A mixture of (1.5g, 1.70mmol) and t-BuXPhos (1.4g, 3.34mmol) in dioxane (80mL) and H₂O (4mL) at 100 ℃ for 4 hours. Subjecting the mixture to hydrogenation with H₂Dilute O and extract with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with petroleum ether/EtOAc (75/25, v/v) and then by reverse phase flash column chromatography with CH₃CN/H₂O (60/40, v/v) to give the title compound as a white solid (2.5g, 59%). LCMS (ESI, M/z) [ M + H ]]⁺＝264.2。

N- [ (1R) -5- [ (5- [ [ (5R) -5- [ (tert-butoxycarbonyl) amino ] carbonyl ] amino]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]Pentyl) oxy group]-1,2,3, 4-tetrahydronaphthalen-1-yl]T-butyl carbamate (compound I-7): compound I-6(502mg, 1.90mmol), 4-methylbenzenesulfonic acid 5- [ (4-methylbenzenesulfonyl) oxy group]Pentyl ester (408mg, 0.99mmol) and K₂CO₃A mixture of (1.1g, 8.10mmol) in DMF (15mL) was heated at 65 ℃ for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and then filtered. Subjecting the filtrate to reverse phase flash column chromatography with CH₃CN/H₂O (1/0, v/v) purification to give the title compound as an off-white solid (520mg, 45%)。LCMS(ESI,m/z):[M+H]⁺＝595.4。

(1R) -5- [ (5- [ [ (5R) -5-amino-5, 6,7, 8-tetrahydronaphthalen-1-yl)]Oxy radical]Pentyl) oxy group]1,2,3, 4-tetrahydronaphthalen-1-amine dihydrochloride (compound I-8): to a solution of compound I-7(520mg, 0.87mmol) in dioxane (3mL) was added HCl/dioxane (8.0mL, 4 mol/L). The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was evaporated in vacuo to give the title compound (706mg, crude product) as a pale yellow solid. LCMS (ESI, M/z) [ M + H ]]⁺＝395.2。

N- [ (1S) -1- [ [ (1S) -2- [ (2S) -2- [ [ (1R) -5- [ (5- [ [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- [ [ (benzyloxy) carbonyl ] carbonyl](methyl) amino group]Propionamido group]-2-Cyclohexylacetyl]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]Pentyl) oxy group]-1,2,3, 4-tetrahydronaphthalen-1-yl]Carbamoyl radical]Pyrrolidin-1-yl radical]-1-cyclohexyl-2-oxoethyl group]Carbamoyl radical]Ethyl radical]-benzyl N-methylcarbamate (Compound I-9): to a solution of compound I-4(706mg, 1.49mmol) in DMF (15mL) was added compound I-8(1.0g, 2.16mmol) and DIEA (2.0mL, 11.5 mmol). Then in N₂HATU (1.4g, 3.76mmol) was added to the mixture at 0 ℃. The mixture was stirred at 0 ℃ for 2 hours. After completion of the reaction, the reaction mixture was purified by reverse phase flash column chromatography with CH₃CN/H₂O (1/0, v/v) and then purified by flash column chromatography with DCM/MeOH (94/6, v/v) to give the title compound as an off-white solid (580mg, 29%). LCMS (ESI, M/z) [ M + H ]]⁺＝1305.7。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido]Acetyl group]-N- [ (1R) -5- [2- [4- (2- [ [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propanamido]Acetyl group]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]Ethyl) phenyl]Ethoxy radical]-1,2,3, 4-tetrahydronaphthalen-1-yl]Pyrrolidine-2-carboxamide (compound I): to a solution of compound I-9(580mg, 0.44mmol) in EtOAc (15mL) and EtOH (20mL) was added Pd/C (370mg, dry). The mixture is left at room temperature in H₂Stirred for 16 hours. After completion of the reaction, the mixture was filtered. The filtrate was evaporated in vacuo. Passing the residue through preparative form HPLC was purified under the following conditions: column: XBridge prep OBD C18 column, 30 × 150mm, 5 um; mobile phase A: water (10mmol/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 49% B to 57% B in 7 minutes; 254 nm; room temperature: 8.5 min to give the title compound as a white solid (74.9mg, 16%). LCMS (ESI, M/z) [ M + H ]]⁺＝1037.8。¹H NMR(400MHz,DMSO-d₆,ppm):δ8.06(d,J＝8.4Hz,2H),7.84(d,J＝9.2Hz,2H),7.13-7.02(m,2H),6.88-6.75(m,4H),4.93-4.81(m,2H),4.48-4.37(m,2H),4.33-4.26(m,2H),4.03-3.89(m,4H),3.76-3.66(m,2H),3.65-3.55(m,2H),2.98-2.88(m,2H),2.61-2.53(m,3H),2.16(s,6H),2.09-1.90(m,6H),1.88-1.53(m,31H),1.19-0.85(m,16H)。

Following the procedure described above for example 1 and substituting appropriate reagents, starting materials and purification methods known to those skilled in the art, the compounds listed below were prepared.

(S) -1- ((S) -2- (methylamino) propionamido) -2- (tetrahydro-2H-pyran-4-yl) acetyl) -N- ((R) -5- ((5- (((R) -5- ((S) -1- ((S) -2- (methylamino) propionamido) -2- (tetrahydro-2H-pyran-4-yl) acetyl) pyrrolidine-2-carboxamido) -5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) pentyl) oxy) -1,2,3, 4-tetrahydronaphthalen-1-yl) pyrrolidine-2-carboxamide (compound I-a):

LCMS(ESI,m/z):[M+H]⁺＝1041.6。¹H NMR(300MHz,DMSO-d₆):δ8.22-8.09(m,2H),8.01-7.89(m,2H),7.18-7.03(m,2H),6.91-6.77(m,4H),4.99-4.80(m,2H),4.60-4.45(m,2H),4.40-4.27(m,2H),4.07-3.94(m,4H),3.93-3.53(m,8H),3.30-3.18(m,4H),3.05-2.91(m,2H),2.69-2.55(m,4H),2.25-2.14(m,6H),2.12-1.89(m,8H),1.89-1.53(m,22H),1.39-1.19(m,4H),1.17-1.05(m,6H)。

(2S,4S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) -N- ((R) -5- ((5- (((R) -5- ((2S,4S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) -4-hydroxypyrrolidine-2-carboxamido) -5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) pentyl) oxy) -1,2,3, 4-tetrahydronaphthalen-1-yl) -4-hydroxypyrrolidine-2-carboxamide (compound I-B):

LCMS(ESI,m/z):[M+H]⁺＝1069.9。¹H NMR(300MHz,DMSO-d₆):δ8.30-8.14(m,2H),7.99-7.86(m,2H),7.15-7.01(m,2H),6.95-6.85(m,2H),6.84-6.77(m,2H),5.47-5.35(m,2H),4.98-4.81(m,2H),4.42-4.30(m,4H),4.28-4.18(m,2H),4.07-3.96(m,4H),3.95-3.83(m,2H),3.50-3.40(m,4H),3.05-2.94(m,2H),2.68-2.56(m,4H),2.37-2.24(m,2H),2.23-2.13(m,6H),1.90-1.55(m,28H),1.18-0.90(m,16H)。

(2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] propionyl ] -N- [ (1R) -5- [ (5- [ [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] propionyl ] pyrrolidine-2-amido ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] oxy ] pentyl) oxy ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound I-C):

LCMS(ESI,m/z):[M+H]⁺＝901.5。¹H NMR(300MHz,DMSO-d₆):δ8.55-7.86(m,4H),7.21-7.00(m,2H),6.99-6.67(m,4H),5.02-4.75(m,2H),4.73-4.48(m,2H),4.47-4.19(m,2H),4.11-3.87(m,4H),3.67-3.55(m,2H),3.03-2.83(m,2H),3.72-2.55(m,4H),2.32-1.50(m,32H),1.32-1.00(m,12H)。

(2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (1R) -5- [ (5- [ [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] oxy ] pentyl) oxy ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compounds I-D):

LCMS(ESI,m/z):[M+H]⁺＝929.7。¹H NMR(300MHz,DMSO-d₆):δ8.50-8.05(m,2H),8.01-7.83(m,2H),7.17-7.04(m,2H),6.90-6.77(m,4H),4.98-4.85(m,2H),4.59-4.46(m,2H),4.40-4.29(m,2H),4.09-3.91(m,4H),3.73-3.50(m,4H),3.03-2.89(m,2H),2.67-2.56(m,4H),2.18(s,6H),2.14-1.49(m,28H),1.19-1.05(m,6H),0.97-0.78(m,6H)。

(2S,4S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -5- [ [ (2E) -4- [ [ (5R) -5- [ (2S,4S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -4-hydroxypyrrolidine-2-amido ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] oxy ] but-2-en-1-yl ] oxy ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] -4-hydroxypyrrolidine-2-me thylol Amide (Compounds I-E):

LCMS(ESI,m/z):[M+H]⁺＝1053.6。¹H NMR(300MHz,DMSO-d₆):δ8.28-8.17(m,2H),8.01-7.86(m,2H),7.15-7.02(m,2H),6.96-6.88(m,2H),6.87-6.79(m,2H),6.10-6.03(m,2H),5.52-5.42(m,2H),4.98-4.85(m,2H),4.65-4.55(m,4H),4.45-4.28(m,4H),4.27-4.18(m,2H),3.93-3.85(m,2H),3.53-3.43(m,2H),3.07-2.96(m,2H),2.67-2.57(m,4H),2.36-2.25(m,2H),2.18(s,6H),1.93-1.53(m,24H),1.22-0.95(m,16H)。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -5- [ [4- ([ [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] oxy ] methyl) phenyl ] methoxy ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound I-F):

LCMS(ESI,m/z):[M+H]⁺＝1071.7。¹H NMR(400MHz,DMSO-d₆)δ8.08(d,J＝8.8Hz,2H),7.84(d,J＝8.8Hz,2H),7.47(s,4H),7.16-7.04(m,2H),6.93-6.85(m,4H),5.11(s,4H),4.95-4.85(m,2H),4.47-4.38(m,2H),4.34-4.26(m,2H),3.77-3.67(m,2H),3.65-3.54(m,2H),2.99-2.89(m,2H),2.67-2.60(m,4H),2.20-2.16(m,7H),2.10-1.90(m,5H),1.89-1.76(m,10H),1.76-1.55(m,14H),1.18-0.88(m,16H)。

(2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (1R) -5- [ (5- [ [ (5R) -5- [ (2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] oxy ] pentyl) oxy ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound I-G):

LCMS(ESI,m/z):[M+H]⁺＝957.7。¹H NMR(300MHz,DMSO-d₆):δ8.20-8.09(m,2H),8.02-7.78(m,2H),7.17-7.00(m,2H),6.93-6.74(m,4H),4.98-4.81(m,2H),4.51-4.40(m,2H),4.38-4.27(m,2H),4.04-3.95(m,4H),3.74-3.60(m,6H),3.10-2.98(m,2H),2.67-2.55(m,4H),2.18(s,6H),2.10-1.59(m,24H),1.19-1.08(m,6H),0.99-0.78(m,12H)。

example 2: synthesis of Compound II:

n- [ (1R) -5- [2- (2- [ [ (5R) -5- [ (tert-butoxycarbonyl) amino ] carbonyl ] amino]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]Ethoxy) ethoxy]-1,2,3, 4-tetrahydronaphthalen-1-yl]T-butyl carbamate (compound II-1): to a solution of Compound I-6(500mg, 1.90mmol) in DMF (15.0mL) was added 2- [2- [ (4-methylphenylsulfonyl) oxy]Ethoxy radical]Ethyl-4-methylbenzenesulfonate (394mg, 0.95mmol) and K₂CO₃(131mg, 0.95 mmol). The resulting mixture was stirred at 65 ℃ for 48 hours. Will react with H₂Diluted O and extracted with EtOAc. The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with petroleum ether/EtOAc (2/1, v/v) to give the title compound as a white solid (500mg, 44%). LCMS (ESI, M/z) [ M + H ]]⁺＝597.4。

(1R) -5- [2- (2- [ [ (5R) -5-amino-5, 6,7, 8-tetrahydronaphthalen-1-yl)]Oxy radical]Ethoxy) ethoxy]1,2,3, 4-tetrahydronaphthalen-1-amine dihydrochloride (compound II-2): a mixture of compound II-1(450mg, 0.75mmol) in HCl/dioxane (20.0mL, 4mol/L) was stirred at room temperature for 2 hours. After the reaction is complete, the resulting mixture is washed with H₂And (4) diluting with oxygen. The pH of the mixture was adjusted with saturated NaHCO₃The (aqueous solution) was adjusted to 7. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated in vacuo. Subjecting the residue to reverse phase flash column chromatography with 5-100% CH₃CN/H₂Purification of O afforded the title compound as a white solid (130mg, 44%). LCMS (ESI, M/z) [ M + H ]]⁺＝397.2。

N- [ (1S) -1- [ [ (1S) -2- [ (2S) -2- [ [ (1R) -5- [2- (2- [ [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- [ [ (benzyloxy) carbonyl ] carbonyl](methyl) amino group]Propionamido group]-2-Cyclohexylacetyl]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]Ethoxy) ethoxy]-1,2,3, 4-tetrahydronaphthalen-1-yl]Carbamoyl radical]Pyrrolidin-1-yl radical]-1-cyclohexyl-2-oxoethyl group]Carbamoyl radical]Ethyl radical]-benzyl N-methylcarbamate (compound II-3): to a solution of compound II-2(100mg, 0.25mmol) in DMF (10mL) was added compound I-4(263mg, 0.56mmol) and DIEA (163mg, 1.26 mmol). HATU (240mg, 0.63mmol) was then added to the mixture at 0 ℃. The resulting mixture was stirred at 0 ℃ for 2 hours. Will react with H₂Diluted O and extracted with EtOAc. The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with DCM/MeOH (10/1, v/v) to give the title compound as a brown solid (250mg, 76%). LCMS (ESI, M/z) [ M + H ]]⁺＝1307.7。

(2S) -1- [ (2S) -2-Cyclohexanediyl) cyclohexane2- [ (2S) -2- (methylamino) propionamido]Acetyl group]-N- [ (1R) -5- [2- (2- [ [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propanamido]Acetyl group]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]Ethoxy) ethoxy]-1,2,3, 4-tetrahydronaphthalen-1-yl]Pyrrolidine-2-carboxamide (compound II): to a solution of compound II-3(200mg, 0.15mmol) in EtOAc (8mL) and EtOH (4mL) was added Pd/C (68.0mg, dry). The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction was filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with DCM/MeOH (10/1, v/v) and then by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150mm, 5 um; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 13% B to 34% B in 7 minutes; 254/220 nm; room temperature: 7.22 min to give the title compound as a white solid (19.1mg, 12%). LCMS (ESI, M/z) [ M + H ]]⁺＝1039.7。¹H NMR(300MHz,DMSO-d₆,ppm):δ8.38-8.23(m,1H),8.09(d,J＝8.7Hz,2H),7.92(d,J＝9.0Hz,2H),7.10-7.04(m,2H),6.88-6.79(m,4H),4.95-4.81(m,2H),4.51-4.39(m,2H),4.36-4.24(m,2H),4.14-4.04(m,4H),3.89-3.79(m,4H),3.77-3.67(m,2H),3.66-3.55(m,2H),3.50-3.23(m,1H),3.07-2.94(m,2H),2.63-2.54(m,3H),2.18(s,6H),2.02-1.90(m,4H),1.89-1.47(m,25H),1.22-0.87(m,17H)。

Following the procedure described above for example 2 and substituting appropriate reagents, starting materials and purification methods known to those skilled in the art, the compounds listed below were prepared.

