METAP-2 inhibitors, pharmaceutical compositions, and methods of treatment therewith

Abstract

The present invention provides inhibitors of methionine aminopeptidase 2 (MetAP-2) and pharmaceutical compositions thereof, as well as their use and methods in the treatment, amelioration, or prevention of certain diseases or conditions associated with MetAP-2 (e.g., cancer, obesity, rheumatoid arthritis, and psoriasis).

Description

[Technical field]

[0001] (Priority claims and related applications) This application claims the benefit of priority to U.S. Provisional Application No. 63 / 167,078, filed March 28, 2021, the entire contents of which are incorporated herein by reference for all purposes.

[0002] TECHNICAL FIELD OF THE PRESENT APPLICATION The present invention relates generally to compounds and their therapeutic uses. More specifically, the present invention provides novel compounds, such as inhibitors of methionine aminopeptidase 2 (MetAP-2) and pharmaceutical compositions thereof, as well as their use and methods in the treatment, amelioration, or prevention of certain diseases or conditions associated with MetAP-2, such as cancer, obesity, rheumatoid arthritis, and psoriasis. [Background technology]

[0003] Methionine aminopeptidase (MetAP) catalyzes the synthesis of the initiator NH 2 -terminal methionine, thereby facilitating intracellular transport from the ribosome. 2 - It is required for the co- and / or post-translational modifications of various proteins, such as terminal myristoylation or acetylation.

[0004] In general, two types of MetAP enzymes, MetAP-1 and MetAP-2, have been discovered, which have similar three-dimensional structures despite low sequence homology (Biochim Biophys Acta 2000;1477:157-167). Recent studies have suggested that MetAP-1 may play an important role in the G2 / M phase of the cell cycle and may serve as a promising target for the development of new anticancer drugs (Proc Natl Acad Sci USA 2006;103:18148-18153). MetAP-2 has attracted more attention than MetAP-1 because it has been identified as a target molecule for antiangiogenic compounds. Various studies suggest that MetAP-2 may play a central role in endothelial cell proliferation, with higher concentrations of MetAP-2 detected in tumors compared to normal tissues (Am J Pathol 2001;159:721-731. Lab Invest 2002;82:893-901). MetAP-2 inhibition can induce G1 cell cycle arrest and cytostasis of tumor cells in vitro and reduce tumor growth in vivo (Biochemistry 2003;42:5035-5042. Proc Natl Acad Sci USA 2000;97:6427-6432). Furthermore, a physical interaction between MetAP-2 and the metastasis-associated protein S100A4 and the impact of this association on endothelial cell proliferation and tumor metastasis have been demonstrated (J Biol Chem 2002;277:26396-26402). Due to their potential ability to inhibit tumor angiogenesis and metastasis, MetAP-2 inhibitors may be useful in the treatment of a wide variety of cancers. Furthermore, MetAP-2 inhibition also holds promise for the treatment of cell proliferative disorders, including rheumatoid arthritis and psoriasis.

[0005] Various preclinical and clinical studies have been reported on the use of MetAP-2 inhibitors in the treatment of various diseases and conditions.Nevertheless, the currently available treatments and methods for managing MetAP-2-related diseases or conditions are still insufficient.There is an urgent and ongoing need for new and improved therapeutic methods for effectively treating such diseases and conditions. Summary of the Invention

[0006] The present invention is based, in part, on the unexpected discovery of novel MetAP-2 inhibitors, methods for their synthesis, and pharmaceutical compositions, and methods thereof for treating, preventing, or ameliorating various diseases or conditions associated with MetAP-2, such as cancer, obesity, diabetes, rheumatoid arthritis, and psoriasis.

[0007] In one aspect, the present invention generally relates to a compound having the structural formula of Formula (I), or a pharma- ceutically acceptable form or isotopic derivative thereof:

[0008] [ka] (In the formula, R 1 and R 2 are independently selected from F, Cl, Br, and I; Q is (a) an unsubstituted or substituted 5- or 6-membered aromatic ring, or (b) an unsubstituted or substituted 5- or 6-membered aromatic ring fused to a second unsubstituted or substituted 5- or 6-membered ring.

[0009] In another aspect, the invention generally relates to pharmaceutical compositions comprising a compound disclosed herein and a pharma- ceutically acceptable excipient, carrier, or diluent.

[0010] In another aspect, the present invention generally relates to a compound having a quantity of structural formula (I), or a pharma- ceutically acceptable form or isotopic derivative thereof:

[0011] [ka] (In the formula, R 1 and R 2 are independently selected from F, Cl, Br, and I; Q is (a) an unsubstituted or substituted 5- or 6-membered aromatic ring, or (b) an unsubstituted or substituted 5- or 6-membered aromatic ring fused to a second unsubstituted or substituted 5- or 6-membered ring.

[0012] In yet another aspect, the invention generally relates to unit dosage forms comprising the pharmaceutical compositions of the invention.

[0013] In yet another aspect, the invention generally relates to a method for treating, ameliorating, or preventing a disease or condition, comprising administering to a subject in need thereof a compound having the structural formula (I), or a pharma- ceutically acceptable form or isotopic derivative thereof, effective to treat, prevent, or ameliorate one or more of cancer, obesity, diabetes, rheumatoid arthritis, psoriasis, or related diseases or conditions in a mammal, including a human, having the structural formula (I):

[0014] [ka] (In the formula, R 1 and R 2 are independently selected from F, Cl, Br, and I; Q is (a) an unsubstituted or substituted 5- or 6-membered aromatic ring, or (b) an unsubstituted or substituted 5- or 6-membered aromatic ring fused to a second unsubstituted or substituted 5- or 6-membered ring; and administering a pharma- ceutically acceptable excipient, carrier, or diluent.

[0015] In yet another aspect, the invention generally relates to the use of the compounds of the invention to treat or ameliorate a disease or condition.

[0016] In yet another aspect, the invention generally relates to the use of a compound of the invention and a pharma- ceutically acceptable excipient, carrier, or diluent in the preparation of a medicament for treating or ameliorating a disease or condition.

[0017] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry, as well as specific functional moieties and reactivities, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0018] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds as falling within the scope of the present invention, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0019] Isomeric mixtures containing any of a variety of isomer ratios can be utilized in accordance with the present invention. For example, when combining only two isomers, mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are contemplated by the present invention. Those skilled in the art will readily appreciate that similar ratios are contemplated for more complex isomer mixtures.

[0020] For example, if a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting diastereomeric mixture separated, and the auxiliary cleaved to give the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, a diastereomeric salt can be formed with an appropriate optically active acid or base, and the diastereomers thus formed can then be separated by fractional crystallization or chromatographic methods well known in the art, after which the pure enantiomer is recovered.

[0021] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0022] Definitions of certain functional groups and chemical terms are described in more detail below. When a range of values ​​is listed, it is intended to include each value and subrange within the range. For example, "C 1~6 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Alkyl is intended to be included.

[0023] As used herein, the term "alkyl" refers to a straight-chain, branched-chain or cyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 10 carbon atoms (e.g., C 1~10 Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer within the given range, for example, "1 to 10 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, "alkyl" refers to any of the C 1~6 It can be an alkyl group, hi some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms.

[0024] Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond.

[0025] Unless stated otherwise in the specification, an alkyl group can be acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo(F, Cl, Br, I), haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a ) 3 , -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a )S(O) t N(R a ) 2 (t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a ) 2 and each R ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which can be optionally substituted as defined herein. In non-limiting embodiments, the substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0026] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" refers to a monocyclic C ring that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the remainder of the molecule. 3 ~C 6 Exemplary aliphatic groups are linear or branched, substituted or unsubstituted C 1 ~C 8 Alkyl group, C 2 ~C 8 Alkenyl group, C 2 ~C 8 Alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0027] As used herein, the term "aromatic" or "aryl" refers to a radical having 6 to 14 ring atoms (e.g., C 6~14 Aromatic or C 6~14 In some embodiments, aryl refers to C 6~10An aryl radical. For example, a divalent radical formed from a substituted benzene derivative and having a free valence at a ring atom is called a substituted phenylene radical. In other embodiments, a divalent radical derived from a monovalent polycyclic hydrocarbon radical whose name ends in "-yl" by removing one hydrogen atom from a carbon atom having a free valence is named by adding "-idene" to the name of the corresponding monovalent radical. For example, a naphthyl group with two points of attachment is called naphthylidene. As used herein, a numerical range such as "6-14 aryl" refers to each integer within the given range. For example, "6-14 ring atoms" means that an aryl group can consist of six ring atoms, seven ring atoms, and up to 14 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings that share pairs of adjacent ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, and the like. In a polycyclic group, only one ring needs to be aromatic, so groups such as indanyl are included in the definition of aryl. Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl, indanyl, and the like. Unless stated otherwise in the specification, an aryl moiety can be acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a ) 3 , -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a, -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a )S(O) t N(R a ) 2 (t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a ) 2 and each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which can be optionally substituted as defined herein.

[0028] As used herein, the terms "cycloalkyl" and "carbocyclyl" refer to monocyclic or polycyclic radicals, respectively, that contain only carbon and hydrogen and may be saturated or partially unsaturated. Partially unsaturated cycloalkyl groups can be referred to as "cycloalkenyls" if the carbocyclic ring contains at least one double bond, and "cycloalkynyls" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups include groups having 3 to 13 ring atoms (i.e., C 3~13As used herein, numerical ranges such as "3 to 10" refer to each integer within the given range. For example, "3 to 13 carbon atoms" means that the cycloalkyl group can consist of up to 13 carbon atoms, such as 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" refers to C 3~8 In some embodiments, "cycloalkyl" is a C 3~5 Specific examples of cycloalkyl groups include, but are not limited to, the following moieties: C 3~6 Carbocyclyl groups include cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), but is not limited to. 3~7 An example of a carbocyclyl group is norbornyl (C 7 ) are listed. C 3~8 Examples of carbocyclyl groups include the above-mentioned C 3~7 In addition to the carbocyclyl group, cycloheptyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, etc. 3~13 Examples of carbocyclyl groups include the above-mentioned C 3~8In addition to carbocyclyl groups, octahydro-1H indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, etc. Unless otherwise stated in the specification, cycloalkyl groups include acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a ) 3 , -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a )S(O) t N(R a ) 2 (t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a ) 2 and each Ra are independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which can be optionally substituted as defined herein. The terms "cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl", with the prefix "alk" replacing "alkene" or "alkyne", respectively, and the parent "alkenyl" or "alkynyl" terms as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

[0029] As used herein, the term "inhibit" refers to a measurable decrease in biological activity. Thus, as used herein, "inhibit" or "inhibition" may be referred to as a percentage of normal levels of activity.

[0030] As used herein, the term "effective amount" or "therapeutically effective amount" of an active agent refers to an amount sufficient to induce a desired biological response. An effective amount, when administered in an appropriate dosing regimen, is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the progression of the disorder being treated, regress the disorder being treated, or enhance or improve the prophylactic effect(s) or therapeutic effect(s) of another therapy. As will be appreciated by those skilled in the art, the effective amount of the compound of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the method of administration, and the patient. An effective amount can be readily determined by a skilled physician, for example, by administering a low dose of the pharmacological agent(s) initially, and then gradually increasing the dose until the desired therapeutic effect is achieved with minimal or no undesirable side effects.

[0031] As used herein, the term "treatment" or "treating" of a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it occurs. Treatment may be directed at one or more effects or symptoms of the disease and / or underlying pathology. Treatment may be any reduction or may be, but is not limited to, complete elimination of the disease or symptoms of the disease. The reduction or degree of such prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%, as measured by any standard technique, compared to an equivalent untreated control.

[0032] As used herein, the terms "prevent", "preventing" or "prevention" refer to a method for preventing, delaying, avoiding or halting the onset, incidence, severity or recurrence of a disease or condition. For example, a method is considered to be prophylactic if the onset, incidence, severity or recurrence of a disease or condition, or one or more symptoms thereof, is reduced or delayed in a subject susceptible to the disease or condition, as compared to a subject not receiving the method. The disclosed methods are also considered to be prophylactic if the onset, incidence, severity or recurrence of osteoporosis, or one or more symptoms of the disease or condition, is reduced or delayed in a subject susceptible to the disease or condition after receiving the method, as compared to the progression of the subject before receiving treatment. Thus, the reduction or delay in the onset, incidence, severity or recurrence of osteoporosis can be about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount therebetween.

[0033] As used herein, a "pharmaceutically acceptable form" of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers, prodrugs, and isotopically labeled derivatives thereof. In one embodiment, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, prodrugs, and isotopically labeled derivatives thereof. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable isomers and stereoisomers, prodrugs, and isotopically labeled derivatives thereof.

[0034] In certain embodiments, the pharma- ceutically acceptable form is a pharma- ceutically acceptable salt. As used herein, the term "pharma- ceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharma- ceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharma- ceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic or malonic acids, or by using other methods used in the art such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of the salts include phonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0035] Salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of the parent compound with an appropriate base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-type salts. + (C 1~4 (advance) 4 The pharmaceutically acceptable salts include salts of the following basic groups: salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, including, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts can be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0036] In certain embodiments, the pharma- ceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to a compound further comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate may be of the disclosed compound or a pharma- ceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. As used herein, the term "compound" will be understood to include the compound and solvates of the compound, as well as mixtures thereof.

[0037] In certain embodiments, the pharma- ceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or "pro-drug") refers to a compound that is converted in vivo to produce a pharma- ceutically acceptable form of the disclosed compound or compounds. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). In some cases, a prodrug has improved physical and / or delivery properties compared to the parent compound. A prodrug can increase the bioavailability of a compound when administered to a subject (e.g., by increasing absorption into the blood after oral administration) or can increase delivery to a biological compartment of interest (e.g., the brain or lymphatic system) compared to the parent compound. Exemplary prodrugs include derivatives of the disclosed compounds that have enhanced aqueous solubility or active transport across intestinal membranes compared to the parent compound.

[0038] Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. Exemplary advantages of prodrugs can include, but are not limited to, physical properties such as improved water solubility when administered parenterally at physiological pH, as compared to the parent compound, or which can enhance absorption from the digestive tract, or which can enhance the stability of the drug for long-term storage.

[0039] Prodrugs generally known in the art include well-known acid derivatives, such as, for example, esters prepared by reacting a parent acid with an appropriate alcohol, amides prepared by reacting a parent acid compound with an amine, and basic groups reacting to form acylated base derivatives. Of course, other prodrug derivatives can be combined with other features disclosed herein to enhance bioavailability. Thus, one of ordinary skill in the art will appreciate that certain of the compounds of the present disclosure that have free amino, amide, hydroxy, or carboxyl groups can be converted into prodrugs. Prodrugs include compounds that have an amino acid residue or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues covalently bonded via peptide bonds to a free amino, hydroxy, or carboxylic acid group of a compound of the present disclosure. Amino acid residues include the 20 naturally occurring amino acids, commonly represented by three-letter symbols, and further include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs also include compounds having a carbonate, carbamate, amide, or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.

[0040] As used herein, the term "pharmaceutically acceptable" excipient, carrier, or diluent refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in the carrying or transport of a subject drug from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which may function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate, ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifying agents, and lubricants (e.g., sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers), as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants may also be present in the composition.

[0041] As used herein, the terms "isolated" or "purified" refer to material that is substantially or essentially free from components that normally accompany it in its natural state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography.

[0042] As used herein, the term "subject" refers to any animal (e.g., mammal) that is to undergo a particular treatment, including, but not limited to, humans, non-human primates, rodents, etc. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to human subjects.

[0043] As used herein, the term "low dose" refers to at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dose of a particular compound formulated for a given route of administration to treat any disease or condition in humans. For example, a low dose of a drug formulated for administration by inhalation is different from a low dose of the same drug formulated for oral administration.

[0044] As used herein, the term "high dose" means at least 5% (e.g., at least 10%, 20%, 50%, 100%, 200%, or even 300%) more than the highest standard recommended dose of a particular compound for treating any disease or condition in humans.

[0045] Isotopically labeled compounds are also within the scope of the present disclosure.As used herein, "isotopically labeled compounds" or "isotopic derivatives" refer to compounds disclosed herein, including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Examples include Cl.

[0046] By isotopically labelling the compounds of the present disclosure, the compounds may be useful in drug and / or substrate tissue distribution assays. 3 H) labeled compounds and carbon-14( 14 C) labeled compounds are particularly preferred in terms of ease of preparation and detectability. 2 Substitution with heavier isotopes such as H may be preferred in some circumstances since they may confer certain therapeutic advantages due to higher metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the present disclosure (including pharmaceutical salts, esters, and prodrugs thereof) can be prepared by any means known in the art. Typically, abundant 12 C 13 Advantages may also be obtained from substituting C (see WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361 and WO 2007 / 016431).

[0047] For example, deuterium ( 2 H) can be incorporated into the compounds disclosed herein for the purpose of manipulating the oxidative metabolism of the compounds through the primary kinetic isotope effect. The primary kinetic isotope effect is the change in rate for a chemical reaction resulting from the exchange of an isotope nucleus, caused by the change in the ground state energy required for covalent bond formation following isotope exchange. Exchanging a heavier isotope usually results in a slowing down of the rate-limiting bond cleavage due to a decrease in the ground state energy of the chemical bond. If the bond cleavage occurs in or near a saddle point region along the coordinate of a multi-product reaction, the product distribution rate can change significantly. To illustrate, if deuterium is attached to a carbon atom in a non-exchangeable position, k M / k D A rate difference of 2-7 is common. If this rate difference is successfully applied to a compound disclosed herein that is susceptible to oxidation, the in vivo profile of the compound can be significantly altered, resulting in improved pharmacokinetic properties.

[0048] When discovering and developing therapeutic agents, one of skill in the art can optimize pharmacokinetic parameters while maintaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. Currently available in vitro liver microsomal assays provide valuable information regarding the process of this type of oxidative metabolism, thereby enabling the rational design of deuterated compounds disclosed herein with improved stability through resistance to such oxidative metabolism. This results in a significant improvement in the pharmacokinetic profile of the compounds disclosed herein, which is reflected in the in vivo half-life (t / 2), concentration at maximum therapeutic effect (C max ), which can be quantified in terms of increased area under the dose-response curve (AUC) and F, as well as reduced clearance, dose and material costs.

