Process for synthesis of complement factor D inhibitors and intermediates thereof

Abstract

The present disclosure provides methods for the synthesis of complement factor D inhibitors and intermediates thereof.

Description

Background Technology

[0001] The complement system is part of the innate immune system, which does not adapt to changes in the host's life processes but is recruited and used by the adaptive immune system. For example, it assists or complements the ability of antibodies and phagocytes to clear pathogens. This complex regulatory pathway allows for a rapid response to pathogenic objects while simultaneously protecting host cells from damage. More than thirty proteins and protein fragments constitute the complement system. These proteins function through opsonization (enhancing the phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing the membranes of foreign cells), and aggregation (pathogens assembling and binding together).

[0002] The complement system has three pathways: the classical pathway, the alternative pathway, and the lectin pathway. Complement factor D plays an early and central role in the activation of the alternative pathway within the complement cascade. Activation of the alternative complement pathway is initiated by the spontaneous hydrolysis of the thioester bond within the C3 protein to produce C3(H2O), which associates with factor B to form the C3(H2O)B complex. Complement factor D acts to cleave factor B within the C3(H2O)B complex to form Ba and Bb. The Bb fragment remains associated with C3(H2O) to form the alternative pathway C3 convertase C3(H2O)Bb. Additionally, C3b generated from any C3 convertase also associates with factor B to form C3bB, which is cleaved by factor D to generate the later alternative pathway C3 convertase C3bBb. The latter form of the alternative pathway, C3 convertase, provides important downstream amplification within all three identified complement pathways, ultimately leading to the recruitment and assembly of additional factors in the complement cascade pathway, including the cleavage of C5 into C5a and C5b. C5b plays a role in the assembly of factors C6, C7, C8, and C9 into a membrane attack complex, which can destroy pathogenic cells by lysing cells.

[0003] Dysfunction or overactivation of complement has been associated with certain autoimmune diseases, inflammatory diseases, neurodegenerative diseases, ischemia-reperfusion injury, and cancer. For example, activation of the alternative pathway of the complement cascade contributes to the production of C3a and C5a (both potent anaphylatoxins), which also play a role in many inflammatory conditions. Therefore, in some cases, it is desirable to reduce the response of the complement pathway, including the alternative complement pathway. Some examples of conditions mediated by the complement pathway include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and rheumatoid arthritis.

[0004] Additional complement-mediated disorders include those classified as component 3 glomerulonephropathy (C3G). C3G is a recently defined entity consisting of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), which encompasses a population of chronic kidney diseases in which increased activity of the alternative complement pathway and the terminal complement pathway results in glomerular deposits made solely by complement C3 without immunoglobulins (Ig).

[0005] Immunocomplex membranoproliferative glomerulonephritis (IC-MPGN) is a nephropathy that shares many clinical, pathological, genetic, and laboratory features with C3G and can therefore be considered a sister disease of C3G. In most patients with IC-MPGN, an underlying disease or condition has been identified—most commonly infection, autoimmune disease, or monoclonal gammaglobulinosis—from which the nephropathy is secondary. Patients with idiopathic IC-MPGN may have low C3 and normal C4 levels, similar to those observed in C3G, as well as many of the same genetic or acquired factors associated with aberrant alternative pathway activity. Although there is a current hypothesis that most IC-MPGN is attributable to overactivity of the classical pathway, those with low C3 and normal C4 may have significant overactivity of the alternative pathway. Patients with IC-MPGN who have low C3 and normal C4 may benefit from suppression of the alternative pathway.

[0006] Other conditions associated with complement cascade include atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), abdominal aortic aneurysm, complications of hemodialysis, hemolytic anemia or hemodialysis, neuromyelitis optica (NMO), myasthenia gravis (MG), fatty liver, non-alcoholic steatohepatitis (NASH), hepatitis, cirrhosis, liver failure, dermatomyositis, and amyotrophic lateral sclerosis.

[0007] Factor D is an attractive target for inhibiting or modulating complement cascades due to its early and major role in the alternative complement pathway, and its potential role in signal amplification within the classical and lectin complement pathways. Inhibition of factor D effectively disrupts the pathway and attenuates the formation of membrane attack complexes.

[0008] To this end, numerous small molecule factor D inhibitors have been developed and their potential therapeutic uses investigated. Examples of these factor D inhibitory compounds and methods for their preparation are described, for example, in PCT publications WO2015 / 130838, WO2017 / 035353, WO2017 / 035409, WO2018 / 160889, WO2020 / 041301 and WO2021 / 168320.

[0009] New methods for synthesizing small molecule factor D inhibitors and their intermediates are desirable. Summary of the Invention

[0010] This disclosure generally relates to an improved method for preparing compounds that can be used to treat conditions mediated by complement factor D and its intermediates.

[0011] Specifically, this disclosure relates to compounds of formula (VI):

[0012] (VI),

[0013] Where P 1 and P 2 As defined in this paper, it is an intermediate for the synthesis of complement factor D inhibitors of formula (XI):

[0014] (XI),

[0015] Where variable R 1 R 2 R 3 R 4 R 5 R 6 X 1 X 2 X 3 X 4 X 5 m and B are as defined in this article.

[0016] This disclosure is based in part on the unexpected discovery that compounds of formula (VI) can be prepared via cyclopropanation without the use of hazardous reagents (e.g., diethylzinc) required for the Simmons-Smith cyclopropanation reaction. In addition to eliminating the use of hazardous reagents, these methods offer improved cyclopropanation selectivity, the ability to use readily available starting materials, a reduction in the total number of reaction steps required to prepare compounds of formula (VI), and improved yields.

[0017] Therefore, in one aspect, this disclosure provides a method for preparing a compound of formula (VI). The method includes providing a compound of formula (V):

[0018] (V),

[0019] Where P 1 and P 2 As defined herein; and compounds of formula (VI) formed from compounds of formula (V). Formation of compounds of formula (VI) includes contacting compounds of formula (V) with a Co(II) catalyst in the presence of Zn and CH2Br2.

[0020] This document also provides a method for preparing compounds of formula (XI) from compounds of formula (VI) prepared by any of the methods disclosed herein:

[0021] (XI).

[0022] definition

[0023] To facilitate understanding of this disclosure, several terms are defined below. The terms defined herein have meanings commonly understood by one of ordinary skill in the art relating to this disclosure. Terms such as “a,” “an,” and “the,” are not intended to refer only to a singular entity, but rather to include general categories whose specific examples may be used to illustrate the invention. The terms herein are used to describe specific embodiments of the invention, but their use does not limit the invention unless set forth in the claims.

[0024] As used in this article, any value provided within the range includes both the upper and lower limits, as well as any value contained within the upper and lower limits.

[0025] As used herein, the term "pharmaceutically acceptable salt" refers to those salts of the described compound that, to a reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, anaphylactic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (edited by PHStahl and CGWermuth), Wiley-VCH, 2008. These salts can be acid addition salts involving inorganic or organic acids. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or prepared separately by reacting a free base group with a suitable acid. Methods for preparing suitable salts are recognized in the art.

[0026] As used herein, the term "acyl" refers to a monovalent group having the structure -COR, where R is alkyl, alkenyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl. The acyl group may optionally be substituted as defined for each R group.

[0027] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic group containing only C and H when unsubstituted. The monovalent nature of an alkyl group does not include optional substituents on that alkyl group. For example, if an alkyl group is attached to a compound, the monovalent nature of the alkyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl group. In some embodiments, the alkyl group may contain, for example, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 2 carbon atoms (e.g., C1-C1). 12 C1-C 10 (C1-C8, C1-C6, C1-C4, or C1-C2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, and tert-butyl.

[0028] As used herein, the term "alkylene" refers to a divalent group obtained by removing a hydrogen atom from a carbon atom of an alkyl group. The divalent nature of an alkylene group does not include optional substituents on the alkylene group.

[0029] As used herein, the term "alkenyl" refers to a branched or straight-chain monovalent unsaturated aliphatic group containing at least one carbon-carbon double bond and no carbon-carbon triple bond, and containing only C and H when unsubstituted. The monovalent nature of an alkenyl group does not include optional substituents on the alkenyl group. For example, if an alkenyl group is attached to a compound, the monovalent nature of the alkenyl group means that it is attached to the compound and does not include any additional substituents that may be present on the alkenyl group. In some embodiments, the alkenyl group may contain, for example, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms (e.g., C2-C). 12 C2-C 10 (C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, etc.

[0030] As used herein, the term "alkenyloxy" refers to a monovalent group having the structure -O-alkenyl, where "alkenyl" is as defined herein. Examples include, but are not limited to, ethyleneoxy and propyleneoxy.

[0031] As used herein, the term "alkoxy" refers to a monovalent group having the structure -O-alkyl, where "alkyl" is as defined herein. Examples include, but are not limited to, methoxy, ethoxy, and n-butoxy, isobutoxy, tert-butoxy, etc.

[0032] As used herein, the term "alkynyl" refers to a branched or straight-chain monovalent unsaturated aliphatic group containing at least one carbon-carbon triple bond and, when unsubstituted, only containing C and H. The monovalent nature of an alkynyl group does not include optional substituents on the alkynyl group. For example, if an alkynyl group is attached to a compound, the monovalent nature of the alkynyl group means that it is attached to the compound and does not contain any additional substituents that may be present on the alkynyl group. In some embodiments, the alkynyl group may contain, for example, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms (e.g., C2-C). 12 C2-C 10 (C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, ethynyl, 1-propynyl, and 3-butynyl.

[0033] As used herein, the term "aryl" refers to a monovalent monocyclic, fused-ring, bicyclic, or polycyclic system that exhibits aromatic properties in terms of the electron distribution throughout the ring system, such as phenyl, naphthyl, or phenanthrene. The aryl group may have, for example, six to sixteen carbons (e.g., C6-C). 16 Aryl, C6-C 14 Aryl, C6-C 13 Aryl or C6-C 10 Aryl).

[0034] As used herein, the term "aralkyl" refers to a monovalent group having the structure -R'R" where R' is alkylene and R" is aryl. Aralkyl groups may optionally be substituted in the same manner as defined for each R' and R" group.

[0035] As used herein, the term "carbocyclic" refers to a monovalent saturated or unsaturated nonaromatic cyclic group containing only C and H when unsubstituted. Carbocyclic groups (e.g., cycloalkyl or cycloalkenyl) may have, for example, three to fourteen carbons (e.g., C3-C7, C3-C8, C3-C9, C3-C10, C3-C2 ... 10 C3-C 11 C3-C 12 C3-C 14 (Carbocyclic group). The term "carbocyclic group" also includes bicyclic and polycyclic (e.g., tricyclic and tetracyclic) fused ring structures.

[0036] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkyl" also includes cyclic groups having a bridging polycyclic structure, wherein one or more carbons bridge two non-adjacent members of a monocyclic ring, such as bicyclic [2.2.1]heptyl and adamantyl. The term "cycloalkyl" also includes bicyclic, tricyclic, and tetracyclic fused-ring structures, such as naphthanes and spirocyclic compounds.