(2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (1R) -5- [2- (2- { [ (5R) -5- [ (2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] oxy } ethoxy) ethoxy ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound II-A):

LCMS(ESI,m/z):[M+H]⁺＝959.6。¹H NMR(300MHz,DMSO-d₆,ppm):δ8.38-8.13(m,2H),7.91-7.87(m,2H),7.13-7.04(m,2H),6.89-6.79(m,4H),4.95-4.80(m,2H),4.45-4.28(m,4H),4.12-4.07(m,4H),3.87-3.80(m,4H),3.69-3.51(m,4H),2.97-2.92(m,2H),2.58-2.50(m,4H),2.16(s,6H),2.02-1.57(m,20H),1.17-1.04(m,6H),0.97-0.75(m,12H)。

(2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] -2- (oxa-4-yl) acetyl ] -N- [ (1R) -5- [2- (2- { [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] -2- (oxa-4-yl) acetyl ] pyrrolidine-2-amido ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] oxy } ethoxy) ethoxy ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound II-B):

LCMS(ESI,m/z):[M+H]⁺＝1043.5。¹H NMR(300MHz,DMSO-d₆,ppm):δ8.42-8.09(m,2H),7.97-7.73(m,2H),7.20-7.01(m,2H),6.91-6.76(m,4H),4.95-4.81(m,2H),4.54-4.43(m,2H),4.40-4.25(m,2H),4.15-4.03(m,4H),3.91-3.56(m,12H),3.30-3.15(m,4H),3.03-2.87(m,2H),2.64-2.53(m,4H),2.16(s,6H),2.10-1.90(m,8H),1.89-1.72(m,8H),1.72-1.49(m,8H),1.45-1.19(m,4H),1.17-1.00(m,6H)。

(2S,4S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) -N- ((R) -5- (2- (2- (((R) -5- ((2S,4S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) -4-hydroxypyrrolidine-2-carboxamide) -5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) ethoxy) -1,2,3, 4-tetrahydronaphthalen-1-yl) -4-hydroxypyrrolidine-2-carboxamide carboxylic acid (compound II-C):

LCMS(ESI,m/z):[M+H]⁺＝1071.7。¹H NMR(300MHz,DMSO-d₆)δ8.32-8.23(m,3H),8.16-7.90(m,2H),7.14-7.00(m,2H),6.98-6.87(m,2H),6.87-6.73(m,2H),4.95-4.80(m,2H),4.42-4.28(m,7H),4.23-4.01(m,5H),3.93-3.80(m,7H),3.50-3.40(m,2H),3.08-2.98(m,2H),2.61-2.55(m,3H),2.34-2.17(m,8H),1.89-1.49(m,23H),1.25-1.05(m,13H),1.05-0.81(m,4H)。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -6- [2- (2- [ [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-2-yl ] oxy ] ethoxy) ethoxy ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide carboxylic acid (Compound II-D):

LCMS(ESI,m/z):[M+H]⁺＝1039.7。¹H NMR(400MHz,DMSO-d₆):δ8.19(s,1H),8.04(d,J＝8.4Hz,2H),7.92(d,J＝8.8Hz,2H),7.14(d,J＝8.4Hz,2H),6.70-6.64(m,4H),4.90-4.80(m,2H),4.50-4.40(m,2H),4.39-4.21(m,2H),4.08-4.03(m,4H),3.79-3.68(m,6H),3.65-3.55(m,2H),3.10-2.95(m,2H),2.73-2.62(m,4H),2.19(s,6H),2.10-1.93(m,4H),1.90-1.55(m,26H),1.27-1.09(m,11H),1.08-0.88(m,5H)。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -7- [2- (2- [ [ (8R) -8- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-2-yl ] oxy ] ethoxy) ethoxy ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide carboxylic acid (Compound II-E):

LCMS(ESI,m/z):[M+H]⁺＝1039.7。¹H NMR(300MHz,DMSO-d₆)δ8.27-8.18(m,2H),7.87-7.69(m,2H),7.00-6.93(m,2H),6.87(d,J＝2.1Hz,2H),6.77-6.67(m,2H),4.97-4.85(m,2H),4.54-4.38(m,2H),4.33-4.16(m,4H),4.08-3.96(m,2H),3.87-3.70(m,6H),3.67-3.55(m,2H),3.01-2.89(m,2H),2.74-2.61(m,4H),2.17(s,6H),2.13-1.94(m,4H),1.92-1.51(m,25H),1.32-0.80(m,17H)。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -4- [2- (2- [ [ (1R) -1- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -2, 3-dihydro-1H-inden-4-yl ] oxy ] ethoxy) ethoxy ] -2, 3-dihydro-1H-inden-1-yl ] pyrrolidine-2-carboxamide (Compound II-F):

LCMS(ESI,m/z):[M+H]⁺＝1011.7。¹H NMR(300MHz,DMSO-d₆)δ8.22-8.05(m,4H),7.22-7.04(m,2H),6.90-6.78(m,4H),5.31-5.17(m,2H),4.53-4.37(m,2H),4.35-4.25(m,2H),4.20-4.05(m,4H),3.89-3.80(m,4H),3.79-3.57(m,4H),3.25-3.12(m,2H),2.94-2.79(m,2H),2.73-2.50(m,2H),2.40-2.28(m,2H),2.25(s,6H),2.13-1.91(m,4H),1.91-1.53(m,19H),1.24-0.87(m,17H)。

example 3: synthesis of Compound III:

n- [ (1R) -5- [4- [ (5R) -5- [ (tert-butoxycarbonyl) amino group]-5,6,7, 8-tetrahydronaphthalen-1-yl]Phenyl radical]-1,2,3, 4-tetrahydronaphthalen-1-yl]T-butyl carbamate (compound III-1): to 4,4,5, 5-tetramethyl-2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]1,3, 2-Dioxolane borane (500mg, 1.52mmol) in CH₃CN (5mL) and H₂To a solution of O (0.5mL) were added Compound I-5(988.5mg, 3.03mmol), Pd (dppf) Cl₂(111mg, 0.15mmol) and K₂CO₃(168mg, 1.21 mmol). Mixing the mixture in N₂The mixture was stirred at 80 ℃ for 3 hours. Subjecting the mixture to hydrogenation with hydrogen₂O diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. Passing the residue through a filterFlash column chromatography was purified using ethyl acetate/petroleum ether (1/2, v/v) to give the title compound as a yellow solid (300mg, 35%). LCMS (ESI, M/z) [ M + H ]]⁺＝569.3。

(1R,1'R) -5,5' - (1, 4-phenylene) bis (1,2,3, 4-tetrahydronaphthalen-1-amine) dihydrochloride (Compound III-2): a mixture of compound III-1(200mg, 0.35mmol) in HCl/dioxane (10.0mL, 4mol/L) was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo to give the title compound as a white solid (150mg, crude product). LCMS (ESI, M/z) [ M + H ]]⁺＝369.2。

N- [ (1S) -1- { [ (1S) -2- [ (2S) -2- { [ (1R) -5- {4- [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- { [ (benzyloxy) carbonyl](methyl) amino } propionamido]-2-Cyclohexylacetyl]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]Phenyl } -1,2,3, 4-tetrahydronaphthalen-1-yl]Carbamoyl } pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl group]Carbamoyl } ethyl group]-benzyl N-methylcarbamate (compound III-3): to a solution of compound III-2(150mg, 0.40mmol) in DMF (5mL) was added compound I-4(386mg, 0.81mmol), DIEA (263mg, 2.04 mmol). Then in N₂HATU (310mg, 0.81mmol) was added to the mixture at 0 ℃. The resulting mixture was stirred at 0 ℃ for 3 hours. After the reaction is complete, the mixture is washed with H₂O diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified twice by flash column chromatography with DCM/MeOH (10/1, v/v) to give the title compound as a yellow oil (220mg, 47%). LCMS (ESI, M/z) [ M + H ]]⁺＝1279.7。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido]Acetyl group]-N- [ (1R) -5- [4- [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido]Acetyl group]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]Phenyl radical]-1,2,3, 4-tetrahydronaphthalen-1-yl]Pyrrolidine-2-carboxamide (compound III): to a solution of compound III-3(200mg, 0.16mmol) in EtOH (5mL) and EtOAc (10mL) was added Pd/C (40.0mg, dry). The mixture is left at room temperature in H₂Stirred for 16 hours.After completion of the reaction, the mixture was filtered. The filtrate was evaporated in vacuo. The residue was purified by preparative HPLC under the following conditions: column: XBridge prep OBD C18 column, 30 × 150mm, 5 um; mobile phase A: water (10mmol/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 39% B to 69% B in 7 minutes; 254 nm; room temperature: 6.08 min to give the title compound as a white solid (53.9mg, 34%). LCMS (ESI, M/z) [ M + H ]]⁺＝1011.7。¹H NMR(300MHz,DMSO-d₆,ppm):δ8.27-8.19(m,2H),7.92-7.88(m,2H),7.34-7.29(m,6H),7.25-7.19(m,2H),7.13-7.09(m,2H),5.25-4.79(m,2H),4.59-4.31(m,4H),3.82-3.68(m,4H),3.05-3.89(m,2H),2.71-2.58(m,4H),2.30-2.18(m,7H),2.17-1.94(m,4H),1.93-1.60(m,25H),1.39-0.92(m,16H)。

Following the procedure described above for example 3 and substituting appropriate reagents, starting materials and purification methods known to those skilled in the art, the compounds listed below were prepared.

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -5- {3- [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] phenyl } -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound III):

LCMS(ESI,m/z):[M+H]⁺＝1011.7。¹H NMR(300MHz,DMSO-d₆,ppm):δ8.55-8.12(m,2H),7.93-7.72(m,2H),7.64-7.46(m,1H),7.37-7.08(m,9H),5.10-4.93(m,2H),4.54-4.39(m,2H),4.38-4.28(m,2H),3.81-3.55(m,4H),3.03-2.89(m,2H),2.70-2.55(m,4H),2.17(s,6H),2.11-1.93(m,6H),1.92-1.52(m,24H),1.28-0.88(m,16H)。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -5- {6- [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidin-2-ylamino ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] naphthalen-2-yl } -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound III-B):

LCMS(ESI,m/z):[M+H]⁺＝1062.6；¹H NMR(300MHz,DMSO-d₆,ppm):δ8.52-8.22(m,2H),8.00(d,J＝8.4Hz,2H),7.90-7.84(m,4H),7.52-7.42(m,2H),7.39-7.29(m,2H),7.29-7.21(m,2H),7.20-7.12(m,2H),5.08-4.95(m,2H),4.54-4.28(m,4H),3.81-3.55(m,4H),3.01-2.88(m,2H),2.71-2.55(m,4H),2.18(s,6H),2.12-1.93(m,6H),1.92-1.55(m,24H),1.26-0.84(m,16H)。

(2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] propionyl ] -N- [ (1R) -5- [3- [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] propionyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] phenyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound III-C):

LCMS(ESI,m/z):[M+H]⁺＝875.5。¹H NMR(300MHz,DMSO-d₆)δ8.66-8.17(m,2H),8.07-7.92(m,2H),7.55-7.46(m,1H),7.37-7.20(m,6H),7.18-7.08(m,3H),5.07-4.94(m,2H),4.65-4.52(m,2H),4.39-4.27(m,2H),3.72-3.50(m,4H),3.00-2.87(m,2H),2.70-2.55(m,4H),2.19(s,6H),2.13-1.57(m,18H),1.27-1.17(m,6H),1.14-1.05(m,6H)。

(2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] butyryl ] -N- [ (1R) -5- [3- [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] butyryl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] phenyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound III-D):

LCMS(ESI,m/z):[M+H]⁺＝903.6。¹H NMR(300MHz,DMSO-d₆)δ8.62-8.24(m,2H),7.98-7.85(m,2H),7.53-7.45(m,1H),7.30-7.21(m,6H),7.16-7.11(m,3H),5.05-4.95(m,2H),4.54-4.30(m,4H),3.70-3.53(m,4H),2.99-2.90(m,2H),2.61-2.55(m,4H),2.22-2.18(m,6H),2.13-1.53(m,22H),1.15-1.09(m,6H),0.92-0.80(m,6H)。

(2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (1R) -5- [3- [ (5R) -5- [ (2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] phenyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound III-E):

LCMS(ESI,m/z):[M+H]⁺＝931.7。¹H NMR(300MHz,DMSO-d₆)δ8.28(d,J＝8.7Hz,2H),7.94(d,J＝9.0Hz,2H),7.57-7.47(m,1H),7.34-7.10(m,9H),5.05-4.95(m,2H),4.47-4.39(m,2H),4.37-4.28(m,2H),3.82-3.48(m,4H),3.07-2.95(m,2H),2.71-2.57(m,4H),2.24-2.20(m,6H),2.13-1.97(m,6H),1.97-1.53(m,14H),1.18-1.11(m,6H),0.97-0.87(m,12H)。

(2S) -1- [ (2S) -3, 3-dimethyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (1R) -5- [3- [ (5R) -5- [ (2S) -1- [ (2S) -3, 3-dimethyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidin-2-ylamino ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] phenyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound III-F):

LCMS(ESI,m/z):[M+H]⁺＝959.6。¹H NMR(300MHz,DMSO-d₆)δ8.50-8.33(m,2H),7.86(d,J＝9.6Hz,2H),7.58-7.48(m,1H),7.43-7.33(m,2H),7.32-7.24(m,2H),7.24-7.08(m,5H),5.08-4.95(m,2H),4.61-4.48(m,2H),4.42-4.29(m,2H),3.81-3.59(m,4H),3.05-2.90(m,2H),2.68-2.57(m,4H),2.26-2.13(m,8H),2.13-1.98(m,4H),1.92-1.62(m,12H),1.20-1.10(m,6H),1.05(s,16H),0.92(s,2H)。