[0049] The following is intended to illustrate the above. Compounds with multiple potential attack sites for oxidative metabolism (e.g., benzylic hydrogen atoms and hydrogen atoms attached to nitrogen atoms) are prepared as a series of analogs in which various combinations of hydrogen atoms are replaced with deuterium atoms, so that some, most, or all of these hydrogen atoms are replaced with deuterium atoms. Determination of the half-life allows a good and accurate determination of the extent to which resistance to oxidative metabolism has been improved. In this way, it has been found that the half-life of the parent compound can be extended by up to 100% as a result of this type of deuterium-hydrogen exchange.

[0050] Deuterium-hydrogen exchange in the compounds disclosed herein can also be used to achieve favorable modification of the metabolic product spectrum of the starting compound to reduce or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises from oxidative carbon-hydrogen (CH) bond cleavage, it can be reasonably assumed that a deuterated analog will significantly reduce or eliminate the production of the unwanted metabolite, even if the specific oxidation is not the rate determining step. Further information on the state of the art regarding deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al., Biochemistry 33(10) 2927-2937, 1994, and Jarman et al., Carcinogenesis 16(4), 683-688, 1993.

[0051] Following their preparation, the compounds of the invention are preferably isolated and purified to obtain compositions containing 95% by weight or more ("substantially pure"), which are then used or formulated as described herein. In certain embodiments, the compounds of the invention are greater than 99% pure.

[0052] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds that have sufficient stability to permit their manufacture and maintain their integrity for a period of time sufficient to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0053] The recitation of a list of chemical groups in a definition of a variable herein includes a definition of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] The present invention provides novel, selective and potent MetAP-2 inhibitors, methods for their synthesis, and pharmaceutical compositions, as well as methods thereof for treating, preventing or ameliorating various diseases or conditions associated with MetAP-2, such as cancer, obesity, diabetes, rheumatoid arthritis, and psoriasis.

[0055] The MetAP-2 inhibitors of the present invention are orally and / or topically available and suitable for oral or topical administration. These compounds are designed to have excellent oral absorption and excellent in vivo stability, and to exhibit excellent potency against MetAP-2.

[0056] In one aspect, the present invention generally relates to a compound having the structural formula of Formula (I), or a pharma- ceutically acceptable form or isotopic derivative thereof:

[0057] [ka] (In the formula, R 1 and R 2 are independently selected from F, Cl, Br, and I; Q is (a) an unsubstituted or substituted 5- or 6-membered aromatic ring, or (b) an unsubstituted or substituted 5- or 6-membered aromatic ring fused to a second unsubstituted or substituted 5- or 6-membered ring.

[0058] In certain embodiments of (I), the compound is A )

[0059] [ka]

[0060] (I A In certain embodiments of formula (I), Q is an unsubstituted or substituted 5- or 6-membered aromatic ring, Q 1and the compound has the structural formula (I A 1 ).

[0061] [ka]

[0062] (I A 1 In certain embodiments of 1 is a substituted six-membered aromatic ring.

[0063] In certain embodiments, the compound has the following structural formula: A ):

[0064] [ka] wherein X is N or CH; Y 1 and Y 2 are each independently N or CH, but Y 1 and Y 2 when one of is N, the other is CH; R 3 is a group containing a P(=O)(R')(R") or S(R')(R")(R''') group, R', R" and R'" are each H and C 1~6 alkyl.

[0065] In certain embodiments, R 3 is in the para position, and the compound has the structural formula (II A 1 ).

[0066] [ka]

[0067] In certain embodiments, R 3 is in the meta position, and the compound has the structural formula (II A2 ).

[0068] [ka]

[0069] In certain embodiments, X, Y 1 and Y 2 Each of the is CH.

[0070] In certain embodiments, X, Y 1 and Y 2 One of them is not CH.

[0071] In certain embodiments, X is CH and Y 1 is CH and Y 2 is N.

[0072] In certain embodiments, X is N and Y 1 is CH and Y 2 is N.

[0073] In certain embodiments, X is CH and Y 1 is N and Y 2 is CH.

[0074] In certain embodiments, R 3 is a group that includes a P(═O)(R′)(R″) group. In certain embodiments, R′ and R″ are the same and each are C 1~2 In certain embodiments, R′ and R″ are the same and each is C 3~4 It is cycloalkyl.

[0075] In certain embodiments, R 3 is a group that includes the group S(R')(R")(R'"). In certain embodiments, R', R" and R'" are the same and each are 1~3 It is an alkyl.

[0076] In certain embodiments, R 3is -AP(=O)(R')(R"), and A is a single bond, (CH 2 ) m , (CH 2 ) m -NR a , N.R. a -(CH 2 ) m , (CH 2 ) m -O, O-(CH 2 ) m , (CH 2 ) m -C(=O)-(CH 2 ) m , (CH 2 ) m -NR a -(CH 2 ) m m is 0, 1, 2, 3, or 4; R a is H or C 1~6 In certain embodiments, A is a single bond and P(=O)(R')(R") is connected to Q through a single bond. 1 Bind to.

[0077] (I A In certain embodiments of formula (I), Q is a second 5- or 6-membered ring, Q 2 A substituted or unsubstituted 5- or 6-membered aromatic ring Q condensed with 1 and the compound has the structural formula (I A 2 ).

[0078] [ka]

[0079] (I A 2 In certain embodiments of 1 is a six-membered aromatic ring, and Q 2 is a five-membered ring and has the following structural formula (III A ):

[0080] [ka] wherein X is N or CH; Y 1 and Y 2 are each independently N or CH, but Y 1 and Y 2 when one of is N, the other is CH; Z 1 is NH or CH 2 and Z 2 is C=O, S(=O) 2 , CR' or CR'R'', where R' and R'' are independently H or C 1~3 is alkyl, --- is Z 2 C=O, S(=O) 2 or CR'R", then not present or Z 2 is CR' and R 5 represents a bond when not present, R 4 and R 5 is, if present, independently H and C 1~6 alkyl, optionally R 4 and R 5 together with the carbon atom to which they are attached form a 3- to 6-membered aliphatic ring.

[0081] (III A In certain embodiments of Z 1 is NH and Z 2 is CH, and the compound has the structural formula (III A 1 ).

[0082] [ka]

[0083] (III A In certain embodiments of Z 1 is NH and Z 2 CH 2 and the compound has the structural formula (III A2 ).

[0084] [ka]

[0085] (III A In certain embodiments of Z 1 is NH and Z 2 is C=O, and the compound has the structural formula (III A 3 ).

[0086] [ka]

[0087] (III A In certain embodiments of Z 1 is NH and Z 2 is S(=O) 2 and the compound has the structural formula (III A 4 ).

[0088] [ka]

[0089] In certain embodiments, X, Y 1 and Y 2 Each of the is CH.

[0090] In certain embodiments, X, Y 1 and Y 2 One of them is not CH.

[0091] In certain embodiments, X is CH and Y 1 is CH and Y 2 is N.

[0092] In certain embodiments, X is N and Y 1 is CH and Y 2is N.

[0093] In certain embodiments, X is CH and Y 1 is N and Y 2 is CH.

[0094] (I A 2 In certain embodiments of 1 is a five-membered aromatic ring, and Q 2 is a five-membered ring and has the following structural formula (IV A ):

[0095] [ka] wherein Y is S or O; Z is independently N or CH; R 6 is H, an alkyl, COOH, or an amide group.

[0096] In certain embodiments, Y is S and Z is NH.

[0097] In certain embodiments of (I), the compound is B )

[0098] [ka]

[0099] (I B In certain embodiments of formula (I), Q is an unsubstituted or substituted 5- or 6-membered aromatic ring, Q 1 and the compound has the structural formula (I B 1 ).

[0100] [ka]

[0101] (I B1 In certain embodiments of 1 is a substituted six-membered aromatic ring.

[0102] (I B 1 In certain embodiments of the compound, the compound has the following structural formula (II A ):

[0103] [ka] wherein X is N or CH; Y 1 and Y 2 are each independently N or CH, but Y 1 and Y 2 when one of is N, the other is CH; R 3 is a group containing a P(=O)(R')(R") or S(R')(R")(R''') group, R', R" and R'" are each H and C 1~6 alkyl.

[0104] (II B In certain embodiments of 3 is in the para position, and the compound has the structural formula (II B 1 ).

[0105] [ka]

[0106] (II B In certain embodiments of 3 is in the meta position, and the compound has the structural formula (II B 2 ).

[0107] [ka]

[0108] In certain embodiments, X, Y 1 and Y 2 Each of the is CH.

[0109] In certain embodiments, X, Y 1 and Y 2 One of them is not CH.

[0110] In certain embodiments, X is CH and Y 1 is CH and Y 2 is N.

[0111] In certain embodiments, X is N and Y 1 is CH and Y 2 is N.

[0112] In certain embodiments, X is CH and Y 1 is N and Y 2 is CH.

[0113] In certain embodiments, R 3 is a group that includes a P(═O)(R′)(R″) group. In certain embodiments, R′ and R″ are the same and each are C 1~2 In certain embodiments, R′ and R″ are the same and each is C 3~4 It is cycloalkyl.

[0114] In certain embodiments, R 3 is a group that includes the group S(R')(R")(R'"). In certain embodiments, R', R" and R'" are the same and each are 1~3 It is an alkyl.

[0115] In certain embodiments, R 3 is -AP(=O)(R')(R"), and A is a single bond, (CH 2 ) m , (CH 2 ) m -NR a , N.R. a -(CH 2) m , (CH 2 ) m -O, O-(CH 2 ) m , (CH 2 ) m -C(=O)-(CH 2 ) m , (CH 2 ) m -NR a -(CH 2 ) m m is 0, 1, 2, 3, or 4; R a is H or C 1~6 In certain embodiments, A is a single bond and P(=O)(R')(R") is connected to Q through a single bond. 1 Bind to.

[0116] (I B In certain embodiments of formula (I), Q is a second 5- or 6-membered ring, Q 2 A substituted or unsubstituted 5- or 6-membered aromatic ring Q condensed with 1 and has the structural formula (I B 2 ).

[0117] [ka]

[0118] (I B 2 In certain embodiments of 1 is a six-membered aromatic ring, and Q 2 is a five-membered ring, and the compound has the following structural formula (III B ):

[0119] [ka] wherein X is N or CH; Y 1 and Y 2 are each independently N or CH, but Y 1 and Y 2when one of is N, the other is CH; Z 1 is NH or CH 2 and Z 2 is C=O, S(=O) 2 , CR' or CR'R'', where R' and R'' are independently H or C 1~3 is alkyl, --- is Z 2 C=O, S(=O) 2 or CR'R", then not present or Z 2 is CR' and R 5 represents a bond when not present, R 4 and R 5 is, if present, independently H and C 1~6 alkyl, optionally R 4 and R 5 together with the carbon atom to which they are attached form a 3- to 6-membered aliphatic ring.

[0120] (III B In certain embodiments of Z 1 is NH and Z 2 is CH, and the compound has the structural formula (III B 1 ).

[0121] [ka]

[0122] (III B In certain embodiments of Z 1 is NH and Z 2 CH 2 and the compound has the structural formula (III B 2 ).

[0123] [ka]

[0124] (III B In certain embodiments of Z 1 is NH and Z 2 is C=O, and the compound has the structural formula (III B 3 ).

[0125] [ka]

[0126] (III B In certain embodiments of Z 1 is NH and Z 2 is S(=O) 2 and the compound has the structural formula (III B 4 ).

[0127] [ka]

[0128] In certain embodiments, X, Y 1 and Y 2 Each of the is CH.

[0129] In certain embodiments, X, Y 1 and Y 2 One of them is not CH.

[0130] In certain embodiments, X is CH and Y 1 is CH and Y 2 is N.

[0131] In certain embodiments, X is N and Y 1 is CH and Y 2 is N.

[0132] In certain embodiments, X is CH and Y 1 is N and Y 2 is CH.

[0133] (I B 2 In certain embodiments of 1 is a five-membered aromatic ring, and Q 2 is a five-membered ring and has the following structural formula (IV B ):

[0134] [ka] wherein Y is S or O; Z is independently N or CH; R 6 is H, an alkyl, COOH, or an amide group.

[0135] (IV B In certain embodiments of formula (I), Y is S and Z is NH.

[0136] Non-limiting examples of compounds of the present invention include:

[0137] [ka]

[0138] Non-limiting examples of compounds of the present invention include:

[0139] [ka]

[0140] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharma- ceutically acceptable excipient, carrier, or diluent.

[0141] In another aspect, the present invention generally relates to a compound having a quantity of structural formula (I), or a pharma- ceutically acceptable form or isotopic derivative thereof:

[0142] [ka] (In the formula, R 1 and R 2 are independently selected from F, Cl, Br, and I; Q is (a) an unsubstituted or substituted 5- or 6-membered aromatic ring, or (b) an unsubstituted or substituted 5- or 6-membered aromatic ring fused to a second unsubstituted or substituted 5- or 6-membered ring.

[0143] In certain embodiments of the pharmaceutical composition, the compound of (I) has the structural formula (I A ).

[0144] [ka]

[0145] In certain embodiments of the pharmaceutical composition, the compound of (I) has the structural formula (I B ).

[0146] [ka]

[0147] In certain embodiments, the pharmaceutical composition of the present invention is effective for treating, preventing, or alleviating a disease or condition selected from cancer, obesity, diabetes, rheumatoid arthritis, psoriasis, or a related disease or condition. In certain embodiments, the pharmaceutical composition of the present invention is effective for treating, preventing, or alleviating cancer, or a related disease or condition. In certain embodiments, the pharmaceutical composition of the present invention is effective for treating, preventing, or alleviating obesity, or a related disease or condition. In certain embodiments, the pharmaceutical composition of the present invention is effective for treating, preventing, or alleviating diabetes, or a related disease or condition. In certain embodiments, the pharmaceutical composition of the present invention is effective for treating, preventing, or alleviating rheumatoid arthritis, or a related disease or condition. In certain embodiments, the pharmaceutical composition of the present invention is effective for treating, preventing, or alleviating psoriasis, or a related disease or condition.

[0148] In yet another aspect, the invention generally relates to unit dosage forms comprising the pharmaceutical compositions of the invention.

[0149] In yet another aspect, the invention generally relates to a method for treating, ameliorating, or preventing a disease or condition, comprising administering to a subject in need thereof a compound having the structural formula (I), or a pharma- ceutically acceptable form or isotopic derivative thereof, effective to treat, prevent, or ameliorate one or more of cancer, obesity, diabetes, rheumatoid arthritis, psoriasis, or related diseases or conditions in a mammal, including a human, having the structural formula (I):

[0150] [ka] (In the formula, R 1 and R 2 are independently selected from F, Cl, Br, and I; Q is, (a) an unsubstituted or substituted 5- or 6-membered aromatic ring, or (b) an unsubstituted or substituted 5- or 6-membered aromatic ring fused to a second unsubstituted or substituted 5- or 6-membered ring; and administering a pharma- ceutically acceptable excipient, carrier, or diluent.

[0151] In certain embodiments of the method, the compound has the structural formula (I A ).

[0152] [ka]

[0153] In certain embodiments of the method, the compound has the structural formula (I B ).

[0154] [ka]

[0155] In yet another aspect, the present invention generally relates to a method for treating, preventing, or alleviating a disease or condition treatable by modulation, regulation, or inhibition of methionine aminopeptidase (MetAP-2), comprising administering to a subject in need thereof an effective amount of a compound disclosed herein.

[0156] In certain embodiments, the methods of the present invention are effective for treating, preventing, or alleviating a disease or condition selected from cancer, obesity, diabetes, rheumatoid arthritis, psoriasis, or a related disease or condition. In certain embodiments, the methods of the present invention are effective for treating, preventing, or alleviating cancer, or a related disease or condition. In certain embodiments, the methods of the present invention are effective for treating, preventing, or alleviating obesity, or a related disease or condition. In certain embodiments, the methods of the present invention are effective for treating, preventing, or alleviating diabetes, or a related disease or condition. In certain embodiments, the methods of the present invention are effective for treating, preventing, or alleviating rheumatoid arthritis, or a related disease or condition. In certain embodiments, the methods of the present invention are effective for treating, preventing, or alleviating psoriasis, or a related disease or condition.

[0157] In certain embodiments, the methods of the invention further comprise administering to the subject a second therapeutic agent.

[0158] In yet another aspect, the invention generally relates to the use of the compounds of the invention to treat or ameliorate a disease or condition.

[0159] In yet another aspect, the invention generally relates to the use of a compound of the invention and a pharma- ceutically acceptable excipient, carrier, or diluent in the preparation of a medicament for treating or ameliorating a disease or condition.

[0160] In certain embodiments of the use of the compounds of the present invention, the disease or condition to be treated or alleviated is cancer, obesity, diabetes, rheumatoid arthritis, psoriasis, or a disease or condition related thereto.

[0161] In particular embodiments of the use of the compounds of the invention, the disease or condition to be treated or alleviated is cancer, or a related disease or condition.

[0162] In certain embodiments of the use of the compounds of the present invention, the disease or condition to be treated or alleviated is obesity, or a related disease or condition.

[0163] In certain embodiments of the use of the compounds of the present invention, the disease or condition to be treated or alleviated is diabetes, or a related disease or condition.

[0164] In particular embodiments of the use of the compounds of the present invention, the disease or condition to be treated or alleviated is rheumatoid arthritis, or a related disease or condition.

[0165] In certain embodiments of the use of the compounds of the present invention, the disease or condition to be treated or alleviated is psoriasis, or a related disease or condition.

[0166] In certain embodiments, the compounds according to the invention can be used to treat or reduce any carcinoma that has a significant degree of vascularization, such as lung cancer, breast cancer, prostate cancer, head and neck cancer, esophageal cancer, pancreatic cancer, liver cancer, colon cancer or kidney cancer, or carcinomas that induce metastasis, such as colon cancer, breast cancer, liver cancer, head and neck cancer, gastric cancer and melanoma. These compounds can be used as a monotherapy or in combination with radiation therapy or chemotherapy.