[0037] As used herein, the term "cyano" refers to a monovalent group having the structure -CN.

[0038] As used herein, the term "cycloalkenyl" refers to a monovalent unsaturated carbocyclic group comprising at least one carbon-carbon double bond, no carbon-carbon triple bonds, containing only C and H when unsubstituted, and not being entirely aromatic. Cycloalkenyl groups can have, for example, four to fourteen carbons (e.g., C4-C7, C4-C8, C4-C9, C4-C10, C4-C2 ... 10 C4-C 11 C4-C 12 C4-C 13 Or C4-C 14 Cycloalkenyl groups. Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. The term "cycloalkenyl" also includes cyclic groups having a bridging polycyclic structure, wherein one or more carbons bridge two non-adjacent members of a monocyclic ring, such as bicyclo[2.2.2]oct-2-ene. The term "cycloalkenyl" also includes fused-ring bicyclic and polycyclic systems containing one or more double bonds, such as fluorene.

[0039] As used herein, the term "halogenated" refers to a fluorine (fluorinated), chlorine (chloroinated), bromine (brominated), or iodine (iodinated) group.

[0040] As used herein, the term “heteroaryl” refers to a monovalent group of the structure -R'R”, where R' is an alkylene group and R” is a heteroaryl group. Heteroaryl groups may optionally be substituted in the same manner as defined for each R' and R” group.

[0041] As used herein, the term "heterocyclic group" refers to a saturated or unsaturated monocyclic or fused-ring bicyclic or polycyclic system having one or more carbon atoms and at least one heteroatom, such as one to four heteroatoms selected from N, O, and S (e.g., one to four, one to three, one or two, one, two, three, or four heteroatoms). Heterocyclic groups include both non-aromatic and aromatic systems. Aromatic heterocyclic groups are referred to as "heteroaryl" groups. In some embodiments, the heterocyclic group is a 3- to 8-membered ring system, a 3- to 6-membered ring system, a 4- to 6-membered ring system, a 4- to 10-membered ring system, a 6- to 10-membered ring system, a 6- to 12-membered ring system, a 5-membered ring, or a 6-membered ring, or a ring or ring system having a number of ring atoms falling within any of the above ranges. An exemplary 5-membered heterocyclic group may have zero to two double bonds, and an exemplary 6-membered heterocyclic group may have zero to three double bonds. Exemplary 5-membered groups include, for example, optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted tetrahydrothiophene, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetraazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxtriazole, and optionally substituted 1,2,3,4-thiatriazole. Exemplary 6-membered heterocyclic groups include, but are not limited to, optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, and optionally substituted tetrahydropyran. Exemplary 7-membered heterocyclic groups include, but are not limited to, optionally substituted azirconium, optionally substituted 1,4-diazazolinium, optionally substituted thioheptatriene, and optionally substituted 1,4-thiazazolinium. Exemplary 8- to 10-membered bicyclic groups include, but are not limited to, optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyridinyl, optionally substituted thiazo[5,4-b]pyridinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyridinyl, 1H-thieno[3,2-c]pyrazolyl, imidazo[1,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1H-benzo[d]imidazolyl.

[0042] As used herein, the term "carboxyl protecting group" refers to any group that protects the oxygen atom of the -OH functional group of the carboxyl group from participating in one or more undesirable reactions during chemical synthesis. A carboxyl protecting group is installed by reacting a molecule containing an unprotected carboxyl group with a carboxyl protecting agent, which can be removed by a carboxyl protecting group remover. Carboxyl protecting groups, their corresponding carboxyl protecting agents, and carboxyl protecting group removers suitable for removing carboxyl protecting groups are known in the art, for example, as described in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th edition, 2006. Exemplary carboxyl protecting groups include, but are not limited to, alkyl (e.g., methyl, ethyl, or tert-butyl), benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, pentamethylbenzyl, diphenylmethyl, 3,4-methylenedioxybenzyl, 4,4-dimethoxytriphenylmethyl, 4,4',4"-trimethoxytriphenylmethyl, 2-phenylpropyl, trimethylsilyl, tert-butyldimethylsilyl, benzoylmethyl, 2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, and 1-(trimethylsilylmethyl)propenyl.

[0043] As used herein, the term "N-protecting group" refers to a group that protects a nitrogen atom in a molecule from participating in one or more undesirable reactions during chemical synthesis. N-protecting groups are attached by reacting a nitrogen-containing molecule with an N-protecting reagent and can be removed using N-protecting group removal agents. Commonly used N-protecting groups, their corresponding N-protecting reagents, and N-protecting group removal agents are disclosed in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th edition, 2006. Exemplary N-protecting groups include acyl groups (e.g., formyl, acetyl, trifluoroacetyl, propionyl, p-pentanoyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, and 4-bromobenzoyl); sulfonyl groups (e.g., benzylsulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl); and carbamate-forming groups (e.g., benzyloxycarbonyl, p-chlorobenzeneoxycarbonyl, p-methoxybenzeneoxycarbonyl, p-nitrobenzeneoxycarbonyl, 2-nitrobenzeneoxycarbonyl, p-bromobenzeneoxycarbonyl, 3,4-dimethoxybenzeneoxycarbonyl, 3,5-dimethoxybenzeneoxycarbonyl, 2,4-dimethoxy...). Benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, tert-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorene-9-methoxycarbonyl, cyclopentoxycarbonyl, adamantaneoxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl), aralkyl (e.g., triphenylmethyl); silyl group (e.g., trimethylsilyl); and imine-forming group (e.g., diphenylmethylene). Other examples of N protecting groups include acetyl, benzoyl, benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, o-nitrobenzenesulfonyl, tert-butoxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0044] As used in this article, the term "oxo-group" refers to a divalent oxygen atom represented by the structure =O.

[0045] As used herein, the term “thioalkyl” refers to a monovalent group having the structure -S-alkyl, where “alkyl” is as defined herein.

[0046] As used herein, the phrase “optionally substituted X” is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein the alkyl group is optionally substituted”). It is not intended to imply that the characteristic “X” (e.g., alkyl group) itself is optional. As used herein, the term “optionally substituted” refers to having 0, 1, or more substituents (e.g., 0 to 10, 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, 0 to 3, 0 to 2, 0 or 1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents).

[0047] Alkyl, alkylene, alkenyl, alkynyl, carbocyclic, cycloalkyl, cycloalkenyl, aryl, and heterocyclic groups may be substituted with one or more of the following: carbocyclic, cycloalkyl; cycloalkenyl; aryl; heterocyclic; heteroaryl; halogenated; OH; cyano; alkoxy; alkenyloxy; thioalkyl; NO2; N3; NRR'; wherein each of R and R' is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclic; SO2R, wherein R is H, alkyl, or aryl; SO2NRR', wherein each of R and R' is independently H, alkyl, or aryl; or NRSO2R, wherein R and R' are substituted with H, alkyl, or aryl. ' Each of these groups is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclic. Aryl, carbocyclic, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic groups may also be substituted with alkyl, alkenyl, or alkynyl groups. Alkyl, alkoxy, carbocyclic, cycloalkyl, cycloalkenyl, and unsaturated heterocyclic groups may also be substituted with oxo groups. In some embodiments, the substituents are further substituted as described herein. For example, a C6 aryl group, i.e., a phenyl group, may be substituted with an alkyl group, which may be further substituted with a heterocyclic group. Attached Figure Description

[0048] Figure 1 This is a schematic diagram of a continuous flow apparatus used for synthesizing compound 2d as described in Example 3. Detailed Implementation

[0049] This disclosure provides a method for synthesizing small molecule complement factor D inhibitors and intermediates thereof. Complement factor D inhibitors are compounds of formula (XIII):

[0050] (XIII),

[0051] Or a pharmaceutically acceptable salt thereof, wherein variable R 1 -R 6 X 1 -X 5m and B are as defined herein. Exemplary compounds of formula (XIII) are described in, for example, PCT publications WO2015 / 130838, WO2017 / 035353, WO2017 / 035409, WO2018 / 160889, WO2020 / 041301 and WO2021 / 168320, the entire contents of which are incorporated herein by reference.

[0052] Specifically, the method described herein relates to the preparation of compounds of formula (VI):

[0053] (VI),

[0054] Where P 1 It is protected by an H or N protecting group (e.g., tert-butoxycarbonyl), and P 2 The protecting group is H or a carboxyl group (e.g., an alkyl group, such as methyl). This method involves providing a compound of formula (V):

[0055] (V),

[0056] Where P 1 It is an H or N protecting group, and P 2 It is an H or carboxyl protecting group (e.g., an alkyl group, such as methyl); and a compound of formula (VI) is formed from a compound of formula (V) via a cyclopropanation reaction carried out with a Co(II) catalyst in the presence of Zn and CH2Br2. In some embodiments, the reaction is carried out with a Co(II) catalyst in the presence of Zn, CH2Br2 and ZnCl2.

[0057] In some embodiments, Zn is in the form of zinc powder (e.g., having a particle size of less than 10 micrometers). In some embodiments, Zn (e.g., in the form of zinc powder) is activated (e.g., with HCl). Methods for preparing activated Zn are generally known in the art.

[0058] In some embodiments, Zn is present in an amount of 2 to 10 equivalents (e.g., 3 to 8 equivalents, 4 to 6 equivalents, 3, 4, 5, 6, 7, 8, 9, or 10 equivalents) relative to the compound of formula (V). In some embodiments, Zn is present in an amount of 5 equivalents relative to the compound of formula (V). In some embodiments, Zn is added sequentially in more than one part. In some embodiments, Zn is added sequentially in two parts (e.g., a first part of 3 equivalents relative to the compound of formula (V), followed by a second part of 2 equivalents relative to the compound of formula (V).

[0059] In some embodiments, ZnCl2 is present in an amount of 2 to 10 equivalents (e.g., 3 to 8 equivalents, 4 to 6 equivalents, 3, 4, 5, 6, 7, 8, 9, or 10 equivalents) relative to the compound of formula (V). In some embodiments, ZnCl2 is present in an amount of 5 equivalents relative to the compound of formula (V). In some embodiments, ZnCl2 is added sequentially in more than one part. In some embodiments, ZnCl2 is added sequentially in two parts (e.g., a first part of 3 equivalents relative to the compound of formula (V), followed by a second part of 2 equivalents relative to the compound of formula (V).

[0060] In some embodiments, CH2Br2 is present in an amount of 1 to 10 equivalents (e.g., 2 to 9 equivalents, 3 to 7 equivalents, 4 to 6 equivalents, 2, 3, 4, 5, 6, 7, 8, 9, or 10 equivalents) relative to the compound of formula (V). In some embodiments, CH2Br2 is present in an amount of 4 equivalents relative to the compound of formula (V). In some embodiments, CH2Br2 is added sequentially in more than one part. In some embodiments, CH2Br2 is added sequentially in three parts (e.g., a first part of 1.5 equivalents relative to the compound of formula (V), a second part of 1 equivalent relative to the compound of formula (V), and then a third part of 1.5 equivalents relative to the compound of formula (V).

