阅读说明：本技术 抗癌剂及其制备 (Anticancer agent and preparation thereof ) 是由 阿伦·K·高希 于 2014-11-19 设计创作，主要内容包括：本申请涉及抗癌剂及其制备。本发明的一些实施方案提供了剪接体抑制化合物家族等化合物,其可用作治疗性抗癌剂。所述化合物在包括环状环氧醇与酰胺之催化性交叉复分解的方法中合成。(The present application relates to anticancer agents and their preparation. Some embodiments of the present invention provide compounds, such as a family of spliceosome inhibiting compounds, that are useful as therapeutic anti-cancer agents. The compounds are synthesized in a process that includes catalytic cross metathesis of a cyclic epoxy alcohol with an amide.)

1. A compound of formula I:

wherein the content of the first and second substances,

R¹selected from H, OH, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyloxy, - (CH)₂)_nC(O)NR¹⁶R¹⁷；

R²Selected from OH, C_1-6Alkoxy and C_2-6An alkenyloxy group; wherein

R¹⁶And R¹⁷Independently selected from H, C_1-6Alkyl, and is independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 groups of alkoxy and aryl_1-6An alkyl group;

or R¹⁶And R¹⁷Together with the nitrogen atom to which they are bound form a 5-to 6-membered heterocyclic or heteroaromatic ring,

and C1-6 alkyl substituted with 1 to 3 groups independently selected from halogen, hydroxy, C1-6 alkoxy, and O-hydroxy protecting groups;

R³and R⁴Independently selected from OH and C_1-6Alkyl (optionally substituted by Cl, F, NO)₂OH or LG wherein LG is a leaving group), C (O) R¹³、F、Cl、NO₂Wherein

Each R¹³Independently is H or C_1-6An alkyl group;

or R³And R⁴Together with the carbon atom to which they are bound, form an epoxy ring;

R⁵selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵；

R⁶Selected from H and C_1-6An alkyl group; and is

R⁷Is C_1-6An alkyl group; and is

R⁸、R⁹、R¹⁰And R¹¹Independently selected from H andC_1-6an alkyl group;

R¹²is C (O) NR¹⁴R¹⁵；

Each R¹³Independently is H or C_1-6Alkyl radical, and

R¹⁴and R¹⁵Independently selected from H and C_1-6An alkyl group; or

R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

R¹Selected from H, C_1-6Alkyl and C_1-6An alkoxy group;

R³and R⁴Together with the carbon atom to which they are bound, form an epoxy ring;

R⁵selected from H, hydroxy protecting group and C_1-6An alkyl group.

3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein

R⁵Is H; and is

R⁸Is C_1-6An alkyl group.

4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound corresponds to the formula:

wherein the content of the first and second substances,

x is selected from O, NH, NMe and CO₂Et; and is

R is selected from Me, Et, i-Pr, phenyl and benzyl.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein X is NH.

6. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound is:

7. an antibody conjugate comprising at least one compound according to any one of claims 1 to 6 conjugated to an antibody.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, excipients, or a combination thereof.

9. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use in the treatment of a patient in need of cancer remission.

10. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a patient in need of cancer remission.

Technical Field

Some embodiments of the invention relate to compounds useful for treating diseases (e.g., cancer), as well as compositions and prodrugs comprising or producing such compounds. Methods of making the compounds are also disclosed.

Background

The American Cancer Society estimates that Cancer costs us $ 2000 million each year due to medical costs (about $ 800 million per year) and lost productivity due to death and/or disability (about $ 1200 million per year). Of course, there is also a loss of personnel (human toll) who have relatives (loved ones) diagnosing, treating, and sometimes dying from many forms of cancer. Due to the high social and economic costs of cancer, new cancer treatments are the top priority of institutions (e.g., the national institutes of health) as well as major pharmaceutical companies.

Disclosure of Invention

Proliferative diseases, such as cancer, cause damage to the body as cells that interfere with the healthy function of adjacent (or distant) tissues grow rapidly. Because of the rapid replication of cells, compounds that disrupt the transcriptional pathway are valuable in combating the disease. That is, if the function of one or more proteins that function in the transcriptional pathway can be disrupted, the proliferation (and potential metastasis) of cancer cells will be limited. Such destruction will at least help to extend the patient's life by an additional number of months or years.

One family of protein complexes involved in the transcriptional pathway are spliceosomes. Spliceosomes typically comprise more than 100 proteins that act together to control the excision of exons (i.e., splicing of introns) from genomic material during transcription. Compounds that interfere with the function of spliceosomes or spliceosome-regulated proteins are valuable for slowing or stopping the spread of proliferative diseases.

Some embodiments of the invention include compounds that are effective in limiting the growth of proliferating cells and that are useful as cancer therapeutics. Some embodiments of the invention also include compositions comprising these compounds, as well as prodrugs that yield the compounds when administered to a patient. The compounds are useful for the treatment of cancer, particularly solid tumor cell cancers, such as breast, lung, cervical, prostate, ovarian, pancreatic and renal cell carcinoma. The compounds, compositions, and prodrugs can be administered to a patient in need of treatment for proliferative diseases, such as cancer.

Some embodiments of the invention also include methods of making the therapeutic compounds of various embodiments of the invention. The process comprises cross-metathesis (cross metathesis) of epoxy alcohol fragments (epoxide alcohol fragments) with amide fragments (amide fragments) in the presence of a catalyst. In one embodiment, the method comprises: an epoxy alcohol fragment is formed from (R) -isopropylidene glyceraldehyde, an amide fragment is formed using Corey-Bakshi-Shibata (CBS) reduction, achromatovich rearrangement (Achmatowicz rearraring), stereoselective Michael addition (Michael addition), and the first and second fragments are coupled using a cross-metathesis reaction. The process can be carried out within about 20 steps under standard reaction conditions and with high enantiomeric efficiency (> 98% ee) and good yield.

Detailed Description

Some embodiments of the invention include a novel family of compounds useful as therapeutic anti-cancer agents. As described herein, the agents can be synthesized in a direct synthesis that includes catalytic cross-metathesis of cyclic epoxy alcohols (cyclic epoxide alcohols) with amides.

