Sonrotoclax intermediates and their preparation methods

Abstract

The present invention relates to a compound of formula (I) having a carbonyl-protecting group, which is used as an intermediate to prepare 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Sonrotoclax). JPEG2026503231000054.jpg47161 and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azadispiro[5.1.5 8 .1 6 [0010] A process for preparing a compound of formula (I) comprising methyl benzoate is provided.

Description

[Technical Field]

[0001] As used herein, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Sonrotoclax), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azadispiro[5.1.5]nonan-7-yl)benzamide (Sonrotoclax) are compounds of formula (I). 8 .1 6

[0010] A process for preparing a compound of formula (I) comprising methyl tetradecan-11-yl)benzoate is disclosed. [Background technology]

[0002] International Publication WO 2019 / 210828 discloses a series of Bcl-2 inhibitors, in particular 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (hereinafter Sonrotoclax), which selectively inhibit the Bcl-2 protein for the treatment of dysregulated apoptotic diseases such as cancer, autoimmune diseases, and prothrombotic conditions. [ka] However, the process for preparing Sonrotoclax also needs to be optimized. Current reaction yields are relatively low, and current intermediates are not stable enough for industrial processing. Therefore, new reaction intermediates and processes for preparing Sonrotoclax are needed. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2019 / 210828 Summary of the Invention [Means for solving the problem]

[0004] As used herein, a compound of formula (I): [ka] and salts, stereoisomers, and derivatives thereof. Further provided herein are methods for making compounds of formula (I). Further provided herein are methods for making Sonrotoclax from compounds of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0005] The following terms have the meanings indicated throughout this specification.

[0006] As used herein, and in this specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural and singular referents unless the context clearly indicates otherwise.

[0007] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent that is within 30%, within 20%, within 15%, within 10%, or within 5% of the specified dose, amount, or weight percent.

[0008] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a numerical value or range of values ​​provided to characterize a particular solid form, such as a particular temperature or temperature range, e.g., one describing melting, dehydration, desolvation, or glass transition temperature; mass change, e.g., mass change as a function of temperature or humidity; solvent or water content (e.g., in terms of mass or percentage); or peak position, e.g., in analysis by IR or Raman spectroscopy or XRPD, indicates that the value or range of values ​​may deviate to an extent that would be considered reasonable by one of ordinary skill in the art, yet still describe the solid form. In certain embodiments, the terms "about" and "approximately," when used in this context, indicate that the numerical value or range of values ​​may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values.

[0009] An "alkyl" group is a saturated, partially saturated, or unsaturated straight or branched chain acyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8 carbon atoms, or in some embodiments, from 1 to 6, 1 to 4, or 2 to 6 carbon atoms. Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; saturated branched chain alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH), and -CHC≡C(CHCH), among others. Alkyl groups can be substituted or unsubstituted. When alkyl groups described herein are said to be "substituted," they can be substituted with any substituent or substituents such as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonato, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, B(OH), or O(alkyl)aminocarbonyl.

[0010] An "alkenyl" group is a straight-chain or branched-chain acyclic hydrocarbon having 2 to 10 carbon atoms, typically 2 to 8 carbon atoms, and containing at least one carbon-carbon double bond. Representative straight-chain and branched (C2C8) alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, 2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, 3-octenyl, and the like. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Alkenyl groups can be substituted or unsubstituted.

[0011] An "alkynyl" group refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more carbon-carbon triple bonds. Alkynyl is optionally substituted and can be straight-chained, branched, or cyclic. Alkynyl includes radicals having 2 to 20 carbon atoms, i.e., C 2-20 Alkynyl radicals, radicals having 2 to 12 carbon atoms, i.e., C 2-12 Alkynyl radicals, radicals having 2 to 8 carbon atoms, i.e., C 2-8 Alkynyl radicals, radicals having 2 to 6 carbon atoms, i.e., C 2-6 Alkynyl radicals and radicals having 2 to 4 carbon atoms, i.e., C 2-4 Examples of alkynyl radicals include, but are not limited to, ethynyl, propynyl, and butynyl.