[0061] The implementation of the method disclosed herein unexpectedly provides compounds of formula (VI) with high stereoselectivity (approximately 97:3), which continues in subsequent reactions in the multi-step synthesis of compounds of formula (XI), for example.

[0062] Prior to this disclosure, compounds of formula (VI) were typically prepared using the process reported in U.S. Publication No. 2011 / 0274648 A1, which provides a mixture of approximately 1:3 diastereomers of the compound of formula (VI) and its diastereomers. Other disclosed processes use silyl protecting groups (Bioorg.Med.Chem., 21 (2013) 5725-5737), which makes the product difficult to purify compared to the reaction disclosed herein. Another disclosed process relies on LiHMDS and methyl iodide to insert a methyl group into the compound of formula (I), resulting in a mixture of monomethylated and dimethylated compounds in addition to the unreacted starting material, thus requiring additional chromatographic separation.

[0063] The ability to prepare intermediates in the synthesis of compounds of formula (VI) with high stereoselectivity significantly improves the overall yield of the entire method for preparing compounds of formula (XI).

[0064] In some embodiments, the Co(II) catalyst is a Co(II) complex containing a pyridine (diimide) (PDI) ligand. In some embodiments, the Co(II) complex has the following structure:

[0065] ,

[0066] Each X is independently Cl, Br, or I; each R is independently C1-C6 alkyl; each R is independently H or C1-C6 alkyl; and R" is H, halogroup, C1-C6 haloalkyl, C1-C6 alkoxy, or C6-C 10 Aryl. For example, Co(II) complexes can have the following structures:

[0067] ,

[0068] Each X is independently Br or I; and each R is independently C1-C6 alkyl. In some embodiments, the Co(II) catalyst is used as a pre-formed complex (i.e., the opposite of in-situ assembly).

[0069] In some embodiments, each X is independently Cl and Br. In some embodiments, each X is independently Cl or I. In some embodiments, each X is independently Br or I. In some embodiments, each X is Cl. In some embodiments, each X is Br. In some embodiments, each X is I.

[0070] In some embodiments, each R is independently ethyl, n-propyl, isopropyl, or tert-butyl. In some embodiments, each R is ethyl. In some embodiments, each R is n-propyl. In some embodiments, each R is isopropyl. In some embodiments, each R is tert-butyl.

[0071] Compound of formula (V)

[0072] In some implementations, the compound of formula (V):

[0073] (V),

[0074] Where P 1 and P 2 As defined above, by making the compound of formula (IV):

[0075] (IV),

[0076] It is prepared by undergoing a dehydration reaction (elimination reaction), wherein P 1 It is an N-protecting group (e.g., tert-butoxycarbonyl), and P 2The carboxyl protecting group is used (e.g., an alkyl group, such as methyl). This dehydration reaction is typically carried out at elevated temperatures in the presence of a strong acid (such as sulfuric acid, phosphoric acid, or trifluoroacetic acid (e.g., formed by the hydrolysis of trifluoroacetic anhydride)). Dehydration can also be carried out in refluxed dichloromethane in the presence of catalytic p-toluenesulfonic acid (TsOH). Such reactions are well known in the art. In some embodiments, compounds of formula (V) are prepared by reacting a compound of formula (IV) with trifluoroacetic anhydride, for example, in the presence of 2,6-dimethylpyridine.

[0077] Compounds of formula (IV)

[0078] In some implementations, the compound of formula (IV):

[0079] (IV),

[0080] Where P 1 and P 2 As defined above, it is prepared by using a compound of reducing formula (III):

[0081] (III),

[0082] Where P 1 It is an N-protecting group (e.g., tert-butoxycarbonyl), and P 2 It is a carboxyl protecting group (e.g., an alkyl group, such as methyl). Compounds of formula (IV) can be reduced using reducing agents such as lithium triethylborohydride (“Superhydride”) or sodium borohydride. In some embodiments, compounds of formula (IV) are reduced with lithium triethylborohydride.

[0083] Compounds of formula (III)

[0084] In some implementations, the compound of formula (III):

[0085] (III),

[0086] Where P 1 and P 2 As defined above, by making the compound of formula (II):

[0087] (II),

[0088] It is prepared by hydrogenolysis in the presence of a hydrogenation catalyst, wherein P 1 It is protected by an H or N protecting group (e.g., tert-butoxycarbonyl), and P 2The protecting group is H or a carboxyl group (e.g., an alkyl group, such as methyl). Suitable hydrogenation catalysts include, but are not limited to, carbon-supported palladium, platinum oxide (IV), palladium hydroxide (II), Raney nickel, and platinum metal. In some embodiments, the hydrogenolysis reaction is carried out in the presence of carbon-supported palladium (Pd / C).

[0089] Compound of formula (II)

[0090] In some implementations, the compound of formula (II):

[0091] (II),

[0092] Where P 1 and P 2 As defined above, by making the compound of formula (I):

[0093] (I),

[0094] Where P 1 It is an N-protecting group (e.g., tert-butylcarbonyl) and P 2 It is prepared by reacting a carboxyl protecting group (e.g., an alkyl group, such as methyl) with a Bredereck reagent (tert-butoxybis(dimethylamino)methane; see, for example, Rosso, Synlett. 2006; 5: 0809-0810).

[0095] Compounds of formulas (VI'), (VII) and (VIII)

[0096] In some implementations, the compound of formula (VI):

[0097] (VI),

[0098] Where P 1 It is protected by an H or N protecting group (e.g., tert-butoxycarbonyl) and P 2 A carboxyl protecting group (e.g., an alkyl group, such as methyl) reacts with a carboxyl protecting group remover to obtain a compound of formula (VI'):

[0099] (VI'),

[0100] Where P 1The protecting group is either H or N. In some embodiments, the carboxyl protecting group is alkyl (e.g., methyl), and the carboxyl protecting group remover is a base (e.g., NaOH, LiOH, or KOH). Suitable carboxyl protecting agents and reaction conditions required for attaching and removing carboxyl protecting groups are well known in the art (see, for example, Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th edition, 2006). In some embodiments, the carboxyl protecting group remover is NaOH. In some embodiments, NaOH is added in an amount sufficient to achieve a pH > 11.

[0101] In some embodiments, the compound of formula (VI') is purified by first reacting it with an organic amine to form an organoammonium salt of the compound of formula (I) (e.g., in an organic solvent such as THF or toluene), and then reacting the organoammonium salt of the compound of formula (I) with an acid to reform the compound of formula (I). Suitable organic amines include, but are not limited to, benzylamine and chiral amines such as (R)-α-methylbenzylamine. In some embodiments, the organic amine is benzylamine, which forms a benzylammonium salt of the compound of formula (I). In some embodiments, the organic amine is (R)-α-methylbenzylamine, which forms a (R)-α-methylbenzylammonium salt of the compound of formula (I).

[0102] Then the compound of formula (VI') can be combined with the compound of formula (VII):

[0103] (VII),

[0104] Or its salt coupling, where R 1 H or optionally substituted C1-C6 alkyl; R 2 and R 3 Each of these is independently H or methyl; m is 0, 1, or 2; B is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 14 Aryl, optionally substituted 5- to 10-membered heterocyclic groups, or optionally substituted 5- to 10-membered heteroaryl groups; the coupling is carried out in an amidation reaction to form a compound of formula (VIII):

[0105] (VIII),

[0106] Where P 1 The protecting group is N (e.g., tert-butoxycarbonyl), and all other variables are as defined for formula (VII). Alternatively, P can be first made to protect the N group. 1The compound of formula (VI') with H is reacted with an N-protecting agent (e.g., d-tert-butyl dicarbonate), and then the compound is coupled with a compound of formula (VII) or a salt thereof to form a compound of formula (VIII). Subsequently, the P-terminus of the N-protecting group in the compound of formula (VIII) is removed with an N-protecting group remover. 1 Compounds of formula (IX) are provided:

[0107] (IX),

[0108] Or its salts, wherein all variables are as defined for formula (VIII). Suitable N-protecting reagents and reaction conditions required for the installation and removal of N-protecting groups are well known in the art (see, for example, Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th edition, 2006).

[0109] In some embodiments, the N-protecting agent is di-tert-butyl dicarbonate (Boc₂O), and the reaction is carried out in an organic solvent (e.g., acetonitrile) in the presence of a base (e.g., 4-dimethylaminopyridine), and the N-protecting group is tert-butoxycarbonyl (Boc). In some embodiments where the N-protecting group is Boc, the deprotection reaction includes treating the compound of formula (VIII) in an organic solvent with an acid as the N-protecting group remover. In some embodiments, the N-protecting group remover is hydrogen chloride (a solution of 4 N HCl in dioxane), the reaction is carried out in, for example, dioxane, and the deprotection reaction forms the hydrochloride salt of the compound of formula (IX). In some embodiments, the acid is hydrogen bromide (e.g., a solution of 33% HBr in acetic acid), the reaction is carried out in, for example, ethyl acetate, and the deprotection reaction forms the hydrobromide salt of the compound of formula (IX). In some embodiments, the acid is trifluoroacetic acid, the reaction is carried out in, for example, dichloromethane, and the deprotection reaction forms the trifluoroacetate salt of the compound of formula (IX).

[0110] In some embodiments, the compounds of formula (VI') and (VII) or their salts are coupled in an organic solvent in the presence of a base and a coupling agent. In some embodiments, the organic solvent is dimethylformamide. In some embodiments, the base is diisopropylethylamine. In some embodiments, the coupling agent is (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU). Other suitable coupling agents include, but are not limited to, n-propanephosphonic anhydride (T3P) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HBTU).

[0111] Exemplary compounds of formulas (VIII) and (IX) and methods for preparing such compounds are described, for example, in U.S. Patent Nos. PCT Publications WO2015 / 130838, WO2017 / 035353, WO2017 / 035409, WO2018 / 160889, WO2020 / 041301 and WO2021 / 168320, the entire contents of which are incorporated herein by reference.