[0167] In certain embodiments, compounds according to the invention may also be used to treat or reduce the size of hepatocellular carcinoma, cholangiocarcinoma and malignant mesothelioma, pancreatic cancer, head and neck cancer, and hemangiomas.

[0168] In certain embodiments, compounds according to the present invention may also be used to treat or alleviate type II diabetes, non-alcoholic steatohepatitis, obesity, or to provide therapeutic weight loss.

[0169] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention include aqueous or oily suspensions. These suspensions are formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations are also sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as, for example, solutions in 1,3-butanediol. Vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0170] For this purpose, any non-irritating fixed oil can be used, including synthetic monoglycerides or diglycerides.Fatty acids such as oleic acid and its glyceride derivatives are useful for the preparation of injections, as are pharmaceutically acceptable natural oils such as olive oil or castor oil, especially in their polyoxyethylated versions.These oil solutions or suspensions also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used for the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions.Other commonly used surfactants, such as Tween, Span and other emulsifiers or bioavailability enhancers, which are commonly used for the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms, can also be used for formulation purposes.

[0171] The pharma- ceutically acceptable composition of the present invention is orally administered in any orally acceptable dosage form.The example of oral dosage form is capsule, tablet, aqueous suspension or aqueous solution.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also usually added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspension is required for oral use, active ingredient is combined with emulsifying and suspending agents.If necessary, certain sweeteners, flavors or colorants are also optionally added.

[0172] Alternatively, the pharma- ceutically acceptable compositions of the present invention are administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[0173] The pharma- ceutically acceptable compositions of the present invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0174] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches can also be used.

[0175] For topical application, the provided pharma- ceutically acceptable composition is formulated in a suitable ointment, which contains the active ingredient suspended or dissolved in one or more carriers.The examples of carriers for topical administration of the compound are mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, the provided pharma-ceutically acceptable composition can be formulated in a suitable lotion or cream, which contains the active ingredient suspended or dissolved in one or more pharma-ceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0176] Pharmaceutically acceptable compositions of this invention are optionally administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and are prepared as solutions in saline using benzyl alcohol or other appropriate preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0177] Most preferably, the pharma- ceutically acceptable composition of the present invention is formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharma- ceutically acceptable composition of the present invention is administered without food. In other embodiments, the pharma- ceutically acceptable composition of the present invention is administered with food.

[0178] The amount of the compounds of the present invention that are optionally combined with carrier materials to produce a composition in a single dosage form will vary depending on the host treated, the particular mode of administration. Preferably, the compositions provided should be formulated so that a dosage of 0.01-100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[0179] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician, and the severity of the particular disease of the subject being treated. The amount of a compound of the invention in a composition will also depend on the particular compound in the composition. EXAMPLES

[0180] As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods are illustrated for the synthesis of specific compounds of the invention, it will be understood that the following general methods, as well as other methods known to those of skill in the art, may be applied to all compounds, and each subclass and species of these compounds, as described herein.

[0181] The compound numbers used in the following examples correspond to the compound numbers set forth above.

[0182] 1 H was recorded at 400 MHz on a Varian Mercury400 spectrometer. 13 C NMR was recorded at 100 MHz. Proton chemical shifts were internally referenced to the residual proton resonance in CDCl3 (7.26 ppm). Carbon chemical shifts were internally referenced to the deuterated solvent signal in CDCl3 (77.20 ppm).

[0183] LC-MS spectra were recorded on a Shimadzu LC-MS2020 using an Agilent C18 column (Eclipse XDB-C18, 5um, 2.1x50mm) at a flow rate of 1mL / min. Mobile phase A: 0.1% formic acid in water; Mobile phase B: 0.1% formic acid in acetonitrile. A general gradient method was used.

[0184] [Table 1]

[0185] Analytical HPLC was performed on an Agilent 1200 HPLC equipped with a Zorbax Eclipse XDB C18 column (2.1 x 150 mm) at a flow rate of 1 mL / min. Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile. The following general method gradient was used:

[0186] [Table 2]

[0187] Preparative HPLC was performed on a Varian ProStar using a Hamilton C18PRP-1 column (15 x 250 mm) at a flow rate of 20 mL / min. Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile. A typical gradient method was used.

[0188] [Table 3]

[0189] Example 1. (S)-N-(3,5-difluorobenzyl)-1-(4-(dimethylphosphoryl)phenyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (1)

[0190] [ka]

[0191] [ka]

[0192] Step 1: To a mixture of 4-bromoaniline (1-1) (500 mg, 2.9 mmol, 1.0 equiv.) in EtOH (5 mL) was added 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (1-2) (741 mg, 4.36 mmol, 1.5 equiv.). The mixture was refluxed in MW at 100° C. for 30 min. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then filtered and the residue was purified by column chromatography on silica gel (DCM:MeOH, 1:1) to give 1-(4-bromophenyl)-2-oxopyrrolidine-3-carboxylic acid (1-3) (670 mg, 82%). TLC (DCM:MeOH, 10:1):R f =0.2.

[0193] Step 2: To a mixture of 1-(4-bromophenyl)-2-oxopyrrolidine-3-carboxylic acid (1-3) (670 mg, 2.37 mmol, 1.0 equiv.) in DCM (5 mL) was added (3,5-difluorophenyl)methanamine (1-4) (338 mg, 2.37 mmol, 1.0 equiv.), EDCI (590 mg, 3.08 mmol, 1.3 equiv.), HOBt (989 mg, 3.08 mmol, 1.3 equiv.), and DIEA (917 mg, 7.11 mmol, 3.0 equiv.). The mixture was stirred at room temperature overnight. TLC analysis of the reaction mixture showed complete conversion to the desired product. The residue was purified by HPLC using NaCl. 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA, 3:1 to 1:1) to give 1-(4-bromophenyl)-N-(3,5-difluorobenzyl)-2-oxopyrrolidine-3-carboxamide (1-5) (590 mg, 61%) as a white solid. TLC (PE:EA, 1:1):R f =0.6.

[0194] Step 3: To a mixture of 1-(4-bromophenyl)-N-(3,5-difluorobenzyl)-2-oxopyrrolidine-3-carboxamide (1-5) (300 mg, 0.735 mmol, 1.0 equiv.) in DMF (3 mL), dimethylphosphine oxide (1-6) (63 mg, 0.808 mmol, 1.1 equiv.), Pd(OAc) 2 (8.25 mg, 0.036 mmol, 0.05 equiv.), Xantphos (25.5 mg, 0.0225 mmol, 0.06 equiv.) and K 3 PO 4 (215 mg, 0.808 mmol, 1.1 equiv.) was added. The mixture was stirred in the MW at 120° C. for 30 min. TLC analysis of the reaction mixture showed complete conversion to the desired product. The residue was purified by Na 2 SO 4 The mixture was dried over 100 ml and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM to DCM:MeOH, 30:1) to give N-(3,5-difluorobenzyl)-1-(4-(dimethylphosphoryl)phenyl)-2-oxopyrrolidine-3-carboxamide (1-7) (200 mg, 67%). TLC (DCM:MeOH, 10:1):R f =0.8.

[0195] Step 4: To a mixture of N-(3,5-difluorobenzyl)-1-(4-(dimethylphosphoryl)phenyl)-2-oxopyrrolidine-3-carboxamide (1-7) (200 mg, 0.49 mmol, 1.0 equiv.) in IPA (3 mL) was added CeCl 3 7H 2 O (73.4 mg, 0.196 mmol, 0.4 equiv) was added. The mixture was diluted with O 2 The mixture was stirred at 85° C. overnight under reduced pressure. TLC analysis of the reaction mixture showed complete conversion to the desired product. The residue was purified by hexane-HCl. 2 SO 4The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH, 20:1) and preparative HPLC to give N-(3,5-difluorobenzyl)-1-(4-(dimethylphosphoryl)phenyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (1-8) (25 mg, 12%) as a yellow solid. TLC (DCM:MeOH, 10:1):R f =0.3. 1 H NMR(DMSO,400 MHz):δ 8.72-8.69(t,J=6.2 Hz,1H),7.81-7.73(m,4H),7.06-7.01(m,1H),6.96-6.94(d,J=6.4 Hz,2H),4.39-4.34(dd,J=16.0 Hz,6.6 Hz,1H),4.25-4.20(dd,J=15.6 Hz,5.8 Hz,1H),3.89-3.86(t,J=6.6 Hz,2H),2.59(m,1H),2.14-2.11(m,1H),1.62(s,3H),1.59(s,3H).m / z:423.2[M+H] +

[0196] Step 5: N-(3,5-difluorobenzyl)-1-(4-(dimethylphosphoryl)phenyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (1-8) (50 mg) was applied to a Chiralcel OD column (5×25 cm, 20 μm) using a solvent system of n-heptane / ethanol=70:30 at a flow rate of 100 mL / min. The (S)-enantiomer (compound 1) was collected in the first fraction, which was concentrated to give (S)-N-(3,5-difluorobenzyl)-1-(4-(dimethylphosphoryl)phenyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (1). Enantiomer 1a was collected in the second fraction, which was concentrated to give (R)-N-(3,5-difluorobenzyl)-1-(4-(dimethylphosphoryl)phenyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (1a).

[0197] Example 2. (S)-N-(3,5-difluorobenzyl)-1-(3-(dimethylphosphoryl)phenyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (2)

[0198] [ka]

[0199] [ka]

[0200] Step 1: To a mixture of compound 2-1 (1.0 g, 5.8 mmol) in EtOH (10 mL) was added compound 1-2 (1.29 g, 7.6 mmol). The mixture was refluxed at 100 °C for 10 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with 25%-50% EtOAc in petroleum ether to give compound 2-2 (1.05 g, 3.7 mmol, 64%). TLC (PE:EA=2:1): Rf(compound 2-2)=0.2, Rf(compound 2-1)=0.9.

[0201] Step 2: A solution of compound 2-2 (930 mg, 3.27 mmol), compound 1-4 (562 mg, 3.93 mmol), DIPEA (1.26 g, 9.81 mmol), and HATU (1.86 g, 4.91 mmol) in DCM (20 mL) was stirred at room temperature for 2 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The residue was purified by Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA, 3:1 to 1:1) to give compound 2-3 (1.16 g, 2.84 mmol, 87%) as a white solid. TLC (PE:EA, 2:1): Rf (compound 2-2) = 0.1, Rf (compound 2-3) = 0.3.

[0202] Step 3: To a mixture of compound 2-3 (400 mg, 0.98 mmol) in DMF (3 mL), compound 1-6 (84 mg, 1.08 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), Xantphos (34 mg, 0.06 mmol), and K 3 PO 4 (288 mg, 1.08 mmol) was added. The mixture was stirred in a microwave at 120° C. for 30 min. TLC analysis of the reaction mixture showed complete conversion to the desired product. The residue was purified by Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by distillation with CH 2 Cl 2 Medium 5%CH 3 Purification by column chromatography on silica gel eluted with DCM:MeOH gave compound 2-4 (270 mg, 0.67 mmol, 66%). TLC (DCM:MeOH, 10:1): Rf (compound 2-4) = 0.4, Rf (compound 2-3) = 0.8.

[0203] Step 4: To a mixture of compound 2-4 (270 mg, 0.66 mmol) in IPA (15 mL), CeCl 3 7H 2 O (99 mg, 0.27 mmol) was added. The mixture was diluted with O 2 The mixture was stirred at 85° C. overnight under reduced pressure. TLC analysis of the reaction mixture showed complete conversion to the desired product. The residue was purified by hexane-HCl. 2 SO 4 The mixture was dried over 100 ml and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-5 (99 mg, 0.23 mmol, 36%) as a yellow solid. TLC (DCM:MeOH, 10:1): Rf (compound 2-4) = 0.5, Rf (compound 2-5) = 0.3. LCMS: [M+1]: 423. 1H NMR(400 MHz,DMSO)δ8.75(t,J=6.4 Hz,1H),8.02(dd,J=13.6,1.1 Hz,1H),7.94-7.86(m,1H),7.62-7.53(m,2H),7.07(tt,J=9.4,2.3 Hz,1H),7.03-6.96(m,2H),4.41(dd,J=15.8,6.7 Hz,1H),4.27(dd,J=15.8,6.0 Hz,2H),3.96-3.88(m,2H),2.63(dt,J=11.8,5.7 Hz,1H),2.17(dt,J=13.0,7.6 Hz,1H),1.69(s,3H),1.65(s,3H).

[0204] Step 5: Similar to the chiral separation procedure of compounds 1 and 1a, compounds 2-5 were applied to a Chiralcel OD column to give compounds 2 and 2a.

[0205] Example 3. (S)-1-(4-(diethylphosphoryl)phenyl)-N-(3,5-difluorobenzyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (3)

[0206] [ka]

[0207] [ka]

[0208] Compounds 3 and 3a were prepared using a similar procedure to compound 2. Regarding compound 3-3. 1 H NMR (400 MHz, CDCl 3)δ7.74(d,J=7.2 Hz,2H),7.64(t,J=9.2 Hz,2H),7.40(s,1H),6.79(d,J=5.8 Hz,2H),6.69(s,1H),4.44-4.39(m,2H),4.15-4.10(m,1H),3.87-3.81(m,1H),2.81 -2.74(m,1H),2.31~2.24(m,1H),2.03-1.84(m,4H),1.18-1.03(m,6H).LCMS:[M+1]:451.

[0209] Example 4. (S)-N-(3,5-difluorobenzyl)-1-(4-(diisopropylphosphoryl)phenyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (4)

[0210] [ka]

[0211] [ka]

[0212] Step 1: Compound 4-2 (20 mL, 2 M solution in THF, 40 mmol) was added to a solution of compound 4-1 (1.38 g, 10 mmol) in anhydrous ether (30 mL) with N 2 The mixture was stirred at room temperature for 5 h. The mixture was quenched with 1M HCl solution (40 mL) at 0° C. Then the mixture was concentrated and the residue was dissolved in CH 2 Cl 2 10% of CH 3 The mixture was filtered and the filtrate was concentrated in vacuo to give compound 4-3 (600 mg, 4.47 mmol, 44.7%) as a colorless oil. TLC (DCM:MeOH, 15:1):R f (Compound 4-1)=0.8, R f (Compound 4-3)=0.5.

[0213] Compounds 4 and 4a were prepared using a similar procedure to compound 2. For racemic compounds 4-5.1 H NMR (400 MHz, DMSO-d 6 )δ8.72(t,J=6.3 Hz,1H),7.86-7.79(m,2H),7.66(t,J=8.8 Hz,2H),7.03(t,J=9.4 Hz,1H),6.95(d,J=6.7 Hz,2H),4.28(ddd,J=21.6,15.8,6.3 Hz,2H),3.87(t,J=6.7 Hz,2H),2.62-2.51(m,1H),2.30(dq,J=14.4,7.2 Hz,2H),2.16-1.97(m,1H),2.17-2.04(m,1H),1.01(dd,J=14.8,7.0 Hz,6H),0.86(dd,J=15.6,7.0 Hz,6H).LCMS:[M+1]:479

[0214] Example 5. (S)-N-(3-chloro-5-fluorobenzyl)-1-(4-(dicyclobutylphosphoryl)phenyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (5)

[0215] [ka]

[0216] [ka]

[0217] Step 1: A solution of compound 1-3 (2.5 g, 8.83 mmol), compound 5-1 (1.55 g, 9.71 mmol), DIPEA (3.40 g, 26.5 mmol), and HATU (5.02 g, 13.25 mmol) in DCM (100 mL) was stirred at room temperature for 2 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The residue was purified by Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA, 3:1 to 1:1) to give compound 5-2 (3.0 g, 7.08 mmol, 80%) as a white solid. TLC (PE:EA, 2:1):R f(Compound 1-3)=0.1, R f (Compound 5-2)=0.3.

[0218] Step 2 and Step 3: A 1 L three-neck RBF was equipped with a mechanical stirrer, reflux condenser, and addition funnel, and exhaust / N 2 Charge (3 times) and add Mg powder (2.23 g, 16.49 mmol, 3.3 equiv.) and I 2 (0.1 mmol) and then evacuate again / N 2 The tube was filled (three times). Then, 20 mL of dry Et 2 O was added via cannula. 2 A solution of compound 5-3 (2.23 g, 16.49 mmol, 3.3 equiv) in 2H2O (5 mL) was added. After refluxing for 2 h, the brown reaction mixture became clear to give compound 5-4, which was used directly in the next step. The solution of 5-4 was cooled to 0 °C and diluted with Et 2 Diethyl phosphite 4-1 (690 mg, 5 mmol, 1 equiv) in 2HO (10 mL) was added dropwise over 15 min. The mixture was stirred at 25 °C for 18 h, then cooled to 0 °C and carefully quenched with 0.1 N HCl solution (10 mL). 50 mL of MTBE was added and the mixture was stirred well for 5 min. The upper organic phase was decanted from the gel and saved. The remaining gel was washed with 25 mL of CH4OH. 2 Cl 2 was added and the mixture was stirred well for 5 min. The resulting mixture was then filtered through a pad of Celite and the pad was washed with CH 2 Cl 2 The combined organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by distillation with CH 2 Cl 2 3% of CH 3 Purification by silica gel eluted with DCM:MeOH gave compound 5-5 (210 mg, 1.62 mmol, 32%, 2 steps) as a colorless oil. TLC (DCM:MeOH, 10:1):R f (Compound 5-3)=0.5, R f (Compound 5-5)=0.3. 1 H NMR (400 MHz, CDCl 3)δ7.22-6.03(m,1H),2.69(d,J=7.9 Hz,4H),2.47-1.93(m,10H).

[0219] Steps 3-5: Compounds 5 and 5a were prepared using a similar procedure to compound 2. For compounds 5-7, LCMS: [M+1]: 519; 1 H NMR (400 MHz, CDCl 3 )δ7.86(s,1H),7.58(s,2H),7.47(s,2H),7.07(s,1H),6.93(t,J=9.2 Hz,2H),4.47(dd,J=15.5,6.5 Hz,1H),4.33(dd,J=15.2,5.6 Hz,1H),4.00(d,J=7.6 Hz,1H),3.77(s,1H),2.92- 2.76(m,3H),2.48-2.36(m,3H),2.27-2.05(d,J=45.8 Hz,6H),2.00-1.83(m,4H).