Various embodiments of the present invention are directed to compounds having formula I and stereoisomers, pharmaceutically acceptable salts, prodrugs (e.g., esters), or antibody conjugates thereof (see, e.g., U.S. patent No.8, 663, 643, which is incorporated by reference as if fully set forth herein):

wherein the content of the first and second substances,

R¹and R²Independently selected from H, OH, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyloxy, - (CH)₂)_nC(O)NR¹⁶R¹⁷(wherein R is¹⁶And R¹⁷Independently selected from H, C_1-6Alkyl, and is independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 groups of alkoxy and aryl_1-6An alkyl group; or R¹⁶And R¹⁷Together with the nitrogen atom to which they are bound form a 5-to 6-membered heterocyclic or heteroaromatic ring), and are independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 of the alkoxy and O-hydroxy protecting groups_1-6An alkyl group;

R³and R⁴Independently selected from OH and C_1-6Alkyl (optionally substituted by Cl, F, NO)₂OH or LG, wherein LG is a leaving group, e.g. -O-mesyl, -O-tosyl or-O-phenylsulfonyl leaving group), C (O) R¹³、F、Cl、NO₂Wherein each R is¹³Independently is H or C_1-6An alkyl group; or R³And R⁴Together with the carbon atom to which they are bound, form an epoxy ring;

R⁵and R¹²Independently selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Wherein each R is¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring;

R⁶selected from H and C_1-6An alkyl group; and is

R⁷Is C_1-6An alkyl group; and is

R⁸、R⁹、R¹⁰And R¹¹Independently selected from H and C_1-6An alkyl group.

Various other embodiments of the present invention are directed to compounds having formula Ia and stereoisomers, pharmaceutically acceptable salts, prodrugs (e.g., esters), or antibody conjugates thereof:

wherein the content of the first and second substances,

R¹and R²Independently selected from H, OH, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyloxy, - (CH)₂)_nC(O)NR¹⁶R¹⁷(wherein R is¹⁶And R¹⁷Independently selected from H, C_1-6Alkyl, and is independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 groups of alkoxy and aryl_1-6An alkyl group; or R¹⁶And R¹⁷Together with the nitrogen atom to which they are bound form a 5-to 6-membered heterocyclic or heteroaromatic ring), and are independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 of the alkoxy and O-hydroxy protecting groups_1-6An alkyl group;

R³and R⁴Independently selected from OH and C_1-6Alkyl (optionally substituted by Cl, F, NO)₂OH or LG, wherein LG is a leaving group, e.g. -O-mesyl, -O-tosyl or-O-phenylsulfonyl leaving group), C (O) R¹³、F、Cl、NO₂Wherein each R is¹³Independently is H or C_1-6An alkyl group; or R³And R⁴Together with the carbon atom to which they are bound, form an epoxy ring;

R⁵and R¹²Independently selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Wherein each R is¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring;

R⁶selected from H and C_1-6An alkyl group; and is

R⁷Is C_1-6An alkyl group; and is

R⁸、R⁹、R¹⁰And R¹¹Independently selected from H and C_1-6An alkyl group.

Still further embodiments of the present invention relate to methods for preparing compounds having formula I and stereoisomers, pharmaceutically acceptable salts, prodrugs (e.g., esters), or antibody conjugates thereof:

wherein the content of the first and second substances,

R¹and R²Independently selected from H, OH, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyloxy, - (CH)₂)_nC(O)NR¹⁶R¹⁷(wherein R is¹⁶And R¹⁷Independently selected from H, C_1-6Alkyl, and is independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 groups of alkoxy and aryl_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound form a 5-to 6-membered heterocyclic or heteroaromatic ring), and are independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 of the alkoxy and O-hydroxy protecting groups_1-6An alkyl group;

R³and R⁴Independently selected from OH and C_1-6Alkyl (optionally substituted by Cl, F, NO)₂OH or LG, wherein LG is a leaving group, e.g. -O-mesyl, -O-tosyl or-O-phenylsulfonyl leaving group), C (O) R¹³、F、Cl、NO₂Wherein each R is¹³Independently is H or C_1-6An alkyl group; or R³And R⁴Together with the carbon atom to which they are bound, form an epoxy ring;

R⁵and R¹²Independently selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Wherein each R is¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring;

R⁶selected from H and C_1-6An alkyl group; and is

R⁷Is C_1-6An alkyl group;

R⁸、R⁹、R¹⁰and R¹¹Independently selected from H and C_1-6An alkyl group;

the process comprises converting a compound of formula II to a compound of formula III:

wherein R is¹、R²、R³、R⁴And R⁵Each as defined herein;

and

contacting a compound of formula III with a compound of formula IV in the presence of an olefin metathesis catalyst to form a compound of formula I:

wherein R is⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²As defined herein.

The term "C" as used herein_1-6Alkyl "refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. The term includes, but is not limited to, straight and branched chain hydrocarbyl groups such as methyl (CH)₃-, ethyl (CH)₃CH₂-), n-propyl (CH)₃CH₂CH₂-, isopropyl ((CH)₃)₂CH-), n-butyl (CH)₃CH₂CH₂CH₂-, isobutyl ((CH)₃)₂CHCH₂-, sec-butyl ((CH)₃)(CH₃CH₂) CH-), tert-butyl ((CH-)₃)₃C-), n-pentyl (CH)₃CH₂CH₂CH₂CH₂-) and neopentyl ((CH)₃)₃CCH₂-). Term C_1-6Alkyl also includes cycloalkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "C" as used herein_2-6Alkenyl "(e.g. at C)_2-6In alkenyloxy) refers to a monovalent unsaturated hydrocarbon group having 2 to 6 carbon atoms. The term includes, but is not limited to, straight and branched chain hydrocarbyl groups, such as vinyl (CH)₂CH-), propenyl (CH-)₂＝CH₂CH₂-) and isopropenyl ((CH)₃)(CH₂) C-). Term C_2-6Alkenyl also includes cycloalkenyl groups including, but not limited to, cyclopentenyl and cyclohexenyl.

The term "heteroaryl" as used herein refers to a 5 to 14-membered (e.g., 5 to 6-membered) aromatic heterocyclic ring having at least 1 heteroatom selected from nitrogen, oxygen, and sulfur and containing at least 1 carbon atom. Heteroaryl groups can be monocyclic, bicyclic, or tricyclic ring systems. Representative heteroaryl groups are triazolyl, tetrazolyl, triazolyl, tetrazolyl, triazolyl, tetrazolyl, triazolyl, tetrazolyl, and heteroaryl,Oxadiazolyl, pyridyl, furanyl, benzofuranyl, thienyl, benzothienyl, quinolinyl, pyrrolyl, indolyl, substituted or unsubstituted,Azolyl, benzoAzolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoimidazolylAzolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidinyl, aza-azanylOxygen radical and oxygen radicalAnd quinoxalinyl.

The term "aryl" as used herein broadly refers to a cyclic aromatic hydrocarbon that does not contain heteroatoms in the ring. Such aryl groups may be substituted or unsubstituted. Aryl groups include, but are not limited to, phenyl, biphenyl, fluorenyl, phenanthryl, and naphthyl.