[0112] Compounds of formula (XI)

[0113] In some implementations, the compound of formula (IX):

[0114] (IX),

[0115] Or its salts and compounds of formula (X):

[0116] (X),

[0117] Couplet, in which:

[0118] R 4 H; halogroup; OH; NH2; cyano; optionally substituted C1-C6 alkyl; optionally substituted C2-C6 alkenyl; optionally substituted 3- to 8-membered heterocyclic group; -C(O)NR a R a ', where R a and R a ' Each of these is independently H, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 ynyl, or an optionally substituted C3-C8 cycloalkyl; -C(O)R b ;-OC(O)R b ;or

[0119] -C(O)OR b ;where R b In each case, it is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy and optionally substituted C3-C8 carbocyclic groups;

[0120] R 5 and R 6 Each of them is independently H, a halogroup, or an optionally substituted C1-C6 alkyl group;

[0121] X 1 For N or CR c , where R c It can be H, a halogroup, an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C6 alkoxy group;

[0122] X 2 and X 5 Each of them is independently N or CR d , where each R d Independently selected from H, halogroup, cyanogroup, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 carbocyclic, and optionally substituted 5- to 8-membered heteroaryl groups; and

[0123] X 3 and X 4 One of them is selected from N and CR e And X 3 and X 4 The other one is CR f , where R e Selected from H, halogroup, cyanogroup, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and -C(O)OR g , where R g H is an H or optionally substituted C1-C6 alkyl group; and R f Selected from optional C4-C 10 Aryl, optional substituted 5- to 10-membered heteroaryl groups containing one, two, or three heteroatoms selected from N, O, and S, and optional substituted 4- to 10-membered saturated or unsaturated non-aromatic heterocyclic groups containing one to four heteroatoms selected from N, O, and S.

[0124] Compounds of formula (XI):

[0125]

[0126] (XI),

[0127] Or a pharmaceutically acceptable salt thereof, wherein all variables are as defined for formulas (IX) and (X). In some embodiments, the reaction is carried out in dimethylformamide with the hydrochloride salt of the compound of formula (IX) and the compound of formula (X) in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and N,N-diisopropylethylamine. In some embodiments, the reaction is carried out in acetonitrile with the hydrobromide salt of the compound of formula (IX) and the compound of formula (X) in the presence of propanephosphonic anhydride and N,N-diisopropylethylamine. In some embodiments, the reaction is carried out in dimethylformamide with a trifluoroacetate of the compound of formula (IX) and a compound of formula (X) in the presence of N,N-diisopropylethylamine and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate.

[0128] Exemplary compounds of formulas (IX), (X), and (XI) and their synthesis procedures are described, for example, in PCT publications WO2015 / 130838, WO2017 / 035353, WO2017 / 035409, WO2018 / 160889, WO2020 / 041301, and WO2021 / 168320, the entire contents of which are incorporated herein by reference.

[0129] Other embodiments of this disclosure

[0130] In some embodiments of any aspect of the present invention (e.g., equations (VII), (VIII), (IX), and (XI)), R 1 For H. In some embodiments of any aspect described herein (e.g., equations (VII), (VIII), (IX), and (XI)), R 1 It is CH3.

[0131] In some embodiments of any aspect of the present invention (e.g., equations (VII), (VIII), (IX), and (XI)), m is 0. In some embodiments of any aspect of the present invention (e.g., equations (VII), (VIII), (IX), and (XI)), m is 1. In some embodiments of any aspect of the present invention (e.g., equations (VII), (VIII), (IX), and (XI)), m is 2.

[0132] In some embodiments of any aspect of the present invention (e.g., equations (VII), (VIII), (IX), and (XI)), R2 and R 3 Each of them is H. In some embodiments of any aspect of the present invention (e.g., equations (VII), (VIII), (IX), and (XI)), R 2 For H and R 3 CH3. In some embodiments of any aspect described herein (e.g., equations (VII), (VIII), (IX), and (XI)), R 2 and R 3 Each of them is CH3.

[0133] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted 5- to 10-membered heteroaryl group.

[0134] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted 6-membered heteroaryl group, such as optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl.

[0135] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted pyridyl group, for example... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or In some implementations, B is... In some implementations, B is... .

[0136] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted pyrazinyl group, for example, , , , or .

[0137] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted pyrimidinyl group, for example, , , , or .

[0138] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted pyridazinyl group, for example, .

[0139] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted five-membered heteroaryl group, for example, , , , , , , , , ,

[0140] , , , , , , , , ,or .

[0141] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is a bicyclic 9- or 10-membered heteroaryl group, for example, or .

[0142] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted C6-C14 Aryl, for example, optionally substituted phenyl, such as , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

[0143] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted 5- to 9-membered unsaturated heterocyclic group, for example, , , , ,or .

[0144] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted C3-C 10 cycloalkyl, for example, , , , , , , ,or .

[0145] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted C2-C6 alkenyl group, for example, , , , , , , , ,or .

[0146] In some embodiments of any aspect described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted C1-C6 alkyl group, for example, , , , , , , , , , , , , , , , , , , , ,or .

[0147] In some implementations of any aspect of the present invention (e.g., equations (X) and (XI)), X 1 Let N be the number of embodiments of any aspect described herein (e.g., equations (X) and (XI)). 1 For CR d In some embodiments of any aspect described herein (e.g., equations (X) and (XI)), X 1 For C(CH3). In some embodiments of any aspect described herein (e.g., equations (X) and (XI)), X 1 For CH.

[0148] In some implementations of any aspect of the present invention (e.g., equations (X) and (XI)), X 2 For CR d In some embodiments of any aspect described herein (e.g., equations (X) and (XI)), X 2It is a C(C1-C6 alkyl). In some embodiments of any aspect described herein (e.g., formulas (X) and (XI)), X 2 For C(CH3). In some embodiments of any aspect described herein (e.g., equations (X) and (XI)), X 2 For CH.

[0149] In some implementations of any aspect of the present invention (e.g., equations (X) and (XI)), X 5 For CR d In some embodiments of any aspect described herein (e.g., equations (X) and (XI)), X 5 For CH.

[0150] In some implementations of any aspect of the present invention (e.g., equations (X) and (XI)), X 3 For CR f And X 4 Let N be the number of embodiments of any aspect described herein (e.g., equations (X) and (XI)). 3 For CR f And X 4 For CH.

[0151] In some implementations of any aspect of the present invention (e.g., equations (X) and (XI)), X 4 For CR f And X c Let N be the number of embodiments of any aspect described herein (e.g., equations (X) and (XI)). 4 For CR f And X 3 For CH.

[0152] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R f It is a 5- to 10-membered heteroaryl group with one, two, or three heteroatoms selected from N, O, and S, which are optionally substituted.

[0153] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R f For example, a pyrimidinyl group with optional substitution. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or In some implementations, R f for .

[0154] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R f The substituted pyridyl group, the substituted pyrazinyl group, or the substituted pyridazinyl group may be, for example, , , , , , , , ,or .

[0155] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R f This refers to an 8- to 10-membered bicyclic heteroaryl group containing one, two, or three heteroatoms selected from N, O, and S, with optional substitution. In some embodiments, R... f Optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyrimidinyl, optionally substituted thiazo[5,4-b]pyrimidinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyrimidinyl, 1H-thieno[3,2-c]pyrazolyl, imidazo[1,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1H-benzo[d]imidazoyl, for example, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or In some implementations, R f for In some implementations, R f for .

[0156] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R f C6-C as an optional substitute 14 Aryl groups, such as optionally substituted phenyl groups, for example, , ,or .

[0157] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R f These are optional substituted 6- to 9-membered unsaturated heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, or S. For example, R f It can be a heterocyclic group in which the carbon ring atoms contained therein are bonded to the carbon atoms to which they are attached, for example , , , , , ,or , In other examples, R f It can be a heterocyclic group that bonds between the nitrogen atom it contains and the carbon atom to which it is attached, for example... , , , , ,or .

[0158] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R f For example, a 5-membered heteroaryl group containing one, two, or three heteroatoms selected from N, O, and S, with optional substitution. , , , ,or .

[0159] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R 4 -C(O)R b In some embodiments of any aspect described herein (e.g., equations (X) and (XI)), R 4 for , or In some embodiments of any aspect described herein (e.g., equations (X) and (XI)), R 4 for .

[0160] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R 4 -C(O)NR a R a ’In some embodiments of any aspect described herein (e.g., equations (X) and (XI)), R 4 for , , , , , , , , , , , ,or In some embodiments of any aspect described herein (e.g., equations (X) and (XI)), R 4 for .

[0161] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R 4 -C(O)OR b In some embodiments of any aspect described herein (e.g., equations (X) and (XI)), R 4 For -C(O)OCH3. In some embodiments of any aspect described herein (e.g., formulas (X) and (XI)), R 4 It is -C(O)OH.

[0162] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R 4 R is an optionally substituted C1-C6 alkyl group. In some embodiments of any aspect described herein (e.g., formulas (X) and (XI)), R 4 for In some embodiments of any aspect described herein (e.g., equations (X) and (XI)), R 4 for .

[0163] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R 4 for .

[0164] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R 4 It is cyano. In some embodiments of any aspect described herein (e.g., formulas (X) and (XI)), R 4 It is a halogenated group, such as Br.

[0165] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R 5 For H.

[0166] In some implementations of any aspect of the aspects described herein (e.g., equations (X) and (XI)), R 6 For H.

[0167] In some implementations, the compound of formula (XI) is:

[0168] ,

[0169] Or its pharmaceutically acceptable salt.

[0170] In some implementations, the compound of formula (XI) is:

[0171] ,

[0172] Or its pharmaceutically acceptable salt.

[0173] In some implementations, the compound of formula (XI) is:

[0174] ,

[0175] Or its pharmaceutically acceptable salt.

[0176] In some implementations, the compound of formula (XI) is:

[0177] ,

[0178] Or its pharmaceutically acceptable salt.

[0179] In some implementations, the compound of formula (XI) is:

[0180] ,

[0181] Or its pharmaceutically acceptable salt.

[0182] In some implementations, the compound of formula (XI) is:

[0183] ,

[0184] Or its pharmaceutically acceptable salt.

[0185] In some implementations, the compound of formula (XI) is:

[0186] ,

[0187] Or its pharmaceutically acceptable salt.

[0188] Example

[0189] The embodiments described herein are for illustrative purposes only, and this disclosure is not limited to the embodiments given.

[0190] Example 1. (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid Acid Synthesis

[0191]

[0192] Step 1: 2-Methyl(S,E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-) Synthesis of butyl ester (2b)

[0193]

[0194] Bredereck reagent (93.14 g, 0.534 mol) was added to a stirred solution of methyl-(S)-Boc-5-pyrrolidone-2-carboxylic acid ester (2a) (100 g, 0.411 mol) in toluene (250 mL) at room temperature, and the reaction was stirred at 75 °C to 80 °C for 6 h. After the reaction was complete, the mixture was cooled to -5 °C and stirred for 0.5 h to 1.5 h. The obtained solid was filtered at -5 °C and washed with cold cyclohexane (200 mL). The product was dried under reduced pressure, yielding 2-methyl(E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester (2b) (100 g, 82% yield) as a white solid. 1 H NMR(400MHz, CDCl3): δ 7.06 (s, 1H), 4.56 (dd, 1H), 3.75 (s, 3H), 3.28− 3.23 (m,1H), 3.02 (s, 6H), 2.91−2.87 (m, 1H), 1.49 (s, 9H).