[0220] Example 6. (S)-N-(3,5-difluorobenzyl)-1-(6-(dimethylphosphoryl)pyridin-3-yl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (6)

[0221] [ka]

[0222] [ka]

[0223] Step 1: To a mixture of compound 6-1 (1.0 g, 5.8 mmol, 1.0 equiv.) in ethanol (10 mL) was added compound 1-2 (1.5 g, 8.8 mmol, 1.5 equiv.). The mixture was microwaved at 100° C. for 45 min under nitrogen atmosphere. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound 6-2 (400 mg, 23%). TLC (DCM:MeOH, 5:1):R f (Compound 6-1)=1;R f (Compound 6-2)=0.3.

[0224] Step 2: To a mixture of compound 6-2 (400 mg, 1.4 mmol, 1.0 equiv.) in dimethylformamide (5 mL), compound 1-4 (201 mg, 1.4 mmol, 1.0 equiv.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (349 mg, 1.82 mmol, 1.3 equiv.), 1-hydroxybenzotriazole (584 mg, 1.82 mmol, 1.3 equiv.), and triethylamine (541.8 mg, 4.2 mmol, 3.0 equiv.) were added. The mixture was stirred at room temperature overnight. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate, 3:1 to 1:1) to give crude compound 6-3 (517 mg, 90%) as a white solid. TLC (petroleum ether:ethyl acetate, 1:1):R f (Compound 6-2)=0;R f (Compound 6-3)=0.5.

[0225] Step 3: A mixture of compound 6-3 (800 mg, 1.95 mmol, 1.0 equiv), compound 1-6 (168 mg, 2.15 mmol, 1.1 equiv), Xantphos (68 mg, 0.117 mmol, 0.06 equiv), palladium(II) acetate (22 mg, 0.097 mmol, 0.05 equiv), and tripotassium phosphate (571 mg, 1.1 mmol, 1.1 equiv) in dimethylformamide (10 mL) was microwaved at 120° C. for 30 min under nitrogen atmosphere. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then cooled to room temperature and filtered. The filtrate was poured into water and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography (dichloromethane:methanol=30:1) to give compound 6-4 (480 mg, 51%). TLC (dichloromethane:methanol, 10:1):R f (Compound 6-3)=0.7;R f (Compound 6-4)=0.4.

[0226] Step 4: To a mixture of compound 6-4 (600 mg, 1.47 mmol, 1.0 equiv) in i-pranoline (5 mL) was added cerium(III) chloride heptahydrate (220 mg, 0.588 mmol, 0.4 equiv). The mixture was stirred overnight at 85° C. under oxygen atmosphere. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-5 (102 mg, 16%) as a white solid. LCMS: [M+1]: 424; 1 H NMR (CD 3OD,400 MHz):δ 9.22(d,J=2.4 Hz,1H),8.28-8.26(m,1H),8.02-8.00(m,1H),6.92-6.91(d,J=6.0 Hz,2H),6.81-6.76(t,J=9.2 Hz,1H),4.56(s,1H),4.35(m,2H),4.02(m,2H),2.76-2.72(m,2H),2.29-2.25(m,1H),1.80(s,3H) and 1.77(s,3H).

[0227] Step 5: Similar to the chiral separation procedure of compound 1, compound 6-5 was applied to a Chiralcel OD column to give compounds 6 and 6a.

[0228] Example 7. (S)-N-(3-chloro-5-fluorobenzyl)-1-(4-(diisopropylphosphoryl)phenyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (7)

[0229] [ka]

[0230] [ka]

[0231] Step 1: To a mixture of compound 5-2 (400 mg, 0.94 mmol) in DMF (3 mL), compound 4-3 (84 mg, 1.08 mmol), Pd(OAc) 2 (11 mg, 0.05 mmol), Xantphos (34 mg, 0.06 mmol), and K 3 PO 4 (288 mg, 1.08 mmol) was added. The mixture was stirred in the MW at 120° C. for 30 min. TLC analysis of the reaction mixture showed complete conversion to the desired product. The residue was purified by Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by distillation with CH 2 Cl 2 Medium 5%CH 3Purification by column chromatography on silica gel eluted with DCM:MeOH, 10:1, gave compound 7-1 (120 mg, 0.25 mmol, 27%). TLC (DCM:MeOH, 10:1):R f (Compound 7-1)=0.4, R f (Compound 5-2)=0.8.

[0232] Step 2: To a mixture of compound 7-1 (120 mg, 0.25 mmol) in IPA (5 mL), CeCl 3 7H 2 O (40 mg, 0.11 mmol) was added. The mixture was diluted with O 2 The mixture was stirred at 85° C. overnight under reduced pressure. TLC analysis of the reaction mixture showed complete conversion to the desired product. The residue was purified by hexane-HCl. 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 7-2 (33 mg, 0.07 mmol, 28%) as a white solid. TLC (DCM:MeOH, 10:1):R f (Compound 7-1)=0.5, R f (Compound 7-2)=0.3. LCMS:[M+1]:495.1H NMR(400MHz,CD 3 OD) δ7.94(dd,J=8.7,2.0 Hz,2H),7.74(t,J=9.0 Hz,2H),7.17(s,1H),7.07-6.94(m,2H),4.46(d,J=15.6 Hz,1H),4.36(d,J=15.6 Hz,1H),4.07-3.89(m,2H),2.72(ddd,J=13.1,7.6,3.5 Hz,1H),2.44(td,J=14.5,7.1 Hz,2H),2.25(dt,J=13.1,8.1 Hz,1H),1.18-1.12(m,6H),1.06-0.98(m,6H).

[0233] Step 3: Similar to the chiral separation procedure of compounds 1 and 1a, compound 7-2 was applied to a Chiralcel OD column to give compounds 7 and 7a.

[0234] Example 8. (S)-N-(3-chloro-5-fluorobenzyl)-1-(4-(dicyclopropylphosphoryl)phenyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (8)

[0235] [ka]

[0236] [ka]

[0237] Step 1: Evacuate / N a 100 mL RB flask equipped with a dropping funnel. 2 (3 times), then cyclopropylmagnesium chloride 8-1 (1M in THF, 16.5 mL, 3.3 equiv.) and the solution was purified with N 2 The mixture was cooled to 0°C under reduced pressure. A solution of diethyl phosphite 4-1 (690 mg, 5 mmol, 1.0 equiv) in 10 mL of THF was added dropwise over 15 min. The mixture was stirred at 0°C for 15 min and at 25°C for 2 h. The reaction was cooled to 0°C. 0.1 N HCl (15 mL) was added dropwise over 20 min, followed by MTBE (25 mL). The upper organic phase was decanted from the gel and saved. The remaining gel was washed with 25 mL of CH 2 Cl 2 was added and the mixture was stirred well for 5 min. The resulting mixture was then filtered through a pad of Celite and the pad was washed with CH 2 Cl 2 The filtrate phases were separated and the organic phases were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified by distillation with CH 2 Cl 2 Medium 3%CH 3 Purification by silica gel eluted with DCM:MeOH gave compound 8-2 (210 mg, 1.62 mmol, 32% yield) as a colorless oil. TLC (DCM:MeOH, 10:1):R f (Compound 8-1)=0.5, R f (Compound 8-2)=0.3. 1 H NMR (400 MHz, CDCl 3)δ6.55(d,J=468 Hz,1H),1.09-0.62(m,10H).

[0238] Compounds 8 and 8a were prepared using a similar procedure to compound 2. For compound 8-4, LCMS: [M+1]: 491; 1 H NMR (400 MHz, CDCl 3 )δ7.66(d,J=7.2 Hz,3H),7.53(d,J=7.2 Hz,2H),7.04(s,1H),6.92(dd,J=22.6,8.6 Hz,2H),4.43(dd,J=15.1,6.6 Hz,1H),4.32(dd,J=15.7,6.0 Hz,1H),3.93(d,J=8.0 Hz,1H),3.62(s,1H),2.77-2.68(m,1H),2.28(d,J=12.7 Hz,1H),0.90(d,J=12.9 Hz,10H).

[0239] Example 9. (S)-N-(3-chloro-5-fluorobenzyl)-1-(4-(dimethylphosphoryl)phenyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (9)

[0240] [ka]

[0241] [ka]

[0242] Step 1: A mixture of compound 5-2 (300 mg, 0.705 mmol, 1.0 equiv), compound 1-6 (60.51 mg, 0.775 mmol, 1.1 equiv), palladium(II) acetate (9.49 mg, 0.042 mmol, 0.06 equiv), Xantphos (28.55 mg, 0.049 mmol, 0.07 equiv), and potassium carbonate (164.51 mg, 0.775 mmol, 1.1 equiv) in dimethylformamide (5 mL) was stirred at 120° C. for 3 h in a sealed tube. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The mixture was filtered, water (5 mL) was added, and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 94:6) to give compound 9-2 (55 mg, 18%) as a yellow solid.

[0243] Step 2: To a mixture of compound 9-1 (130 mg, 0.307 mmol, 1.0 equiv) in IPA (10 mL) was added cerium(III) chloride heptahydrate (45.8 mg, 0.123 mmol, 0.4 equiv). The mixture was stirred overnight at 85° C. under oxygen atmosphere. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was diluted with water (10 mL) and extracted with dichloromethane (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give 9-2 (49.4 mg, 37%) as a white solid. TLC (dichloromethane:methanol, 15:1):R f (Compound 9-1)=0.6, R f (Compound 9-2)=0.5. LCMS:[M+1]:439. 1 H NMR (CD 3OD,400 MHz):δ 7.96(m,2H),7.94-7.82(m,2H),7.22(s,1H),7.09-7.06(m,2H),4.52-4.38(dd,J=40.4 Hz,15.6 Hz,2H), 4.05-4.00(m,2H), 2.76-2.74(m,1H), 2.30-2.27(m,1H) and 1.82-1.79(d,J=13.2 Hz,6H).

[0244] Step 3: Similar to the chiral separation procedure of compounds 1 and 1a, compound 9-2 was applied to a Chiralcel OD column to give compounds 9 and 9a.

[0245] Example 10. (S)-1-(4-(dicyclopropylphosphoryl)phenyl)-N-(3,5-difluorobenzyl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (10)

[0246] [ka]

[0247] [ka]

[0248] Step 1: A mixture of compound 1-5 (300 mg, 0.70 mmol, 1.0 equiv), compound 8-2 (100.1 mg, 0.77 mmol, 1.1 equiv), palladium(II) acetate (9.49 mg, 0.042 mmol, 0.06 equiv), Xantphos (28.6 mg, 0.049 mmol, 0.07 equiv), and potassium carbonate (164.5 mg, 0.775 mmol, 1.1 equiv) in dimethylformamide (5 mL) was microwaved at 120 °C for 30 min under nitrogen atmosphere. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The mixture was filtered, water (5 mL) was added, and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 94:6) to give compound 10-1 (69.7 mg, 20%) as a yellow solid.

[0249] Step 2: To a mixture of compound 10-1 (130 mg, 0.31 mmol, 1.0 equiv) in IPA (10 mL) was added cerium(III) chloride heptahydrate (45.8 mg, 0.12 mmol, 0.4 equiv). The mixture was stirred overnight at 85° C. under oxygen atmosphere. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was diluted with water (10 mL) and extracted with dichloromethane (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol, 10:1) to give 10-2 (48.9 mg, 33%) as a white solid. TLC (dichloromethane:methanol, 15:1):R f (Compound 10-1)=0.6, R f (Compound 10-2)=0.5. LCMS:[M+1]:475. 1H NMR(DMSO,400 MHz):δ 8.45-8.31(t,J=6.4 Hz,1H),7.83-7.76(m,4H),7.04-7.01(m,1H),6.97-6.94(m,2H),6.83(s,1H),4.39-4.34(dd,J=15.6 Hz,6.8 Hz,1H),4.25-4.19(dd,J=15.6 Hz,6.0 Hz,1H),3.89-3.86(t,J=6.8 Hz,1H), 2.56-2.46(m,1H), 2.16-2.11(m,1H), 1.21-1.15(m,2H), 0.80-0.67(m,6H) and 0.59-0.53(m,2H).

[0250] Step 3: Similar to the chiral separation procedure of compounds 1 and 1a, compound 10-2 was applied to a Chiralcel OD column to give compounds 10 and 10a.

[0251] Example 11. (S)-N-(3,5-difluorobenzyl)-3-hydroxy-2-oxo-1-(4-(trimethylsilyl)phenyl)pyrrolidine-3-carboxamide (11)

[0252] [ka]

[0253] [ka]

[0254] Step 1: To a mixture of compound 1-5 (320 mg, 0.781 mmol) in t-BuOH (10 mL) at room temperature, EtONa (21% in EtOH, 500 mg, 1.54 mmol) and t-BuOOH (H 2 70% in 200, 200 mg, 1.55 mmol) was slowly added. The mixture was then stirred at 40° C. for 1 h under nitrogen atmosphere. After the reaction was complete, the mixture was diluted with saturated Na 2 SO 3 The mixture was quenched with DCM (20 mL x 2) and extracted with DCM (20 mL x 2). The organic layer was washed with brine and anhydrous Na 2 SO4 The mixture was dried over 1000 ml, filtered and concentrated. The residue was purified by silica gel column (eluted with 5% MeOH in DCM) to give the title compound 11-1 (145 mg, 43% yield) as a white solid. TLC (DCM:MeOH / 20:1):R f (Compound 1-5)=0.65;R f (Compound 11-1)=0.55.

[0255] Step 2: To a solution of compound 11-1 (50 mg, 0.117 mmol) in HMPT (2 mL) was added KOMe (16 mg, 0.228 mmol) at 0° C. under nitrogen atmosphere. After stirring for 30 min, hexamethyldisilane (74 mg, 0.467 mmol) was added dropwise and the mixture was stirred at room temperature for an additional 4 h. After completion of the reaction, the mixture was diluted with saturated NH 4 The mixture was quenched with Cl solution and extracted with DCM (10 mL x 2). The organic layer was washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel column (eluted with 5% MeOH in DCM) to give 11-2 (8.5 mg, 17% yield) as a white solid. 1 H NMR(500 MHz,chloroform-d)δ7.62(d,J=8.1 Hz,2H),7.55(d,J=8.4 Hz,2H),7.40(d,J=6.4 Hz,1H),6.84-6.78(m,2H),6.74-6.68(m,1H),4.43(qd,J=15.4,6.2 Hz,2H),4.21(td,J=9.1,6.9 Hz,1H),4.13(s,1H),3.86(t,J=9.0 Hz,1H),2.80(ddd,J=12.8,7.0,1.5 Hz,1H),2.31(dt,J=12.8,9.2 Hz,1H),0.28(s,9H).LCMS:C 21 H 24 F 2 N 2 O 3 m / z calculated for Si: 418.52; Found: 419.3 [M+H] + .

[0256] Step 3: Similar to the chiral separation procedure of compounds 1 and 1a, compound 11-2 was applied to a Chiralcel OD column to give compounds 11 and 11a.

[0257] Example 12. (S)-N-(3,5-difluorobenzyl)-3-hydroxy-2-oxo-1-(spiro[cyclopropane-1,3'-indoline]-5'-yl)pyrrolidine-3-carboxamide (12)

[0258] [ka]

[0259] [ka]

[0260] Step 1: To a solution of compound 12-1 (10 g, 47.4 mmol) in THF (100 mL) was added LDA (2 M, 95 mL, 4 equiv.) dropwise at 0 °C. The reaction mixture was stirred for 0.5 h, then 1,2-dibromoethane (12-2) (11.7 g, 62.25 mmol) was added at 0 °C. The reaction was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with water. The mixture was extracted with ethyl acetate (3*100 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting residue was purified by column chromatography (30% EtOAc in petroleum) to give compound 12-3 (6 g) as a pale red solid. TLC (PE:EA=1:3):R f (Compound 12-1)=0.3, R f (Compound 12-3)=0.4. LCMS[M+1]:238.10.

[0261] Step 2: LAH (2.5 M, 34 mL, 5 equiv.) was added to a solution of compound 12-3 (4 g, 1 equiv.) in THF (40 mL) at 0° C., then the mixture was stirred at 50° C. for 16 h. LCMS showed the reaction mixture was complete, and the mixture was then cooled to 50° C. for 16 h. 22H2O (3.3 mL), 3.3 mL of aqueous NaOH (10%), 9.9 mL of H2O 2 The mixture was quenched with O and filtered. The filtrate was extracted with EtOAc (50 mL*2). The combined organic layers were washed with anhydrous Na 2 Drying over SO4, concentration and purification by column chromatography (30% EtOAc in petroleum) gave compound 12-4 (1.3 g). LCMS [M+1] + :224.10;

[0262] Step 3: Compound 12-4 (3.1 g, 1 equiv.) in DCM (40 mL) was treated with Boc 2 HO (6.0 g, 2 eq.), TEA (4.1 g, 3 eq.) were added at 0° C., and then the mixture was stirred at room temperature for 2 h. LCMS showed the reaction mixture was complete, and the mixture was concentrated and purified by column chromatography (5% EtOAc in petroleum) to give compound 12-5 (2.1 g). LCMS: [M+23] + 346.10; Rf(4,PE:EA=5:1)=0.8.

[0263] Step 4: To a solution of compound 12-5 (200 mg, 0.62 mmol) in MePh (3 mL) was added ethyl 2-oxopyrrolidine-3-carboxylate 12-6 (149 mg, 0.95 mmol), CuI (23 mg, 0.12 mmol), DMEDA (10.4 mg, 0.12 mmol), and K 3 PO 4 (327 mg, 1.55 mmol) 2 The reaction mixture was stirred at 110° C. for 4 h. 2 The mixture was quenched with O and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting residue was purified by column chromatography (25% EtOAc in petroleum ether) to give compound 12-7 (90 mg) as a yellow solid. LCMS: [M+23] + 423.10;

[0264] Step 5: EtOH / H in ice bath 2To compound 12-7 (90 mg, 0.23 mmol) in O (1:1, 3 mL) was added LiOH (11 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 1 h. The combined organics were concentrated by rotary evaporation to give compound 12-8 (70 mg).