(S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) -N- ((R) -5- (4'- ((R) -5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamide) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [1,1' -biphenyl ] -4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) pyrrolidine-2-carboxamide (compound III-G):

LCMS(ESI,m/z):[M+H]⁺＝1088.3。¹H NMR(300MHz,DMSO-d₆)δ8.26(d,J＝8.7Hz,2H),7.89(d,J＝9.0Hz,2H),7.78(d,J＝8.1Hz,4H),7.40(d,J＝8.1Hz,4H),7.33(d,J＝7.5Hz,2H),7.26-7.21(m,2H),7.12(d,J＝6.3Hz,2H),5.10-4.95(m,2H),4.51-4.39(m,2H),4.39-4.29(m,2H),3.81-3.70(m,2H),3.70-3.56(m,2H),2.99-2.90(m,2H),2.71-2.55(m,4H),2.18(s,6H),2.10-1.93(m,4H),1.92-1.54(m,25H),1.28-0.87(m,17H)。

(2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] propionyl ] -N- [ (1R) -5- [4- [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] propionyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] phenyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound III-H):

LCMS(ESI,m/z):[M+H]⁺＝875.7。¹H NMR(300MHz,DMSO-d₆):δ8.32-8.16(m,2H),8.09-7.91(m,2H),7.41-7.21(m,8H),7.19-7.05(m,2H),5.09-4.96(m,2H),4.67-4.52(m,2H),4.49-4.29(m,2H),3.73-3.56(m,4H),3.04-2.89(m,2H),2.76-2.57(m,4H),2.27-2.18(m,6H),2.15-1.57(m,16H),1.32-1.19(m,6H),1.18-1.06(m,6H)。

(2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] butyryl ] -N- [ (1R) -5- [4- [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] butyryl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] phenyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound III-I):

LCMS(ESI,m/z):[M+H]⁺＝903.8。¹H NMR(300MHz,DMSO-d₆):δ8.64-8.20(m,2H),8.03-7.84(m,2H),7.41-7.33(m,4H),7.33-7.21(m,4H),7.16-7.08(m,2H),5.12-4.93(m,2H),4.60-4.28(m,4H),3.81-3.39(m,4H),3.01-2.91(m,2H),2.71-2.55(m,4H),2.31-2.15(m,8H),2.11-1.52(m,20H),1.19-1.05(m,6H),0.97-0.80(m,6H)。

(2S) -1- [ (2S) -3, 3-dimethyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (1R) -5- [4- [ (5R) -5- [ (2S) -1- [ (2S) -3, 3-dimethyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidin-2-ylamino ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] phenyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound III-J):

¹H NMR(300MHz,DMSO-d₆):δ8.50-8.35(m,2H),7.93-7.83(m,2H),7.43-7.35(m,6H),7.24-7.10(m,4H),5.12-4.91(m,2H),4.66-4.51(m,2H),4.45-4.29(m,2H),3.81-3.59(m,4H),3.06-2.90(m,2H),2.77-2.58(m,4H),2.26-2.00(m,12H),1.94-1.65(m,12H),1.19-1.09(m,6H),1.08-0.90(m,18H)。

(2S,4S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -5- [4- [ (5R) -5- [ (2S,4S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -4-hydroxypyrrolidine-2-amido ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] phenyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] -4-hydroxypyrrolidine-2-carboxamide (Compound III-K):

LCMS(ESI,m/z):[M+H]⁺＝1043.9。¹H NMR(300MHz,DMSO-d₆):δ8.35-8.30(m,2H),8.04-7.94(m,2H),7.44-7.28(m,6H),7.28-7.19(m,2H),7.17-7.07(m,2H),5.58-5.39(m,2H),5.13-4.97(m,2H),4.48-4.31(m,4H),4.31-4.18(m,2H),3.99-3.86(m,2H),3.56-3.45(m,2H),3.10-2.98(m,2H),2.70-2.59(m,4H),2.39-2.20(m,8H),2.08-1.40(m,24H),1.24-0.93(m,16H)。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -6- [4- [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-2-yl ] phenyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound III-L):

LCMS(ESI,m/z):[M+H]⁺＝1011.8。¹H NMR(300MHz,DMSO-d₆)δ8.50-8.15(m,2H),7.93-7.84(m,2H),7.80-7.69(m,4H),7.54-7.41(m,4H),7.40-7.29(m,2H),5.02-4.91(m,2H),4.52-4.40(m,2H),4.40-4.28(m,2H),3.81-3.70(m,2H),3.70-3.56(m,2H),3.02-2.90(m,2H),2.86-2.79(m,4H),2.17(s,6H),2.13-1.52(m,30H),1.28-0.90(m,16H)。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -7- [4- [ (8R) -8- [ (2R) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-2-yl ] phenyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound III-M):

LCMS(ESI,m/z):[M+H]⁺＝1011.6。¹H NMR(300MHz,DMSO-d₆)δ8.38-8.23(m,2H),7.91-7.81(m,6H),7.70-7.59(m,2H),7.58-7.45(m,2H),7.24-7.08(m,2H),5.04-4.94(m,2H),4.50-4.39(m,2H),4.39-4.29(m,2H),3.78-3.70(m,2H),3.70-3.58(m,2H),3.00-2.87(m,2H),2.82-2.74(m,4H),2.15(s,6H),2.15-1.95(m,6H),1.95-1.64(m,18H),1.60-1.41(m,6H),1.18-1.08(m,7H),1.08-0.85(m,9H)。

(2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (1R) -5- [4- [ (5R) -5- [ (2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] phenyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound III-N):

LCMS(ESI,m/z):[M+H]⁺＝931.7。¹H NMR(300MHz,DMSO-d₆):δ8.60-8.26(m,2H),7.97-7.76(m,2H),7.44-7.31(m,6H),7.28-7.19(m,2H),7.16-7.08(m,2H),5.09-4.97(m,2H),4.56-4.40(m,2H),4.39-4.28(m,2H),3.79-3.50(m,4H),3.03-2.91(m,2H),2.69-2.54(m,4H),2.26-1.96(m,14H),1.95-1.76(m,8H),1.76-1.58(m,4H),1.19-1.04(m,6H),1.00-0.78(m,12H)。

example 4: synthesis of compound IV:

4-Methylbenzenesulfonic acid 2- (4- [2- [ (4-methylbenzenesulfonyl) oxy group]Ethyl radical]Phenyl) ethyl ester (compound IV-1): to 2- [4- (2-hydroxyethyl) phenyl]A solution of ethanol (1.0g, 6.01mmol) in DCM (50mL) was added TEA (1.6g, 16.2mmol), DMAP (177mg, 1.44mmol) and TsCl (2.6g, 13.6 mmol). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was evaporated in vacuo. The residue was purified by flash column chromatography with DCM/petroleum ether (100/0, v/v) to give the title compound as a white solid (2.0g, 70%). LCMS (ESI, M/z) [ M + H ]]⁺＝475.1。

N- [ (1R) -5- [2- [4- (2- [ [ (5R) -5- [ (tert-butoxycarbonyl) amino ] carbonyl ] amino]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]Ethyl) phenyl]Ethoxy radical]-1,2,3, 4-tetrahydronaphthalen-1-yl]Carbamic acid tert-butyl esterButyl ester (Compound IV-2): mixing Compound IV-1(346mg, 0.72mmol), Compound I-6(318mg, 1.20mmol) and K₂CO₃A mixture of (622mg, 4.49mmol) in DMF (10mL) was heated at 65 ℃ for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature and then purified by reverse phase flash column chromatography with CH₃CN/H₂O (100/0, v/v) to give the title compound as a white solid (135mg, 17%). LCMS (ESI, M/z) [ M + H ]]⁺＝657.4。

(1R) -5- [2- [4- (2- [ [ (5R) -5-amino-5, 6,7, 8-tetrahydronaphthalen-1-yl)]Oxy radical]Ethyl) phenyl]Ethoxy radical]1,2,3, 4-tetrahydronaphthalen-1-amine dihydrochloride (compound IV-3): a mixture of compound IV-2(254mg, 0.38mmol) in HCl/dioxane (10.0mL, 4mol/L) was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was evaporated in vacuo to give the title compound (310mg, crude product) as a yellow solid. LCMS (ESI, M/z) [ M + H ]]⁺＝457.3。

N- [ (1S) -1- [ [ (1S) -2- [ (2S) -2- [ [ (1R) -5- [2- [4- (2- [ [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- [ [ (benzyloxy) carbonyl ] carbonyl](methyl) amino group]Propionamido group]-2-Cyclohexylacetyl]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]Ethyl) phenyl]Ethoxy radical]-1,2,3, 4-tetrahydronaphthalen-1-yl]Carbamoyl radical]Pyrrolidin-1-yl radical]-1-cyclohexyl-2-oxoethyl group]Carbamoyl radical]Ethyl radical]-benzyl N-methylcarbamate (compound IV-4): in N₂Compound I-4(440mg, 0.92mmol) and DIEA (1.5mL) were added to a solution of compound IV-3(310mg, 0.58mmol) in DMF (10mL) at 0 deg.C. HATU (615mg, 1.61mmol) was then added to the mixture. The mixture was stirred at 0 ℃ for 2 hours. After the reaction was complete, the mixture was purified by reverse phase flash column chromatography with CH₃CN/H₂O (100/0, v/v) to give the title compound as an off-white solid (280mg, 24%). LCMS (ESI, M/z) [ M + H ]]⁺＝1367.8。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido]Acetyl group]-N- [ (1R) -5- [2- [4- (2- [ [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propanamido]Acetyl group]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]Ethyl) benzeneBase of]Ethoxy radical]-1,2,3, 4-tetrahydronaphthalen-1-yl]Pyrrolidine-2-carboxamide (compound IV): to a solution of compound IV-4(280mg, 0.20mmol) in EtOAc (10mL) and EtOH (5mL) was added Pd/C (191mg, dry). The mixture is left at room temperature in H₂Stirred for 16 hours. After completion of the reaction, the mixture was filtered. The filtrate was evaporated in vacuo. The residue was purified by preparative HPLC under the following conditions: column: XBridge prep OBD C18 column, 30 × 150mm, 5 um; mobile phase A: water (10mmol/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 51% B to 81% B in 7 minutes; 254 nm; room temperature: 5.83 min to give the title compound as a white solid (83.5mg, 37%). LCMS (ESI, M/z) [ M + H ]]⁺＝1099.7。¹H NMR(300MHz,DMSO-d₆,ppm):δ8.46-8.02(m,2H),7.94-7.68(m,2H),7.26(s,4H),7.09-7.04(m,2H),6.86-6.79(m,4H),4.93-4.79(m,2H),4.49-4.37(m,2H),4.31-4.27(m,2H),4.15-4.06(m,4H),3.78-3.66(m,2H),3.65-3.54(m,2H),3.03-2.95(m,6H),2.16(s,6H),2.09-1.89(m,4H),1.88-1.50(m,25H),1.15-0.94(m,17H)。

Following the procedure described above for example 4 and substituting appropriate reagents, starting materials and purification methods known to those skilled in the art, the compounds listed below were prepared.

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -5- [ [ (2E) -4- [ [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidin-2-ylamino ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] oxy ] but-2-en-1-yl ] oxy ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound IV-A):

LCMS(ESI,m/z):[M+H]⁺＝1021.6。¹H NMR(300MHz,DMSO-d₆,ppm):δ8.50-8.09(m,2H),7.84-7.65(m,2H),7.10-7.05(m,2H),6.89-6.80(m,4H),6.07(s,2H),4.91-4.80(m,2H),4.50(s,4H),4.45-4.28(m,4H),3.71-3.60(m,4H),2.95-2.90(m,2H),2.69-2.53(m,4H),2.14(s,6H),2.10-1.91(m,4H),1.86-1.58(m,26H),1.18-0.94(m,16H)。

(S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) -N- ((R) -5- (4- ((R) -5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamide) -5,6,7, 8-tetrahydronaphthalen-1-yloxy) but-2-yloxy) -1,2,3, 4-tetrahydronaphthalen-1-yl) pyrrolidine-2-carboxamide (compound IV-B):

LCMS(ESI,m/z):[M+H]⁺＝1019.6。¹H NMR(300MHz,DMSO-d₆,ppm):δ8.50-8.11(m,2H),7.88-7.65(m,2H),7.11-7.06(m,2H),6.93-6.84(m,4H),4.91-4.86(m,6H),4.46-4.40(m,2H),4.32-4.28(m,2H),3.77-3.70(m,2H),3.67-3.57(m,2H),2.96-2.91(m,2H),2.56-2.50(m,4H),2.17(s,6H),2.06-1.96(m,4H),1.85-1.59(m,26H),1.19-0.95(m,16H)。

example 5: synthesis of compound V:

(R) - (4-bromo-2, 3-dihydro-1H-inden-1-yl) carbamic acid tert-butyl ester (Compound V-2): to the compound V-1(4.7g, 18.91mmol) in CH₂Cl₂(100.0mL) solution TEA (5.4g, 52.95mmol) and Boc were added₂O (5.4g, 24.58 mmol). The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (93/7, v/v) to give the title compound as a pale pink solid (5.4g, 91%). LCMS (ESI, M/z) [ M + H ]]⁺＝312.1。

(R) - (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) carbamic acid tert-butyl ester (Compound V-3): to a solution of compound V-2(300.0mg, 0.96mmol) in 1, 4-dioxane (10.0mL) was added 4,4,4',4',5,5,5',5' -octamethyle at room temperature2,2' -bis (1,3, 2-dioxaborolan) (732.0mg, 2.88mmol), KOAc (282.9mg, 2.88mmol) and Pd (dppf) Cl₂(70.3mg, 0.10 mmol). The resulting mixture is stirred under N₂The mixture was stirred at 80 ℃ for 16 hours. After the reaction is complete, the resulting mixture is washed with H₂O diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (89/11) to give the title compound (450.0mg, crude product) as a colorless oil. LCMS (ESI, M/z) [ M + H ]]⁺＝360.2。

((1R,1' R) -2,2',3,3' -tetrahydro-1H, 1' H- [4,4' -bisindane]Di-tert-butyl-1, 1' -diyl) dicarbamate (compound V-4): to compound V-3(400.0mg, 1.11mmol) in CH at room temperature₃CN/H₂To a solution in O (10.0mL/2.0mL) was added tert-butyl (R) - (4-bromo-2, 3-dihydro-1H-inden-1-yl) carbamate (347.6mg, 1.11mmol), K₂CO₃(461.6mg, 3.34mmol) and Pd (dppf) Cl₂(81.5mg, 0.11 mmol). The resulting mixture is stirred under N₂The mixture was stirred at 80 ℃ for 16 hours. Subjecting the mixture to hydrogenation with hydrogen₂O diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (80/20, v/v) to give the title compound as a white solid (320.0mg, 62%). LCMS (ESI, M/z) [ M + H ]]⁺＝465.3。