[0195] Step 2: Synthesis of 2-methyl(2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester (2c)

[0196]

[0197] Compound 2-methyl(S,E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester (2b) (20 g, 67.1 mmol), 10% Pd / C (50% wet) (2.0 g, 0.1 w / w), and IPA (140 mL) were charged into a 300 mL HEL PolyBlock reactor. The reaction mixture was purged twice with nitrogen, and then the internal reaction temperature was raised to 50 °C and pressurized to 45 psi with hydrogen. After the reaction was complete, the reactants were passed through a diatomaceous earth bed, and the filtrate was concentrated under reduced pressure at 45 °C to obtain a light brown viscous oil. Cyclohexane (40 mL) was added to the oil, and the mixture was stirred at -5 °C for 30 to 50 min. The obtained solid was filtered at -5 °C. The product was dried under reduced pressure to obtain 2-methyl(4S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylic acid (tert-butyl) ester (2c) as a white solid with high diastereoselectivity (dr=88:12) (14.48 g, 84% yield). 1 H NMR (400MHz, CDCl3): δ 4.59 – 4.45 (m, 1H), 3.77 (s, 3H), 2.71 – 2.49 (m, 2H), 1.68 – 1.57 (m, 1H), 1.48 (s, 9H), 1.30 –1.17 (m, 3H).

[0198] Step 3: Synthesis of 2-methyl(2S)-5-hydroxy-4-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester (2d)

[0199]

[0200] In a 5-liter round-bottom flask with four necks under nitrogen atmosphere, 180 g (699.6 mmol; 1.00 equivalent) of 1-(tert-butyl) ester of 1,2-dicarboxylic acid (2c) was added and dissolved in toluene (1.7 L). The reaction solution was cooled to -78 °C, and a 1.0 M solution of Superhydride (1.3 equivalent) in THF was slowly added using a syringe pump (4 h). The mixture was stirred at approximately -75 °C for 2 h. After the reaction was complete, 180 mL of a 10% aqueous solution of NH4Cl was added to the reaction mixture at -75 °C, and the reaction mixture was gradually warmed to room temperature. The organic layer was separated, and the aqueous layer was further extracted with toluene (180 mL). The combined organic phases were used directly in the next step.

[0201] Step 4: 2-Methyl(S)-4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl) ester (2e) synthesis

[0202]

[0203] The crude reaction mixture from the previous step was loaded into a 5 L reactor (180 g, 694.1 mmol, 1 equivalent). The reaction solution was cooled to 0 °C, and 2,6-dimethylpyridine (371.9 mL, 3.193 mol, 4.6 equivalent) was added. TFAA (221.9 mL, 1.597 mol, 2.3 equivalent) was slowly added to the reaction mixture while maintaining the internal reaction temperature below 5 °C. The mixture was then stirred at 60 °C for 14 h. After the reaction was complete, the reaction mixture was cooled to room temperature. Water (180 mL) was added, and the mixture was stirred for 10 min, after which the aqueous layer was collected. The combined organic layers were washed with 1 M HCl (360 mL). The reaction mixture was further washed with 10% NaHCO3 (360 mL) solution. The organic layer was collected, dried over Na2SO4, filtered, and concentrated under vacuum to obtain 2-methyl-4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl) ester (2e), which was a yellow oil (116.9 g, yield of 70% in two steps). 1 H NMR (400MHz, CDCl3): δ 6.28 (dd, J =45.6, 1.9Hz, 1H), 4.61 (ddd, J = 31.2, 11.8, 5.3Hz, 1H), 3.76 (s, 3H), 2.96 (q, J = 14.5Hz, 1H), 2.52 (ddd, J = 22.3, 16.4, 5.3Hz, 1H), 1.68 (d, J =1.7Hz, 3H), 1.45 (s, 9H).

[0204] Step 5: 3-Methyl(1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl) Synthesis of 2f esters

[0205]

[0206] Step A: Add the pre-prepared Co(PDI)I₂ complex (2.3 g, 3.11 mmol, 25 mol%) and THF (10 v) to a clean, dry 100g three-necked RB container equipped with a magnetic stirrer, followed by the addition of Zn powder (2.44 g, 37.3 mmol) (activated with dilute HCl). Stir the reaction mixture for 20 to 40 minutes, until a deep purple color appears. Dissolve 2-methyl-4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl) ester (2e) (3.0 g, 12.43 mmol) in THF (7.5 mL) and degas with N₂ for 10 minutes. Weigh CH₂Br₂ (8.65 g, 49.73 mmol) into a vial containing THF (22.5 mL) and degas with N₂ for 10 minutes. A degassed solution of 1-(tert-butyl) ester (2e) of 2-methyl-4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylic acid in THF was added dropwise to the reaction mixture, and stirring was allowed for the next 10 minutes. A degassed solution of CH2Br2 (1 / 3 of the total volume) in THF was added dropwise to the reaction mixture over 30 minutes, and the mixture was stirred at room temperature for 1 hour. The internal temperature was gradually increased to 41°C and then decreased to 22°C over 1 hour. A second portion of Zn (1.63 g, 24.87 mmol, 2.0 equivalent) was added to the reaction mixture, and the mixture was stirred for 10 to 20 minutes. Then, a second portion of CH2Br2 (1 / 3 of the total solution) was added dropwise over 10 minutes, and the mixture was stirred for 1 hour. The remaining third portion of Zn (1.63 g, 24.87 mmol) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The third portion of CH2Br2 (the remaining 1 / 3 portion) was added dropwise over 10 min, and the reaction mixture was stirred for 2 h. After complete conversion was detected by HPLC, it was diluted with EtOAc (30 mL) and washed with 0.1 M HCl (40 mL). The aqueous layer was extracted with EtOAc, and the organic layer was filtered through a short diatomaceous earth bed to remove solid impurities. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude reaction mixture was purified by rapid column chromatography with 5% to 20% EtOAc / hexane to obtain a liquid 3-methyl(1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl) ester (2f) (2.7 g, 85% yield) with high diastereoselectivity (dr=97:3). 1H NMR (400MHz, CDCl3)δ 3.89-3.91 (m, 1H), 3.71-3.76 (s, 3H), 3.17 (m, 1H), 2.46 – 2.30 (m, 1H),1.93 (dt, J = 13.7, 6.2Hz, 1H), 1.37 (s, 9H), 1.18 (s, 3H), 0.63-0.58 (m,1H), 0.57 (d, J = 6.4Hz, 1H); 13 C NMR (101MHz, CDCl3) δ 172.63, 80.27, 59.98,52.10, 42.99, 38.65, 37.96, 28.26, 23.16, 22.03, 20.68。

[0207] Step B: In a clean, dry 1L three-necked round-bottom flask equipped with a magnetic stirrer, add the first portion of the Co(PDI)Br2 complex (0.43 g, 0.66 mmol, 8 mol%), THF (20 mL), ZnCl2 (0.56 g, 4.14 mmol), and the first portion of Zn powder (1.08 g, 16.58 mmol; used directly from a commercially available bottle). Stir the reaction mixture until a deep purple color appears. Add 2-methyl-4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-( tert-butyl ester (2e) (2.0 g, 8.29 mmol) was dissolved in THF (5 mL) and degassed with N2 for 10 min. CH2Br2 (5.76 g, 33.16 mmol) was weighed into a vial containing THF (15 mL) and degassed with N2 for 10 min. The degassed solution of 2e in THF was added dropwise to the reaction mixture, allowing stirring for 10 min. The first portion of the degassed CH2Br2 solution (1 / 3 of the total solution) in THF was added dropwise to the reaction mixture over 10 min, and the reaction mixture was stirred. The mixture was stirred at room temperature for 1 hour. The internal reaction temperature was gradually increased to 28.3°C. A second portion of the Co(PDI)Br2 complex (0.43 g, 0.66 mmol, 8 mol%) and Zn (1.08 g, 16.58 mmol) was added to the reaction mixture and stirred for 10 minutes. A second portion of CH2Br2 (1 / 3 of the total solution) was added dropwise over 10 minutes, and the reaction mixture was stirred for 1 hour. Finally, a third portion of the Co(PDI)Br2 complex (0.43 g, 0.66 mmol, 8 mol%) was added. 2.0 equivalents of Zn (1.08 g, 16.58 mmol) were added to the mixture and stirring was allowed for 10 min. A third portion of CH2Br2 (the remaining 1 / 3 portion) was added dropwise over 10 min. The mixture was stirred for 16 h. After the reaction was complete, the reaction was post-processed as described above, and the crude product 3-methyl(1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl) ester (2f) with high diastereoselectivity (dr=97:3) was obtained.

[0208] Step 6: (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid Synthesis of (2g)

[0209]

[0210] Step A: LiOH (0.85 g, 36.23 mmol) was added to a stirred solution of compound 2f (3.7 g, 14.49 mmol) in a 3:1 mixture of EtOH / H₂O (37 mL), and the mixture was stirred for the next 6 to 8 hours. After the reaction was complete, the reaction mixture was diluted with EtOAc (14.8 mL), and the aqueous layer was further washed with 7.4 mL of EtOAc. The aqueous layer was collected, and the pH of the aqueous layer was adjusted to between 1 and 2 by adding 2 M HCl aqueous solution. The solution was extracted with EtOAc (18.5 mL), and the combined organic layers were washed with 10% NaCl solution (7.4 mL). The organic layers were collected and concentrated under reduced pressure at 45 °C to give a product (3.0 g, 85% yield) as a pale yellow viscous oil. 1 H NMR (400MHz, CDCl3): δ 11.28 (s, 1H), 4.09 (dd, J =31.9, 18.4Hz, 1H), 3.20 (d, J = 49.3Hz, 1H), 2.57 – 2.39 (m, 1H), 2.25 – 2.08(m, 1H), 1.63 – 1.30 (m, 11H), 1.25 (s, 3H), 0.79 – 0.53 (m, 2H).

[0211] Step B: Add NaOH (0.85 g, 36.23 mmol) to a stirred solution of compound 2f (5 g, 14.49 mmol) in a 3:1 mixture of EtOH / H₂O (50 mL) and stir for 6 to 8 hours. After the reaction is complete, dilute the reaction mixture with EtOAc (20 mL) and wash the aqueous layer further with 10 mL of EtOAc. Collect the aqueous layer and adjust its pH to between 1 and 2 by adding 2 M HCl aqueous solution. Extract the solution with EtOAc (25 mL) and wash the combined organic layers with 10% NaCl solution (10 mL). Collect the organic layers and concentrate under reduced pressure at 45 °C to give the product (compound 2 g) as a pale yellow viscous oil (3.0 g, 85% yield). 1 H NMR (400MHz, CDCl3): δ 11.28 (s, 1H), 4.09 (dd, J =31.9, 18.4Hz, 1H), 3.20 (d, J = 49.3Hz, 1H), 2.57 – 2.39 (m, 1H), 2.25 – 2.08(m, 1H), 1.63 – 1.30 (m, 11H), 1.25 (s, 3H), 0.79 – 0.53 (m, 2H).