As used herein, the term "heterocycle" or "heterocycloalkyl" as used herein refers to a 5 to 14 membered ring system, for example a 5 to 6 membered ring system, which is saturated or unsaturated and which contains 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heterocycle may be a monocyclic, bicyclic or tricyclic ring system. The bicyclic or tricyclic ring system may be spiro-fused. The bicyclic and tricyclic systems can encompass heterocycles or heteroaryls fused to a benzene ring. The heterocyclic ring may be attached through any heteroatom or carbon atom. Heterocycles include heteroaryls as defined above. Representative examples of heterocycles include, but are not limited to, aziridinyl, oxacyclopropane, thiiranyl (thiaranyl), triazolyl, tetrazolyl, aziridinyl (azirinyl), diazirinyl (diazirinyl), oxaziridinyl (oxaziridinyl), azetidinyl (azetidinyl), azetidinone (azetidinyl), oxetanyl (oxataneyl), thietanyl (thietanyl), piperidinyl, piperazinyl, morpholinyl, pyrrolyl, piperidinyl, piperazinyl, piperidinyl, and piperazinyl,Oxazinyl, thiazinyl, diazinylAlkyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isozylOxazolyl, furyl, furazanyl, pyridyl,Azolyl, benzoAzolyl, benzisoylOxazolyl, thiazolyl, benzothiazolyl, thienyl, pyrazolyl, triazolyl, pyrimidinyl, benzimidazolyl, isoindolyl, indazolyl, benzodiazolyl, benzotriazolylAzolyl, benzisoylAzolyl, purinyl, indolyl, isoquinolyl, quinolinyl, and quinazolinyl groups.

The term "hydroxy" refers to an-OH group.

The term "hydroxy protecting group" refers to a protecting group for the-OH group. Suitable hydroxyl protecting groups and suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, a number of such PROTECTING GROUPS are described IN t.w.greene and p.g.m.wuts, PROTECTING group IN ORGANIC synthiess, 3 rd edition, Wiley, New York. Such hydroxy protecting groups include C_1-6Alkyl ethers, benzyl ethers, p-methoxybenzyl ethers, silyl ethers, and the like.

The term "C_1-6Alkoxy means-O- (C)_1-6Alkyl) radical, in which C_1-6Alkyl groups are defined herein. C_1-6Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, and n-pentoxy.

In some embodiments, the compound of formula III is a compound of the formula:

wherein R is¹、R²And R⁵As defined herein.

In some embodiments, the compound of formula IV is a compound of the formula:

wherein R is⁶To R¹²As defined herein.

In some embodiments, a compound of formula IV, or a stereoisomer, pharmaceutically acceptable salt, prodrug (e.g., ester), or antibody conjugate thereof, is prepared from a compound of formula V:

wherein R is⁸As defined herein. The compound of formula IV can be prepared by a process comprising: reacting a compound of formula V with a suitable reducing agent (e.g., using borane and chirality)A Critical-Barkhush-Chaetoda (CBS) reduction of oxazaborolidine to obtain a compound of formula VI:

wherein R is⁸As defined herein;

contacting a compound of formula VI with a suitable metal catalyst (e.g., VO (acac)₂To cause an ahermatovain rearrangement) to obtain a compound of formula VII:

wherein R is⁸Herein, the textThe definition in (1);

reacting a compound of formula VII with R⁷A compound of Li (wherein R⁷As defined herein), with a suitable metal salt (e.g., CuBr · S (CH)₃)₂) Contacting to obtain a compound of formula VIII:

wherein R is⁷And R⁸As defined herein, contacting a compound of formula VIII with a suitable olefin metathesis catalyst (e.g., a suitable Grubbs (Grubbs) second generation olefin metathesis catalyst) to obtain a compound of formula IX:

wherein R is⁶、R⁷And R⁸As defined herein;

converting the compound of formula IX to a compound of formula X under reductive amination conditions:

wherein R is⁶、R⁷、R⁸And R⁹As defined herein;

and

contacting a compound of formula X with a compound of formula XI to obtain a compound of formula IV:

in some embodiments, the compound of formula VI is a compound of the formula:

in some embodiments, the compound of formula VII is a compound of the formula:

in some embodiments, the compound of formula VIII is a compound of the formula:

in some embodiments, the compound of formula IX is a compound of the formula:

in some embodiments, the compound of formula X is a compound of the formula:

in some embodiments, the compound of formula XI is a compound of the formula:

in some embodiments, the compound of formula I is a compound of the formula:

or a pharmaceutically acceptable salt, prodrug (e.g., ester), or antibody conjugate thereof.

In other embodiments, the compound of formula I is a compound of the formula:

or a pharmaceutically acceptable salt, prodrug (e.g., ester), or antibody conjugate thereof.

Some embodiments of the present invention include any one of compounds Z1 through Z7, and combinations thereof, which are potent spliceosome inhibitors and can be administered as anticancer agents, and which can be synthesized by the methods described herein:

and pharmaceutically acceptable salts, prodrugs (e.g., esters), or antibody conjugates thereof. The compounds may be included in a composition or delivered as a prodrug. The compounds Z1 to Z7 may be prepared by the processes described herein for the compounds of formula I.

"pharmaceutically acceptable salts" generally refer to pharmaceutically acceptable salts of compounds derived from a wide variety of organic and inorganic counter ions well known in the art, and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium; and salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate and oxalate salts, when the molecule contains a basic functionality.

The term "prodrug" as used herein means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of some embodiments of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds of the present invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. A particular prodrug of a compound having a carboxyl functionality is a lower alkyl ester of a carboxylic acid. The carboxylic acid ester is conveniently formed by esterifying any carboxylic acid moieties present on the molecule. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 6 th edition (Donald J. Abraham, eds., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard, eds., 1985, Harwood Academic Publishers GmbH).

One of ordinary skill in the art will recognize that the compounds described herein (e.g., compounds Z1 through Z7) comprise chiral centers. All diastereomers and racemates of the compounds described herein are contemplated herein. One of ordinary skill in the art will also recognize that the compounds described herein (e.g., compounds Z1 through Z7) comprise three two double bonds, each of which may have an e (engegen) or Z (zusammen) configuration. All isomers of the compounds described herein (e.g., E, E, E; Z, Z, Z; E, Z, E; E, E, Z; Z, E, E; Z, E, Z, and Z, Z, E) are contemplated herein.

Embodiments of the present invention also contemplate pharmaceutical compositions comprising one or more compounds of embodiments of the present invention (e.g., compounds Z1-Z7), and one or more pharmaceutically acceptable carriers, diluents, excipients, or a combination thereof. "pharmaceutical composition" refers to a chemical or biological composition suitable for administration to a subject (e.g., a mammal). Such compositions may be specifically formulated for administration by one or more of a variety of routes including, but not limited to: buccal (buccal), transdermal, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardiac, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal (intraspinal), intrathecal, intravenous, oral, parenteral, pulmonary, rectal, subcutaneous, subdermal, sublingual, transdermal and transmucosal by enema or suppository. Furthermore, the administration can be carried out by: capsules, drops, foams, gels, gums (gum), injections, liquids (liquid), patches, pills, porous pouches (porus pouch), powders, tablets, or other suitable modes of administration.