(1R,1' R) -2,2',3,3' -tetrahydro-4, 4' -bis (1H-indene) -1,1' -diamine dihydrochloride (Compound V-5): a solution of compound V-4(320.0mg, 0.69mmol) in HCl/1, 4-dioxane (6.0mL, 4mol/L) was stirred at room temperature for 1 hour. After completion of the reaction, the resulting mixture was concentrated in vacuo to give the title compound (250.0mg, crude product) as a yellow solid. LCMS (ESI, M/z) [ M + H ]]⁺＝265.2。

(S) -benzyl 1- ((S) -2- (tert-butoxycarbonylamino) -2-cyclohexylacetyl) pyrrolidine-2-carboxylate (Compound V-6): in N₂By the reaction of (S) - [ (tert-butoxycarbonyl) amino group at 0 deg.C](Cyclohexanaphthalene)Yl) acetic acid (10.0g, 38.86mmol), (2S) -pyrrolidine-2-carboxylic acid benzyl ester (7.9g, 38.86mmol) and DIEA (15.1g, 116.58mmol) in DMF (25.0mL) was added HATU (17.7g, 46.63 mmol). The mixture was stirred at 0 ℃ for 2 hours. Subjecting the mixture to hydrogenation with H₂Diluted O and extracted with EtOAc. The combined organic layers were washed with brine, over Na₂SO₄Dried and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography over CH₂Cl₂/CH₃OH (10/1, v/v) was purified to give the title compound as a white solid (11.1g, 64%). LCMS (ESI, M/z) [ M + H ]]⁺＝445.3。

(S) -benzyl 1- ((S) -2-amino-2-cyclohexylacetyl) pyrrolidine-2-carboxylate (Compound V-7): to a solution of V-6(11.1g, 8.23mmol) in CH₂Cl₂To the mixture (75.0mL) was added TFA (15.0 mL). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was evaporated in vacuo. The residue was purified by reverse phase flash column chromatography over CH₃CN/H₂O (97/3, v/v) was purified to give the title compound as a yellow-green oil (3.1g, 36%). LCMS (ESI, M/z) [ M + H ]]⁺＝345.2。

Benzyl (S) -1- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -2-cyclohexylacetyl) pyrrolidine-2-carboxylate (compound V-8): in N₂Then, to the compound V-7(3.0g, 8.82mmol), (2S) -2- [ (tert-butoxycarbonyl) (methyl) amino group at 0 deg.C]A mixture of propionic acid (1.8g, 8.82mmol) and DIEA (3.4g, 26.47mmol) in DMF (15.0mL) was added HATU (4.0g, 10.59 mmol). The mixture was stirred at 0 ℃ for 2 hours. Subjecting the mixture to hydrogenation with H₂Diluted O and extracted with EtOAc. The combined organic layers were washed with brine, over Na₂SO₄Dried and filtered. The filtrate was evaporated in vacuo. Subjecting the mixture to flash column chromatography with CH₂Cl₂/CH₃OH (10/1, v/v) was purified to give the title compound as a pale green oil (1.2g, 25%). LCMS (ESI, M/z) [ M + H ]]⁺＝530.3。

(S) -1- ((S) -2- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -2-cyclohexylacetyl) pyrrolidine-2-carboxylic acid (Compound V-9):to a solution of compound V-8(1.2g, 2.26mmol) in EtOAc (15.0mL) and EtOH (15.0mL) was added Pd/C (240.0mg, dry). The mixture is left at room temperature in H₂Stirred for 16 hours. After completion of the reaction, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give the title compound as a white solid (900.0mg, crude product). LCMS (ESI, M/z) [ M + H ]]⁺＝440.3。

((S) -1- (((S) -2- ((S) -2- (((1R,1'R) -1' - ((S) -1- ((S) -2- ((S) -2- ((tert-butoxycarbonyl) (methyl) amino) propionamido) -2-cyclohexylacetyl) pyrrolidine-2-carboxamido) -2,2',3,3' -tetrahydro-1H, 1'H- [4,4' -bisindene)]-1-yl) carbamoyl) pyrrolidin-1-yl) -1-cyclohexyl-2-oxyethyl) amino) -1-oxopropan-2-yl) (methyl) carbamic acid tert-butyl ester (compound V-10): to a solution of compound V-5(250.0mg, 0.74mmol) in DMF (3.0mL) was added V-9(651.6mg, 1.48mmol) and DIEA (957.9mg, 7.41 mmol). Then in N₂HATU (986.3mg, 2.59mmol) was added to the mixture at 0 ℃. The resulting mixture was stirred at 0 ℃ for 2 hours. After the reaction was complete, the mixture was purified by reverse phase flash column chromatography with CH₃CN/H₂O (80/20, v/v) to give the title compound as a yellow solid (600.0mg, 73%). LCMS (ESI, M/z) [ M + H ]]⁺＝1107.7。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido]Acetyl group]-N- [ (1R,1'R) -1' - [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido]Acetyl group]Pyrrolidine-2-carboxamides]-1H,1'H,2H,2' H,3H,3'H- [4,4' -bisindane]-1-yl]Pyrrolidine-2-carboxamide (compound V): to compound V-10(550.0mg, 0.49mmol) in CH₂Cl₂To a solution (10.0mL) was added TFA (6.0 mL). The mixture was stirred at room temperature for 2 hours. After the reaction is complete, NaHCO is used₃The solution adjusted the pH of the mixture to 8. Subjecting the mixture to hydrogenation with H₂Diluting with O and using CH₂Cl₂And (4) extracting. The combined organic layers were washed with brine, over Na₂SO₄Dried and filtered. The filtrate was evaporated in vacuo. The residue was purified by preparative HPLC under the following conditions: column: column: YMC-Actus Triart C18, 20X 250mm, 5um, 12 nm; mobile phaseA: water (10mmol/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 40% B to 70% B in 7 minutes; 254 nm; room temperature 1: 6.25 min to give the title compound as a white solid (166.1mg, 36%). LCMS (ESI, M/z) [ M + H ]]⁺＝907.5。¹H NMR(300MHz,DMSO-d₆)δ8.55-8.17(m,2H),8.00-7.72(m,2H),7.37-7.21(m,4H),7.20-7.04(m,2H),5.42-5.23(m,2H),4.58-4.27(m,4H),3.90-3.47(m,4H),3.03-2.91(m,2H),2.90-2.75(m,2H),2.65-2.55(m,2H),2.40-1.95(m,14H),1.94-1.53(m,18H),1.28-0.85(m,16H)。

Following the procedure described above for example 5 and substituting appropriate reagents, starting materials and purification methods known to those skilled in the art, the compounds listed below were prepared.

(2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] propionyl ] -N- [ (4R) -8- [ (4R) -4- [ (2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] propionyl ] pyrrolidine-2-carboxamide ] -3, 4-dihydro-2H-1-benzopyran-8-yl ] -3, 4-dihydro-2H-1-benzopyran-4-yl ] pyrrolidine-2-carboxamide (Compound V-A):

LCMS(ESI,m/z):[M+H]⁺＝803.3。¹H NMR(300MHz,DMSO-d₆):δ8.80-8.30(m,2H),8.10-7.90(m,2H),7.30-7.11(m,2H),7.03-6.96(m,2H),6.95-6.80(m,2H),5.12-4.99(m,2H),4.68-4.52(m,2H),4.50-4.26(m,2H),4.18-3.98(m,4H),3.70-3.52(m,4H),3.01-2.88(m,2H),2.22-2.19(m,6H),2.13-1.80(m,12H),1.32-1.17(m,6H),1.16-1.02(m,6H)。

(2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] butyryl ] -N- [ (4R) -8- [ (4R) -4- [ (2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] butyryl ] pyrrolidine-2-carboxamide ] -3, 4-dihydro-2H-1-benzopyran-8-yl ] -3, 4-dihydro-2H-1-benzopyran-4-yl ] pyrrolidine-2-carboxamide (Compound V-B):

LCMS(ESI,m/z):[M+H]⁺＝831.4。¹H NMR(300MHz,DMSO-d₆):δ8.83-8.35(m,2H),8.10-7.80(m,2H),7.41-7.12(m,2H),7.02-6.96(m,2H),6.95-6.80(m,2H),5.15-4.92(m,2H),4.59-4.25(m,4H),4.18-3.85(m,4H),3.78-3.48(m,4H),3.03-2.90(m,2H),2.25-2.18(m,6H),2.16-1.92(m,6H),1.91-1.70(m,8H),1.68-1.48(m,2H),1.18-1.02(m,6H),0.96-0.78(m,6H)。

(2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (4R) -8- [ (4R) -4- [ (2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -3, 4-dihydro-2H-1-benzopyran-8-yl ] -3, 4-dihydro-2H-1-benzopyran-4-yl ] pyrrolidine-2-carboxamide (Compound V-C):

LCMS(ESI,m/z):[M+H]⁺＝859.4。¹H NMR(300MHz,DMSO-d₆):δ8.52-8.37(m,2H),7.97-7.88(m,2H),7.25-7.12(m,2H),7.08-6.96(m,2H),6.95-6.80(m,2H),5.12-4.94(m,2H),4.57-4.40(m,2H),4.39-4.24(m,2H),4.18-4.05(m,4H),3.79-3.56(m,4H),3.04-2.91(m,2H),2.24-2.17(m,6H),2.15-1.75(m,16H),1.21-1.09(m,6H),1.00-0.80(m,12H)。

(2S) -1- [ (2S) -3, 3-dimethyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (4R) -8- [ (4R) -4- [ (2S) -1- [ (2S) -3, 3-dimethyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -3, 4-dihydro-2H-1-benzopyran-8-yl ] -3, 4-dihydro-2H-1-benzopyran-4-yl ] pyrrolidine-2-carboxamide (Compound V-D):

LCMS(ESI,m/z):[M+H]⁺＝887.4。¹H NMR(300MHz,DMSO-d₆):δ8.70-8.42(m,2H),7.96-7.70(m,2H),7.25-7.20(m,2H),7.05-6.93(m,2H),6.87-6.78(m,2H),5.14-4.82(m,2H),4.67-4.50(m,2H),4.45-4.26(m,2H),4.19-4.10(m,4H),3.81-3.60(m,4H),3.07-2.85(m,2H),2.38-2.15(m,8H),2.14-1.94(m,6H),1.93-1.71(m,6H),1.23-1.09(m,6H),1.08-0.97(m,16H),0.95-0.92(m,2H)。

(2S) -1- [ (2S) -2-cyclopropyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (4R) -8- [ (4R) -4- [ (2S) -1- [ (2S) -2-cyclopropyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -3, 4-dihydro-2H-1-benzopyran-8-yl ] -3, 4-dihydro-2H-1-benzopyran-4-yl ] pyrrolidine-2-carboxamide (Compound V-E):

LCMS(ESI,m/z):[M+H]⁺＝855.4。¹H NMR(300MHz,DMSO-d₆):δ8.80-8.28(m,2H),8.06-7.80(m,2H),7.38-7.12(m,2H),7.05-6.96(m,2H),6.95-6.80(m,2H),5.12-4.94(m,2H),4.57-4.36(m,2H),4.31-4.25(m,2H),4.20-4.00(m,4H),3.72-3.56(m,4H),3.05-2.94(m,2H),2.24-2.19(m,6H),2.13-1.95(m,6H),1.93-1.78(m,6H),1.25-1.05(m,8H),0.57-0.25(m,8H)。

(2S) -1- [ (2S) -2-cyclopentyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (4R) -8- [ (4R) -4- [ (2S) -1- [ (2S) -2-cyclopentyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -3, 4-dihydro-2H-1-benzopyran-8-yl ] -3, 4-dihydro-2H-1-benzopyran-4-yl ] pyrrolidine-2-carboxamide (Compound V-F):

LCMS(ESI,m/z):[M+H]⁺＝911.5。¹H NMR(300MHz,DMSO-d₆):δ8.75-8.26(m,2H),8.08-7.80(m,2H),7.52-7.14(m,2H),7.08-6.96(m,2H),6.95-6.80(m,2H),5.12-4.90(m,2H),4.63-4.45(m,2H),4.37-4.31(m,2H),4.21-3.96(m,4H),3.80-3.58(m,4H),3.05-2.90(m,2H),2.35-1.95(m,16H),1.94-1.76(m,6H),1.75-1.45(m,12H),1.39-1.21(m,4H),1.19-1.00(m,6H)。

(2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (1R,1'R) -1' - [ (2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -1H,1'H,2H,2' H,3H,3'H- [4,4' -biindenyl ] -1-yl ] pyrrolidine-2-carboxamide (Compound V-G):

LCMS(ESI,m/z):[M+H]⁺＝827.4。¹H NMR(300MHz,DMSO-d₆):δ8.38-8.20(m,2H),8.01-7.85(m,2H),7.33-7.21(m,4H),7.20-7.03(m,2H),5.43-5.25(m,2H),4.52-4.41(m,2H),4.39-4.23(m,2H),3.80-3.58(m,4H),3.05-2.92(m,2H),2.90-2.71(m,2H),2.64-2.55(m,2H),2.44-2.16(m,10H),2.15-1.95(m,6H),1.93-1.66(m,6H),1.18-1.05(m,6H),1.02-0.82(m,12H)。

(2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] propionyl ] -N- [ (5R,5' R) -5' - [ (2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] propionyl ] pyrrolidine-2-carboxamide ] -5H,5' H,6H,6' H,7H,7' H,8H,8' H- [1,1' -binaphthyl ] -5-yl ] pyrrolidine-2-carboxamide (Compound V-H):

LCMS(ESI,m/z):[M+H]⁺＝799.6。¹H NMR(300MHz,DMSO-d₆)δ8.64-8.15(m,2H),8.10-7.91(m,2H),7.36-7.15(m,4H),6.97-6.82(m,2H),5.05-4.93(m,2H),4.68-4.52(m,2H),4.43-4.28(m,2H),3.72-3.47(m,4H),3.01-2.89(m,2H),2.38-2.25(m,3H),2.26-2.17(m,7H),2.17-1.53(m,18H),1.29-1.18(m,6H),1.16-1.05(m,6H)。

(2S) -1- [ (2S) -2- (methylamino) propionamido ] butyryl ] -N- [ (5R,5' R) -5' - [ (2S) -1- [ (2S) -2- (methylamino) propionamido ] butyryl ] pyrrolidine-2-carboxamide ] -5H,5' H,6' H,7' H,8' H- [1,1' -binaphthyl ] -5-yl ] pyrrolidine-2-carboxamide; bis (formic acid) (compound V-I):