[0212] Example 2. Preparation of Co(PDI)X2 complex

[0213] Co(PDI)X2 complexes can be prepared based on the following steps.

[0214] Step 1. Synthesis of PDI ligands

[0215]

[0216] At room temperature and under N2, a solution of 2,6-diacetylpyridine (50 g, 1 equivalent) in toluene (350 mL) was added to a clean, dry 1 L round-bottom flask equipped with a magnetic stirrer. 2-tert-butylaniline (50 mL, 2.2 equivalents) was added to the reaction mixture at room temperature. After adding p-TsOH (500 mg), the solution was refluxed and distilled for 6 h. Upon cooling to room temperature, 1 M NaOH (2 V) was added, and the reaction mixture was filtered through a funnel. The product was diluted with ethanol and refluxed for 0.5 h. Upon cooling, the slurry was filtered through a filter flask and washed with cold ethanol, then dried overnight in a vacuum oven (50 °C) (separation yield: 93 g, 62%). 1 H NMR and 13 C NMR confirmed the product's identity.

[0217] Following the above procedure, other spatially and electronically different PDI ligands can be prepared using suitable pyridine and aniline synthons.

[0218]

[0219] Step 2: Synthesis of Co(PDI)X2 complex

[0220]

[0221] General procedures

[0222] Under a nitrogen atmosphere, the desired amounts of PDI ligand (1.0 equivalent) and CoX2 salt (1.0 equivalent; X = I or Br) are added to 100 ml to 1000 ml of clean, dry RB containing THF at 20 V to 45 V and equipped with a magnetic stirrer. The reaction mixture is stirred under nitrogen for 48 h to 60 h, then concentrated under reduced pressure. Hexane (3 V) is added to the resulting solid, and the mixture is sonicated for 5 min to 10 min, then filtered to obtain the Co(PDI)X2 complex, which is dried under vacuum overnight. The prepared complex can be used without any further purification.

[0223] Co( t Bu-PDI)Br2 complex

[0224] THF (4 v) was charged into a 5 L reactor, followed by the addition of PDI ligand (200 g, 469.9 mmol, 1.0 equivalent) under a nitrogen flow. Then, additional THF (11 v) was added to the reactor, and stirring was allowed for 10 to 30 min to obtain a homogeneous solution. CoBr2 (102.8 g, 469.9 mmol, 1.0 equivalent) was added to the reaction mixture under a nitrogen flow, followed by THF (5 v). The reaction mixture was stirred under a nitrogen flow at room temperature for 60 to 72 h. After 60 to 72 h, the reaction mixture was filtered and vacuum dried at room temperature for 8 to 12 h, and was ready for use without further purification. The isolated yields were quantitative.

[0225] Other PDI complexes were prepared using the above-disclosed PDI ligands through the above-described procedures.

[0226] Example 3. (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid Improved synthesis of acids

[0227]

[0228] Step 1: 2-Methyl(S,E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-) Synthesis of butyl ester (2b)

[0229]

[0230] A top-mounted stirrer, thermocouple, and nitrogen line were installed in a 2L reactor. Compound 2a (250 g, 1027.71 mmol, 1.0 equivalent) was added to the reactor, followed by toluene (2.5 v, 625 mL). Bredereck reagent (250.75 g, 1336.02 mmol, 1.3 equivalent) was added to the reactor, and the reaction mixture was heated at 75 °C ± 3 °C for 6 to 8 h. Upon completion of the reaction, the reaction mixture was cooled to -5 °C ± 3 °C. The cooled reaction mixture was filtered, and the filter cake was washed with cold cyclohexane (2.5 v). The filter cake was then vacuum dried at room temperature for 18 to 24 h. Compound 2b was given as a pale yellow solid in 86% yield and 99.99% by weight. 1 H NMR (400MHz, CDCl3): δ 7.06 (s, 1H), 4.56 (dd,1H), 3.75 (s, 3H), 3.28− 3.23 (m, 1H), 3.02 (s, 6H), 2.91−2.87 (m, 1H), 1.49(s, 9H); 13C NMR (100MHz, CDCl3): δ 172.60, 168.40, 150.40, 146.41,128.18. 90.83. 82.36, 82.17, 55.91, 52.29, 41.97, 28.20, 28.02, 27.81, 26.22.

[0231] Step 2: Synthesis of 2-methyl(2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester (2c)

[0232]

[0233] Compound 2b (40 g, 298.34 mmol, 1.0 equivalent) was charged into the reactor, followed by IPA (4 V to 7 V, 160 mL to 280 mL) and 10% w / w 10% Pd / C (50% wet) (0.5 w / w Pd content). The reactor was equipped with a top stirrer, sealed, and placed in a polymer block at 1500 rpm for 12 to 18 hours. After the early reaction was complete, the material was passed through a bed of diatomaceous earth (2 w / w to 4 w / w). IPA was removed by azeotropic reaction with toluene, and the solution of the compound was then used directly in the next step. 1 H NMR(400MHz, CDCl3) (dr = 8.8:1.2) δ 4.59 – 4.45 (m, 1H), 3.77 (s, 3H), 2.71 –2.49 (m, 2H), 1.68 – 1.57 (m, 1H), 1.48 (s, 9H), 1.30 – 1.17 (m, 3H); 1 H NMR(100MHz, CDCl3) δ 175.62, 172.03, 171.82, 149.58, 149.44, 83.65, 83.53,57.35, 56.87, 52.56, 52.48, 37.51, 36.60, 30.46, 29.71, 27.92, 27.88, 16.11,15.13.

[0234] Multiple batches of compound 2c were prepared according to this procedure, with separation and correction yields of 81% to 89% determined by quantitative NMR and output purity of 75% to 89% determined by HPLC.

[0235] Step 3: Synthesis of 2-methyl(2S)-5-hydroxy-4-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester (2d)

[0236]

[0237] Continuous flow scheme

[0238] The use of continuous flow chemical synthesis of compound 2d was also considered. For the synthesis, a 1 / 4" OD PFA tubular reactor (170 mL) was used. Figure 1 This is a continuous flow apparatus providing a flux of 148 g / h. Feed 1: Compound 2c (411.5 g, 1612.80 mmol, 1.0 equivalent) and toluene (3320 mL, 8 v) are loaded into a small-mouth large glass bottle (Carboy) under N2 atmosphere. Feed 2: Superhydride (1 M THF solution, 2096.9 mL, 1.3 equivalent) is supplied from a 2 L glass bottle under N2 atmosphere. When the superhydride bottle is empty, a three-way valve is used to switch between the superhydride bottle containing the stock solution (Sure / Seal). Methanol for quenching is supplied via a third stream. Each stream includes a 1 / 8" OD PFA 7mL precooling loop. The reaction and precooling loops are cooled and maintained at -78°C to -70°C. The stream containing compound 2c and the superhydride are fed into the reaction loop at flow rates of 21.81 mL / min and 12.19 mL / min, respectively (via peristaltic pump), for a continuous flow period of t. R =5 min. After the solution passes through the first loop, a continuous additional flow of methanol is supplied at a flow rate of 7.72 mL / min (via HPLC pump). R =2min.

[0239] Phased Plan

[0240] Under nitrogen atmosphere, compound 2c (238.52 g, 1.0 equivalent) was charged into a 5 L four-necked RB container connected to a top-mounted stirrer and dissolved in toluene (10 v). The reaction solution was cooled to -78 °C, and a 1.0 M superhydride (834.34 mL, 0.9 equivalent) THF solution was slowly added using a peristaltic pump (4 mL / min). The mixture was stirred at approximately -75 °C to -70 °C for 2 h. 1 The H NMR analysis process was monitored. Based on the conversion rate of compound 2c, an additional 0.16 equivalent of the superhydride was slowly added using a peristaltic pump (4 mL / min), and the reaction was stirred at approximately -75°C to -70°C for 30 min. 1 The process was monitored by ¹H NMR. Based on the conversion rate of compound 2c, an additional 0.09 equivalent of superhydride was slowly added using a peristaltic pump (4 mL / min), and the reaction mixture was stirred at approximately -75°C to -70°C for 30 min. 1The reaction was monitored by ¹H NMR. Upon completion of the reaction, an aqueous solution of NH₄Cl (1 v) was slowly added to the reaction mixture using a peristaltic pump (4 mL / min) at -75°C to -65°C, followed by slow warming to room temperature. The reaction mixture was then transferred to a 5 L reactor and the aqueous layer was removed. The organic layer was washed with water (1 v) and brine (1 v), and then distilled under vacuum to 4 v to 5 v while maintaining the jacket temperature at 50°C to 55°C to azeotropically remove water content and ensure the water content was no more than 0.3%.

[0241] Step 4: 2-Methyl(S)-4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl) ester (2e) synthesis

[0242]

[0243] Under a nitrogen stream, a solution of compound 2d (240.4 g, 927.1 mmol, 1.0 equivalent) in 10 V toluene (2.4 L) was loaded into a 5 L reactor using a wide funnel. The reaction temperature was cooled to 0 °C. 2,6-Dimethylpyridine (280.7 mL, 2410.4 mmol, 2.6 equivalent) was added under a nitrogen stream. Trifluoroacetic anhydride (TFAA) (167.5 mL, 1205.2 mmol, 1.3 equivalent) was added dropwise to the reaction mixture using a dropping funnel (connected to a long tube to drop TFAA onto the surface of the reaction mixture), while maintaining the reaction temperature below -10 °C ± 5 °C. After the addition was complete, the reactants were slowly heated to 60 °C ± 5 °C, and stirring was allowed for the next 14 to 16 h. 1 The reaction was monitored by ¹H NMR analysis. After the reaction was complete, the reactants were slowly cooled to 22 °C ± 5 °C. The reactants were washed with water (1 v), then twice with 1 N HCl, and then combined with 10% NaHCO3 (1 v) and 10% brine (1 v). Toluene was distilled down to 1 v to 2 v of the reactants, and then the reactants were diluted with cyclohexane (2 v to 4 v) and distilled to remove as much of the toluene contents as possible. The pale yellow liquid was vacuum dried for the next 8 h to 10 h. Compound 2e (176.1 g) was obtained as a pale yellow liquid with a purity of 94 wt% based on quantitative NMR, and a separation yield of 74% in the two steps (corrected for starting material purity). 1H NMR (400MHz, CDCl3) δ6.28 (dd, J = 45.6, 1.9Hz, 1H), 4.61 (ddd, J = 31.2, 11.8, 5.3Hz, 1H), 3.76(s, 3H), 2.96 (q, J = 14.5Hz, 1H), 2.52 (ddd, J = 22.3, 16.4, 5.3Hz, 1H), 1.68 (d, J = 1.7Hz, 3H), 1.45 (s, 9H).