[0265] Step 6: To a solution of compound 12-8 (70 mg, 0.18 mmol) in DMF (3 mL) was added compound 1-4 (31 mg, 0.22 mmol), HATU (102.6 mg, 0.27 mmol) and DIEA (74.5 mg, 0.56 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water. The mixture was extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated by rotary evaporation. The resulting residue was purified by column chromatography (40% EtOAc in petroleum ether) to give compound 12-9 (70 mg) as a white solid. LCMS: [M+1]+497.10;

[0266] Step 7: Compound 12-9 (70 mg, 0.14 mmol) in IPA (3 mL) was treated with CeCl 3 *7H 2 O (31 mg, 0.08 mmol) was added and the mixture was treated with O 2 Stirred at 70°C under atmosphere for 18 hours. TLC showed complete conversion. Quenched the mixture with water. Extracted the mixture with ethyl acetate (3*5mL). Combined organic layers were washed with water, dried over sodium sulfate, and concentrated by rotary evaporation under vacuum. The resulting residue was purified by column chromatography (50% EtOAc in petroleum ether) to give compound 12-10 (40mg). LCMS: [M+1] 514.2;

[0267] Step 8: To a solution of 12-10 (40 mg, 0.1 mmol) in DCM (2 mL) was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and purified by preparative HPLC to give compound 12-11 (21 mg) as an off-white solid. 1 H NMR (400 MHz, CD 3OD)δ8.80(s,1H),7.59(d,J=8.6 Hz,1H),7.43-7.26(m,2H),6.91(d,J=6.6 Hz,2H),6.78(t,J=9.1 Hz,1H),4.48(dd,J=15.7,6.6 Hz,1H),4.35(dd,J=15.7,5.8 Hz,1H),4.02-3.84(m,2H),3.78(s,2H),2.74-2.62(m,1H),2.23(dt,J=13.1,8.0 Hz,1H),1.25-1.17(m,4H).LCMS:[M+1] + 414.25;

[0268] Step 9: Similar to the chiral separation procedure of compounds 1 and 1a, compounds 12-11 were applied to a Chiralcel OD column to give compounds 12 and 12a.

[0269] Example 13. (S)-N-(3-chloro-5-fluorobenzyl)-3-hydroxy-2-oxo-1-(2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)pyrrolidine-3-carboxamide (13)

[0270] [ka]

[0271] [ka]

[0272] Step 1: To a mixture of compound 12-3 (17.8 g, 74.76 mmol) in anhydrous DMF (80 mL) was added NaH (60% in mineral oil, 5.98 g, 149 mmol) in portions at 0 °C under nitrogen. After stirring at 0 °C for 30 min, SEM-Cl (18.7 g, 112 mmol) was added to the mixture. The reaction was stirred at room temperature for 16 h. After completion of the reaction, ice was added to quench the reaction. The resulting mixture was partitioned between EtOAc (300 mL) and water (100 mL). The organic layer was washed with brine (200 mL) and anhydrous Na 2 SO 4The mixture was dried over 100 ml and concentrated. The crude product was purified by silica gel column (eluted with 5% EtOAc in petroleum ether) to give the title compound 13-1 (22.8 g, 82% yield) as white crystals. TLC (petroleum ether: EtOAc / 20:1): R f (12-3)=0.1; R f (13-1)=0.45.

[0273] Step 2: Compound 13-1 (9.0 g, 24.43 mmol), compound 12-6 (5 g, 31.82 mmol), compound 13-2 (1.73 g, 12.16 mmol), CuI (2.32 g, 12.18), and K in dioxane (90 mL) under nitrogen. 3 PO 4 (15.6 g, 73.49 mmol) was stirred at 115° C. for 4 h. The mixture was filtered over Celite, diluted with water (100 mL) and extracted with EtOAc (200 mL×2). The organic layer was washed with brine and anhydrous Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated. The residue was purified by silica gel column (eluted with 30% EtOAc in petroleum ether) to give the title compound 13-3 (6.6 g, 60% yield) as a pale yellow oil. TLC (petroleum ether: EtOAc / 2:1): R f (Compound 13-1)=0.8;R f (Compound 13-3)=0.35.

[0274] Step 3: EtOH (20mL), THF (10mL) and H 2 A solution of compound 13-3 (6.6 g, 14.86 mmol) in 20HO (20 mL) was added to LiOH H 2 2H2O (1.25 g, 29.79 mmol) was added at 0 °C. After the mixture was stirred at room temperature for 1 h, the mixture was concentrated to remove the organic solvent. The remaining aqueous solution was adjusted to pH = 2 and extracted with EtOAc (50 mL × 2). The organic layer was washed with brine and anhydrous Na 2 SO 4 After drying over 100° C., filtration and concentration afforded the title compound 13-4 (5.8 g, 93% yield) as a pale yellow oil, which was used directly in the next step. TLC (petroleum ether:EtOAc / 2:1):Rf (Compound 13-3)=0.35;R f (Compound 13-4)=0.1.

[0275] Step 4: A mixture of compound 13-4 (3.0 g, 7.2 mmol), compound 5-1 (1.72 g, 10.78 mmol), HOBt (970 mg, 7.18 mmol), DIPEA (2.32 g, 17.98 mmol), and EDCI (2.47 g, 12.93 mmol) in anhydrous DCM (30 mL) was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with EtOAc (100 mL) and washed with water, 1N HCl, and brine. The organic layer was extracted with anhydrous Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated. The residue was purified by silica gel column (eluted with 30% EtOAc in petroleum ether) to give the title compound 13-5 (3.6 g, 90% yield) as a foam. TLC (petroleum ether: EtOAc / 2:1): R f (Compound 13-4)=0.1;R f (Compound 13-5)=0.4.

[0276] Step 5: Compound 13-5 (5.14 g, 9.21 mmol) and CeCl in isopropanol (50 mL) 3 7H 2 A mixture of 13-3H2O (1.37 g, 3.67 mmol) and 13-3H2O (1.37 g, 3.67 mmol) was stirred at 75 °C under oxygen atmosphere for 3 h. After the reaction was completed, the mixture was concentrated. The residue was purified by silica gel column (eluted with 5% MeOH in DCM) to give the title compound 13-6 (3.54 g, 64% yield) as a white solid. TLC (DCM:MeOH / 20:1):R f (Compound 13-5)=0.46;R f (Compound 13-6)=0.35.

[0277] Step 6: A solution of compound 13-6 (3.5 g, 6.09 mmol) and TBAF (1M in THF, 30 mL, 30 mmol) in DMF (30 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature and diluted with EtOAc (100 mL) and water (100 mL). The mixture was separated and the organic layer was washed with 1N HCl, saturated NaHCO 3 and brine, and anhydrous Na 2 SO 4 The residue was purified by silica gel column (eluted with 5% MeOH in DCM) to give 13-7 (1.2 g, 44% yield) as a white powder. 1 H NMR(400 MHz,DMSO-d6)δ10.60(s,1H),8.73(t,J=6.4 Hz,1H),7.49(dd,J=8.4,2.2 Hz,1H),7.28(dt,J=8.9,2.2 Hz,1H),7.24-7.15(m,2H),7.10(dt,J=9.6,1.8 Hz,1H),6.91(d,J=8.3 Hz,1H),6.72(s,1H),4.38(dd,J=15.8,6.7 Hz,1H),4.24(dd,J=15.7,6.1 Hz,1H),3.80(dd,J=7.9,5.6 Hz,2H),2.57(dt,J=12.1,5.9 Hz,1H),2.09(dt,J=13.0,7.5 Hz,1H),1.55(t,J=3.3 Hz,2H),1.48(q,J=4.1,3.4 Hz,2H).LCMS:C 22 H 19 ClFN 3 O 4 m / z calculated for: 443.86; Found: 444.16. [M+H] + .TLC(DCM:MeOH / 20:1):R f (Compound 13-6)=0.35, R f (Compound 13-7)=0.25.

[0278] Step 7: Similar to the chiral separation procedure of compounds 1 and 1a, compound 13-7 was applied to a Chiralcel OD column to give compounds 13 and 13a.

[0279] Example 14. (S)-N-(3-chloro-5-fluorobenzyl)-3-hydroxy-2-oxo-1-(2'-oxospiro[cyclobutane-1,3'-indoline]-5'-yl)pyrrolidine-3-carboxamide (14)

[0280] [ka]

[0281] [ka]

[0282] Step 1: To a solution of compound 12-1 (5 g, 23.6 mmol) in anhydrous THF (50 mL) at -5°C, LDA (2 M solution in THF, 48 mL, 96 mmol) was added dropwise under nitrogen atmosphere. After stirring at -5°C for 30 min, compound 14-1 (14.3 g, 70.8 mmol) was added in one portion. The mixture was then stirred at room temperature for 16 h. After completion of the reaction, water (150 mL) was slowly added to quench the reaction, and the mixture was extracted with EtOAc (200 mL x 2). The organic layer was washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was triturated with EtOAc to give the title compound 14-2 (2.6 g, 43% yield) as a pink solid. TLC (petroleum ether: EtOAc / 5:1): R f (Compound 12-1)=0.2;R f (Compound 14-2)=0.3.

[0283] Step 2: To a mixture of compound 14-2 (2.4 g, 9.50 mmol) in anhydrous DMF (20 mL) was added NaH (60% in mineral oil, 759 mg, 18.98 mmol) in portions at 0 °C under nitrogen. After stirring at 0 °C for 30 min, SEM-Cl (2.37 g, 14.21 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, ice was added to quench the reaction. The resulting mixture was partitioned between EtOAc (150 mL) and water (100 mL). The organic layer was washed with brine (100 mL) and diluted with anhydrous 2 SO 4 After drying over 100° C., the mixture was concentrated. The crude product was purified by silica gel column (eluted with 5% EtOAc in petroleum ether) to give the title compound 14-3 (2.83 g, 77% yield) as a colorless oil. TLC (petroleum ether: EtOAc / 20:1): R f (Compound 14-2)=0.05;R f (Compound 14-3)=0.5.

[0284] Step 3: Compound 14-3 (1.85 g, 4.83 mmol), compound 12-6 (1.0 g, 6.36 mmol), compound 13-2 (348 mg, 2.44 mmol), CuI (466 mg, 2.45 mmol), and K in dioxane (20 mL) under nitrogen. 3 PO 4 (15.6 g, 14.70 mmol) was stirred at 115° C. for 4 h. After completion of the reaction, the mixture was filtered over Celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (50 mL×2). The organic layer was washed with water and brine, and then extracted with anhydrous Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated. The residue was purified by silica gel column (eluted with 30% EtOAc in petroleum ether) to give the title compound 14-4 (1.03 g, 46% yield) as a pale yellow oil. TLC (petroleum ether: EtOAc / 5:1): R f (Compound 14-3)=0.8;R f (Compound 14-4)=0.2.

[0285] Step 4: EtOH (4 mL), THF (2 mL) and H2 A solution of compound 14-4 (1.03 g, 2.24 mmol) in HO (4 mL) was added to LiOH H 2 2H2O (188 mg, 4.48 mmol) was added at 0 °C. After the reaction was stirred at room temperature for 1 h, the mixture was concentrated to remove the organic solvent. The remaining aqueous solution was adjusted to pH = 2 and extracted with EtOAc (50 mL x 2). The organic layer was washed with brine and anhydrous Na 2 SO 4 After drying over 100° C., filtration and concentration afforded the title compound 14-5 (890 mg, 92% yield) as a pale yellow oil, which was used directly in the next step. TLC (petroleum ether:EtOAc / 2:1):R f (Compound 14-4)=0.48;R f (Compound 14-5)=0.1.

[0286] Step 5: A mixture of compound 14-5 (890 mg, 2.06 mmol), compound 5-1 (530 mg, 3.32 mmol), HOBt (300 mg, 2.22 mmol), DIPEA (722 mg, 5.60 mmol), and EDCI (770 mg, 4.03 mmol) in anhydrous DCM (10 mL) was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water, 1N HCl, and brine. The organic layer was extracted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml, filtered and concentrated. The residue was purified by silica gel column (eluted with 30% EtOAc in petroleum ether) to give the title compound 14-6 (890 mg, 75% yield) as a foam. TLC (petroleum ether: EtOAc / 2:1): R f (Compound 5-1)=0.1;R f (Compound 14-6)=0.4.

[0287] Step 6: Compound 14-6 (500 mg, 0.873 mmol) and CeCl in isopropanol (10 mL) 3 7H 2A mixture of 14-3H2O (160 mg, 0.430 mmol) was stirred at 75° C. under oxygen atmosphere for 3 h. After completion of the reaction, the mixture was concentrated. The residue was purified by silica gel column (eluted with 5% MeOH in DCM) to give compound 14-7 (400 mg, 78% yield) as a pale yellow oil. TLC (DCM:MeOH / 20:1):R f (Compound 14-6)=0.75;R f (Compound 14-7)=0.55.

[0288] Step 7: A solution of compound 14-7 (400 mg, 0.680 mmol) and TBAF (1M in THF, 4 mL, 4 mmol) in DMF (5 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The mixture was separated and the organic layer was washed with 1N HCl, saturated NaHCO 3 and brine, and anhydrous Na 2 SO 4 The residue was purified by silica gel column (eluted with 5% MeOH in DCM) to give 14-8 (70 mg, 22% yield) as a white powder. 1 H NMR(400 MHz,chloroform-d)δ8.18(s,1H),7.78(s,1H),7.56(s,1H),7.22(s,1H),7.06(s,1H),6.98-6.86(m,2H),6.74(d,J=8.0 Hz,1H),4.80(s,1H),4.42(dd,J=6.5,3.3 Hz,2H),4.16(d,J=8.8 Hz,1H),3.84(s,1H),2.61(s,2H),2.33(s,4H),1.65(s,2H).LCMS:C 23 H 21 ClFN 3 O 4 m / z calculated for: 457.89; Measured: 458.29 [M+H] + .TLC(DCM:MeOH / 20:1):R f (Compound 14-7)=0.55;R f (Compound 14-8)=0.45.

[0289] Step 8: Similar to the chiral separation procedure of compounds 1 and 1a, compound 14-8 was applied to a Chiralcel OD column to give compounds 14 and 14a.

[0290] Example 15. (S)-N-(3,5-difluorobenzyl)-3-hydroxy-2-oxo-1-(2'-oxospiro[cyclopentane-1,3'-indoline]-5'-yl)pyrrolidine-3-carboxamide (15)

[0291] [ka]

[0292] [ka]

[0293] Step 1: To a solution of compound 12-1 (5 g, 23.6 mmol) in anhydrous THF (50 mL) at -5°C, LDA (2 M solution in THF, 48 mL, 96 mmol) was added dropwise under nitrogen atmosphere. After stirring at -5°C for 30 min, compound 15-1 (15.3 g, 70.8 mmol) was added in one portion. The mixture was then stirred at room temperature for 16 h. After completion of the reaction, water (150 mL) was slowly added to quench the reaction, and the mixture was extracted with EtOAc (200 mL x 2). The organic layer was washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was triturated with EtOAc to give compound 15-2 (3.4 g, 54% yield) as a pink solid. TLC (petroleum ether: EtOAc / 5:1): R f (Compound 12-1)=0.2;R f (Compound 15-2)=0.25.

[0294] Step 2: To a mixture of compound 15-2 (3.2 g, 12.02 mmol) in anhydrous DMF (30 mL) was added NaH (60% in mineral oil, 960 mg, 24.00 mmol) in portions at 0 °C under nitrogen. After stirring at 0 °C for 30 min, SEM-Cl (3.00 g, 18.00 mmol) was added to the mixture. The reaction was stirred at room temperature for 16 h. After completion of the reaction, ice was added to quench the reaction. The resulting mixture was partitioned between EtOAc (150 mL) and water (100 mL). The organic layer was washed with brine (100 mL) and diluted with anhydrous 2 SO 4 After drying over 100° C., the mixture was concentrated. The crude product was purified by silica gel column (eluted with 5% EtOAc in petroleum ether) to give the title compound 15-3 (2.8 g, 58% yield) as a colorless oil. TLC (petroleum ether: EtOAc / 20:1): R f (Compound 15-2)=0.1;R f (Compound 15-3)=0.45.

[0295] Step 3: Compound 15-3 (1.95 g, 4.92 mmol), compound 12-6 (1.0 g, 6.36 mmol), compound 13-2 (348 mg, 2.45 mmol), CuI (466 mg, 2.45), K in dioxane (20 mL) under nitrogen. 3 PO 4 (3.12 g, 14.7 mmol) was stirred at 115° C. for 4 h. After completion of the reaction, the mixture was filtered over Celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (50 mL×2). The organic layer was washed with water and brine, and then extracted with anhydrous Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated. The residue was purified by silica gel column (eluted with 30% EtOAc in petroleum ether) to give the title compound 15-4 (1.23 g, 52% yield) as a pale yellow oil. TLC (petroleum ether: EtOAc / 5:1): R f (Compound 15-3)=0.8;R f (Compound 15-4)=0.15.

[0296] Step 4: EtOH (4 mL), THF (2 mL) and H 2A solution of compound 15-4 (1.23 g, 2.60 mmol) in HO (4 mL) was added to LiOH H 2 2H2O (218 mg, 5.20 mmol) was added at 0 °C. After the reaction was stirred at room temperature for 1 h, the mixture was concentrated to remove the organic solvent. The remaining aqueous solution was adjusted to pH = 2 and extracted with EtOAc (50 mL x 2). The organic layer was washed with brine and anhydrous Na 2 SO 4 After drying over 100° C., filtration and concentration afforded the title compound 15-5 (1.0 g, 86% yield) as a pale yellow oil, which was used directly in the next step. TLC (petroleum ether:EtOAc / 2:1):R f (Compound 15-4)=0.65;R f (Compound 15-5)=0.1.