LCMS(ESI,m/z):[M+H]⁺＝827.5。¹H NMR(300MHz,DMSO-d₆)δ8.33-8.19(m,3H),8.19-7.95(m,2H),7.32-7.15(m,4H),6.96-6.81(m,2H),5.03-4.97(m,2H),4.60-4.47(m,2H),4.42-4.30(m,2H),3.77-3.55(m,4H),3.21-3.08(m,2H),2.35-2.20(m,9H),2.16-1.95(m,5H),1.95-1.51(m,16H),1.22-1.06(m,6H),0.97-0.80(m,6H)。

(2S) -1- [ (2S) -3, 3-dimethyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (5R,5' R) -5' - [ (2S) -1- [ (2S) -3, 3-dimethyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -5H,5' H,6H,6' H,7H,7' H,8H,8' H- [1,1' -dinaphthalene ] -5-yl ] pyrrolidine-2-carboxamide (Compound V-J):

LCMS(ESI,m/z):[M+H]⁺＝883.6。¹H NMR(300MHz,DMSO-d₆):δ:8.42-8.35(m,2H),7.89-7.80(m,2H),7.39-7.35(m,2H),7.18-7.13(m,2H),6.92-6.84(m,2H),5.02-4.95(m,2H),4.60-4.53(m,2H),4.37-4.33(m,2H),3.80-3.65(m,4H),3.03-2.96(m,2H),2.42-1.98(m,16H),1.85-1.64(m,12H),1.17-0.93(m,24H)。

(S) -1- ((S) -2- (methylamino) propionamido) -2- (tetrahydro-2H-pyran-4-yl) acetyl) -N- ((5R,5' R) -5' - ((S) -1- ((S) -2- (methylamino) propionamido) -2- (tetrahydro-2H-pyran-4-yl) acetyl) pyrrolidine-2-carboxamide) -5,5',6,6',7,7',8,8' -octahydro- [1,1' -binaphthyl ] -5-yl) pyrrolidine-2-carboxamide (compound V-K):

LCMS(ESI,m/z):[M+H]⁺＝939.6。¹H NMR(300MHz,DMSO-d₆)δ8.56-8.25(m,2H),8.03-7.93(m,2H),7.36-7.25(m,2H),7.25-7.12(m,2H),6.95-6.81(m,2H),5.05-4.89(m,2H),4.61-4.44(m,2H),4.40-4.26(m,2H),3.97-3.56(m,8H),3.30-3.18(m,4H),3.03-2.90(m,2H),2.38-1.92(m,18H),1.90-1.69(m,10H),1.68-1.50(m,6H),1.42-1.18(m,4H),1.18-1.05(m,6H)。

(2S,4S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (5R,5'R) -5' - [ (2S,4S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -4-hydroxypyrrolidine-2-carboxamide ] -5H,5' H,6H,6' H,7H,7' H,8H,8' H- [1,1' -bisnaphthalen ] -5-yl ] -4-hydroxypyrrolidine-2-carboxamide (Compound V-L):

LCMS(ESI,m/z):[M+H]⁺＝967.7。¹H NMR(300MHz,DMSO-d₆):δ8.49-8.33(m,2H),8.01-7.88(m,2H),7.41-7.30(m,2H),7.28-7.15(m,2H),6.96-6.77(m,2H),5.59-5.45(m,2H),5.13-4.92(m,2H),4.49-4.30(m,4H),4.29-4.15(m,2H),3.99-3.85(m,2H),3.55-3.43(m,2H),3.03-2.91(m,2H),2.38-2.28(m,4H),2.23-2.11(m,8H),1.98-1.47(m,24H),1.24-0.96(m,16H)。

(2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (5R,5' R) -5' - [ (2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -5H,5' H,6H,6' H,7H,7' H,8H,8' H- [1,1' -binaphthyl ] -5-yl ] pyrrolidine-2-carboxamide (Compound V-M):

LCMS(ESI,m/z):[M+H]⁺＝855.7。¹H NMR(300MHz,DMSO-d₆):δ8.59-8.22(m,2H),8.00-7.76(m,2H),7.60-7.29(m,2H),7.28-7.13(m,2H),6.97-6.82(m,2H),5.09-4.91(m,2H),4.54-4.30(m,4H),3.86-3.57(m,4H),3.08-2.91(m,2H),2.39-1.98(m,18H),1.94-1.57(m,12H),1.21-1.08(m,6H),1.04-0.80(m,12H)。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -5- [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidin-2-ylamino ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound V-N):

LCMS(ESI,m/z):[M+H]⁺＝935.8。¹H NMR(300MHz,DMSO-d₆)δ8.33-8.20(m,2H),7.97-7.87(m,2H),7.35-7.28(m,2H),7.24-7.14(m,2H),6.97-6.83(m,2H),5.09-4.91(m,2H),4.51-4.41(m,2H),4.40-4.28(m,2H),3.83-3.70(m,2H),3.68-3.58(m,2H),3.04-2.90(m,2H),2.40-2.31(m,1H),2.27-2.13(m,8H),2.11-1.96(m,6H),1.91-1.53(m,25H),1.25-0.92(m,16H)。

(2S,2'S) -N, N' - ((1R,1'R) -2,2',3,3 '-tetrahydro-1H, 1' H- [4,4 '-bisindenyl ] -1,1' -diyl) bis (1- ((S) -2- (methylamino) propionamido) butyryl) pyrrolidine-2-carboxamide) (compound V-O):

[M+H]⁺＝799.4。¹H NMR(300MHz,DMSO-d₆):δ8.34-8.17(m,2H),8.08-7.93(m,2H),7.45-7.21(m,4H),7.19-7.08(m,2H),5.42-5.27(m,2H),4.61-4.50(m,2H),4.38-4.30(m,2H),3.78-3.56(m,4H),3.02-2.92(m,2H),2.90-2.77(m,2H),2.62-2.56(m,2H),2.38-2.28(m,2H),2.25-2.17(m,7H),2.16-1.98(m,5H),1.93-1.69(m,8H),1.66-1.50(m,2H),1.16-1.07(m,6H),0.96-0.82(m,6H)。

(S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) -N- ((4R,4' R) -4' - ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamide) - [8,8' -chroman ] -4-yl) pyrrolidine-2-carboxamide (compound V-P):

LCMS(ESI,m/z):[M+H]⁺＝939.6。¹H NMR(300MHz,DMSO-d₆):δ8.74-8.33(m,2H),7.98-7.73(m,2H),7.55-7.12(m,2H),7.08-6.98(m,2H),6.97-6.82(m,2H),5.13-4.92(m,2H),4.56-4.25(m,4H),4.21-3.99(m,4H),3.83-3.58(m,4H),3.06-2.91(m,2H),2.28-2.15(m,6H),2.14-1.96(m,6H),1.96-1.40(m,20H),1.29-0.89(m,16H)。

(S) -1- ((S) -2- (methylamino) propionamido) -2- (tetrahydro-2H-pyran-4-yl) acetyl) -N- ((4R,4' R) -4' - ((S) -1- ((S) -2- (methylamino) propionamido) -2- (tetrahydro-2H-pyran-4-yl) acetyl) pyrrolidine-2-carboxamide) - [8,8' -chroman ] -4-yl) pyrrolidine-2-carboxamide (compound V-Q):

LCMS(ESI,m/z):[M+H]⁺＝943.5。¹H NMR(300MHz,DMSO-d₆):δ8.78-8.33(m,2H),8.07-7.75(m,2H),7.59-7.10(m,2H),7.07-6.98(m,2H),6.94-6.83(m,2H),5.10-4.89(m,2H),4.60-4.42(m,2H),4.39-4.27(m,2H),4.22-4.00(m,4H),3.93-3.63(m,8H),3.25-3.17(m,2H),3.02-2.92(m,2H),2.27-1.69(m,24H),1.68-1.52(m,2H),1.52-0.99(m,12H)。

(S) -1- ((S) -2- (methylamino) propionamido) -2- (tetrahydro-2H-pyran-4-yl) acetyl) -N- ((1R,1'R) -1' - ((S) -1- ((S) -2- (methylamino) propionamido) -2- (tetrahydro-2H-pyran-4-yl) acetyl) pyrrolidine-2-carboxamide) -2,2',3,3' -tetrahydro-1H, 1'H- [4,4' -bisindenyl ] -1-yl) pyrrolidine-2-carboxamide (compound V-R):

LCMS(ESI,m/z):[M+H]⁺＝911.6。¹H NMR(300MHz,DMSO-d₆):δ8.61-8.20(m,2H),8.08-7.81(m,2H),7.27-7.25(m,4H),7.15-7.12(m,2H),5.35-5.32(m,2H),4.54-4.48(m,2H),4.34-4.30(m,2H),3.85-3.69(m,7H),3.41-3.36(m,2H),3.31-3.19(m,4H),2.99-2.97(m,2H),2.85-2.73(m,2H),2.61-2.55(m,2H),2.40-2.00(m,15H),1.89-1.56(m,10H),1.48-1.18(m,4H),1.11(d,J＝6.6Hz,6H)。

example 6: synthesis of Compound VI:

(R) -benzyl 5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-ylcarbamate (Compound VI-1): in N₂(R) -5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-amine (500.0mg, 2.21mmol) in dioxane/H at 0 deg.C₂Solution in O (4.0/10.0mL) NaHCO was added₃(557.3mg, 6.63mmol) and Cbz-Cl (452.7mg, 2.65 mmol). The resulting mixture was stirred at room temperature for 16 hours. After the reaction is complete, the mixture is washed with H₂O diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (1/10, v/v) to give the title compound as a white solid (570.0mg, 72%). LCMS (ESI, M/z) [ M + H ]]⁺＝360.1。

(R) -benzyl 5- (diphenylmethyleneamino) 1,2,3, 4-tetrahydronaphthalen-1-ylcarbamate (Compound VI-2): to a solution of compound VI-1(500.0mg, 1.39mmol) in toluene (10.0mL) were added benzhydrylamine (264.1mg, 1.46mmol), Pd₂(dba)₃(127.1mg, 0.14mmol), BINAP (172.8mg, 0.28mmol) and t-BuONa (200.1mg, 2.08 mmol). Mixing the mixture in N₂The mixture was stirred at 80 ℃ for 16 hours. After the reaction is complete, the mixture is washed with H₂O diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (1/2, v/v) to give the title compound as a yellow solid (240.0mg, 38%). LCMS (ESI, M/z) [ M + H ]]⁺＝461.2。

(R) -benzyl 5-amino-1, 2,3, 4-tetrahydronaphthalen-1-ylcarbamate hydrochloride (Compound VI-3): to a solution of compound VI-2(315.0mg, 0.98mmol) in THF (5.0mL) was added HCl (1 m)L, 2 mol/L). The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated in vacuo to give the title compound (160.0mg, crude product) as a yellow solid. LCMS (ESI, M/z) [ M + H ]]⁺＝297.2。

N- [ (1R) -5- { [ (5R) -5- { [ (benzyloxy) carbonyl]Amino } -5,6,7, 8-tetrahydronaphthalen-1-yl]Amino } -1,2,3, 4-tetrahydronaphthalen-1-yl]Benzyl carbamate (Compound VI-4): to a solution of compound VI-3(120.0mg, crude) in dioxane (10.0mL) was added (R) -benzyl 5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-ylcarbamate (145.9mg, 0.41mmol), BrettPhos Pd G3(36.7mg, 0.04mmol), BrettPhos (43.5mg, 0.08mmol) and Cs₂CO₃(263.9mg, 0.81 mmol). Mixing the mixture in N₂The mixture was stirred at 100 ℃ for 16 hours. After the reaction is complete, the mixture is washed with H₂Diluted O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. Subjecting the residue to reverse phase flash column chromatography with 5-100% CH₃CN/H₂Purification of O afforded the title compound as a yellow solid (200.0mg, 86%). LCMS (ESI, M/z) [ M + H ]]⁺＝576.3。

(R) -N1- ((R) -5-amino-5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydronaphthalene-1, 5-diamine (Compound VI-5): to compound VI-4(200.0mg, 0.35mmol) in CH₃To a solution in OH (10.0mL) was added Pd/C (40.0mg, dry). The mixture is left at room temperature in H₂Stirred for 16 hours. After completion of the reaction, the mixture was filtered. The filtrate was evaporated in vacuo to give the title compound (50.0mg, crude product) as a yellow solid. LCMS (ESI, M/z) [ M + H ]]⁺＝308.3。

((S) -tert-butyl 1- (((S) -2- (((R) -5- ((S) -1- ((S) -2- ((tert-butoxycarbonyl) (methyl) amino) propionamido) -2-cyclohexylacetyl) pyrrolidine-2-carboxamido) -5,6,7, 8-tetrahydronaphthalen-1-yl) amino) -1,2,3, 4-tetrahydronaphthalen-1-yl) carbamoyl) pyrrolidin-1-yl) -1-cyclohexyl-2-oxyethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (compound VI-6): to a solution of compound VI-5(40.0mg, 0.13mmol) in DMF (5.0mL) was added V-9(114.4mg, 0.26mmol), DIEA (84.1)mg, 0.65mmol) and HATU (123.7mg, 0.33 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour. After the reaction is complete, the mixture is washed with H₂O diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with DCM/methanol (10/1, v/v) to give the title compound as a yellow solid (130.0mg, 87%). LCMS (ESI, M/z) [ M + H ]]⁺＝1150.7。

(S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) -N- ((R) -5- (((R) -5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamide) -5,6,7, 8-tetrahydronaphthalen-1-yl) amino) -1,2,3, 4-tetrahydronaphthalen-1-yl) pyrrolidine-2-carboxamide (compound VI): to a solution of VI-6(130.0mg, 0.11mmol) in DCM (10.0mL) was added TFA (2.0 mL). The mixture was stirred at room temperature for 1 hour. After the reaction is complete, the mixture is washed with H₂And (4) diluting with oxygen. The pH of the mixture was adjusted with saturated NaHCO₃The solution was adjusted to 7. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions: column: XBridge prep OBD C18 column, 30 × 150mm, 5 um; mobile phase A: water (10mmol/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 39% B to 69% B in 7 minutes; 220nm to give the title compound as a white solid (26.6mg, 25%). LCMS (ESI, M/z) [ M + H ]]⁺＝950.6。¹H NMR(300MHz,DMSO-d₆)δ8.42-8.15(m,2H),7.91-7.71(m,2H),7.11-6.99(m,2H),6.97-6.88(m,2H),6.71-6.58(s,2H),6.48(s,1H),4.98-4.87(m,2H),4.55-4.40(m,2H),4.39-4.28(m,2H),3.85-3.69(m,2H),3.68-3.52(m,2H),3.01-2.89(m,2H),2.58-2.54(m,3H),2.22-2.10(m,6H),2.09-1.91(m,5H),1.90-1.79(m,9H),1.78-1.51(m,15H),1.29-0.90(m,16H)。

Following the procedure described above for example 6 and substituting appropriate reagents, starting materials and purification methods known to those skilled in the art, the compounds listed below were prepared.