[0012] A "cycloalkyl" group is a saturated, partially saturated, or unsaturated cyclic alkyl group of 3 to 10 carbon atoms having a single cyclic ring or multiple fused or bridged rings, optionally substituted with 1 to 3 alkyl groups. In some embodiments, cycloalkyl groups have 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyls containing more than one ring can be fused, spiro, or bridged, or combinations thereof. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. Examples of unsaturated cycloalkyl groups include, among others, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkyl groups may be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol and the like.

[0013] An "aryl" group is an aromatic carbocyclic group having 6 to 14 carbon atoms, having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups have 6 to 14 carbons, and in other embodiments, 6 to 12 or even 6 to 10 carbon atoms, in the ring portion of the group. Specific aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing condensed rings, for example, fused aromatic aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0014] A "heterocyclyl" is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S, and N. In some embodiments, heterocyclyl groups contain 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. A heterocyclyl can also be attached to another group at any ring atom (i.e., any carbon atom or heteroatom of the heterocyclic ring). Heterocyclyl groups can be substituted or unsubstituted. Heterocyclyl groups can include multiple fused rings, including, but not limited to, bicyclic, tricyclic, and tetracyclic rings, as well as bridged or spirocyclic ring systems. Heterocyclyl groups encompass unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidine-2,4-dionyl) groups. The phrase heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as, for example, 1- and 2-aminotetralin, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing heteroatoms, such as, for example, but not limited to, quinuclidyl. Representative examples of heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, Linyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decanyl, 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane, 1-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5] ]decane, 3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane, 2-oxo-1-oxa-3,9-diazaspiro[5.5]undecane, homopiperazinyl, quinuclidyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), indolinyl, isoindolyl, isoindolinyl, azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, Representative non-aromatic heterocyclyl groups include, but are not limited to, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one, and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups do not include fused ring species that contain fused aromatic groups. Examples of non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups can be mono- or multiply substituted, for example, but not limited to, pyridyl or morpholinyl groups can be di-, 3-, 4-, 5-, or 6-substituted or di-substituted with various substituents such as those described below.

[0015] A "heteroaryl" group is an aryl ring system having 1 to 4 heteroatoms as ring atoms in the heteroaromatic ring system, with the remainder of the atoms being carbon atoms. In some embodiments, heteroaryl groups have 3 to 6 ring atoms, and in other embodiments, 6 to 9 or 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azaindolyl), Examples of such groups include, but are not limited to, benzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0016] As used herein, "spirocyclic ring" refers to two or more rings in which adjacent rings are connected via a single atom. The individual rings within a spirocyclic ring may be the same or different. The individual rings within a spirocyclic ring may be substituted or unsubstituted and may have different substituents than the other individual rings within a set of spirocyclic rings.

[0017] An "aralkyl" group is a radical of the formula: -alkyl-aryl, where alkyl and aryl are defined above. Substituted aralkyl groups can be substituted on the alkyl, aryl, or both the alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.

[0018] "Halogen" means fluorine, chlorine, bromine, or iodine.

[0019] A "hydroxyalkyl" group is an alkyl group as defined above that is substituted with one or more hydroxy groups.

[0020] An "alkoxy" or "alkoxyl" group is an --O-(alkyl), where alkyl is as defined above.

[0021] An "alkoxyalkyl" group is an -(alkyl)-O-(alkyl), where alkyl is defined above.

[0022] An "amino" group is a radical of the formula: --NH.sub.2.

[0023] An "alkylamino" group is a radical of the formula: --NH-alkyl or --N(alkyl)2, where each alkyl is independently as defined above.

[0024] A "carboxy" group is a radical of the formula: --C(O)OH.

[0025] An “aminocarbonyl” group is a group of the formula: —C(O)N(R # )2, -C(O)NH(R # ), or a radical of —C(O)NH2, where each R # are independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclyl group, as defined herein.

[0026] An “acylamino” group refers to a group of the formula: —NHC(O)(R # ) or -N(alkyl)C(O)(R # ) radical, where each alkyl and R # are independently as defined above.

[0027] A "urea" group refers to a group of the formula: -N(alkyl)C(O)N(R # )2, -N(alkyl)C(O)NH(R # ), -N(alkyl)C(O)NH2, -NHC(O)N(R # )2, -NHC(O)NH(R # ), or -NH(CO)NHR # where each alkyl and R # are independently as defined above.