[0297] Step 5: A mixture of compound 15-5 (1.0 g, 2.25 mmol), compound 1-4 (560 mg, 3.91 mmol), HOBt (350 mg, 2.59 mmol), DIPEA (725 mg, 5.62 mmol), and EDCI (900 mg, 4.71 mmol) in anhydrous DCM (10 mL) was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water, 1N HCl, and brine. The organic layer was extracted with anhydrous Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated. The residue was purified by silica gel column (eluted with 30% EtOAc in petroleum ether) to give the title compound 15-6 (1.0 g, 78% yield) as a pale yellow foam. TLC (petroleum ether: EtOAc / 2:1): R f (Compound 1-4)=0.1;R f (Compound 15-6)=0.5.

[0298] Step 6: Compound 15-6 (500 mg, 0.877 mmol) and CeCl in isopropanol (5 mL) 3 7H 2A mixture of 15-3H2O (160 mg, 0.430 mmol) and 1H2O (160 mg, 0.430 mmol) was stirred at 75° C. under oxygen atmosphere for 3 h. After completion of the reaction, the mixture was concentrated. The residue was purified by silica gel column (eluted with 5% MeOH in DCM) to give the title compound 15-7 (420 mg, 81% yield) as a pale yellow oil. TLC (DCM:MeOH / 20:1):R f (Compound 15-6)=0.65;R f (Compound 15-7)=0.3.

[0299] Step 7: A solution of compound 15-7 (420 mg, 0.717 mmol) and TBAF (1M in THF, 4 mL, 4 mmol) in DMF (4 mL) was stirred at 100° C. for 2 h under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The mixture was separated and the aqueous layer was re-extracted with EtOAc (50 mL). The organic layer was washed with 1N HCl, saturated NaHCO 3 and brine, and anhydrous Na 2 SO 4 The residue was purified by silica gel column (eluted with 5% MeOH in DCM) to give 15-8 (75 mg, 23% yield) as a white powder. 1 H NMR (400 MHz, chloroform-d) δ 8.69 (s, 1H), 7.67 (d, J = 6.2 Hz, 1H), 7.46 (s, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.84-6.69 (m, 3H), 6.63 (d, J = 9.3 Hz, 1H), 5.25 (s, 1H), 4.46-4.33 (m, 2H), 4.11 (d, J = 8.5 Hz, 1H), 3.80 (d, J = 9.9 Hz, 1H), 2.81-2.71 (m, 1H), 2.34-2.24 (m, 1H), 2.09 (d, J = 9.2 Hz,2H),2.00(s,2H),1.91(s,2H),1.83(s,2H).LCMS:C 24 H 23 F 2 N 3 O 4 m / z calculated for: 455.46; Found: 456.17 [M+H] + .TLC(DCM:MeOH / 20:1):Rf (Compound 15-7)=0.3, R f (Compound 15-8)=0.2.

[0300] Step 8: Similar to the chiral separation procedure of compounds 1 and 1a, compound 15-8 was applied to a Chiralcel OD column to give compounds 15 and 15a.

[0301] Example 16. (S)-N-(3,5-difluorobenzyl)-3-hydroxy-2-oxo-1-(2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)pyrrolidine-3-carboxamide (16)

[0302] [ka]

[0303] [ka]

[0304] Step 1: A mixture of compound 13-4 (300 mg, 0.72 mmol), compound 1-4 (150 mg, 1.04 mmol), HOBt (97 mg, 0.72 mmol), DIPEA (218 mg, 1.69 mmol), and EDCI (250 mg, 1.31 mmol) in anhydrous DCM (3 mL) was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with EtOAc (20 mL) and washed with water, 1N HCl, and brine. The organic layer was extracted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated. The residue was purified by silica gel column (eluted with 30% EtOAc in petroleum ether) to give the title compound 10 (310 mg, 76% yield) as a foam. TLC (petroleum ether: EtOAc / 2:1): R f (Compound 1-4)=0.1;R f (Compound 16-1)=0.4.

[0305] Step 2: Compound 16-1 (310 mg, 0.572 mmol) and CeCl in isopropanol (6 mL) 3 7H 2 A mixture of 16-3H (106 mg, 0.285 mmol) and 1H2O (106 mg, 0.285 mmol) was stirred at 75° C. under oxygen atmosphere for 3 h. After completion of the reaction, the mixture was concentrated. The residue was purified by silica gel column (eluted with 5% MeOH in DCM) to give the title compound 16-2 (193 mg, 60% yield) as a white solid. TLC (DCM:MeOH / 20:1):R f (Compound 16-1)=0.5;R f (Compound 16-2)=0.4.

[0306] Step 3: A solution of compound 16-2 (190 mg, 0.341 mmol) and TBAF (1M in THF, 1.7 mL, 1.7 mmol) in DMF (2 mL) was stirred at 100° C. for 2 h under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature and diluted with EtOAc (20 mL) and water (20 mL). The mixture was separated and the organic layer was washed with 1N HCl, saturated NaHCO 3 and brine, and anhydrous Na 2 SO 4 The residue was purified by silica gel column (eluted with 5% MeOH in DCM) to give 16-3 (50 mg, yield 34%) as a white powder. 1 H NMR (400 MHz, methanol-d 4 )δ7.35(dd,J=8.4,2.2 Hz,1H),7.22(d,J=2.1 Hz,1H),6.97(d,J=8.3 Hz,1H),6.94-6.88(m,2H),6.78(ddd,J=9.3,8.0,2.4 Hz,1H),4.47(d,J=15.7 Hz,1H),4.36(d,J=15.6 Hz,1H),3.94(dt,J=9.7,7.5 Hz,1H),3.86(dt,J=12.6,6.2 Hz,1H),2.69(ddd,J=13.4,7.7,3.5 Hz,1H),2.21(ddd,J=13.0,8.8,7.1 Hz,1H),1.61(d,J=3.4 Hz,4H).LCMS:C 22 H 19 F 2N 3 O 4 m / z calculated for: 427.41; Measured: 428.04 [M+H] + .TLC(DCM:MeOH / 20:1):R f (Compound 16-2)=0.4, R f (16-3)=0.3.

[0307] Step 4: Similar to the chiral separation procedure of compounds 1 and 1a, compound 16-3 was applied to a Chiralcel OD column to give compounds 16 and 16a.

[0308] Example 17. (S)-N-(3-chloro-5-fluorobenzyl)-3-hydroxy-2-oxo-1-(2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-5'-yl)pyrrolidine-3-carboxamide (17)

[0309] [ka]

[0310] [ka]

[0311] Step 1: To a solution of compound 17-1 (2.0 g, 9.39 mmol) in anhydrous THF (10 mL) at -5°C, LDA (2 M solution in THF, 18.6 mL, 37.56 mmol) was added dropwise under nitrogen atmosphere. After stirring at -5°C for 30 min, compound 12-2 (5.29 g, 28.16 mmol) was added in one portion. The mixture was then stirred at room temperature for 17 h. After completion of the reaction, water (40 mL) was slowly added to quench the reaction, and the mixture was extracted with EtOAc (30 mL x 2). The organic layer was washed with brine and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated. The crude product was purified by silica gel column (petroleum ether: EtOAc = 5:1) to give the title compound 17-2 (480 mg, yield 21.4%) as a pink solid. TLC (petroleum ether: EtOAc / 2:1): R f (Compound 17-1):=0.3, R f (Compound 17-2):=0.4.

[0312] Step 2: To a mixture of compound 17-2 (480 mg, 2.01 mmol) in anhydrous DMF (4 mL) was added NaH (60% in mineral oil, 241 mg, 6.02 mmol) in portions at 0 °C under nitrogen. After stirring at 0 °C for 30 min, SEM-Cl (670 mg, 4.01 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 17 h. After completion of the reaction, the mixture was partitioned between EtOAc (40 mL) and water (40 mL). The organic layer was washed with brine (40 mL) and extracted with anhydrous 2 SO 4 After drying over 100° C., the mixture was concentrated. The crude product was purified by silica gel column (eluted with 20% EtOAc in petroleum ether) to give the title compound 17-3 (300 mg, 40% yield) as a colorless oil. TLC (petroleum ether: EtOAc / 5:1): R f (Compound 17-2):=0.1, R f (Compound 17-3):=0.5.

[0313] Step 3: Compound 17-3 (300 mg, 0.812 mmol), compound 12-6 (128 mg, 0.812 mmol), compound 13-2 (116 g, 0.821 mmol), CuI (155 mg, 0.812 mmol), and K in dioxane (3 mL) under nitrogen. 3 PO 4 (604 mg, 2.84 mmol) was stirred at 115° C. for 3 h. After completion of the reaction, the mixture was filtered over Celite. The filtrate was diluted with water (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layer was washed with water and brine, and then extracted with anhydrous Na 2 SO 4The mixture was dried over hexane, filtered and concentrated. The residue was purified by silica gel column (eluted with 50% EtOAc in petroleum ether) to give the title compound 17-4 (204 mg, yield 56.5%) as a colorless oil. TLC (petroleum ether: EtOAc / 2:1): R f (Compound 17-3):=0.9, R f (Compound 17-4):=0.1.

[0314] Step 4: EtOH (1.0 mL), THF (0.5 mL) and H 2 A solution of compound 17-4 (200 mg, 0.449 mmol) in HO (1.0 mL) was added to LiOH H 2 HO (38 mg, 0.898 mmol) was added at 0 °C. After the reaction was stirred at room temperature for 0.5 h, the mixture was concentrated to remove the organic solvent. The remaining aqueous solution was adjusted to pH = 2 and extracted with EtOAc (20 mL x 2). The organic layer was washed with brine and anhydrous Na 2 SO 4 After drying over 100° C., filtration and concentration afforded the title compound 17-5 (143 mg, 75% yield) as a colorless oil, which was used directly in the next step. TLC (DCM:MeOH / 20:1):R f (Compound 17-4):=0.5, R f (Compound 17-5):=0.25.

[0315] Step 5: Under nitrogen atmosphere, a mixture of compound 17-5 (140 mg, 0.335 mmol), compound 5-1 (64.0 mg, 0.402 mmol), HOBt (45 mg, 0.335 mmol), DIPEA (86 mg, 0.67 mmol), and EDCI (96 g, 0.503 mmol) in anhydrous DCM (1 mL) was stirred at room temperature for 17 hours. After completion of the reaction, the mixture was diluted with EtOAc (20 mL) and washed with water, 1N HCl, and brine. The organic layer was extracted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml, filtered and concentrated. The residue was purified by silica gel column (eluted with 5% MeOH in DCM) to give the title compound 17-6 (107 mg, 57% yield) as a colorless oil. TLC (DCM:MeOH / 10:1):R f(Compound 17-5):=0.25, R f (Compound 17-6):=0.4.

[0316] Step 6: Compound 17-6 (105 mg, 0.188 mmol) and CeCl in isopropanol (2 mL) 3 7H 2 A mixture of 17-3H (70 mg, 0.188 mmol) and 1H2O (70 mg, 0.188 mmol) was stirred at 70° C. for 2 h under oxygen atmosphere. After completion of the reaction, the mixture was concentrated. The residue was purified by silica gel column (eluted with 5% MeOH in DCM) to give the title compound 17-7 (80 mg, 78% yield) as a colorless oil. TLC (DCM:MeOH / 20:1):R f (Compound 17-6):=0.3, R f (Compound 17-7):=0.25.

[0317] Step 7: A solution of compound 17-7 (80 mg, 0.14 mmol) and TBAF (1M in THF, 2.78 mL, 2.78 mmol) in DMF (1 mL) was stirred at 100° C. for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and diluted with EtOAc (10 mL) and water (10 mL). The mixture was separated and the organic layer was washed with 1N HCl, saturated NaHCO 3 Wash with anhydrous NaCl solution and brine. 2 SO 4 The residue was purified by preparative HPLC (C18 column, acetonitrile / H 2 The mixture was purified by elution with O, HCl conditions to give 17-8 (1.7 g, 3% yield). LCMS: 21 H 18 ClFN 4 O 4 m / z calculated for: 444.1; Found: 445.12. [M+H] + .

[0318] Step 8: Similar to the chiral separation procedure of compounds 1 and 1a, compound 17-8 was applied to a Chiralcel OD column to give compounds 17 and 17a.

[0319] Example 18. (S)-N-(3,5-difluorobenzyl)-1-(2,2-dioxido-1H-spiro[benzo[c]isothiazole-3,1'-cyclobutan]-5-yl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (18)

[0320] [ka]

[0321] [ka]

[0322] Step 1: To a solution of compound 18-1 (2.0 g, 11.8 mmol) and DIPEA (3.0 g, 23.2 mmol) in anhydrous DCM (20 mL) at room temperature was added SEM-Cl (2.9 g, 14.4 mmol). After stirring for 1.5 h, the reaction mixture was diluted with DCM (30 mL) and washed with brine. The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated. The crude product was purified by column chromatography (eluted with 15% EtOAc in petroleum ether) to give compound 18-2 (2.9 g, 83% yield) as a white solid. TLC (petroleum ether: EtOAc / 5:1): R f (Compound 18-1)=0.1;R f (Compound 18-2)=0.37.

[0323] Step 2: To a solution of compound 18-2 (1.0 g, 3.34 mmol) in anhydrous DMF (10 mL) at 0 °C, NBS (713 mg, 4.00 mmol) was added. After stirring at room temperature for 1 h, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The organic layer was washed with brine and extracted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated. The crude product was purified by column chromatography (eluted with 15% EtOAc in petroleum ether) to give compound 18-3 (1.1 g, 87% yield) as a yellow solid. TLC (petroleum ether: EtOAc / 5:1): R f(Compound 18-2)=0.2;R f (Compound 18-3)=0.3.

[0324] Step 3: Under nitrogen atmosphere, to a mixture of compound 18-3 (770 mg, 2.04 mmol) and compound 18-4 (1.21 g, 4.07 mmol) in anhydrous THF (5 mL) was added LiHMDS (1 M, 6.11 mL, 6.11 mmol) dropwise at -78 °C. After the reaction was stirred at -78 °C for 1 h, the mixture was quenched by adding cold water and extracted with EtOAc (20 mL x 2). The organic layer was washed with brine and anhydrous Na 2 SO 4 The mixture was dried over 100 ml and concentrated. The crude product was purified by column (eluted with 5% EtOAc in petroleum ether) to give compound 18-5 (477 mg, 56% yield) as a yellow oil. TLC (petroleum ether: EtOAc / 20:1): R f (Compound 18-3)=0.2;R f (Compound 18-5)=0.3.

[0325] Step 4: Compound 18-5 (474 ​​mg, 1.13 mmol), compound 12-6 (230 mg, 1.46 mmol), compound 13-2 (160 mg, 1.12 mmol), CuI (215 mg, 1.27 mmol) and K were dissolved in anhydrous dioxane (4 mL) under nitrogen atmosphere. 3 PO 4 (720 mg, 3.39 mmol) was stirred at 115° C. for 3.5 h. After the reaction was completed, the mixture was filtered. The filtrate was diluted with water (30 mL) and extracted with EtOAc (30 mL×2). The organic layer was washed with brine and extracted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml and concentrated. The crude product was purified by column (eluted with 30% EtOAc in petroleum ether) to give compound 18-6 (268 mg, 48% yield) as a yellow oil. TLC (petroleum ether: EtOAc / 2:1): R f (Compound 18-5)=0.7;R f (Compound 18-6)=0.3.

[0326] Step 5: A solution of compound 18-6 (268 mg, 0.54 mmol) in EtOH (1.2 mL) and THF (0.6 mL) was treated with LiOH H in water (1.2 mL). 2 A solution of 2H2O (45.5 mg, 1.08 mmol) was added at 0 °C. After stirring at room temperature for 1 h, the mixture was concentrated under reduced pressure to remove the organic solvent. The aqueous solution was acidified to pH = 3 with 1N HCl and then extracted with EtOAc (20 mL x 2). The organic layer was washed with brine and anhydrous Na 2 SO 4 After drying and concentration, compound 18-7 (191 mg, 75% yield) was obtained as a yellow oil. TLC (DCM:MeOH / 20:1):R f (Compound 18-6)=0.4;R f (Compound 18-7)=0.1.

[0327] Step 6: A mixture of compound 18-7 (241 mg, 0.52 mmol), DIPEA (0.27 mL, 1.56 mmol), compound 1-4 (110.7 mg, 0.78 mmol), HOBt (70.1 mg, 0.52 mmol), and EDCI (295.8 mg, 1.56 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. After the reaction was completed, the mixture was diluted with EtOAc (30 mL) and washed with 1N HCl (30 mL). The organic layer was washed with brine and anhydrous Na 2 SO 4 The mixture was dried over 100 ml and concentrated. The crude product was purified by column (eluted with 50% EtOAc in petroleum ether) to give compound 18-8 (188 mg, 61% yield) as a yellow oil. TLC (DCM:MeOH / 10:1):R f (Compound 18-7)=0.2;R f (Compound 18-8)=0.4.

[0328] Step 7: Compound 18-8 (188 mg, 0.32 mmol) and CeCl in isopropanol (3 mL) 3 7H 2A mixture of 18-3H (59.2 mg, 0.16 mmol) and 1H2O (59.2 mg, 0.16 mmol) was stirred at 70° C. under oxygen atmosphere for 1 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The crude product was purified by column (eluted with 70% EtOAc in petroleum ether) to give compound 18-9 (89 mg, 46% yield) as a yellow oil. TLC (DCM:MeOH / 20:1):R f (Compound 18-8)=0.5;R f (Compound 18-9)=0.4.