(S) -1- ((S) -2- (methylamino) propionamido) -2- (tetrahydro-2H-pyran-4-yl) acetyl) -N- ((R) -5- (((R) -5- ((S) -1- ((S) -2- (methylamino) propionamido) -2- (tetrahydro-2H-pyran-4-yl) acetyl) pyrrolidine-2-carboxamide) -5,6,7, 8-tetrahydronaphthalen-1-yl) amino) -1,2,3, 4-tetrahydronaphthalen-1-yl) pyrrolidine-2-carboxamide (compound VI-a):

LCMS(ESI,m/z):[M+H]⁺＝954.0。¹H NMR(300MHz,DMSO-d₆):δ8.22(d,J＝8.7Hz,2H),7.98(d,J＝8.7Hz,2H),7.11-6.95(m,2H),6.88(d,J＝7.5Hz,2H),6.59(d,J＝7.5Hz,2H),6.50(s,1H),4.99-4.85(m,2H),4.56-4.44(m,2H),4.41-4.27(m,2H),3.91-3.68(m,8H),3.32-3.17(m,5H),3.06-2.92(m,2H),2.22-2.17(m,7H),2.15-1.52(m,24H),1.28-1.09(m,12H)。

(S) -1- (methyl-L-alanyl-L-valyl) -N- ((R) -5- (((R) -5- ((S) -1- (methyl-L-alanyl-L-valyl) pyrrolidine-2-carboxamido) -5,6,7, 8-tetrahydronaphthalen-1-yl) amino) -1,2,3, 4-tetrahydronaphthalen-1-yl) pyrrolidine-2-carboxamide (compound VI-B):

LCMS(ESI,m/z):[M+H]⁺＝870.6。¹H NMR(300MHz,DMSO-d₆):δ8.23(d,J＝8.7Hz,2H),7.95(d,J＝9.0Hz,2H),7.07-6.86(m,4H),6.64-6.54(m,2H),6.50(s,1H),5.00-4.90(m,2H),4.50-4.28(m,4H),3.79-3.56(m,4H),3.10-2.96(m,3H),2.60-2.54(m,3H),2.23-2.16(m,7H),2.14-1.94(m,6H),1.91-1.51(m,13H),1.20-1.07(m,6H),1.01-0.77(m,12H)。

(2S,2' S) -N, N ' - ((1R,1' R) -azepinylbis (1,2,3, 4-tetrahydronaphthalen-5, 1-diyl)) bis (1- ((S) -2- (methylamino) propionamido) butyryl) pyrrolidine-2-carboxamide) (compound VI-C):

LCMS(ESI,m/z):[M+H]⁺＝842.5。¹H NMR(300MHz,DMSO-d₆):δ8.62-7.95(m,6H),7.07-6.95(m,2H),6.88-6.85(m,2H),6.63-6.48(m,3H),5.02-4.90(m,2H),4.59-4.46(m,3H),4.38-4.29(m,3H),3.73-3.58(m,5H),3.15-3.05(m,2H),2.30-2.21(m,6H),2.12-1.50(m,21H),1.22-1.10(m,6H),0.96-0.77(m,6H)。

example 7: synthesis of compound VII:

(R) -methyl 5- (tert-butoxycarbonylamino) -5,6,7, 8-tetrahydronaphthalene-1-carboxylate (Compound VII-1): to a solution of tert-butyl (R) -5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-ylcarbamate (500.0mg, 1.53mmol) in CH₃Solution in OH (20.0mL) and DMF (6.0mL) was added Pd (dppf) Cl₂(112.1mg, 0.15mmol) and TEA (465.3mg, 4.60 mmol). The resulting mixture was stirred under CO at 80 ℃ for 16 hours. After the reaction is complete, the resulting mixture is washed with H₂Diluted O and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography with petroleum ether/EtOAc (83/17, v/v) to give the title compound as a pale yellow solid (150.0mg, 32%). LCMS (ESI, M/z) [ M + H ]]⁺＝306.2。

(R) -5- (tert-Butoxycarbonylamino) -5,6,7, 8-tetrahydronaphthalene-1-carboxylic acid (Compound VII-2): to compound VII-1(250.0mg, 0.82mmol) in THF (5.0mL) and H₂To a solution in O (5.0mL) was added LiOH (78.4mg, 3.28 mmol). The resulting mixture was stirred at 40 ℃ for 16 hours. After the reaction was complete, the pH of the mixture was adjusted to 4 with HCl (1 mol/L). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated in vacuo to give the title compound as a pale yellow solidMaterial (260.0mg, crude). LCMS (ESI, M/z) [ M + H ]]⁺＝292.1。

(R) -5-carbamoyl-1, 2,3, 4-tetrahydronaphthalen-1-ylcarbamic acid tert-butyl ester (Compound VII-3): in N₂To a solution of compound VII-2(200.0mg, 0.67mmol) in DMF (8.0mL) at 0 deg.C was added NH₄Cl (146.9mg, 2.75mmol), DIEA (709.8mg, 5.49mmol) and HATU (522.0mg, 1.37 mmol). The resulting mixture was stirred at room temperature for 2 hours. After the reaction is complete, the reaction mixture is washed with H₂Diluted O and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with petroleum ether/EtOAc (56/44, v/v) to give the title compound as a white solid (190.0mg, 95%). LCMS (ESI, M/z) [ M + H ]]⁺＝291.2。

Tert-butyl ((R) -5- (((R) -5- ((tert-butoxycarbonyl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) carbamoyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) carbamate (compound VII-4): to a solution of compound VII-3(150.0mg, 0.52mmol) in DMF (6.0mL) was added tert-butyl (R) -5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-ylcarbamate (168.5mg, 0.52mmol), Pd₂(dba)₃(47.3mg, 0.05mmol), XantPhos (59.8mg, 0.10mmol) and Cs₂CO₃(336.6mg, 1.03 mmol). The resulting mixture is stirred under N₂The mixture was stirred at 100 ℃ for 16 hours. After the reaction is complete, the resulting mixture is washed with H₂Diluted O and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography with petroleum ether/EtOAc (65/35, v/v) to give the title compound as a yellow solid (130.0mg, 47%). LCMS (ESI, M/z) [ M + H ]]⁺＝536.3。

(R) -5-amino-N- ((R) -5-amino-5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydronaphthalene-1-carboxamide dihydrochloride (compound VII-5): a solution of compound VII-4(110.0mg, 0.21mmol) in HCl/1, 4-dioxane (5.0mL, 4mol/L) was stirred at room temperature for 2 hours. After the reaction is complete, the resulting mixture is washed with waterConcentration under air afforded the title compound (100.0mg, crude product) as a white solid. LCMS (ESI, M/z) [ M + H ]]⁺＝408.2。

Tert-butyl (S) -1- (((S) -2- (((R) -5- ((S) -1- ((S) -2- ((tert-butoxycarbonyl) (methyl) amino) propionamido) -2-cyclohexylacetyl) pyrrolidine-2-carboxamido) -5,6,7, 8-tetrahydronaphthalene-1-carboxamido) -1,2,3, 4-tetrahydronaphthalene-1-yl) carbamoyl) pyrrolidin-1-yl) -1-cyclohexyl-2-oxyethyl) amino) -1-oxoprop-2-yl) (methyl) carbamate (compound VII-6): in N₂To a solution of compound VII-5(80.0mg, crude) in DMF (5.0mL) at 0 deg.C were added compound V-9(230.6mg, 0.53mmol), DIEA (246.6mg, 1.91mmol) and HATU (453.4mg, 1.19 mmol). The resulting mixture was stirred at 0 ℃ for 2 hours. After the reaction is complete, the reaction is taken as H₂Diluted O and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over CH₂Cl₂/CH₃OH (95/5, v/v) to give the title compound as a yellow solid (180.0mg, 64%). LCMS (ESI, M/z) [ M + H ]]⁺＝1178.7。

(S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) -N- ((R) -5- (((R) -5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamide) -5,6,7, 8-tetrahydronaphthalen-1-yl) carbamoyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) pyrrolidine-2-carboxamide (compound VII): to compound VII-6(130.0mg, 0.11mmol) in CH₂Cl₂To a solution (4.0mL) was added TFA (2.0 mL). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated NaHCO was used₃The solution adjusts the pH of the mixture to 7-8. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions: (column: XSelect CSH OBD column 30X 150mm, 5 um; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 ml/min(ii) a Gradient: from 5% B to 35% B in 7 minutes; 254/220nm) to give the title compound as a white solid (39.1mg, 36%). LCMS (ESI, M/z) [ M + H ]]⁺＝978.7。¹H NMR(300MHz,DMSO-d₆)δ9.63(s,1H),8.51-8.18(m,2H),7.92-7.70(m,2H),7.50-7.09(m,6H),5.04-4.89(m,2H),4.52-4.26(m,4H),3.81-3.54(m,4H),3.01-2.81(m,4H),2.76-2.64(m,2H),2.24-2.12(m,6H),2.11-1.93(m,6H),1.92-1.50(m,24H),1.24-0.89(m,16H)。

Following the procedure described above for example 7 and substituting appropriate reagents, starting materials and purification methods known to those skilled in the art, the compounds listed below were prepared.

(2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (1R) -5- [ [ (5R) -5- [ (2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] carbamoyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound VII-A):

LCMS(ESI,m/z):[M+H]⁺＝898.6。¹H NMR(300MHz,DMSO-d₆):δ9.66(s,1H),8.31-8.28(m,2H),8.05-7.95(m,2H),7.41-7.35(m,2H),7.29-7.13(m,4H),5.05-4.90(m,2H),4.47-4.42(m,2H),4.34-4.31(m,2H),3.72-3.62(m,4H),3.05-2.95(m,3H),2.90-2.86(m,2H),2.73-2.69(m,2H),2.19(s,6H),2.10-1.60(m,19H)1.19-1.11(m,6H),0.97-0.80(m,12H)。

(2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] -2- (oxa-4-yl) acetyl ] -N- [ (1R) -5- [ [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] -2- (oxa-4-yl) acetyl ] pyrrolidin-2-amido ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] carbamoyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound VII-B):

LCMS(ESI,m/z):[M+H]⁺＝982.5。¹H NMR(300MHz,DMSO-d₆):δ9.66(s,1H),8.37-8.25(m,2H),8.02-7.93(m,2H),7.42-7.11(m,6H),5.03-4.91(m,2H),4.56-4.45(m,2H),4.43-4.27(m,2H),3.91-3.59(m,8H),3.28-3.18(m,4H),3.03-2.87(m,4H),2.73-2.69(m,2H),2.24-1.52(m,30H),1.40-1.24(m,4H),1.22-1.06(m,6H)。

(2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (1R) -5- [ [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] carbamoyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound VII-C):

LCMS(ESI,m/z):[M+H]⁺＝870.5。¹H NMR(300MHz,DMSO-d₆):δ9.67(s,1H),8.30-8.20(m,2H),8.03-7.93(m,2H),7.41-7.03(m,6H),5.05-4.93(m,2H),4.58-4.48(m,2H),4.40-4.26(m,2H),3.73-3.57(m,3H),3.02-2.83(m,4H),2.76-2.67(m,2H),2.26-2.15(m,6H),2.13-1.49(m,23H),1.19-1.06(m,6H),0.96-0.76(m,6H)。

(S) -1- ((S) -3, 3-dimethyl-2- ((S) -2- (methylamino) propionamido) butanoyl) -N- ((R) -5- (((R) -5- ((S) -1- ((S) -3, 3-dimethyl-2- ((S) -2- (methylamino) propionamido) butanoyl) pyrrolidine-2-carboxamide) -5,6,7, 8-tetrahydronaphthalen-1-yl) carbamoyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) pyrrolidine-2-carboxamide (compound VII-D):

LCMS(ESI,m/z):[M+H]⁺＝926.7。¹H NMR(300MHz,DMSO-d₆):δ9.60(s,1H),8.37-8.34(m,2H),7.87-7.70(m,2H),7.70-7.12(m,6H),4.99-4.91(m,2H),4.59-4.53(m,2H),4.35-4.32(m,2H),3.74-3.64(m,4H),3.00-2.83(m,4H),2.72-2.65(m,2H),2.47-2.00(m,12H),1.99-1.65(m,12H),1.17-1.11(m,6H),1.01-0.91(m,18H)。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (4R) -8- [ [ (4R) -4- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -3, 4-dihydro-2H-1-benzopyran-8-yl ] carbamoyl ] -3, 4-dihydro-2H-1-benzopyran-4-yl ] pyrrolidine-2-carboxamide (Compound VII-E):

LCMS(ESI,m/z):[M+H]⁺＝982.4。¹H NMR(300MHz,DMSO-d₆):δ10.60(m,1H),8.78-8.42(m,1H),8.39-8.30(m,2H),8.04-7.95(m,1H),7.94-7.68(m,2H),7.52-7.44(m,1H),7.17-6.84(m,3H),5.29-4.89(m,2H),4.66-4.22(m,8H),3.84-3.45(m,4H),3.06-2.88(m,2H),2.34-1.44(m,32H),1.34-0.84(m,16H)。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -4- [ [ (1R) -1- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -2, 3-dihydro-1H-inden-4-yl ] carbamoyl ] -2, 3-dihydro-1H-inden-1-yl ] pyrrolidine-2-carboxamide (Compound VII-F):

LCMS(ESI,m/z):[M+H]⁺＝950.5。¹H NMR(300MHz,DMSO-d₆):δ9.78(s,1H),8.27-8.20(m,2H),7.92-7.88(m,2H),7.62-7.59(m,1H),7.42-7.40(m,2H),7.33-7.31(m,1H),7.21-7.16(m,1H),7.11-7.09(m,1H),5.35-5.21(m,2H),4.45-4.30(m,4H),3.77-3.65(m,4H),3.22-3.16(m,2H),2.99-2.94(m,4H),2.83-2.72(m,1H),2.40-2.34(m,3H),2.22-2.18(m,6H),2.08-2.02(m,4H),1.84-1.61(m,18H),1.22-0.98(m,16H)。

example 8: synthesis of Compound VIII:

(R) -5- (hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) -1,2,3, 4-tetrahydronaphthalen-1-ylcarbamic acid tert-butyl ester (Compound VIII-1): to a solution of tert-butyl (R) -5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-ylcarbamate (500.0mg, 1.53mmol) in dioxane (10.0mL) was added octahydropyrrole [3,4-c]Pyrrole (515.8mg, 4.60mmol), Pd₂(dba)₃(140.4mg, 0.15mmol), XantPhos (177.4mg, 0.31mmol) and Cs₂CO₃(1248.4mg, 3.83 mmol). Mixing the mixture in N₂Stirred under an atmosphere at 100 ℃ for 16 hours. After the reaction is complete, the mixture is washed with H₂Diluted O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. Subjecting the residue to reverse phase flash column chromatography with 5-100% CH₃CN/H₂Purification of O afforded the title compound as a yellow solid (280.0mg, 51%). LCMS (ESI, M/z) [ M + H ]]⁺＝358.2。

N- [ (1R) -5- [5- [ (5R) -5- [ (tert-butoxycarbonyl) amino group]-5,6,7, 8-tetrahydronaphthalen-1-yl]-hexahydropyrrolo [3,4-c]Pyrrol-2-yl]-1,2,3, 4-tetrahydronaphthalen-1-yl]T-butyl carbamate (compound VIII-2): to a solution of compound VIII-1(200.0mg, 0.55mmol) in DCM (10.0mL) was added (5R) -5- [ (tert-butoxycarbonyl) amino group]-5,6,7, 8-tetrahydronaphthalen-1-ylboronic acid (244.3mg, 0.84mmol), Cu (OAc)₂(203.2mg, 1.12mmol), TEA (226.4mg, 2.24mmol) and 4A MS (50.0 mg). The mixture was at room temperature in O₂Stirred under atmosphere for 16 hours. After the reaction is complete, the mixture is washed with H₂O diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. Subjecting the residue to reverse phase flash column chromatography with 5-100% CH₃CN/H₂Purification of O afforded the title compound as a yellow oil (38.0mg, 11%). LCMS (ESI, M/z) [ M + H ]]⁺＝603.4。

(1R) -5- [5- [ (5R) -5-amino-5, 6,7, 8-tetrahydronaphthalen-1-yl]-hexahydropyrrole [3,4-c]Pyrrol-2-yl]1,2,3, 4-tetrahydronaphthalen-1-amine dihydrochloride (compound VIII-3):a solution of compound VIII-2(38.0mg, 0.06mmol) in HCl/dioxane (5.0mL, 4mol/L) was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated in vacuo to give the title compound as a white solid (40.0mg, crude product). LCMS (ESI, M/z) [ M + H ]]⁺＝403.3。

N- [ (1S) -1- [ [ (1S) -2- [ (2S) -2- [ [ (1R) -5- [5- [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- [ (tert-butoxycarbonyl) (methyl) amino group]Propionamido group]-2-Cyclohexylacetyl]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]-hexahydropyrrole [3,4-c]Pyrrol-2-yl]-1,2,3, 4-tetrahydronaphthalen-1-yl]Carbamoyl radical]Pyrrolidin-1-yl radical]-1-cyclohexyl-2-oxoethyl group]Carbamoyl radical]Ethyl radical]-tert-butyl N-methylcarbamate (compound VIII-4): to a solution of compound V-9(40.0mg, 0.09mmol) in DMF (5.0mL) were added compound VIII-3(95.2mg, 0.20mmol), DIEA (58.8mg, 0.46mmol) and HATU (86.5mg, 0.23 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour. After the reaction is complete, the mixture is washed with H₂O diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with DCM/methanol (10/1, v/v) to give the title compound as a yellow solid (100.0mg, 48%). LCMS (ESI, M/z) [ M + H ]]⁺＝1245.8。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido]Acetyl group]-N- [ (1R) -5- [5- [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido]Acetyl group]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]-hexahydropyrrole [3,4-c]Pyrrol-2-yl]-1,2,3, 4-tetrahydronaphthalen-1-yl]Pyrrolidine-2-carboxamide (compound VIII): to a solution of compound VIII-4(60.0mg, 0.05mmol) in DCM (1.0mL) was added TFA (0.1 mL). The mixture was stirred at room temperature for 1 hour. After the reaction is complete, the mixture is washed with H₂And (4) diluting with oxygen. Aqueous NaHCO₃The pH of the mixture was adjusted to 7 and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions: column:YMC-Actus Triart C18, 20X 250mm, 5um, 12 nm; mobile phase A: water (10mmol/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 62% B to 92% B in 7 minutes; 220nm, room temperature 5.27 min to give the title compound as a white solid (8.9mg, 18%). LCMS (ESI, M/z) [ M + H ]]⁺＝1045.7。¹H NMR(300MHz,DMSO-d₆)δ8.12-8.07(m,2H),7.91-7.69(m,2H),7.30-7.02(m,2H),6.97-6.86(m,4H),4.96-4.86(m,2H),4.47-4.21(m,4H),3.76-3.53(m,4H),3.21-3.04(m,4H),2.99-2.81(m,8H),2.76-2.57(m,4H),2.22-1.91(m,12H),1.90-1.38(m,24H),1.25-0.84(m,16H)。

Following the procedure described above for example 8 and substituting appropriate reagents, starting materials and purification methods known to those skilled in the art, the compounds listed below were prepared.

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -7- [4- [ (8R) -8- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-2-yl ] piperazin-1-yl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound VIII-A):

LCMS(ESI,m/z):[M+H]⁺＝1019.8。¹H NMR(300MHz,DMSO-d₆)δ8.26-8.10(m,2H),7.90-7.78(m,2H),7.03-6.78(m,6H),5.00-4.76(m,2H),4.53-4.35(m,2H),4.35-4.21(m,2H),4.07-3.50(m,4H),3.31-3.18(m,7H),2.99-2.95(m,2H),2.73-2.64(m,4H),2.28-2.17(m,7H),2.17-1.99(m,4H),1.84-1.50(m,25H),1.20-0.93(m,17H)。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] -N- [ (1R) -6- [4- [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido ] acetyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-2-yl ] piperazin-1-yl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound VIII-B):

LCMS(ESI,m/z):[M+H]⁺＝1019.8。¹H NMR(300MHz,DMSO-d₆)δ7.99(d,J＝9.0Hz,2H),7.86(d,J＝9.0Hz,2H),7.11(d,J＝8.4Hz,2H),6.84-6.75(m,2H),6.68(s,2H),4.95-4.77(m,2H),4.55-4.42(m,2H),4.37-4.23(m,2H),3.78-3.56(m,4H),3.29-3.18(m,8H),3.02-2.91(m,2H),2.78-2.65(m,4H),2.17(s,6H),2.11-1.95(m,4H),1.94-1.46(m,26H),1.24-0.89(m,16H)。

(2S,2' S) -N, N ' - ((1R,1' R) -piperazine-1, 4-diylbis (1,2,3, 4-tetrahydronaphthalene-5, 1-diyl)) bis (1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamide) (compound VIII-C):

LCMS(ESI,m/z):[M+H]⁺＝1019.8。¹H NMR(400MHz,CDCl₃):δ7.61(s,2H),7.15-7.07(m,4H),6.98-6.95(m,4H),5.14(s,2H),4.63-4.51(m,4H),3.85-3.81(m,2H),3.63-3.53(m,2H),3.10-2.95(m,10H),2.86-2.82(m,2H),2.72-2.66(m,2H),2.57-2.48(m,2H),2.35(s,6H),2.16-1.95(m,6H),1.93-1.76(m,8H),1.66-1.57(m,12H),1.28-1.24(m,8H),1.13-0.88(m,10H)。

(2S,2' S) -N, N ' - ((1R,1' R) -piperazine-1, 4-diylbis (1,2,3, 4-tetrahydronaphthalene-5, 1-diyl)) bis (1- ((S) -3, 3-dimethyl-2- ((S) -2- (methylamino) propionamido) butyryl) pyrrolidine-2-carboxamide) (compound VIII-D):

LCMS(ESI,m/z):[M+H]⁺＝967.6。¹H NMR(400MHz,CDCl₃):δ7.76(m,2H),7.20-6.94(m,8H),5.21-5.07(m,2H),4.63-4.57(m,2H),4.42-4.40(m,1H),3.63-4.40(m,4H),3.01-2.83(m,10H),2.80-2.70(m,4H),2.48-2.32(m,8H),2.18-1.93(m,8H),1.78-1.53(m,6H),1.32-1.30(m,3H),1.21-0.99(m,18H),0.89-0.82(m,6H)。

(2S,2' S) -N, N ' - ((1R,1' R) -piperazine-1, 4-diylbis (1,2,3, 4-tetrahydronaphthalene-5, 1-diyl)) bis (1- ((S) -2- (methylamino) propionamido) butyryl) pyrrolidine-2-carboxamide) (compound VII-E): LCMS (ESI, M/z) [ M + H ]]⁺＝911.7。

(2S,2' S) -N, N ' - ((1R,1' R) -piperazine-1, 4-diylbis (1,2,3, 4-tetrahydronaphthalene-5, 1-diyl)) bis (1- (methyl-L-alanyl-L-valyl) pyrrolidine-2-carboxamide) (compound VIII-F): LCMS (ESI, M/z) [ M + H ]]⁺＝939.5。

Example 9: synthesis of compound IX:

2- [ (4-Methylphenylsulfonyl) oxy group]Ethanol (Compound IX-1): to a solution of ethylene glycol (65.1g, 1048.85mmol) in DCM (500.0mL) was added p-toluenesulfonyl chloride (20.0g, 104.89mmol) and TEA (53.1g, 524.43 mmol). The mixture was stirred at room temperature under N₂Stirred under atmosphere for 16 hours. After the reaction is complete, the mixture is washed with H₂O diluted and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (1/1, v/v) to give the title compound as a white solid (10.0g, 44%). LCMS (ESI, M/z) [ M + H ]]⁺＝217.0。

N- [ (1R) -5- (2-hydroxyethoxy) -1,2,3, 4-tetrahydronaphthalen-1-yl]T-butyl carbamate (compound IX-2): to (R) -5-hydroxy-1, 2,3, 4-tetrahydronaphthalen-1-ylcarbamic acid tert-butyl ester (C500.0mg, 1.90mmol) in DMF (20.0mL) Compound IX-1(615.9mg, 2.85mmol) and Cs were added₂CO₃(1.2g, 3.80 mmol). Mixing the mixture in N₂Stirred under an atmosphere at 80 ℃ for 16 hours. After the reaction is complete, the mixture is washed with H₂O diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (1/1, v/v) to give the title compound as a yellow solid (155.0mg, 27%). LCMS (ESI, M/z) [ M + H ]]⁺＝308.2。

(R) -methanesulfonic acid 2- (5- (tert-butoxycarbonylamino) -5,6,7, 8-tetrahydronaphthalen-1-yloxy) ethyl ester (Compound IX-3): to a solution of compound IX-2(300.0mg, 0.98mmol) in DCM (5.0mL) were added MsCl (167.7mg, 1.46mmol) and TEA (197.5mg, 1.95 mmol). The mixture was stirred at room temperature under N₂Stirred under atmosphere for 3 hours. After the reaction is complete, the mixture is washed with H₂O diluted and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound (330.0mg, crude product) as a yellow oil. LCMS (ESI, M/z) [ M + H ]]⁺＝386.2。

(R) -tert-butyl 5- (2- (piperazin-1-yl) ethoxy) -1,2,3, 4-tetrahydronaphthalen-1-ylcarbamate (Compound IX-4): to compound IX-3(180.0mg, 0.47mmol) in CH₃To a solution of piperazine (402.2mg, 4.67mmol) in CN (6.0mL) was added. The mixture was stirred at 80 ℃ for 16 hours. After the reaction is complete, the mixture is washed with H₂O diluted and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow oil (120.0mg, crude product). LCMS (ESI, M/z) [ M + H ]]⁺＝376.3。

N- [ (1R) -5- [2- [4- (2- [ [ (5R) -5- [ (tert-butoxycarbonyl) amino ] carbonyl ] amino]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]Ethyl) piperazin-1-yl]Ethoxy radical]-1,2,3, 4-tetrahydronaphthalen-1-yl]T-butyl carbamate (compound IX-5): to a solution of compound IX-4(200.0mg, 0.53mmol) in DMF (10.0mL)IX-3(308.0mg, 0.80mmol) and Cs were added to the solution₂CO₃(347.1mg, 1.07 mmol). The mixture was stirred at 80 ℃ for 16 hours. After the reaction is complete, the mixture is washed with H₂Diluted O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentrating the filtrate under vacuum, and purifying by reverse phase flash column chromatography with 5-100% CH₃CN/H₂Purification of O afforded the title compound as a yellow solid (100.0mg, 28%). LCMS (ESI, M/z) [ M + H ]]⁺＝665.4。

(1R) -5- [2- [4- (2- [ [ (5R) -5-amino-5, 6,7, 8-tetrahydronaphthalen-1-yl)]Oxy radical]Ethyl) piperazin-1-yl]Ethoxy radical]1,2,3, 4-tetrahydronaphthalen-1-amine dihydrochloride (compound IX-6): a solution of compound IX-5(90.0mg, 0.14mmol) in HCl/dioxane (10.0mL, 4mol/L) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to give the title compound as a white solid (80.0mg, crude product). LCMS (ESI, M/z) [ M + H ]]⁺＝465.3。

N- [ (1S) -1- { [ (1S) -2- [ (2S) -2- { [ (1R) -5- {2- [4- (2- { [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- { [ (tert-butoxy) carbonyl](methyl) amino } propionamido]-2-Cyclohexylacetyl]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy } ethyl) piperazin-1-yl]Ethoxy } -1,2,3, 4-tetrahydronaphthalen-1-yl radical]Carbamoyl } pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl group]Carbamoyl } ethyl group]-tert-butyl N-methylcarbamate (compound IX-7): to a solution of compound IX-6(70.0mg, 0.13mmol) in DMF (5.0mL) were added V-9(114.5mg, 0.26mmol), DIEA (84.2mg, 0.65mmol) and HATU (123.8mg, 0.32 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour. After the reaction is complete, the mixture is washed with H₂O diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with DCM/methanol (10/1, v/v) to give the title compound as a yellow solid (100.0mg, 48%). LCMS (ESI, M/z) [ M + H ]]⁺＝1307.8。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido]Acetyl group]-N-[(1R)-5-{2-[4-(2- { [ (5R) -5- [ (2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido group]Acetyl group]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy } ethyl) piperazin-1-yl]Ethoxy } -1,2,3, 4-tetrahydronaphthalen-1-yl radical]Pyrrolidine-2-carboxamide (compound IX): to a solution of compound IX-7(90.0mg, 0.07mmol) in DCM (5.0mL) was added TFA (1.0 mL). The mixture was stirred at room temperature for 1 hour. After the reaction is complete, the mixture is washed with H₂And (4) diluting with oxygen. Aqueous NaHCO₃The pH of the mixture is adjusted to 8 and then with CH₂Cl₂And (4) extracting. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions: column: XBridge prep OBD C18 column, 30 × 150mm, 5 um; mobile phase A: water (10mmol/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 39% B to 69% B in 7 minutes; 220 nm; room temperature 1: 6.08 to give the title compound as a white solid (17.4mg, 23%). LCMS (ESI, M/z) [ M + H ]]⁺＝1107.7。¹H NMR(300MHz,DMSO-d₆)δ8.11-8.09(m,2H),7.88-7.82(m,2H),7.12-7.07(m,2H),6.87-6.78(m,4H),4.94-4.81(m,2H),4.47-4.42(m,2H),4.37-4.27(m,2H),4.11-4.03(m,4H),3.70-3.62(m,4H),2.95-2.91(m,2H),2.76-2.65(m,5H),2.62-2.54(m,5H),2.20-2.15(m,7H),2.14-1.92(m,6H),1.89-1.50(m,27H),1.23-0.86(m,18H)。