"pharmaceutical excipients" or "pharmaceutically acceptable excipients" include carriers, sometimes liquids, in which the active therapeutic agent is formulated. Excipients generally do not impart any pharmacological activity to the formulation, but they may provide chemical and/or biological stability and release characteristics. Examples of suitable formulations can be found, for example, in Remington, The Science And Practice of Pharmacy, 20 th edition (Gennaro, a.r., eds.), philiadelphia College of Pharmacy And Science, 2000, which is incorporated herein by reference in its entirety.

As used herein, "pharmaceutically acceptable carrier" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, which are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier may be suitable for intravenous, intraperitoneal, intramuscular, sublingual or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds may also be incorporated into the composition.

The pharmaceutical compositions may be sterile and stable under the conditions of manufacture and storage. The compositions may be formulated as solutions, microemulsions, liposomes or other ordered structures suitable for high drug concentrations. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating (e.g., lecithin), by the maintenance of the required particle size (in the case of dispersion) and by the use of surfactants.

In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols (e.g. mannitol, sorbitol) or sodium chloride in the composition. Prolonged release of the injectable compositions can be achieved by including in the composition an agent that delays absorption, such as monostearate salts and gelatin. In addition, the compounds described herein can be formulated as time-release formulations, such as compositions comprising slow-release polymers. The active compounds can be prepared with carriers that will protect the compound from rapid release, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic-co-polyglycolic acid (PLG). Many methods for preparing such formulations are known to those skilled in the art.

Oral administration forms are also contemplated herein. The pharmaceutical composition of the invention may be administered orally as: capsules (hard or soft), tablets (film-coated, enteric-coated or uncoated), powders or granules (coated or uncoated) or liquids (solutions or suspensions). The formulations may be conveniently prepared by any method known in the art. The pharmaceutical compositions of the present invention may contain one or more suitable manufacturing aids or excipients, including fillers, binders, disintegrants, lubricants, diluents, flowing agents, buffering agents, wetting agents, preservatives, colorants, sweeteners, flavorants and pharmaceutically compatible carriers.

For each of the embodiments described, the compound may be administered in a variety of dosage forms as known in the art. Any biologically acceptable dosage form and combination thereof known to one of ordinary skill in the art is contemplated. Examples of such dosage forms include, but are not limited to, chewable tablets, fast dissolving tablets, effervescent tablets, reconstitutable powders, elixirs, liquid formulations (1iquid), solutions, suspensions, emulsions, tablets, multi-layered tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads (beads), powders, gums, granules, microgranules, dispersible granules, cachets, douches (douch), suppositories, creams, topical (topicals), inhalants, aerosol inhalants, patches, particulate inhalants, implants, depot implants (depot implants), ingestible agents, injectable agents (including subcutaneous, intramuscular, intravenous and intradermal), infusion solutions, and combinations thereof.

Other compounds which may be included by mixing are, for example, medically inert ingredients (e.g. solid and liquid diluents), such as lactose, dextrose sucrose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules, and water or vegetable oil for suspensions or emulsions; lubricants, for example silicon dioxide, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycol; gelling agents, such as colloidal clay (colloidal clay); thickeners such as tragacanth or sodium alginate; binding agents, such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents, such as starch, alginic acid, alginic acids or sodium starch glycolate; effervescent mixture (effervescing mix); a dye; a sweetener; wetting agents, such as lecithin, polysorbate or lauryl sulfate; and other therapeutically acceptable auxiliary ingredients such as humectants, preservatives, buffers, and antioxidants, all of which are known additives for such formulations.

Liquid dispersions for oral administration may be syrups, emulsions, solutions or suspensions. Syrups may contain, for example, sucrose or sucrose together with glycerol and/or mannitol and/or sorbitol as a carrier. Suspensions and emulsions may contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

The amount of active compound in the therapeutic compositions according to various embodiments of the present invention may vary depending on factors such as: the disease state, age, sex, weight, history of illness, risk factors, predisposition to disease, route of administration, existing treatment regimen (e.g., possible interaction with other drugs), and weight of the individual. The dosage regimen may be adjusted to provide the optimal therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgency of the treatment condition.

As used herein, "dosage unit form" refers to physically discrete units suitable as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention is determined by and directly depends on: the unique characteristics of active compounds and the particular therapeutic effect to be achieved, as well as the inherent limitations in the art of formulating such active compounds with respect to therapeutic sensitivity in an individual. For therapeutic use in treating a condition in a mammal (e.g., a human) for which a compound of the present invention or an appropriate pharmaceutical composition thereof is effective, a compound of the present invention can be administered in an effective amount. Dosages suitable for the present invention may be compositions, pharmaceutical compositions, or any other composition described herein.

For each of the embodiments described, the dose is typically administered once, twice or three times a day, but more frequent dosing intervals are also possible. The doses may be administered as follows: daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, and/or every 7 days (once a week). In one embodiment, the dose may be administered daily for up to and including 30 days, preferably 7 to 10 days. In another embodiment, the dose may be administered twice daily for 10 days. If the patient is in need of treatment for a chronic disease or condition, the dose may be administered as long as signs and/or symptoms continue to be present. The patient may need "maintenance therapy," wherein the patient receives treatment daily for months, years, or the rest of the life. In addition, the compositions of the present invention may achieve prevention of recurrent symptoms. For example, the dose may be administered once or twice a day to prevent the appearance of symptoms in patients at risk, particularly in asymptomatic patients.

The compositions described herein may be administered by any of the following routes: buccal, transdermal, epidural, infusion, inhalation, intraarterial, intracardiac, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectal, subcutaneous, subdermal, sublingual, transdermal and transmucosal. Preferred routes of administration are buccal and oral. The administration can be topical, wherein the composition is administered directly, immediately adjacent to, at the location of, near, at, around, or near the diseased site; or systemic, in which the composition is administered to the patient and is passed extensively through the body, thereby reaching the affected site. Local administration may be to cells, tissues, organs and/or organ systems that are involved in and/or affected by the disease and/or where signs and/or symptoms of the disease are active or may occur. The application may be topical, with a topical effect, the composition being applied directly to the site where its action is desired. Administration may be enteral, wherein the desired effect is systemic (non-topical), the composition being administered through the digestive tract. Administration may be parenteral, where the desired effect is systemic, and the composition is administered by other routes than through the digestive tract.