[0329] Step 8: A mixture of compound 18-9 (89 mg, 0.15 mmol) and TBAF (1M in THF, 1.9 mL, 1.9 mmol) was stirred at 70° C. for 5 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 mL). The mixture was washed with water and brine. The organic layer was extracted with anhydrous Na 2 SO 4 The residue was redissolved in acetonitrile and water and purified by HPLC (C18 column, acetonitrile / H 2 The mixture was purified by elution with O and TFA under the following conditions: The desired component was lyophilized to give compound 18-10 (5.7 mg, 8% yield) as a white solid. 1 H NMR (500 MHz, DMSO-d 6 )δ10.42(s,1H),8.72(t,J=6.4 Hz,1H),7.88(d,J=2.4 Hz,1H),7.58(dd,J=8.6,2.3 Hz,1H),7.07(tt,J=9.4,2.4 Hz,1H),7.03-6.94(m,2H),6.84(d,J=8.6 Hz,1H),6.75(s,1H),4.40(dd,J=15.8,6.7 Hz,1H),4.26(dd,J=15.8,6.0 Hz,1H),3.95-3.84(m,2H),2.91-2.81(m,2H),2.64-2.58(m,1H),2.47-2.43(m,1H),2.21-1.94(m,4H).LCMS:C 22 H 21 F 2 N 3 O 5 m / z calculated for S: 477.48; Found: 478.26. [M+H] + .

[0330] Step 9: Similar to the chiral separation procedure of compounds 1 and 1a, compound 18-10 was applied to a Chiralcel OD column to give compounds 18 and 18a.

[0331] Example 19. (S)-N-(3-chloro-5-fluorobenzyl)-1-(2,2-dioxide-1H-spiro[benzo[c]isothiazole-3,1'-cyclobutan]-5-yl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (19)

[0332] [ka]

[0333] [ka]

[0334] Step 1: A mixture of compound 18-7 (138 mg, 0.30 mmol), DIPEA (115 mg, 0.89 mmol), compound 5-1 (70.8 mg, 0.44 mmol), HOBt (39.9 mg, 0.30 mmol), and EDCI (169.5 mg, 0.89 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. After the reaction was completed, the mixture was diluted with EtOAc (30 mL) and washed with 1N HCl (30 mL). The organic layer was washed with brine and extracted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml and concentrated. The crude product was purified by column (eluted with 50% EtOAc in petroleum ether) to give compound 19-1 (130 mg, 72% yield) as a yellow oil. TLC (DCM:MeOH / 10:1):R f (Compound 18-7)=0.2;R f (Compound 19-1)=0.4.

[0335] Step 2: Compound 19-1 (130 mg, 0.21 mmol) and CeCl in isopropanol (3 mL) 3 7H 2A mixture of 19-2 (39.9 mg, 0.11 mmol) and 2H-MeOH (39.9 mg, 0.11 mmol) was stirred at 70° C. for 1 h under oxygen atmosphere. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The crude product was purified by column (eluted with 70% EtOAc in petroleum ether) to give compound 19-2 (102 mg, 76% yield) as a yellow oil. TLC (DCM:MeOH / 20:1):R f (Compound 19-1)=0.5;R f (Compound 19-2)=0.4.

[0336] Step 3: To a solution of compound 19-2 (45 mg, 0.072 mmol) in EtOAc (0.5 mL) was added a solution of HCl in EtOAc (4N, 0.5 mL). After stirring at room temperature for 2 h, the mixture was concentrated. The residue was redissolved in MeOH (0.5 mL) and diluted with NH 3 H 2 The mixture was treated with 0.2 mL of 1H2O. The mixture was then stirred at room temperature for 16 h. After completion of the reaction, the mixture was concentrated. The residue was purified by preparative HPLC (C18 column, acetonitrile / H2O). 2 The mixture was purified by elution with O and TFA conditions. The desired component was lyophilized to give 19-3 (7.8 mg, 22% yield) as a white powder. 1 H NMR (600 MHz, DMSO-d 6 )δ10.42(s,1H),8.73(t,J=6.4 Hz,1H),7.90(d,J=2.3 Hz,1H),7.58(dd,J=8.6,2.3 Hz,1H),7.28(dt,J=8.7,2.2 Hz,1H),7.22(d,J=1.7 Hz,1H),7.11(dt,J=9.6,1.8 Hz,1H),6.84(d,J=8.6 Hz,1H),6.76(s,1H),4.39(dd,J=15.7,6.8 Hz,1H),4.26(dd,J=15.7,6.0 Hz,1H),3.92-3.86(m,2H),2.89-2.83(m,2H),2.62-2.58(m,1H),2.46-2.43(m,1H),2.22-1.94(m,4H).LCMS:C 22 H 21 ClFN 3 O 5m / z calculated for S: 493.93; Found: 494.04. [M+H] + .

[0337] Step 4: Similar to the chiral separation procedure of compounds 1 and 1a, compound 19-3 was applied to a Chiralcel OD column to give compounds 19 and 19a.

[0338] Example 20. (S)-N-(3-chloro-5-fluorobenzyl)-1-(2,2-dioxide-1H-spiro[benzo[c]isothiazole-3,1'-cyclopropane]-5-yl)-3-hydroxy-2-oxopyrrolidine-3-carboxamide (20)

[0339] [ka]

[0340] [ka]

[0341] Step 1: Under nitrogen atmosphere, LiHMDS (1M, 4.5 mL, 4.5 mmol) was slowly added to a mixture of compound 18-3 (550 mg, 1.45 mmol) and compound 20-1 (327.9 mg, 2.91 mmol) in anhydrous THF (5 mL) at -78 °C. The mixture was then stirred at -78 °C for 1 h. After completion of the reaction, the mixture was diluted with EtOAc, quenched by adding ice water, and separated. The organic layer was washed with brine and anhydrous Na 2 SO 4 The mixture was dried over 100 ml and concentrated. The crude product was purified by silica gel column (eluted with 2% EtOAc in petroleum ether) to give compound 20-2 (203 mg, 34% yield) as a yellow oil. TLC (petroleum ether: EtOAc / 20:1): R f (Compound 18-3)=0.2;R f (Compound 20-2)=0.3.

[0342] Step 2: Compound 20-2 (287 mg, 0.71 mmol), compound 12-6 (145 mg, 0.92 mmol), compound 13-2 (100 mg, 0.71 mmol), CuI (135 mg, 0.71 mmol), and K were dissolved in anhydrous dioxane (4 mL) under a nitrogen atmosphere. 3 PO 4 (452 mg, 2.13 mmol) was stirred at 115° C. for 3.5 h. After the reaction was completed, the mixture was filtered. The filtrate was diluted with water (30 mL) and extracted with EtOAc (30 mL×2). The organic layer was washed with brine and anhydrous Na 2 SO 4 The mixture was dried over 100 ml and concentrated. The crude product was purified by column (eluted with 30% EtOAc in petroleum ether) to give compound 20-3 (209 mg, 61% yield) as a yellow oil. TLC (petroleum:EtOAc / 2:1):R f (Compound 20-2)=0.7;R f (Compound 20-3)=0.3.

[0343] Step 3: To a mixture of compound 20-3 (204 mg, 0.42 mmol) in EtOH (1.0 mL) and THF (0.5 mL), 2 LiOH H in O (1.0 mL) 2 A solution of 2,4-dichloromethane (35.6 mg, 0.85 mmol) was added. The reaction was stirred at 0° C. for 1 h. The mixture was concentrated and acidified to pH=3 with 1N HCl, then extracted with EtOAc (20 mL×2). The organic layer was washed with brine and anhydrous Na 2 SO 4 After drying and concentration, the title compound 20-4 (143 mg, 74% yield) was obtained as a yellow oil. TLC (DCM:MeOH / 20:1):R f (Compound 20-3)=0.4;R f (Compound 20-4)=0.1.

[0344] Step 4: A mixture of compound 20-4 (128 mg, 0.28 mmol), DIPEA (0.15 mL, 0.85 mmol), and compound 5-1 (54.1 mg, 0.31 mmol), HOBt (38.2 mg, 0.28 mmol), and EDCI (162.1 mg, 0.85 mmol) in anhydrous DCM (4 mL) was stirred at room temperature for 2 h. After completion of the reaction, the mixture was diluted with EtOAc and washed with 1N HCl and brine. The organic layer was extracted with anhydrous Na 2 SO 4 The crude product was purified by preparative TLC (SiO 2 , DCM:MeOH / 20:1) to give compound 20-5 (120 mg, 71% yield) as a yellow oil. f (Compound 20-4)=0.1;R f (Compound 20-5)=0.4.

[0345] Step 5: Compound 20-5 (115 mg, 0.19 mmol) and CeCl in isopropanol (2 mL) 3 7H 2 A mixture of 2,4-dimethylformamide (36 mg, 0.10 mmol) and 1,2,3-tetrahydrofuran (1H, 1H) was stirred at 70° C. under oxygen for 1 h. After completion of the reaction, the mixture was concentrated. The crude product was analyzed by preparative TLC (SiO 2 , DCM:MeOH / 20:1) to give compound 20-6 (70 mg, 59% yield) as a yellow oil. f (Compound 20-5)=0.5;R f (Compound 20-6)=0.4.

[0346] Step 6: To a solution of compound 20-6 (65 mg, 0.11 mmol) in EtOAc (0.5 mL) was added a solution of HCl in EtOAc (4N, 0.5 mL). After stirring at room temperature for 2 h, the mixture was concentrated. The residue was redissolved in MeOH (1 mL) and diluted with NH 3 H 2 The mixture was treated with 200 mL of 1H2O (1 mL). The mixture was then stirred at room temperature for 16 h. After completion of the reaction, the mixture was concentrated. The residue was purified by preparative HPLC (C18 column, acetonitrile / H2O). 2The mixture was purified by elution with O and TFA conditions. The desired component was lyophilized to give 20-7 (16 mg, 31% yield) as a white powder. 1 H NMR (600 MHz, DMSO-d 6 )δ10.69(s,1H),8.71(t,J=6.4 Hz,1H),7.63(dd,J=8.6,2.3 Hz,1H),7.27(dt,J=8.8,2.3 Hz,1H),7.23-7.15(m,2H),7.10(d,J=9.2 Hz,1H),6.89(d,J=8.6 Hz,1H),6.73(s,1H),4.37(dd,J=15.7,6.7 Hz,1H),4.25(dd,J=15.7,6.0 Hz,1H),3.85-3.77(m,2H),2.57(ddd,J=12.2,7.0,4.7 Hz,1H),2.10(dt,J=13.0,7.6 Hz,1H),1.77(q,J=5.2 Hz,2H),1.63(d,J=2.9 Hz,2H).LCMS:C 21 H 19 ClFN 3 O 5 m / z calculated for S: 479.91; Found: 480.69. [M+H] + .

[0347] Step 7: Similar to the chiral separation procedure of compounds 1 and 1a, compound 20-7 was applied to a Chiralcel OD column to give compounds 20 and 20a.

[0348] Example 21. N-(3-chloro-5-fluorobenzyl)-3-hydroxy-2-oxo-1-(5H-pyrrolo[2,3-b]pyrazin-2-yl)pyrrolidine-3-carboxamide (21)

[0349] [ka]

[0350] [ka]

[0351] Step 1: To a solution of compound 21-1 (1 g, 5.05 mmol) in DMF (15 mL) was added 60% NaH (282.8 mg, 7.07 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Then, SEMCl (1.1 g, 6.56 mmol) was added to the mixture at 0 °C, warmed to room temperature, and stirred for 2 h. The reaction was quenched with water. The mixture was extracted with ethyl acetate (3 * 30 mL). The combined organics were washed with brine (100 mL * 4), dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting residue was purified by column chromatography (15% EtOAc in petroleum ether) to give compound 21-2 (1.2 g) as a yellow solid.

[0352] Step 2: To a solution of 21-2 (700 mg, 2.13 mmol) in toluene (12 mL) was added ethyl 2-oxopyrrolidine-3-carboxylate 12-6 (368.57 mg, 2.35 mmol), Pd 2 (dba) 3 (97 mg, 0.11 mmol), Xantphos (74 mg, 0.14 mmol), and Cs 2 CO 3 (2.1 g, 6.48 mmol) was added. The reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (3*20 mL). The combined organics were washed with brine (50 mL*4), dried over sodium sulfate, filtered and concentrated by rotary evaporation. The resulting residue was purified by column chromatography (20% EtOAc in petroleum ether) to give compound 21-3 (450 mg) as a white solid.

[0353] Step 3: A solution of compound 21-3 (450 mg, 1.11 mmol) in EtOH / H 2 The mixture was dissolved in 21-3H2O (8 mL / 3 mL) and LiOH (79.9 mg, 3.33 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. The combined organics were concentrated by rotary evaporation to give compound 21-4 (400 mg) as a yellow solid.

[0354] Step 4: To a solution of compound 21-4 (400 mg, 1.06 mmol) in DMF (7 mL) was added compound 5-1 (187 mg, 1.17 mmol), HATU (604.2 mg, 1.59 mmol) and DIEA (439 mg, 3.18 mmol). The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction mixture was monitored by TLC. The reaction was quenched with water (15 mL). The mixture was extracted with ethyl acetate (3*20 mL). The combined organics were washed with brine (60 mL*4), dried over sodium sulfate, filtered and concentrated by rotary evaporation. The resulting residue was purified by column chromatography to give compound 21-5 (400 mg) as a white solid.

[0355] Step 5: A solution of compound 21-5 (200 mg, 0.39 mmol) was dissolved in TFA / DCM (2 mL / 4 mL) with N 2 The reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated by rotary evaporation. The reaction was then diluted with NH 3 *H 2 O / DCM (5 mL / 5 mL) was added. The reaction mixture was stirred at room temperature for 12 h. The combined organics were concentrated by rotary evaporation to give compound 21-6 (100 mg) as a white solid.

[0356] Step 6: To a solution of compound 21-6 (100 mg, 0.26 mmol) in IPA (5 mL), CeCl 3 *7H 2 O (67.5 mg, 0.18 mmol) 2 The reaction mixture was stirred at 70° C. for 12 h. The mixture was filtered through a pad of Celite and washed with EtOAc (20 mL). The filtrate was concentrated and the residue was purified by preparative HPLC to give 21 (26.9 mg) as a white solid. 1 H NMR (400 MHz, CD 3OD) δ8.77(s,1H),8.06(d,J=2.8 Hz,1H),7.93(s,1H),6.93(d,J=6.5 Hz,2H),6.86(d,J=2.9 Hz,1H),6.79(t,J=9.1 Hz,1H),4.52(d,J=15.7 Hz,1H),4.36(d,J=15.7 Hz,1H),4.14(t,J=6.7 Hz,2H),2.81(dd,J=13.1,7.1 Hz,1H),2.42-2.31(m,1H).

[0357] Example 22. N-(3,5-difluorobenzyl)-3-hydroxy-2-oxo-1-(1H-pyrrolo[2,3-c]pyridin-5-yl)pyrrolidine-3-carboxamide (22)

[0358] [ka]

[0359] [ka]

[0360] Step 1: To a solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine 22-1 (1 g, 5.08 mmol) in DMF (15 mL) was added 60% NaH (0.325 g, 8.12 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Then, SEMCl (1.1 g, 6.5 mmol) was added to the mixture at 0 °C. The reaction was then warmed to room temperature and stirred for 2 h. The reaction was quenched with water. The mixture was extracted with ethyl acetate (3 * 200 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting residue was purified by column chromatography to give compound 22-2 (1.7 g) as a yellow oil, which partially solidified under vacuum.

[0361] Step 2: To a solution of 22-2 (600 mg) in toluene (10 mL), ethyl 2-oxopyrrolidine-3-carboxylate 12-6 (511 mg), Pd 2(dba) 3 (90mg), Xantphos (176mg), and Cs 2 CO 3 (1.55g) was added. The reaction mixture was stirred at 100°C for 36 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (3*100mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The resulting residue was purified by column chromatography to give compound 22-3 (310mg) as a white solid.

[0362] Step 3: A solution of compound 22-3 (270 mg) was dissolved in EtOH / H 2 The mixture was dissolved in 2H2O (4 mL / 2 mL) and LiOH (56 mg) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. The combined organics were concentrated by rotary evaporation to give compound 22-4 (250 mg) as a yellow solid.

[0363] Step 4: A solution of compound 22-4 (250 mg) was dissolved in DMF (4 mL) and compound 1-4 (123 mg), HATU (380 mg) and DIEA (257 mg) were added. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction mixture was monitored by TLC. The reaction was quenched with water. The mixture was extracted with ethyl acetate (3*200 mL). The combined organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The resulting residue was purified by column chromatography to give compound 22-5 (390 mg) as a white solid.

[0364] Step 5: A solution of compound 22-5 (390 mg) was dissolved in TFA / DCM (10 mL / 5 mL) with N 2 The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated by rotary evaporation. The reaction was then diluted with NH 3 *H 2 O / DCM (5 mL / 5 mL) was added. The reaction mixture was stirred at room temperature for 12 h. The combined organics were concentrated by rotary evaporation to give compound 22-6 (215 mg) as a yellow solid.

[0365] Step 6: To a solution of compound 22-6 (215 mg) in IPA (5 mL), CeCl 3 *7H 2 O (108 mg) 2. The reaction mixture was stirred at 70° C. for 12 h. The reaction residue was purified by preparative HPLC to give 22 (80 mg) as a white solid. 1 H NMR (400 MHz, cd 3 od)δ8.77(s,1H),8.06(d,J=2.8 Hz,1H),7.93(s,1H),6.93(d,J=6.5 Hz,2H),6.86(d,J=2.9 Hz,1H),6.79(t,J=9.1 Hz,1H),4.52(d,J=15.7 Hz,1H),4.36(d,J=15.7 Hz,1H),4.14(t,J=6.7 Hz,2H),2.81(dd,J=13.1,7.1 Hz,1H),2.42-2.31(m,1H).

[0366] Example 23. 2-(3-(3,5-difluorobenzylcarbamoyl)-3-hydroxy-2-oxopyrrolidin-1-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide (23)

[0367] [ka]

[0368] [ka]

[0369] Step 1: To a solution of compound 23-1 (1 g, 5.5 mmol) in DMF (12 mL) was added 60% NaH (0.375 g, 9.4 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Then, SEMCl (1.2 g, 7.2 mmol) was added to the mixture at 0 °C. The reaction was then warmed to room temperature and stirred for 2 h. The reaction was quenched with water. The mixture was extracted with ethyl acetate (3 * 20 mL). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting residue was purified by column chromatography (10% EtOAc in petroleum) to give compound 23-2 (1.55 g) as a yellow oil, which partially solidified under vacuum. TLC (petroleum ether: EtOAc, 10:1): Rf (23-2) = 0.7.