Example 10: synthesis of Compound X:

n- [ (1R) -5- [ [ (5R) -5- [ (tert-butoxycarbonyl) amino group]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]-1,2,3, 4-tetrahydronaphthalen-1-yl]T-butyl carbamate (compound X-1): to N- [ (1R) -5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl]To a solution of tert-butyl carbamate (300.0mg, 0.92mmol) in dioxane (15.0mL) were added I-6(242.1mg, 0.92mmol), Pd₂(dba)₃(168.4mg, 0.18mmol), t-BuXPhos (156.2mg, 0.36mmol) and Cs₂CO₃(8988mg, 2.75 mmol). The reaction mixture was heated at 100 ℃ under N₂Stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with petroleum ether/EtOAc (85/15, v/v) to give the title compound as a yellow solid (314.0mg, 67%). LCMS (ESI, M/z) [ M + H ]]⁺＝509.3。

(1R) -5- [ [ (5R) -5-amino-5, 6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]1,2,3, 4-tetrahydronaphthalen-1-amine dihydrochloride (compound X-2): a solution of compound X-1(314.0mg, 0.62mmol) in HCl/dioxane (15.0mL, 4mol/L) was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo to give the title compound as a white solid (310.0mg, crude product). LCMS (ESI, M/z) [ M + H ]]⁺＝309.2。

N- [ (1S) -1- [ [ (1S) -2- [ (2S) -2- [ [ (1R) -5- [ [ (5R) -5- [ (2S) -1- [ (2S) -2- [ (2S) -2- [ [ (benzyloxy) carbonyl](methyl) amino group]Propionamido group]-2-Cyclohexylacetyl]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]-1,2,3, 4-tetrahydronaphthalen-1-yl]Carbamoyl radical]Pyrrolidin-1-yl radical]-1-cyclohexyl-2-oxoethyl group]Carbamoyl radical]Ethyl radical]-benzyl N-methylcarbamate (compound X-3): in N₂Next, DIEA (1039.2mg, 8.04mmol), Compound I-4(999.5mg, 2.11mmol) and HATU (1910.8mg, 5.03mmol) were added to a solution of Compound X-2(310.0mg, crude product) in DMF (10.0mL) at 0 ℃. The reaction mixture was stirred at room temperature under N₂Stirred for 2 hours. After the reaction is complete, the reaction mixture is washed with H₂O diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over CH₂Cl₂/MeOH (96/4, v/v) and then by reverse phase flash column chromatography with ACN/H₂O (90/10, v/v) to give the title compound as a white solid (280.0mg, 23%). LCMS (ESI, M/z) [ M + H ]]⁺＝1219.7。

(2S) -1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido]Acetyl group]-N-[(1R)-5-[[(5R)-5-[(2S)-1- [ (2S) -2-cyclohexyl-2- [ (2S) -2- (methylamino) propionamido]Acetyl group]Pyrrolidine-2-carboxamides]-5,6,7, 8-tetrahydronaphthalen-1-yl]Oxy radical]-1,2,3, 4-tetrahydronaphthalen-1-yl]Pyrrolidine-2-carboxamide (compound X): to a solution of compound X-3(280.0mg, 0.23mmol) in EtOAc (10.0mL) and EtOH (5.0mL) was added Pd/C (300.0mg, dry). The reaction mixture is left at room temperature in H₂Stirred for 16 hours. After completion of the reaction, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 × 150mm, 5 um; mobile phase A: water (10mmol/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 32% B to 82% B in 7 minutes; 220 nm; room temperature 1: 5.45 to give the title compound as a white solid (136.6mg, 63%). LCMS (ESI, M/z) [ M + H ]]⁺＝951.6。¹H NMR(300MHz,DMSO-d₆)δ8.52-8.12(m,2H),7.93-7.70(m,2H),7.40-7.06(m,4H),6.58-6.55(m,2H),5.07-4.95(m,2H),4.50-4.41(m,2H),4.34-4.29(m,2H),3.81-3.70(m,2H),3.65-3.57(m,2H),2.95-2.91(m,2H),2.70-2.60(m,4H),2.16(s,6H),2.10-1.93(m,6H),1.93-1.49(m,24H),1.28-0.89(m,16H)。

Following the procedure described above for example 10 and substituting appropriate reagents, starting materials and purification methods known to those skilled in the art, the compounds listed below were prepared.

(2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] -N- [ (1R) -5- [ [ (5R) -5- [ (2S) -1- [ (2S) -3-methyl-2- [ (2S) -2- (methylamino) propionamido ] butanoyl ] pyrrolidine-2-carboxamide ] -5,6,7, 8-tetrahydronaphthalen-1-yl ] carbamoyl ] -1,2,3, 4-tetrahydronaphthalen-1-yl ] pyrrolidine-2-carboxamide (Compound X-A):

LCMS(ESI,m/z):[M+H]⁺＝843.5。¹H NMR(300MHz,DMSO-d₆):δ8.25(d,J＝8.7Hz,2H),7.97(d,J＝8.1Hz,2H),7.25-7.01(m,4H),6.62-6.52(m,2H),5.04-4.93(m,2H),4.59-4.41(m,2H),4.41-4.28(m,2H),3.75-3.48(m,4H),3.02-2.88(m,2H),2.68-2.57(m,4H),2.18(s,6H),2.15-1.44(m,22H),1.16-1.06(m,6H),0.94-0.76(m,6H)。

(S) -1- (methyl-L-alanyl-L-valyl) -N- ((R) -5- (((R) -5- ((S) -1- (methyl-L-alanyl-L-valyl) pyrrolidine-2-carboxamido) -5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) -1,2,3, 4-tetrahydronaphthalen-1-yl) pyrrolidine-2-carboxamide (compound X-B):

LCMS(ESI,m/z):[M+H]⁺＝871.6。¹H NMR(300MHz,DMSO-d₆):δ8.30-8.25(m,2H),7.95-7.92(m,2H),7.11-7.04(m,4H),6.58-6.55(m,2H),5.03-4.95(m,2H),4.47-4.42(m,2H),4.34-4.30(m,2H),3.77-3.62(m,4H),3.06-2.92(m,2H),2.67-2.60(m,4H),2.22-2.18(m,6H),2.09-1.96(m,7H),1.88-1.78(m,9H),1.72-1.62(m,4H),1.16-1.10(m,6H),0.95-0.80(m,12H)。

(S) -1- ((S) -2- (methylamino) propionamido) -2- (tetrahydro-2H-pyran-4-yl) acetyl) -N- ((R) -5- (((R) -5- ((S) -1- ((S) -2- (methylamino) propionamido) -2- (tetrahydro-2H-pyran-4-yl) acetyl) pyrrolidine-2-carboxamide) -5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) -1,2,3, 4-tetrahydronaphthalen-1-yl) pyrrolidine-2-carboxamide (compound X-C):

LCMS(ESI,m/z):[M+H]⁺＝955.6。¹H NMR(300MHz,DMSO-d₆):δ8.53-8.01(m,5H),7.40-7.00(m,4H),6.61-6.54(m,2H),5.06-4.90(m,2H),4.56-4.46(m,3H),4.37-4.26(m,3H),3.89-3.57(m,11H),3.34-3.13(m,6H),2.68-2.59(m,3H),2.30-2.21(m,6H),2.14-1.51(m,20H),1.42-1.21(m,4H),1.21-1.06(m,6H)。

example 11: and (3) biological activity:

assay protocol

IAPs are a major cause of cancer progression and may be caused by overexpression of anti-apoptotic proteins. This protocol established three binding assays for XIAP Bir3 domain, cIAP1 and cIAP2 using FP (fluorescence polarization) technique. The fluorescent probe used was a synthetic peptide conjugated to 5-carboxyfluorescein (AbuRPFK-5 FAM). The fluorescence polarization value (mP) was detected by Envision and used to reflect the extent of binding of the protein to the fluorescent marker.

Table 1: materials and instruments

Numbering	Name (R)	Suppliers of goods	Directory number
				1	HEPES	Life Technologies (Life Technologies)	15630-080
2	NaCl	Sigma Co (Sigma)	S5886
				3	Triton X-100	Sigma Co Ltd	T8787
4	XIAP-BIR3	Reaction Biology Ltd (Reaction Biology)	APT-11-374
				5	cIAP1-BIR3	Reaction organisms Co Ltd	APT-11-370
6	cIAP2-BIR3	Reaction organisms Co Ltd	APT-11-372
				7	AbuRPF-K(5-Fam)-NH2(SM5F)	NJ peptides
8	DMSO	MP	196055
				9	Topseal A	Perkin Elmer (PerkinElmer)	E5341
10	ProxiPlate-384F Plus	PERKINELMER, Inc.	6008260
				11	V96 micro-porous plate	Neken corporation (nunc)	249944
12	384 orifice plate	Corning company (corning)	3657
				13	Envision	PERKINELMER, Inc.	2104
14	Centrifugal machine	Ainde company (Eppendorf)	5810R

Procedure

Reaction reagent

Table 2: 1 Xreaction buffer (200mL) pH 7.5

Name (R)	Raw materials	Volume of	Final concentration
				HEPES	1M(20X)	10mL	50mM
Triton X-100	100％(10000X)	20μL	0.01％
				NaCl	Powder of	2.34g	200mM
ddH2O		190mL

Table 3: enzyme solution

Table 4: 2X substrate SM5F (10mL)

Name (R)	Raw materials	Volume of	2X concentration	Final concentration
					SM5F	10μM(1000X)	10μL	10nM	5nM
1X reaction buffer		9990μL

Test compounds: the feed concentration was 10 mM.

Measuring

a. 100-fold final cpd concentration was prepared in appropriate tubes and 5uL cpd was transferred to 45 uL of 1X reaction buffer containing 10% DMSO.

b. Final reference cpd concentrations were 10000, 3333.3, 1111.1, 370.4, 123.4, 41.2, 13.7, 4.57, 1.52, 0.51, 0.17, and 0 nM. So 100-fold concentrations were 1000, 333.3, 111.1, 37.04, 12.34, 4.12, 1.0.46, 0.15, 0.05, 0.017 and 0 μ M. Final test cpd concentrations were 3333.3, 1111.1, 370.4, 123.4, 41.2, 13.7, 4.57, 1.52, 0.51, 0.17, 0.057, and 0 nM. So 100 times the concentration is 333.3, 111.1, 37.04, 12.34, 4.12, 1.0.46, 0.15, 0.05, 0.017, 0.0057 and 0 Mm.

c. The enzyme doses were added at 8 μ l/well to 384-well microplates (ProxiPlate-384F Plus, 6008260) using a multichannel pipette and prepared in table 3.

d. Centrifuge at 1000 rpm.

e. Prepared in step a) using a multichannel pipette adding 2 μ l/well cpd to 384 well microplates (ProxiPlate-384F Plus, 6008260).

f. Centrifuge at 1000 rpm. Room temperature, 15 minutes.

g. The assay was started by adding 10 uL/well substrate (prepared in table 4) to the same 384-well microplate using a multichannel pipette.

h. Centrifuge at 1000 rpm.

i. The assay plate was covered and incubated at 25 ℃ for 60 minutes.

j. Reading mP on Envision 2104 and plotting IC with mP values₅₀。

k. And (3) data analysis: IC50 was determined based on non-linear regression analysis of the collected data.

Biological data

Compounds of the present technology as described herein are tested or run according to the above protocol and show or are expected to show an IC equal to or below 1uM in one or more of the above assays₅₀The value is obtained. Certain compounds exhibit and are expected to exhibit IC in one or more of the above binding assays₅₀Is 100nM or less and other compounds exhibit or are expected to exhibit IC₅₀10nM or less. Exemplary results for selected compounds are shown in table 5.

TABLE 5

A：1-10nM

B：>10nM-100nM

C：>100nM-1μM

D：>1μM

Equivalent scheme

While certain embodiments have been illustrated and described, alterations, equivalent substitutions, and other types of alterations to the compounds of the present technology, or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers, or racemic mixtures thereof, as set forth herein, may be made by those of ordinary skill in the art upon reading the foregoing description. Each of the aspects and embodiments described above may also have incorporated therein or incorporated therein variations or aspects as disclosed with respect to any or all of the other aspects and embodiments.

The present technology is also not limited to the specific aspects described herein, which are intended as single illustrations of individual aspects of the present technology. It will be apparent to those skilled in the art that various modifications and variations can be made in the present technology without departing from the spirit and scope of the present technology. Functionally equivalent methods within the technical scope of the invention, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that the present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds, or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Accordingly, it is intended that the specification be considered as exemplary only, with a true scope, spirit and scope of the present technology being indicated only by the following claims, definitions therein and any equivalents thereof.

The embodiments illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising", "including", "containing", and the like are to be read broadly and not restrictively. Additionally, the terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the technology claimed. Additionally, the phrase "consisting essentially of … …" will be understood to include those elements specifically enumerated as well as those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of … …" does not include any unspecified elements.

In addition, where features or aspects of the disclosure are described in terms of Markush (Markush) groups, those skilled in the art will recognize that the disclosure is also described in terms of any single member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groups that fall within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

As will be understood by those skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be readily identified as being fully descriptive and enabling the splitting of the same range into at least equal two, three, four, five, ten, etc. As a non-limiting example, each range discussed herein can be readily split into a lower third, a middle third, an upper third, and the like. As will also be understood by those of skill in the art, all language such as "at most," "at least," "greater than," "less than," and the like, are inclusive of the recited value and refer to ranges that may subsequently be divided into subranges as discussed above. Finally, those skilled in the art will understand that a range includes each individual member.

All publications, patent applications, issued patents, and other documents cited in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document were specifically and individually indicated to be incorporated by reference in its entirety. To the extent that a definition in this disclosure is contradictory, a definition contained in the text incorporated by reference is excluded.

Other embodiments are set forth in the following claims, with the full scope of equivalents to which such claims are entitled.