[0028] With the exception of alkyl groups, when groups described herein are said to be "substituted," they can be substituted with any suitable substituent(s). Illustrative examples of substituents include those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonate, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, oxygen (=O), B(OH), O(alkyl)aminocarbonyl, cycloalkyl (which is a monocyclic or fused or non-fused polycyclic rings) (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl (which may be a single ring or a fused or non-fused polycyclic ring) (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl), single ring or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl), aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy.

[0029] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to, those well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA (1995).

[0030] As used herein, and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" refers to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound will contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of that compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of that compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of that compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of that compound. The compounds may contain chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof, and all such isomers, including mixtures thereof, are included in the embodiments disclosed herein.

[0031] The use of stereomerically pure forms of such compounds, as well as mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0032] It should also be noted that the compounds can include E and Z isomers, or mixtures thereof, as well as cis and trans isomers, or mixtures thereof. In certain embodiments, the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are a mixture of E and Z isomers.

[0033] As used herein, and unless otherwise indicated, "atropisomer" refers to a stereoisomer resulting from hindered rotation about a single bond axis, where the rotational barrier is high enough to allow isolation of individual rotamers.

[0034] Throughout this specification and embodiments thereunder, "C n-m The term " refers to a range inclusive of the endpoints, where n and m are integers and refer to the number of carbon atoms. Examples include C 1-8 , and C1-6 Includes:

[0035] In the appended claims and in the foregoing description, unless the context requires otherwise, either by express words or necessary implication, the term "comprise" or variations such as "comprises" or "comprising" are used in their inclusive sense, i.e., to clearly indicate the presence of stated features but not to exclude the presence or addition of further features in various embodiments.

[0036] Provided herein are intermediates that significantly increase the yield and purity of Sonrotoclax, which are also stable enough to provide an industrially robust process. The inventors have found that Sonrotoclax can be obtained in the solid state with greater than 90% purity and greater than 70% yield.

[0037] In one embodiment, disclosed herein is a compound of formula (I): The embodiment includes the following aspects:

[0038] Aspect 1. A compound of formula (I): [ka] or a salt or stereoisomer thereof, wherein each occurrence of R is independently C 2-6 Alkyl or C 3-6 cycloalkyl, wherein C 2-6 Alkyl or C 3-6 Each cycloalkyl may optionally be selected from the group consisting of halogen, -C 1-8 , -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -C(=O)R 1a , -C(=O)OR 1a, -OC(=O)R 1a , -OR 1a , -SO2R 1a , -SR 1a , -NR 1a R 1b , -C(=O)NR 1a R 1b , -OC(=O)NR 1a R 1b , -NR 1a C(=O)NR 1b R 1c , or -NR 1a C(=O)R 1b is replaced by, or Two R's, together with the two oxygen atoms bonded to each, form a 5- to 12-membered ring, which may optionally contain halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -C(=O)R 1a , -C(=O)OR 1a , -OC(=O)R 1a , -OR 1a , -SO2R 1a , -SR 1a , -NR 1a R 1b , -C(=O)NR 1a R 1b , -OC(=O)NR 1a R 1b , -NR 1a C(=O)NR 1b R 1c , or -NR 1a C(=O)R 1b and is substituted with at least one substituent selected from R 1 is C 1-6 Alkyl or C 3-6 cycloalkyl, wherein C 1-6 Alkyl or C 3-6 Each cycloalkyl may optionally be selected from the group consisting of halogen, -C 1-8 Alkyl, -C 2-8Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -C(=O)R 1a , -C(=O)OR 1a , -OC(=O)R 1a , -OR 1a , -SO2R 1a , -SR 1a , -NR 1a R 1b , -C(=O)NR 1a R 1b , -OC(=O)NR 1a R 1b , -NR 1a C(=O)NR 1b R 1c , or -NR 1a C(=O)R 1b is replaced by In each of its occurrences, R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -haloC 1-6 Alkyl, or -haloC 3-6 cycloalkyl.