[0244] Step 5: 3-Methyl(1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl) Synthesis of 2f esters

[0245]

[0246] Exemplary process

[0247] Assemble a clean and dry 5L reactor with a top-mounted agitator. Add pre-prepared Co( tA Bu-PDI Br2 complex (40.06 g, 62.17 mmol, 25 mol%) was charged into the reactor, followed by 15 V THF. ZnCl2 (101.68 g, 745.99 mmol, 3.0 equivalent) was then charged into the reactor, followed by activated Zn powder (48.78 g, 745.99 mmol, 3.0 equivalent), and the reactor was flushed with 3 V THF. The reactants in the reactor were then deeply subsurface purged with N2 for 10 to 15 minutes using a long tube, and stirred for the next 20 to 50 minutes. A deep purple color was observed. Compound 2e (60.0 g, 248.66 mmol, 1.0 equivalent) was dissolved in THF (1.5 V) and degassed with N2 in a separate round-bottom flask for 15 to 20 minutes before being charged into the reactor. The round-bottom flask was rinsed with 0.5V THF and placed into the reactor. The color of the reaction mixture remained unchanged. The reaction mixture was stirred for 20 to 50 minutes. CH2Br2 (64.84 g, 373.0 mmol, 1.5 equivalents) was added dropwise to the reactor over 10 to 25 minutes using a feeding funnel. The reaction mixture was stirred for 1 hour, and then CH2Br2 (43.23 g, 248.66 mmol, 1.0 equivalents) was added dropwise to the reactor over 10 to 25 minutes using a feeding funnel. After stirring for another 1 hour, the remaining ZnCl2 (67.79 g, 497.33 mmol, 2.0 equivalents) and Zn (32.52 g, 497.33 mmol, 2.0 equivalents) were added to the reactor, and the reactor was then purged again with N2 under a deep subsurface tube for 10 to 15 minutes. CH₂Br₂ (64.84 g, 373.0 mmol, 1.5 equivalents) was added dropwise to the reactor over 10 to 25 minutes using a feeding funnel. At the 6th hour of the reaction, the precipitate was measured... 1 The reaction was monitored again by ¹H NMR, and the conversion rate was 97 Å. The reactants were passed through a bed of MTBE-wetted Sloka flocculant (4 w / w) and washed with MTBE at 6 v to 8 v. The filtrate was loaded into a 5 L reactor, followed by a 1:1 mixture of 10% NH₄Cl (2 v) and 10% NaCl solution (2 v) and stirred with RM for 20 to 40 min. Phase cut was performed to remove the aqueous layer. The reaction mixture was distilled to 2 v to 3 v, and the crude RM was used for the next step. 1H NMR (400MHz, CDCl3) δ 3.89-3.91 (m, 1H), 3.71-3.76 (s, 3H), 3.17 (m, 1H), 2.46 – 2.30 (m,1H), 1.93 (dt, J = 13.7, 6.2Hz, 1H), 1.37 (s, 9H), 1.18 (s, 3H), 0.63-0.58(m, 1H), 0.57 (d, J = 6.4Hz, 1H); 13 C NMR (101MHz, CDCl3) δ 172.63, 80.27, 59.98, 52.10, 42.99, 38.65, 37.96, 28.26, 23.16, 22.03, 20.68.

[0248] Step 5 involved testing Zn activated with 1N HCl, unactivated Zn, and different amounts of ZnCl2. The results are shown in Tables 1 to 3 below.

[0249] Table 1. Reaction of Zn activated with 1N HCl using ZnCl2 with a higher loading

[0250]

[0251] *These are solution yields after post-reaction treatment, determined by qNMR. ¥ The zinc particle size is NMT 10mm.

[0252] a All reagents were added to the reaction mixture in two portions. b All reagents were added to the reaction mixture in three portions.

[0253] Table 2. Reaction of Zn activated with 1N HCl using 1 to 1.5 equivalents of ZnCl2.

[0254]

[0255] *These are solution yields after post-reaction treatment, determined by qNMR. ¥ The zinc particle size is no greater than 10mm. a All reagents were divided into twelve equal portions and added to the reaction mixture. a All reagents were added to the reaction mixture in two portions.

[0256] Table 3. Reaction with unactivated zinc

[0257]

[0258]

[0259]

[0260] * Corrected yield of the separation, ¥ Solution yield based on qNMR. a All these reagents were added in four portions. b All these reagents were added in four portions. c All these reagents were added in six portions. d All these reagents were added in 12 portions.

[0261] It was found that using activated Zn and a higher loading of ZnCl2 unexpectedly shortened the reaction time and provided products with high yields and high enantiomeric ratios.

[0262] Step 6: (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid Synthesis of (2g)

[0263]

[0264] A crude mixture of compound 2f (84.6 g, 331.1 mmol, 1.0 equivalent) was diluted with EtOH (5 v) and loaded into a 5 L reactor. An additional 10 v of EtOH was then added to the reactor. The reactants were cooled to 5 °C ± 10 °C with stirring at 500 RPM. NaOH (124.2 g, 3105 mmol, 9.4 equivalent) was added while maintaining the internal temperature below 15 °C until the pH reached >12. The reaction was allowed to reach room temperature and stirred for 4 h.

[0265] When the reaction was confirmed to be complete by HPLC, the reactants were distilled to 3-4 V to remove ethanol via azeotropic distillation with water, and the aqueous reactants were washed with EtOAc. The organic layer was washed with 1 N NaOH (2 V). The aqueous layer was loaded into the reactor and cooled to 0 °C ± 5 °C. An ice-cold solution of 3 M HCl was added to the reactor until the pH reached 1-2. The aqueous layer was extracted twice with IPAc (10-15 V). The IPAc solution was provided to the crystallization team for separation.

[0266] Steps 7 and 8: (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane Chiral resolution and crystallization of alkyl-3-carboxylic acid (2g)

[0267]

[0268] Salts formed with amines (such as benzylamine) can be used to remove process impurities from crude compound 2g. When the chiral purity of crude compound 2g is lower than expected, chiral amines are used for chiral resolution. (R)-α-methylbenzylamine was chosen as the chiral amine because it (1) is readily disposable as a liquid at 25°C and can be added directly to the crude product for salt formation; (2) its salt with compound 2g has lower solubility compared to other chiral amines studied for salt formation; and (3) it also allows for chiral upgrading.

[0269] The reaction mixture (containing approximately 45 g of the compound, 2 g as a solution in approximately 225 mL (5 v) of isopropyl acetate, washed twice with 3 v of water) was charged into a 1 L reactor. 1.35 g of activated charcoal (Acticarbone HPX7) (3% by mass of the compound) was added to the solution. The mixture was stirred at 20°C to 25°C for 2 hours. The slurry was then filtered through diatomaceous earth. The filtrate was collected and washed with approximately 90 mL (2 v) of isopropyl acetate. The filtrate from the charcoal treatment was vacuum distilled at 50°C and 200 Torr to reduce the volume to 225 mL (5.0 v). 225 mL (5.0 v) of isopropyl acetate was charged into the reactor. The solution was vacuum distilled at 50°C and 200 Torr to reduce the volume to 225 mL (5.0 v). The water content in the solution should be <350 ppm (if not, then 5.0 v of isopropyl acetate was charged and reduced to 5.0 v by vacuum distillation). The solution was maintained at 50°C to 55°C. The reaction mixture after charcoal treatment and azeotropic distillation was stirred under a nitrogen atmosphere while maintained at 50°C to 55°C, and (R)-α-methylbenzylamine (0.5 equivalents) was added to the reaction mixture over 2 hours. The system was aged for 1 hour, and additional (R)-α-methylbenzylamine (0.5 equivalents) was added over 2 hours. The final mixture was stirred at 50°C to 55°C for 1 hour. The reaction mixture was then cooled to 20°C with a linear temperature profile over 4 hours and stirred at 20°C for NLT 16 hours.

[0270] During drying, (R)-α-methylbenzylamine salt is dispersed in 10V isopropyl acetate while stirring at 20°C to 25°C. 4.5V of 2M HCl (aqueous solution) is added to the mixture over 15 minutes at 20°C to 25°C. The mixture is then stirred for 10 to 15 minutes. The aqueous layer is removed. 3V of water is added to the remaining organic layer and stirred for 30 minutes. The aqueous layer is removed. The organic layer is heated to 55°C to 60°C while stirring and distilled under vacuum to 1.5V to 2V. 3V of isopropyl acetate is added to the solution, and the solution is distilled under vacuum to 1.5V to 2V.

[0271] While maintaining the temperature at 55°C to 60°C, add 10v of n-heptane over 1 hour with stirring. Distill the solution under vacuum to 10v to 11v. Add seed crystals (1% by mass). Then stir the mixture at 55°C to 60°C for 1 hour. Then distill the mixture under vacuum to 1.5v to 2v. While stirring, add 8v of n-heptane over 1 hour at 55°C to 60°C. Distill the solution under vacuum to 1.5v to 2v. While stirring, add 3v of n-heptane over 0.5 hours at 55°C to 60°C. Stir the mixture at 55°C to 60°C for 1 hour and cool it to 20°C to 25°C over at least 2 hours. Stir the mixture at 20°C to 25°C for at least 16 hours.

[0272] The mixture was filtered under vacuum. The filter cake was washed with n-heptane (2 × 1 v; slurry washing and displacement washing). The filter cake was then vacuum dried at 50°C to 55°C for at least 16 h.

[0273] This process consistently produces 2g of purified compound with a yield >95% and a chiral purity >99.5%, as determined by HPLC.

[0274] Other implementation plans

[0275] Various modifications and variations to the compositions and methods described in this disclosure will be apparent to those skilled in the art without departing from the scope and spirit of this disclosure. Although this disclosure has been described in conjunction with specific embodiments, it should be understood that the claimed disclosure should not be unduly limited to such specific embodiments. In fact, various modifications to the modes of carrying out the disclosed methods that are apparent to those skilled in the art are intended to fall within the scope of this disclosure.

[0276] Other embodiments are described in the claims.

Claims

1. A method for preparing a compound of formula (VI): (WE), Where P 1 It is an H or N protecting group, and P 2 The method comprises providing a compound of formula (V) with an H or carboxyl protecting group. (V)， Where P 1 It is an H or N protecting group, and P 2 It is an H or carboxyl protecting group; and The compound of formula (V) is formed from the compound of formula (V), wherein the formation of the compound of formula (VI) comprises contacting the compound of formula (V) with a Co(II) catalyst in the presence of Zn and CH2Br2.

2. The method according to claim 1, wherein the compound forming formula (VI) comprises contacting the compound of formula (V) with a Co(II) catalyst in the presence of Zn, CH2Br2 and ZnCl2.