In some embodiments, embodiments of the present invention contemplate compositions comprising a therapeutically effective amount of one or more compounds of embodiments of the present invention (e.g., at least one compound Z1-Z7). In some embodiments, the compositions may be used in methods of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds of various embodiments of the invention. In some aspects, various embodiments of the present invention contemplate a compound of various embodiments of the present invention for use as a medicament for treating a patient in need of remission from cancer. In some embodiments, the cancer includes, but is not limited to, solid tumor cell cancers, including, but not limited to, pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancers, including, for example, metastatic renal cell carcinoma; hepatocellular carcinoma; lung cancers including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial cancer or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, squamous cell carcinoma of the head and neck; melanoma; neuroendocrine cancers, including metastatic neuroendocrine tumors; brain tumors, including, for example, gliomas, anaplastic oligodendrogliomas, adult glioblastoma multiforme, and adult anaplastic astrocytomas; bone cancer; and soft tissue sarcomas. Examples of hematological malignancies include: acute Myeloid Leukemia (AML); chronic Myelogenous Leukemia (CML), including accelerated CML and CML catastrophe (CML-BP); acute Lymphocytic Leukemia (ALL); chronic Lymphocytic Leukemia (CLL); hodgkin's Disease (HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; b cell lymphoma; t cell lymphoma; multiple Myeloma (MM); waldenstrom's macroglobulinemia (Waldenstrom's macroglobulinemia); myelodysplastic syndromes (MDS) including Refractory Anemia (RA), refractory anemia with ringed iron granulocytes (RARS), refractory anemia with excess immature cells (RAEB), and RAEB (RAEB in transformation, RAEB-T) and myeloproliferative syndromes such as breast cancer, lung cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer and renal cell carcinoma.

The term "therapeutically effective amount" as used herein, means that amount of one or more compounds of the various embodiments of the present invention (e.g., at least one compound Z1 through Z7) that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. In some embodiments, a therapeutically effective amount is one that can treat or alleviate a disease or disease symptom at a reasonable benefit/risk ratio applicable to any medical treatment. However, it will be understood that the total daily amount of the compounds and compositions described herein can be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including: the condition being treated and the severity of the condition; the activity of the particular compound employed; the particular composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or with the particular compound employed; and similar factors known to researchers, veterinarians, physicians, or other clinicians. It is also understood that a therapeutically effective amount may be selected with reference to any toxic or other undesirable side effects that may occur during administration of one or more compounds described herein.

In some embodiments, a therapeutically effective amount of a compound of various embodiments of the invention may be about 0.05mg to 50mg per kilogram of recipient body weight per day, for example about 0.1 to 25 mg/kg/day, or about 0.5 to 10 mg/kg/day. Thus, for example, for administration to a 70kg human, the dosage range may be about 35 to 70 mg/day.

In some embodiments, one or more compounds of various embodiments of the present invention may be administered in combination with at least one additional anti-cancer agent, including, but not limited to, docetaxel, paclitaxel, bevacizumab (Avastin)^TM)。

Is incorporated by reference

Throughout this disclosure, reference has been made to and citations other documents, such as patents, patent applications, patent publications, periodicals, books, papers, web content. All of these documents are hereby incorporated by reference in their entirety for all purposes. These documents include, but are not limited to:

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all of which are incorporated by reference in their entirety.

Equivalent embodiments

Various modifications of the invention, as well as many other embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the entire content of this document, including reference to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance which can be used to practice the invention in its various embodiments and its equivalents.

The terms and expressions which have been employed 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 invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by some preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

Examples

The invention may be better understood by reference to the following examples, which are provided by way of illustration. The present invention is not limited to the examples given herein.

The synthetic schemes for compounds Z1 to Z7 are shown below with reference to FR901464(1) and the splice inhibin a (heliceostatin a) (2) shown below, which are not compounds of the present invention.

However, it is understood that the term "related to" is used herein, e.g., Thompson, c.f., et al, j.am.chem.soc.12210482-10483 (2000); and Thompson, c.f., et al, j.am.chem.soc.123: 9974-9983(2001) (both incorporated herein by reference as if fully set forth herein) this synthetic scheme is generally unique and greatly simplifies the synthetic steps as compared to the overall synthesis of 1 described. Compounds Z1 to Z7 can be synthesized by appropriate substitution in the synthesis of cyclic epoxy alcohols (compound 3 in scheme 1) as shown in scheme 1 herein.

Example 1:synthesis of epoxy alcohol stage 3

The synthesis of epoxy alcohol stage 3 is shown in scheme 1. Commercially available bromoketone 11 is protected as its dithiane derivative. Lithiation of the resulting dithiane with t-BuLi at 78 ℃ for 1 hour, followed by reaction with (R) -isopropylidene glyceraldehyde, provided a mixture of diastereomers 12 and 13 (1: 1) in 61% yield in two steps. This is somewhat unexpected in view of the lack of stereoselectivity, especially in view of the presence of chelating atoms in both the R-and β -positions of (R) -isopropylidene glyceraldehyde. In an attempt to improve the trans diastereoselectivity, we have performed on a variety of Lewis acids (e.g., CeCl)₃、ZnCl₂And MgBr₂) This addition reaction was studied in THF and ether in the presence of. However, the diastereomer ratio was not further increased.

The isomers were separated by silica gel chromatography. Syn-isomer 12 was converted to the desired anti-isomer 13 as follows: the Mitsunobu reaction is carried out in the presence of p-nitrobenzoic acid, followed by NaOH-mediated hydrolysis of the benzoate. The hydroxyl group of 13Protection was p-methoxybenzyl (PMB) ether and subsequent removal of the isopropylidene group was carried out by adding p-TsOH in a one-pot operation to provide diol 14. Using tosyl chloride (TsCl) and Et in the Presence of dibutyltin oxide₃N selectively mono-tosylates the primary alcohol. The resulting mono-tosylate was reacted with excess Corey-Chaykovsky dimethylsulfonium (methylene compound prepared by treating trimethylsulfonium iodide with n-BuLi) to provide allyl alcohol 15 in 84% yield. Similar functional group transformations were previously reported by Carreira and coworkers. See Bode, j.w. and Carreira e.m., j.org.chem.66: 6410-6424(2001), which is incorporated by reference as if fully set forth herein. Then, by using excess Hg (ClO) in methanol in the presence of anhydrous 2, 6-lutidine₄)₂To remove the dithiane group of 15. This condition resulted in the formation of the corresponding methyl ketal as a mixture of anomers, which upon treatment with catalytic amounts of p-TsOH in methanol at 0 ℃ provided the single diastereomer 16. Removal of the PMB group in 16 with 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) followed by alcohol directed epoxidation stereoselectivity with m-chloroperbenzoic acid (m-CPBA) afforded the desired epoxy alcohol segment (epoxy alcohol segment)3 as a white solid in 19 total yield starting from 11 (8 steps). Methyl ketal 3 is quite stable and easy to handle for subsequent reactions.

Scheme 1

Example 2:synthesis of amide 4

Amide 4 can be synthesized in a two-step process as shown in scheme 2A and scheme 2B below. The preparation of the side chain 7 of Z-allyl acetate is shown in scheme 2A. Optically active alcohol 10 was prepared efficiently to provide an enantiomeric efficiency (ee) of 10 > 98% by using the catalytic asymmetric addition scheme reported by Trost and coworkers. Saponification of the methyl ester 10 with aqueous LiOH followed by acetoacetylation provided the acetate 17 in good yield. Hydrogenation over lindlar catalyst provided the desired cis-olefin 7.