[0039] In particular, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azadispiro[5.1.5 8 .1 6 ]tetradecan-11-yl)methyl benzoate is a key intermediate for the synthesis of Sonrotoclax, which is derived from 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6 ]tetradecane hydrochloride and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate can be obtained by a base-assisted SNAr reaction. 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azadispiro[5.1.5 8.1 6 The synthesis and process of methyl ]tetradecan-11-yl)benzoate (Compound 1) is highly desirable because compound 1 as an intermediate with high purity and high yield can meet the manufacturing requirements of the final product Sonrotoclax. [ka]

[0040] Aspect 2. The compound of Aspect 1, each R is independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, oxo, —CN, —NO2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or two R's, together with the two oxygen atoms bonded thereto, form a 3- to 12-membered ring, which is optionally substituted with at least one substituent selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and optionally substituted with at least one substituent selected from F, Cl, Br, I, oxo, -CN, -NO2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; R 1are each independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is substituted with at least one substituent selected from F, Cl, Br, I, oxo, —CN, —NO2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0041] Aspect 3. The compound of Aspect 1, R is, independently at each occurrence, methyl, ethyl, 1-propyl, or 2-propyl; two R's, together with the two oxygen atoms bonded to each R, form a 3-, 5-, 6-, 7-, or 8-membered ring; R 1 is methyl, ethyl, 1-propyl, or 2-propyl.

[0042] Embodiment 4. The compound of embodiment 2, wherein two R's, together with the two oxygen atoms to which they are bonded, form a ring containing three or more carbon atoms; R 1 is methyl.

[0043] Aspect 5. The compound of aspect 1, having the following structure: [ka]

[0044] Embodiment 6. A method of preparing a compound of Formula (I) according to any one of Embodiments 1-5, said method comprising:

[0045] reacting the compound of formula (II) with the compound of formula (III) in the presence of a base and a solvent to form the compound of formula (I); [ka] wherein X is a halogen, preferably F, Cl, Br, or I, and preferably F.

[0046] To optimize the synthesis of Sonrotoclax and obtain a more stable intermediate of formula (II), pharmaceutically acceptable alcohols, including methanol, ethanol, isopropanol, glycol, and 1,3-propanediol, have been used for the ketone protection of 1-azaspiro[3.5]nonan-2-one. We have found that among these alcohols, only 1,3-propanediol is suitable for the ketone protection of 1,5-dioxa-11-azadispiro[5.1.5]nonan-2-one. 8 .1 6 We found that tetradecane hydrochloride (Compound 2) was produced in a good physical form and with a high purity of 99.9% in the solid state. Furthermore, Compound 2 in the solid state was also found to be highly stable, with no increase in impurities, when stored at 2-8°C for 3.5 months or more.

[0047] Embodiment 7. The method of embodiment 6, comprising: the base is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), me-piperidine, and N,N-diisopropylethylamine (DIPEA), or a combination thereof; Preferably, it is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or a combination thereof; More preferably, it is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0048] Aspect 8. The method according to any one of aspects 6 to 7, comprising: the molar ratio of the base used in the reaction to the compound of formula (II) is 0.9 to 1.3; Preferably, the molar ratio of the base used in the reaction to the compound of formula (II) is about 1.

[0049] Aspect 9. The method according to any one of aspects 6 to 8, comprising: the solvent is selected from the group consisting of N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), 2-methyltetrahydrofuran (2-MeTHF), 4-methyl-2-pentanone (MIBK), or toluene, or a combination thereof; N-methylpyrrolidone (NMP) is preferred. In a further embodiment, NMP provided better conversion and lower impurities.

[0050] Aspect 10. The method of any one of aspects 6 to 9, comprising: the weight ratio of the solvent used in the reaction to the total weight of the compound of formula (II) and the compound of formula (III) is about 4 to 6; Preferably, it is about 5.

[0051] Aspect 11. The method of any one of Aspects 6 to 10, wherein the amount of the compound of Formula (II) used in the reaction ranges from about 1.3 molar equivalents to about 1.8 molar equivalents relative to the amount of the compound of Formula (III); Preferably, it is in the range of about 1.45 molar equivalents to about 1.65 molar equivalents.

[0052] Aspect 12. The method of any one of Aspects 6 to 11, wherein the reaction temperature range is from about 40°C to about 100°C; Preferably, the temperature is about 65°C to about 80°C. More preferably, it is about 75°C.