[0370] Step 2: NBS (178 mg, 1.6 mmol) was added to a solution of compound 23-2 (500 mg, 1.6 mmol) in THF (10 mL) at 0 °C, then the mixture was stirred at 30 °C for 2 h. LCMS showed the reaction mixture was completed, and the mixture was washed with H2O (20 mL) and extracted with EtOAc (20 mL * 2). The combined organic layer was dried over anhydrous Na2SO4, concentrated under vacuum, and purified by column chromatography (10% EtOAc in petroleum) to give compound 23-3 (600 mg) as a yellow solid. TLC (petroleum ether: EtOAc, 10:1): Rf (23-3) = 0.7.

[0371] Step 3: To a solution of compound 23-3 (600 mg, 1.54 mmol) in dioxane (15 mL) was added ethyl 2-oxopyrrolidine-3-carboxylate 12-6 (290 mg, 1.84 mmol), CuI (146 mg, 0.77 mmol), DMEDA (54 mg, 0.616 mmol), and K 3 PO 4 (980 mg, 4.62 mmol) 2The reaction mixture was stirred at 120°C for 3 hours. The reaction mixture was filtered through Celite, washed with ethyl acetate, then the organic layer was quenched with water and extracted with ethyl acetate (3*30mL). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting residue was purified by column chromatography (25% EtOAc in petroleum ether) to give compound 23-4 (270mg) as a yellow solid. TLC (petroleum ether: EtOAc, 3:1): Rf(23-4)=0.5.

[0372] Process 4: LiOH·H 2 O (56 mg, 1.34 mmol) in MeOH / H 2 To a solution of compound 23-4 (270 mg, 0.54 mmol) in 203O / THF (2 mL / 2 mL / 1 mL) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The combined organics were concentrated by rotary evaporation to give compound 23-5 (250 mg) as a yellow solid. TLC (CH 2 Cl 2 :MeOH, 10:1):Rf(23-5)=0.2.

[0373] Step 5: To a solution of compound 23-5 (250 mg, 0.54 mmol) in DMF (5 mL) was added compound 1-4 (86 mg), HATU (246 mg) and DIEA (210 mg). The reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water. The mixture was extracted with ethyl acetate (3*20 mL). The combined organics were washed with water and brine, dried over sodium sulfate and concentrated by rotary evaporation. The resulting residue was purified by column chromatography (50% EtOAc in petroleum ether) to give compound 23-6 (150 mg) as a white solid. TLC (petroleum ether: EtOAc, 1:1): Rf (23-6) = 0.3.

[0374] Process 5:AlMe 3(1M in hexane, 0.8 mL) was added to a solution of compound 23-6 (150 mg, 0.27 mmol) and NH4Cl (200 mg, 2.7 mmol) in toluene (5 mL) and the mixture was stirred at 50 °C for 18 h, TLC showed 50% conversion and conversion did not improve with time. The mixture was quenched with water. The mixture was extracted with ethyl acetate (3 * 10 mL). The combined organics were washed with water, dried over sodium sulfate and concentrated under vacuum. The resulting residue was analyzed by preparative TLC (CH 2 Cl 2 in 10% MeOH) to give compound 23-7 (70 mg) as a yellow oil. 2 Cl 2 :MeOH, 10:1):Rf(23-7)=0.7.

[0375] Step 6: To a solution of compound 23-7 (70 mg) in IPA (2 mL), CeCl 3 *7H 2 O (110 mg, 0.3 mmol) 2 The reaction mixture was stirred at 70°C for 12 hours. The mixture was quenched with water. The mixture was extracted with ethyl acetate (3*10mL). The combined organics were washed with water, dried over sodium sulfate and concentrated under vacuum. The resulting residue was analyzed by preparative TLC (CH 2 Cl 2 Medium 10%CH 3 OH) to give 23-8 (40 mg) as a yellow oil. 2 Cl 2 :MeOH, 10:1):Rf(23-8)=0.5.

[0376] Step 7: TBAF (1M in THF, 2 mL) was added to compound 23-8 (40 mg) and the mixture was stirred at 50 °C for 24 h. The mixture was concentrated in vacuo and analyzed by preparative TLC (CH 2 Cl 2 Medium 10%CH 3 OH) and further purified by preparative HPLC to give compound 23 (7 mg) as a white solid. 1 H NMR (400 MHz, CD 3OD) δ8.82(s,1H),6.88-6.96(d,J=10.4 Hz,3H),6.79(s,1H),6.66(s,1H),4.42(dd,J=15.6,6.0 Hz,2H),4.06-3.88(m,2H),2.75-2.80(m,1H),2.24-2.33(m,1H).LCMS:m / z 435.25[M+1],433.20[M-1];

[0377] Example 24. Methionine aminopeptidase 2 enzyme activity assay

[0378] MetAP-2 activity was measured by an enzyme-coupled assay using the tripeptide Met-Ala-Ser (MAS) and recombinant human MetAP-2 (His-Tev-MetAP-2, prepared in-house) as substrates. The released methionine is converted to Met ox by L-amino acid oxidase (AAO) with the release of hydrogen peroxide. In a second step, horseradish peroxidase catalyzes the oxidation of the leuco dye dianisidine to dianisidine ox with hydrogen peroxide as a cosubstrate. The dianisidine ox produced was detected photometrically as an increase in absorbance at 450 nm. MetAP-2 activity was measured in a kinetic measurement mode. The release of one molecule of methionine corresponds to the production of one molecule of dianisidine ox. MetAP-2 enzyme activity corresponds directly to the increase in absorbance per hour.

[0379] IC of Methionine Aminopeptidase 2 Assay 50 are shown in Table 4.

[0380] [Table 4]

[0381] Pharmaceutical Formulations (A) Injection vials: A solution of 100 g of the active ingredient according to the invention and 5 g of disodium hydrogen phosphate in 3 liters of double distilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilized under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of the active ingredient.

[0382] (B) Suppositories: A mixture of 20 g of an active ingredient according to the invention is dissolved with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and cooled. Each suppository contains 20 mg of active ingredient.

[0383] (C) Solution: The solution is 1 g of the active ingredient according to the invention, 9.38 g of NaHCO in 940 mL of double distilled water. 2 PO 4 2H 2 O, 28.48g Na 2 HPO 4 12H 2 It is prepared from 0.01 g and 0.1 g of benzalkonium chloride. The pH is adjusted to 6.8, the solution is made up to 1 liter and sterilized by irradiation. This solution can be used in the form of eye drops.

[0384] (D) Ointment: 500 mg of an active ingredient according to the invention are mixed under sterile conditions with 99.5 g of petrolatum.

[0385] (E) Tablets: A mixture of 1 kg of the active ingredient according to the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc, and 0.1 kg of magnesium stearate is compressed in a conventional manner to give tablets, each tablet containing 10 mg of the active ingredient.

[0386] (F) Coated tablets: Tablets are compressed as in Example E and then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth, and dye.

[0387] (G) Capsules: 2 kg of the active ingredient according to the invention are placed into hard gelatin capsules in a conventional manner so that each capsule contains 20 mg of the active ingredient.

[0388] (H) Ampoules: a solution of 1 kg of the active ingredient according to the invention in 60 liters of double distilled water is sterile filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions, each ampoule containing 10 mg of the active ingredient.

[0389] (I) Inhalation spray: 14 g of the active ingredient according to the invention are dissolved in 10 liters of isotonic NaCl solution and the solution is transferred into a commercially available spray container equipped with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 mL) corresponds to a dose of approximately 0.14 mg.

[0390] While numerous embodiments of the invention are described herein, it will be apparent that the basic examples can be modified to provide other embodiments which utilize the compounds and methods of the invention. It will therefore be appreciated that the scope of the invention is to be defined by the appended claims rather than by the specific embodiments which have been represented by way of example.

[0391] Applicant's disclosure is described herein in a preferred embodiment with reference to the drawings, in which like numbers represent the same or similar elements. Reference throughout this specification to "one embodiment," "an embodiment," or similar terminology means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Thus, appearances of the phrases "in one embodiment," "in an embodiment," and similar phrases throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0392] The described features, structures, or characteristics of the applicant's disclosure may be combined in any suitable manner in one or more embodiments. In the description herein, many specific details are set forth to provide a thorough understanding of the embodiments of the present invention. However, one of ordinary skill in the art will recognize that the applicant's compositions and / or methods may be practiced without one or more specific details, or with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations have not been shown or described in detail to avoid obscuring aspects of the present disclosure.

[0393] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0394] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, the preferred methods and materials are described herein. The methods described herein can be carried out in any order that is logically possible, in addition to the specific order disclosed.

[0395] Incorporation by Reference In this disclosure, references and citations are made to other documents, such as patents, patent applications, patent publications, journals, books, papers, web content, etc. All such documents are incorporated herein by reference in their entirety for all purposes. Any material or portion thereof that is said to be incorporated herein by reference but that conflicts with existing definitions, descriptions, or other disclosure materials expressly set forth herein is incorporated only to the extent that there is no conflict between the incorporated material and the present disclosure material. In the event of a conflict, the conflict shall be resolved as the disclosure prevailing in this disclosure.

[0396] Equivalent The representative examples are intended to illustrate the invention and are not intended, and should not be construed, as limiting the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the entire contents of this document, including the examples and references to the scientific and patent literature contained herein. The examples contain important additional information, exemplification and guidance that can be applied to the practice of this invention in its various embodiments and equivalents thereof.

Claims

1. Structural formula (I) 【Chemistry 1】 (In the formula, R １ and R ２ are independently selected from F, Cl, Br, and I; Q is, (a) an unsubstituted or substituted 5- or 6-membered aromatic ring, or (b) an unsubstituted or substituted 5- or 6-membered aromatic ring fused to a second unsubstituted or substituted 5- or 6-membered ring, or a pharma- ceutically acceptable form or isotopic derivative thereof.

2. (I Ａ Structural formula of 【Chemistry 2】 2. The compound of claim 1, having the formula:

3. Q is an unsubstituted or substituted 5- or 6-membered aromatic ring Q １ and the compound has the structural formula (I Ａ １ ) 【Chemistry 3】 3. The compound of claim 2, having the formula:

4. Q １ is a substituted 6-membered aromatic ring, and the compound has the following structural formula (II A ): 【Chemistry 4】 (In the formula, X is N or CH; Each of Y 1 and Y 2 is independently N or CH, provided that when one of Y 1 and Y 2 is N, the other is CH; R 3 is a group containing a P(═O)(R′)(R″) or S(R′)(R″)(R′″) group; Each of R', R" and R'" is independently selected from H and C 1-6 alkyl, or a pharma- ceutically acceptable form or isotopic derivative thereof.

5. R 3 is in the para position, and the compound has the structural formula (II A 1 ): 【Chemistry 5】 5. The compound of claim 4, having the formula:

6. R 3 is in the meta position, and the compound has the structural formula (II A 2 ): 【Chemistry 6】 5. The compound of claim 4, having the formula:

7. The compound according to any one of claims 4 to 6, or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein each of X, Y1 and Y2 is CH.

8. The compound according to any one of claims 4 to 6, wherein X is CH, Y 1 is CH and Y 2 is N, or a pharma- ceutically acceptable form or isotopic derivative thereof.

9. Q is a substituted or unsubstituted 5- or 6-membered aromatic ring Q 1 fused to a second 5- or 6-membered ring Q 2 , and the compound has the structural formula (I A 2 ): 【Chemistry 7】 3. The compound of claim 2, having the formula:

10. Q 1 is a 6-membered aromatic ring, Q 2 is a 5-membered ring, and the compound has the following structural formula (III A ): 【Chemistry 8】 (In the formula, X is N or CH; Each of Y 1 and Y 2 is independently N or CH, provided that when one of Y 1 and Y 2 is N, the other is CH; Z 1 is NH or CH 2 ; Z 2 is C═O, S(═O) 2 , CR′ or CR′R″, where R′ and R″ are independently H or C 1-3 alkyl; -- is absent when Z 2 is C═O, S(═O) 2 or CR′R″, or represents a bond when Z 2 is CR′ and R 5 is absent; 10. The compound of claim 9, or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein R4 and R5, if present, are independently selected from H and C1-6 alkyl, and optionally R4 and R5, together with the carbon atom to which they are attached, form a 3-6 membered aliphatic ring.

11. Z 1 is NH and Z 2 is CH, and the compound has the structural formula (III A 1 ): 【Chemistry 9】 11. The compound of claim 10, having the formula:

12. Z 1 is NH and Z 2 is CH 2 , and the compound has the structural formula (III A 2 ): 【Chemistry 10】 11. The compound of claim 10, having the formula:

13. Z 1 is NH, Z 2 is C═O, and the compound has the structural formula (III A 3 ): 【Chemistry 11】 11. The compound of claim 10, having the formula:

14. Z 1 is NH, Z 2 is S(═O) 2 , and the compound has the structural formula (III A 4 ): 【Chemistry 12】 11. The compound of claim 10, having the formula:

15. The compound according to any one of claims 10 to 14, or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein each of X, Y1 and Y2 is CH.

16. The compound according to any one of claims 10 to 14, wherein X is CH, Y 1 is CH and Y 2 is N, or a pharma- ceutically acceptable form or isotopic derivative thereof.

17. Q 1 is a 5-membered aromatic ring, Q 2 is a 5-membered ring, and the compound has the following structural formula (IV A ): 【Chemistry 13】 (In the formula, Y is S or O; Z is independently N or CH; R 6 is H, alkyl, COOH, or an amide group, or a pharma- ceutically acceptable form or isotopic derivative thereof.

18. The compound of claim 17, or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein Y is S and Z is NH.

19. The structural formula of (IB) 【Chemistry 14】 2. The compound of claim 1, having the formula:

20. Q is an unsubstituted or substituted 5- or 6-membered aromatic ring Q 1 , and the compound has the structural formula (IB 1 ): 【Chemistry 15】 20. The compound of claim 19, having the formula:

21. Q 1 is a substituted 6-membered aromatic ring, and the compound has the following structural formula (II A ): 【Chemistry 16】 (In the formula, X is N or CH; Each of Y 1 and Y 2 is independently N or CH, provided that when one of Y 1 and Y 2 is N, the other is CH; R 3 is a group containing a P(═O)(R′)(R″) or S(R′)(R″)(R′″) group; 21. The compound of claim 20, having the formula: wherein each of R', R'', and R''' is independently selected from H and C 1-6 alkyl, or a pharma- ceutically acceptable form or isotopic derivative thereof.

22. R 3 is in the para position, and the compound has the structural formula (II B 1 ): 【Chemistry 17】 22. The compound of claim 21 , having the formula:

23. R 3 is in the meta position, and the compound has the structural formula (II B 2 ): 【Chemistry 18】 22. The compound of claim 21 , having the formula:

24. The compound of any one of claims 21 to 23, or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein each of X, Y1 and Y2 is CH.

25. The compound of any one of claims 21 to 23, wherein X is CH, Y 1 is CH, and Y 2 is N, or a pharma- ceutically acceptable form or isotopic derivative thereof.

26. Q is a substituted or unsubstituted 5- or 6-membered aromatic ring Q 1 fused to a second 5- or 6-membered ring Q 2 , and the compound has the structural formula (IB 2 ): 【Chemistry 19】 20. The compound of claim 19, having the formula:

27. ​​Q 1 is a 6-membered aromatic ring, Q 2 is a 5-membered ring, and the compound has the following structural formula (III B ): 【Chemistry 20】 (In the formula, X is N or CH; Each of Y 1 and Y 2 is independently N or CH, provided that when one of Y 1 and Y 2 is N, the other is CH; Z 1 is NH or CH 2 ; Z 2 is C═O, S(═O) 2 , CR′ or CR′R″, where R′ and R″ are independently H or C 1-3 alkyl; -- is absent when Z 2 is C═O, S(═O) 2 or CR′R″, or represents a bond when Z 2 is CR′ and R 5 is absent; R 4 and R 5 , when present, are independently selected from H and C 1-6 alkyl, and optionally R 4 and R 5 together with the carbon atom to which they are attached form a 3-6 membered aliphatic ring.

27. The compound of claim 26, having the formula:

28. Z 1 is NH, Z 2 is CH, and the compound has the structural formula (III B 1 ): 【Chemistry 21】 28. The compound of claim 27, having the formula:

29. Z 1 is NH, Z 2 is CH 2 , and the compound has the structural formula (III B 2 ): 【Chemical 22】 28. The compound of claim 27, having the formula:

30. Z 1 is NH, Z 2 is C═O, and the compound has the structural formula (III B 3 ): 【Chemistry 23】 28. The compound of claim 27, having the formula:

31. Z 1 is NH, Z 2 is S(═O) 2 , and the compound has the structural formula (III B 4 ): 【Chemistry 24】 28. The compound of claim 27, having the formula:

32. The compound of any one of claims 27 to 31, or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein each of X, Y1 and Y2 is CH.

33. The compound of any one of claims 27 to 31, wherein X is CH, Y 1 is CH, and Y 2 is N, or a pharma- ceutically acceptable form or isotopic derivative thereof.

34. Q 1 is a 5-membered aromatic ring, Q 2 is a 5-membered ring, and the compound has the following structural formula (IV B ): 【Chemistry 25】 (In the formula, Y is S or O; Z is independently N or CH; R 6 is H, alkyl, COOH, or an amide group, or a pharma- ceutically acceptable form or isotopic derivative thereof.

35. The compound of claim 34, or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein Y is S and Z is NH.

36. Below 【Table 1-1】 【Table 1-2】 2. The compound of claim 1 selected from:

37. A pharmaceutical composition comprising a compound according to claim 1 or 36 and a pharma- ceutically acceptable excipient, carrier or diluent.

38. Use of a compound according to claim 1 or 36, and a pharma- ceutically acceptable excipient, carrier, or diluent, in the preparation of a medicament for treating cancer, obesity, diabetes, rheumatoid arthritis, psoriasis, or a disease or condition related thereto.

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