Scheme 2A

The synthesis of amide segment 4 is shown in scheme 2B, where the amide segment 4 has the following structure:

with (S) -2-Me-CBS catalyst (also known as (S) -5, 5-diphenyl-2-methyl-3, 4-propane-1, 3, 2-Oxazaborolidine) and BH 3. Me₂S enantioselectively reduces commercial acetylfuran 18 to afford chiral alcohol 9 (93% ee) in 94% yield. Then passing through a catalytic amount of VO (acac)₂In the presence of t-BuO₂H treatment of alcohol 9 to effect an ahermatovigine rearrangement to afford the hemiketal is directly reduced to enone 19 as a single diastereomer by employing the protocol described by Kishi and coworkers. Our subsequent synthetic scheme requires the addition of stereocenters bearing a C20(S) -methyl group. We chose to perform a 1, 4-addition on enone 19. Thus, with MeLi/CuBr₃·Me₂S treatment at-78 ℃ for 19 hours gave excellent yields (92%) and diastereoselectivities (25: 1dr, by¹H and¹³c NMR analysis) provided the desired pyrone 8. The diastereoselectivity observed can be explained by conformational analysis of enone 19. As shown in transition state model 20, the stereochemical outcome of the michael addition can be rationalized by assuming a sterically favorable axial attack of the cuprate.

The pyrone 8 and known olefin 21 are then subjected to cross-metathesis conditions using a second generation catalyst of the glasscloth type (Scholl, m., et al, org.lett.1: 953-:

the resulting tosylate was treated with t-BuOK in DMSO at 75 deg.C for 12 hours to yield diene 22 in 41% yield over two steps by base-promoted elimination. With amine acetate and NaBH₃CN reductive amination 22, providing the corresponding primary amine 6 (6: 1dr, by¹H-and¹³c NMR analysis). The crude amine 6 and its epimer were directly treated with acid 7 using standard amidation conditions to yield amide 4 and a small amount of C-14 epimer, which was separated by column chromatography.

Scheme 2B

In a final step, as shown in scheme 3, cross metathesis with epoxy alcohol and amide segments 3 and 4 can yield FR901464(1), splice inhibin a (2), compounds of the present invention (i.e., compounds Z1 through Z7), or similar compounds. With the stereoselective synthesis of the epoxy alcohol 3 (scheme 1) and amide 4 (scheme 2A/B) stages, we then turned our attention to the construction of the C6-C7 double bond of the target molecule. As shown in scheme 3, the cross metathesis of the two fragments proceeded smoothly in the presence of the glacloth second generation catalyst to provide the splice statin a (2) as a white solid in 57% isolated yield based on one cycle of unreacted 3 and 4 under the same conditions. Compounds Z1 to Z7 can be formed in approximate yields and enantiomeric efficiencies. By exposing 2 to p-toluenesulfonic acid pyridine in wet THF at 0 deg.C(pyridinium p-toluene sulfonate, PPTS) to achieve the removal of methyl ketal in 2, which provided FR901464(1) as a white powder in good yield. FR901464[ [ alpha ] synthesized by us]_D-13.0(c 0.45，CH₂Cl₂)]Is/are as follows¹H and¹³c NMR and reported natural [ [ alpha ]]_D-12.0(c 0.5，CH₂Cl₂)]The spectrum is the same as that of synthetic FR 901464.

Scheme 3

Thus, embodiments of the present invention provide a compact and enantioselective strategy for the synthesis of FR901464, splice inhibin a or compounds Z1 to Z7 in a total of about 20 steps, with the longest linear order being about 10 steps. The synthesis includes the use of a readily available chiral pool (R) -isopropylidene glyceraldehyde 5 to form the a-ring fragment, CBS reduction, ahermatovain rearrangement and stereoselective michael addition for the construction of the B-ring fragment, and cross-metathesis reactions for coupling the two fragments. This synthesis is short, convergent and suitable for the synthesis of undisclosed structural variants, which are intended to be included in the synthesis process.

Example 3

Compounds of the formula were synthesized according to the synthetic scheme shown in scheme 4 below:

scheme 4

Example 4

Compounds of the formula were synthesized according to the synthetic scheme shown in scheme 5 below:

scheme 5

Example 4

Compounds of the formula were synthesized according to the synthetic scheme shown in scheme 6 below:

scheme 6

Some of the following embodiments are provided, the numbering of which should not be construed as specifying the importance level:

embodiment 1 relates to a process for preparing a compound having formula I or a stereoisomer, pharmaceutically acceptable salt, prodrug (e.g., ester), or antibody conjugate thereof:

wherein the content of the first and second substances,

R¹and R²Independently selected from H, OH, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyloxy, - (CH)₂)_nC(O)NR¹⁶R¹⁷(wherein R is¹⁶And R¹⁷Independently selected from H, C_1-6Alkyl, and is independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 groups of alkoxy and aryl_1-6An alkyl group; or R¹⁶And R¹⁷Together with the nitrogen atom to which they are bound form a 5-to 6-membered heterocyclic or heteroaromatic ring), and are independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 of the alkoxy and O-hydroxy protecting groups_1-6An alkyl group;

R³and R⁴Independently selected from OH and C_1-6Alkyl (optionally substituted by Cl, F, NO)₂OH or LG wherein LG is a leaving group), C (O) R¹³、F、Cl、NO₂Wherein each R is¹³Independently is H or C_1-6An alkyl group; or R³And R⁴Together with the carbon atom to which they are bound, form an epoxy ring;

R⁵and R¹²Independently selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Wherein each R is¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring;

R⁶selected from H and C_1-6An alkyl group; and is

R⁷Is C_1-6An alkyl group;

R⁸、R⁹、R¹⁰and R¹¹Independently selected from H and C_1-6An alkyl group;

the process comprises converting a compound of formula II to a compound of formula III:

wherein R is¹、R²、R³、R⁴And R⁵As defined herein;

and

contacting a compound of formula III with a compound of formula IV in the presence of an olefin metathesis catalyst to form a compound of formula I:

wherein R is⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²As defined herein.

Embodiment 2 relates to the method of embodiment 1, wherein the compound of formula III is a compound of the formula:

R¹and R²Independently selected from H, OH, C_1-6Alkyl, and is independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 of the alkoxy and O-hydroxy protecting groups_1-6An alkyl group;

R⁵selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Wherein each R is¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring.

Embodiment 3 relates to the method of embodiments 1 to 2, wherein R¹Is H; r²Is C_1-6Alkyl and R⁵Is H.

Embodiment 4 relates to the method of embodiments 1 to 3, wherein R²is-CH₃。

Embodiment 5 relates to the method of embodiments 1 to 4, wherein the compound of formula IV is a compound of the formula:

R⁶selected from H and C_1-6An alkyl group; and is

R⁷Is C_1-6An alkyl group;

R⁸、R⁹、R¹⁰and R¹¹Independently selected from H and C_1-6An alkyl group; and is

R¹²Selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Which isEach R in¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring.