3. The method according to claim 1 or 2, wherein the Zn is zinc powder.

4. The method according to claim 3, wherein the Zn is activated zinc powder.

5. The method according to claims 1 to 4, wherein the Zn is present in an amount equivalent to 10 equivalents of compound 2 of formula (V).

6. The method according to any one of claims 2 to 5, wherein the ZnCl2 is present in an amount equivalent to 10 equivalents of compound 2 of formula (V).

7. The method according to any one of claims 1 to 6, wherein the CH2Br2 is present in an amount of 1 to 10 equivalents relative to compound (V).

8. The method according to any one of claims 1 to 7, wherein the Co(II) catalyst is a compound having the following structure: ， Each X is independently Cl, Br, or I; each R is independently C1-C6 alkyl; each R is independently H or C1-C6 alkyl; and R" is H, halogroup, C1-C6 haloalkyl, C1-C6 alkoxy, or C6-C 10 Aryl.

9. The method according to claim 8, wherein the Co(II) catalyst is a compound having the following structure: ， Each X is independently Br or I; and each R is independently C1-C6 alkyl.

10. The method of claim 9, wherein each R is tert-butyl.

11. The method according to claim 9 or 10, wherein each X is Br.

12. The method according to any one of claims 1 to 11, wherein the compound providing formula (V) comprises: Provide compounds of formula (IV): (IV), Where P 1 It is an N-protecting group, and P 2 It is a carboxyl protecting group; and The compound of formula (IV) is subjected to a dehydration reaction.

13. The method of claim 12, wherein the dehydration reaction comprises reacting the compound of formula (IV) with trifluoroacetic anhydride in the presence of 2,6-dimethylpyridine.

14. The method according to claim 12 or 13, wherein the compound providing formula (IV) comprises: Provide compounds of formula (III): (III), Where P 1 It is an N-protecting group, and P 2 It is a carboxyl protecting group; and The compound of formula (III) is reacted with a reducing agent.

15. The method of claim 14, wherein the reducing agent is a superhydride.

16. The method according to claim 13 or 14, wherein the compound providing formula (III) comprises: Provide compounds of formula (II): (II), Where P 1 It is an H or N protecting group, and P 2 It is an H or carboxyl protecting group; and The compound of formula (II) is subjected to hydrogenolysis in the presence of a hydrogenation catalyst.

17. The method of claim 16, wherein the hydrogenation catalyst is a carbon-supported palladium.

18. The method according to claim 16 or 17, wherein the compound providing formula (II) comprises: Provide compounds of formula (I): (I)， Where P 1 It is an N-protecting group, and P 2 It is a carboxyl protecting group; and The compound of formula (I) is reacted with Bredereck reagent.

19. The method according to any one of claims 1 to 18, wherein P in formula (VI) 2 It is a carboxyl protecting group.

20. The method of claim 19, wherein the method further comprises reacting the compound of formula (VI) with a carboxyl protecting group remover to form the compound of formula (VI'): (WE'), Where P 1 It is protected by H or N groups.

21. The method according to claim 20, wherein P in formula (VI') 1 It is an N-protecting group.

22. The method according to claim 20 or 21, wherein the method further comprises: The compound of formula (VI) is reacted with an organic amine to form an organic ammonium salt of the compound of formula (VI); as well as The organic ammonium salt of the compound of formula (I) is reacted with an acid to form the compound of formula (VI).

23. The method according to claim 19, wherein the organic amine is (R)-α-methylbenzylamine, and the organic ammonium salt is (R)-α-methylbenzylammonium salt.

24. The method of claim 23, wherein the method further comprises reacting the compound of formula (VI') with the compound of formula (VII): (VII), Or its salt coupling, wherein R 1 H or optionally substituted C1-C6 alkyl; R 2 and R 3 Each of them is independently either H or methyl; m is 0, 1, or 2; and B is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C3-C 10 Carbocyclic group, optionally substituted C6-C 14 Aryl, optionally substituted 5- to 10-membered heterocyclic groups, or optionally substituted 5- to 10-membered heteroaryl groups; Compounds of formula (VIII): (VIII), in P 1 The N protecting group, and all other variables as defined for equation (VII); and The compound of formula (VIII) is reacted with an N-protecting group remover to form the compound of formula (IX): (IX), or its salt, wherein all variables are as defined for equation (VIII).

25. The method of claim 24, further comprising: Mix the compound of formula (IX) or a salt thereof with the compound of formula (X): (X)， Or its salt coupling, wherein R 4 H; halogroup; OH; NH2; cyano; optionally substituted C1-C6 alkyl; optionally substituted C2-C6 alkenyl; optionally substituted 3- to 8-membered heterocyclic group; -C(O)NR a R a ', where R a and R a ' Each of these is independently H, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 ynyl, or an optionally substituted C3-C8 cycloalkyl; -C(O)R b ;-OC(O)R b ;or -C(O)OR b ;where R b In each case, it is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy and optionally substituted C3-C8 carbocyclic groups; R 5 and R 6 Each of them is independently H, a halogroup, or an optionally substituted C1-C6 alkyl group; X 1 Is it N or CR? c , where R c It can be H, a halogroup, an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C6 alkoxy group; X 2 and X 5 Each of them is independently N or CR d , where each R d Independently selected from H, halogroup, cyanogroup, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 carbocyclic, and optionally substituted 5- to 8-membered heteroaryl groups; and X 3 and X 4 One of them is selected from N and CR e And X 3 and X 4 The other one is CR f , where R e Selected from H, halogroup, cyanogroup, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and -C(O)OR g , where R g H is an H or optionally substituted C1-C6 alkyl group; and R f Selected from optional C4-C 10 Aryl, optional substituted 5- to 10-membered heteroaryl groups containing one, two, or three heteroatoms selected from N, O, and S, and optional substituted 4- to 10-membered saturated or unsaturated non-aromatic heterocyclic groups containing one to four heteroatoms selected from N, O, and S. Compounds of formula (XI): (XI), Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 m and B are defined as in equation (IX), and all other variables are defined as in equation (X).

26. The method according to claim 24 or 25, wherein P 1 It is a tert-butoxycarbonyl group.

27. The method of claim 26, wherein the N-protecting group remover is hydrogen chloride, and the reaction of the compound of formula (VIII) with the N-protecting group remover forms the hydrochloride salt of the compound of formula (IX).

28. The method according to claim 27, wherein the hydrochloride salt of the compound of formula (IX) is coupled to the compound of formula (X) in dimethylformamide in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and N,N-diisopropylethylamine.

29. The method of claim 26, wherein the N-protecting group remover is hydrogen bromide, and the reaction of the compound of formula (VIII) with the N-protecting group remover forms the hydrobromide of the compound of formula (IX).

30. The method of claim 29, wherein the hydrobromide of the compound of formula (IX) is coupled to the compound of formula (X) in acetonitrile in the presence of propanephosphonic anhydride and N,N-diisopropylethylamine.

31. The method of claim 26, wherein the N-protecting group remover is trifluoroacetic acid, and the reaction of the compound of formula (VIII) with the N-protecting group remover forms a trifluoroacetic acid salt of the compound of formula (IX).

32. The method according to claim 31, wherein the trifluoroacetate of the compound of formula (IX) is coupled to the compound of formula (X) in dimethylformamide in the presence of N,N-diisopropylethylamine and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate.

33. The method according to any one of claims 24 to 32, wherein R 1 For H.

34. The method according to any one of claims 24 to 33, wherein m is 1.

35. The method according to any one of claims 24 to 33, wherein m is 0.

36. The method according to any one of claims 24 to 34, wherein R 2 and R 3 Each of them is H.

37. The method according to any one of claims 24 to 36, wherein B is an optionally substituted 5- to 10-membered heteroaryl group.

38. The method of claim 37, wherein B is an optionally substituted 6-membered heteroaryl group.

39. The method of claim 38, wherein B is an optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl.

40. The method of claim 39, wherein B is an optionally substituted pyridinyl group.

41. The method of claim 40, wherein B is or .

42. The method according to any one of claims 24 to 36, wherein B is an optionally substituted C6-C. 14 Aryl.

43. The method of claim 42, wherein B is an optionally substituted phenyl group.

44. The method according to any one of claims 24 to 36, wherein B is an optionally substituted 5- to 9-membered unsaturated heterocyclic group.

45. The method according to any one of claims 24 to 36, wherein B is an optionally substituted C3-C 10 Cycloalkyl.

46. ​​The method according to any one of claims 24 to 36, wherein B is an optionally substituted C2-C6 alkenyl group.

47. The method according to any one of claims 24 to 36, wherein B is an optionally substituted C1-C6 alkyl group.

48. The method according to any one of claims 25 to 47, wherein X 1 Let N be the number of elements in the array.

49. The method according to any one of claims 25 to 47, wherein X 1 For CH.

50. The method according to any one of claims 25 to 49, wherein X 2 For CR d .

51. The method of claim 50, wherein X 2 It is CH or C(CH3).

52. The method according to any one of claims 25 to 51, wherein X 5 For CR d .

53. The method of claim 52, wherein X 5 For CH.

54. The method according to any one of claims 25 to 53, wherein X 4 For CR f .

55. The method of claim 54, wherein X 3 It can be N or CH.

56. The method according to any one of claims 25 to 55, wherein R f It is a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, O, and S with optional substitution.

57. The method of claim 56, wherein R f It is a 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S.

58. The method of claim 57, wherein R f The pyrimidinyl group is optionally substituted.

59. The method of claim 56, wherein R f It is an 8- to 10-membered bicyclic heteroaryl group containing one, two, or three heteroatoms selected from N, O, and S with optional substitution.

60. The method of claim 59, wherein R f The substituted pyrazolo[1,5-a]pyrimidinyl, the substituted [1,2,4]triazolo[1,5-a]pyrimidinyl, the substituted thiazo[5,4-b]pyrimidinyl, the substituted imidazo[1,2-a]pyrimidinyl, the substituted 3H-imidazo[4,5-b]pyrimidinyl, 1H-thieno[3,2-c]pyrazolyl, imidazo[1,2-b]pyridazinyl, the substituted quinazolinyl, the substituted quinolinyl, and 1H-benzo[d]imidazolyl.

61. The method according to any one of claims 25 to 55, wherein R f It is a 6- to 9-membered unsaturated heterocyclic group containing 1 to 4 heteroatoms selected from N, O or S with optional substitution.

62. The method of claim 61, wherein the R f The carbon ring atoms contained therein are bonded to the carbon atoms to which they are attached.

63. The method of claim 56, wherein R f It is a 5-membered heteroaryl group containing one, two, or three heteroatoms selected from N, O, and S with optional substitution.

64. The method according to any one of claims 25 to 63, wherein R 4 for or .

65. The method according to any one of claims 25 to 64, wherein R 5 and R 6 Each of them is H.

66. The method according to any one of claims 25 to 32, wherein the compound of formula (XI) is: , , , , , ,or ; Or its pharmaceutically acceptable salt.

Images