Embodiment 6 relates to the methods of embodiments 1 to 5, wherein R⁶、R⁷、R⁸And R¹¹Independently is C_1-6An alkyl group; r⁹And R¹⁰Is H; and R is¹²Is C (O) R¹³Wherein R is¹³Is C_1-6An alkyl group.

Embodiment 7 relates to the methods of embodiments 1 to 6, wherein R⁶、R⁷、R⁸And R¹¹is-CH₃；R⁹And R¹⁰Is H; and R is¹²Is C (O) R¹³Wherein R is¹³is-CH₃。

Embodiment 8 relates to the method of embodiments 1 to 7, wherein the compound of formula I is a compound selected from the group consisting of:

embodiment 9 relates to a process for preparing a compound having formula IV or a stereoisomer, pharmaceutically acceptable salt, prodrug, or antibody conjugate thereof:

wherein R is⁶Selected from H and C_1-6An alkyl group;

R⁷is C_1-6An alkyl group;

R⁸、R⁹、R¹⁰and R¹¹Independently selected from H and C_1-6An alkyl group; and is

R¹²Selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Wherein each R is¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring;

the method comprises the following steps:

contacting a compound of formula V with a reducing agent to obtain a compound of formula VI:

wherein R is⁸As defined herein, the definition of,

wherein R is⁸As defined herein;

contacting the compound of formula VI with a metal catalyst to obtain a compound of formula VII:

wherein R is⁸As defined herein;

reacting a compound of formula VII with R⁷A compound of Li (wherein R⁷As defined herein) with a metal salt to obtain a compound of formula VIII:

wherein R is⁷And R⁸As defined herein, the definition of,

contacting the compound of formula VIII with an olefin metathesis catalyst to obtain a compound of formula IX:

wherein R is⁷、R⁸、R⁹、R¹⁰And R¹¹As defined herein;

converting said compound of formula IX to a compound of formula X under reductive amination conditions:

wherein R is⁶、R⁷、R⁸And R⁹As defined herein;

and

contacting a compound of formula X with a compound of formula XI to obtain a compound of formula IV:

wherein R is¹⁰、R¹¹And R¹²As defined herein.

Embodiment 10 relates to the method of embodiment 9, wherein the reducing agent is a chiral reducing agent.

Embodiment 11 relates to the method of embodiment 10, wherein the chiral reducing agent comprises chiralityOxazaborolidine.

Embodiment 12 relates to the method of embodiment 9, wherein the metal catalyst causes ahermatovavir rearrangement.

Embodiment 13 relates to the method of embodiment 9, wherein the metal catalyst is vo (acac)₂。

Embodiment 14 relates to the method of embodiment 9, wherein the metal salt comprises CuBr.

Embodiment 15 relates to the method of embodiments 9 to 14, wherein the compound of formula VI is a compound of the formula:

wherein R is⁸Selected from H and C_1-6An alkyl group.

Embodiment 16 relates to the methods of embodiments 9 to 15, wherein R⁸is-CH₃。

Embodiment 17 relates to the methods of embodiments 9 to 16, wherein the compound of formula VII is a compound of the formula:

wherein R is⁸Selected from H and C_1-6An alkyl group.

Embodiment 18 relates to the methods of embodiments 9 to 17, wherein R⁸is-CH₃。

Embodiment 19 relates to the methods of embodiments 9-18 wherein the compound of formula VIII is a compound of the formula:

wherein R is⁷And R⁸Independently is C_1-6An alkyl group.

Embodiment 20 relates to the method of embodiments 9 to 19, wherein the compound of formula IX is a compound of the formula:

wherein R is⁶Selected from H and C_1-6An alkyl group;

R⁷is C_1-6An alkyl group; and is

R⁸Selected from H and C_1-6An alkyl group.

Embodiment 21 relates to the method of embodiments 9 to 20, wherein the compound of formula X is a compound of the formula:

wherein R is⁶Selected from H and C_1-6An alkyl group;

R⁷is C_1-6An alkyl group; and is

R⁸And R⁹Independently selected from H and C_1-6An alkyl group.

Embodiment 22 relates to the method of embodiments 9 to 21, wherein the compound of formula XI is a compound of the formula:

R¹⁰and R¹¹Independently selected from H and C_1-6An alkyl group; and is

R¹²Selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Wherein each R is¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring.

Embodiment 23 relates to the methods of embodiments 9 to 22, wherein R¹¹Is C_1-6An alkyl group; r¹⁰Is H; and R is¹²Is C (O) R¹³Wherein R is¹³Is C_1-6An alkyl group.

Embodiment 24 relates to the methods of embodiments 9 to 23, wherein R¹¹is-CH₃。

Embodiment 25 relates to a compound selected from the group consisting of:

embodiment 26 relates to a pharmaceutical composition comprising one or more compounds of embodiment 25 or salts, prodrugs or antibody conjugates thereof, and a pharmaceutically acceptable carrier or excipient.

Embodiment 27 relates to prodrugs that are converted in vivo to compounds selected from the group consisting of:

embodiment 28 relates to a method of treating cancer in a subject in need of such treatment comprising administering a therapeutically effective amount of one or more compounds of embodiment 25 or salts, prodrugs or antibody conjugates thereof.

Embodiment 29 relates to the method of embodiment 28, wherein the cancer is a solid tumor cancer.

Embodiment 30 relates to the method of embodiment 28, wherein the cancer is selected from the group consisting of cervical cancer, prostate cancer, lung cancer, ovarian cancer, breast cancer, renal cell carcinoma, and pancreatic cancer.

Embodiment 31 relates to the methods of embodiments 28-30, wherein the therapeutically effective amount of the one or more compounds is administered at least twice over a 60 day period.

Embodiment 32 relates to the methods of embodiments 28 to 31, further comprising administering one or more compounds of embodiment 25 in combination with at least one additional anti-cancer agent.

The present application also relates to the following embodiments:

1. a process for preparing a compound having formula I or a stereoisomer, pharmaceutically acceptable salt, prodrug (e.g., ester), or antibody conjugate thereof:

wherein the content of the first and second substances,

R¹and R²Independently selected from H, OH, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyloxy, - (CH)₂)_nC(O)NR¹⁶R¹⁷(wherein R is¹⁶And R¹⁷Independently selected from H, C_1-6Alkyl, and is independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 groups of alkoxy and aryl_1-6An alkyl group; or R¹⁶And R¹⁷Together with the nitrogen atom to which they are bound form a 5-to 6-membered heterocyclic or heteroaromatic ring), and are independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 of the alkoxy and O-hydroxy protecting groups_1-6An alkyl group;

R³and R⁴Independently selected from OH and C_1-6Alkyl (optionally substituted by Cl, F, NO)₂OH or LG wherein LG is a leaving group), C (O) R¹³、F、Cl、NO₂Wherein each R is¹³Independently is H or C_1-6An alkyl group; or R³And R⁴Together with the carbon atom to which they are bound, form an epoxy ring;

R⁵and R¹²Independently selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Wherein each R is¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring;

R⁶selected from H and C_1-6An alkyl group; and is

R⁷Is C_1-6An alkyl group;

R⁸、R⁹、R¹⁰and R¹¹Independently selected from H and C_1-6An alkyl group;

the process comprises converting a compound of formula II to a compound of formula III:

wherein R is¹、R²、R³、R⁴And R⁵As defined herein;

and

contacting a compound of formula III with a compound of formula IV in the presence of an olefin metathesis catalyst to form a compound of formula I:

wherein R is⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²As defined herein.

2. The method of embodiment 1, wherein the compound of formula III is a compound of the formula:

R¹and R²Independently selected from H, OH, C_1-6Alkyl, and is independently selected from halogen, hydroxy, C_1-6C substituted by 1 to 3 of the alkoxy and O-hydroxy protecting groups_1-6An alkyl group;

R⁵selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Wherein each R is¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring.

3. The method of embodiment 2, wherein R¹Is H; r²Is C_1-6Alkyl and R⁵Is H.

4. The method as set forth in embodiment 2, wherein,wherein R is²is-CH₃。

5. The method of embodiment 1, wherein the compound of formula IV is a compound of the formula:

R⁶selected from H and C_1-6An alkyl group; and is

R⁷Is C_1-6An alkyl group;

R⁸、R⁹、R¹⁰and R¹¹Independently selected from H and C_1-6An alkyl group; and is

R¹²Selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Wherein each R is¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring.

6. The method of embodiment 5 wherein R⁶、R⁷、R⁸And R¹¹Independently is C_1-6An alkyl group; r⁹And R¹⁰Is H; and R is¹²Is C (O) R¹³Wherein R is¹³Is C_1-6An alkyl group.

7. The method of embodiment 5 wherein R⁶、R⁷、R⁸And R¹¹is-CH₃；R⁹And R¹⁰Is H; and R is¹²Is C (O) R¹³Wherein R is¹³is-CH₃。

8. The method of embodiment 1, wherein the compound of formula I is a compound selected from the group consisting of:

9. a process for preparing a compound having formula IV or a stereoisomer, pharmaceutically acceptable salt, prodrug, or antibody conjugate thereof:

wherein R is⁶Selected from H and C_1-6An alkyl group;

R⁷is C_1-6An alkyl group;

R⁸、R⁹、R¹⁰and R¹¹Independently selected from H and C_1-6An alkyl group; and is

R¹²Selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Wherein each R is¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring;

the method comprises the following steps:

contacting a compound of formula V with a reducing agent to obtain a compound of formula VI:

wherein R is⁸As defined herein, the definition of,

wherein R is⁸As defined herein;

contacting the compound of formula VI with a metal catalyst to obtain a compound of formula VII:

wherein R is⁸As defined herein;

reacting said compound of formula VII with R⁷R is defined herein⁷A compound of Li, contacted with a metal salt to obtain a compound of formula VIII:

wherein R is⁷And R⁸As defined herein, contacting the compound of formula VIII with an olefin metathesis catalyst to obtain a compound of formula IX:

wherein R is⁷、R⁸、R⁹、R¹⁰And R¹¹As defined herein;

converting said compound of formula IX to a compound of formula X under reductive amination conditions:

wherein R is⁶、R⁷、R⁸And R⁹As defined herein;

and

contacting the compound of formula X with a compound of formula XI to obtain a compound of formula IV:

wherein R is¹⁰、R¹¹And R¹²As defined herein.

10. The method of embodiment 9, wherein the reducing agent is a chiral reducing agent.

11. The method of embodiment 10, wherein the chiral reducing agent comprises chiralityOxazaborolidine.

12. The process of embodiment 9, wherein the metal catalyst causes ahermatovavir rearrangement.

13. The process of embodiment 9 wherein the metal catalyst is VO (acac)₂。

14. The method of embodiment 9, wherein the metal salt comprises CuBr.

15. The method of embodiment 9, wherein the compound of formula VI is a compound of the formula:

wherein R is⁸Selected from H and C_1-6An alkyl group.

16. The method of embodiment 15 wherein R⁸is-CH₃。

17. The method of embodiment 9, wherein the compound of formula VII is a compound of the formula:

wherein R is⁸Selected from H and C₁-₆An alkyl group.

18. The method of embodiment 17, wherein R⁸is-CH₃。

19. The method of embodiment 9, wherein the compound of formula VIII is a compound of the formula:

wherein R is⁷And R⁸Independently is C_1-6An alkyl group.

20. The method of embodiment 9, wherein the compound of formula IX is a compound of the formula:

wherein R is⁶Selected from H and C_1-6An alkyl group;

R⁷is C_1-6An alkyl group; and is

R⁸Selected from H and C_1-6An alkyl group.

21. The method of embodiment 9, wherein the compound of formula X is a compound of the formula:

wherein R is⁶Selected from H and C_1-6An alkyl group;

R⁷is C_1-6An alkyl group; and is

R⁸And R⁹Independently selected from H and C_1-6An alkyl group.

22. The method of embodiment 9 wherein the compound of formula XI is a compound of the formula:

R¹⁰and R¹¹Independently selected from H and C_1-6An alkyl group; and is

R¹²Selected from H, hydroxy protecting group, C_1-6Alkyl, C (O) R¹³、C(O)OR¹³And C (O) NR¹⁴R¹⁵Wherein each R is¹³Independently is H or C_1-6Alkyl, and wherein R¹⁴And R¹⁵Independently selected from H and C_1-6An alkyl group; or R¹⁴And R¹⁵Together with the nitrogen atom to which they are bound, form a 5-to 6-membered heterocyclic or heteroaromatic ring.

23. The method of embodiment 22 wherein R¹¹Is C_1-6An alkyl group; r¹⁰Is H; and R is¹²Is C (O) R¹³Wherein R is¹³Is C_1-6An alkyl group.

24. The method of embodiment 22 wherein R¹¹is-CH₃。

25. A compound selected from the group consisting of:

26. a pharmaceutical composition comprising one or more compounds of embodiment 1 or salts, prodrugs or antibody conjugates thereof, and a pharmaceutically acceptable carrier or excipient.

27. A prodrug which is converted in vivo to a compound selected from the group consisting of:

28. a method of treating cancer in a subject in need of such treatment comprising administering a therapeutically effective amount of one or more compounds of embodiment 25 or salts, prodrugs or antibody conjugates thereof.

29. The method of embodiment 28, wherein the cancer is a solid tumor cancer.

30. The method of embodiment 28, wherein the cancer is selected from the group consisting of cervical cancer, prostate cancer, lung cancer, ovarian cancer, breast cancer, renal cell carcinoma, and pancreatic cancer.

31. The method of embodiment 28, wherein the therapeutically effective amount of the one or more compounds is administered at least twice over a 60 day period.

32. The method of embodiment 28, further comprising administering one or more compounds of embodiment 25 in combination with at least one other anti-cancer agent.