[0053] Aspect 13. The method of any one of Aspects 6-12, wherein said method includes: Step 1): The compound of formula (II) is reacted with the compound of formula (III) in the presence of a base and a solvent. Step 2): After the reaction of step 1) is completed, water, AcOH, and crystal seeds of formula (I) are added to the reaction system, and after filtration, a crude product containing the compound of formula (I) is obtained. Step 3): The crude product containing the compound of formula (I) is slurried with a mixture of solvents, filtered, and dried to provide the compound of formula (I). In one embodiment, the seed crystals of formula (I) were prepared by the following method, including: Step 1-1): The compound of formula (II) is reacted with the compound of formula (III) in the presence of a base and a solvent. Step 2-1): After the reaction of step 1) is completed, water and AcOH are added to the reaction system, and after filtration, a crude product containing the compound of formula (I) is obtained. Step 3-1): The crude product containing the compound of formula (I) is slurried with a mixture of solvents, filtered, and dried to obtain crystalline seeds of formula (I).

[0054] Aspect 14 The method of Aspect 13, wherein the mixture of solvents comprises 2-MeTHF and n-heptane.

[0055] Embodiment 15. The method according to embodiment 14, wherein 2-MeTHF:n-heptane (v:v) is 1 to 4:1.

[0056] Aspect 16. Provided herein is a method of making Sonrotoclax. In one embodiment, the method comprises reacting the compound of formula (I) with an acid or base to produce a compound of formula (SI): [ka] or a salt thereof.

[0057] In one embodiment, the acid is HCl or the base is NaOH.

[0058] Aspect 17. Provided herein is a method of making Sonrotoclax. In one embodiment, the method comprises reacting the compound of formula (SI) with (S)-2-(2-isopropylphenyl)pyrrolidine, or a salt thereof, to produce a compound of formula (SII): [ka] or a salt thereof.

[0059] In one embodiment, the reaction occurs in the presence of NaBH(OAc) 3 .

[0060] In one embodiment, the reaction occurs at less than about 30°C.

[0061] Aspect 18. Provided herein is a method for making Sonrotoclax. In one embodiment, the method comprises: [ka] or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide to produce Sonrotoclax, [ka] Or providing salt.

[0062] In one embodiment, the reaction occurs in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP).

[0063] Aspect 19. Provided herein is a method of making Sonrotoclax. In one embodiment, the method comprises reacting the compound of formula (SII) with an acid or a base to produce (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid, [ka] or a salt thereof.

[0064] In one embodiment, the acid is HCl or the base is NaOH.

[0065] Aspect 20. Provided herein is a method of making Sonrotoclax. In one embodiment, the method comprises: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid; [ka] or a salt thereof, together with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide, [ka] Or providing salt.

[0066] In one embodiment, the reaction occurs in the presence of EDCI and DMAP.

[0067] In one embodiment, provided herein is a method for preparing a pharmaceutical composition comprising Sonrotoclax, comprising mixing Sonrotoclax with a pharmaceutically acceptable excipient, wherein the Sonrotoclax is prepared according to the method provided herein.

[0068] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by those of ordinary skill in the art.

[0069] Numbered embodiments: Embodiment 1. A compound of formula (I): [ka] or a salt or stereoisomer thereof, wherein, at each occurrence, R is independently selected from C 2-6 Alkyl or C 3-6 cycloalkyl, wherein C 2-6 Alkyl or C 3-6 Each cycloalkyl may optionally be selected from the group consisting of halogen, -C 1-8 , -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -C(=O)R 1a , -C(=O)OR 1a , -OC(=O)R 1a , -OR 1a , -SO2R 1a , -SR 1a , -NR 1a R 1b , -C(=O)NR 1a R 1b , -OC(=O)NR 1a R 1b , -NR 1a C(=O)NR 1b R 1c , or -NR 1a C(=O)R 1bis replaced by, or Two R's, together with the two oxygen atoms bonded to each, form a 5- to 12-membered ring, which may optionally contain halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -C(=O)R 1a , -C(=O)OR 1a , -OC(=O)R 1a , -OR 1a , -SO2R 1a , -SR 1a , -NR 1a R 1b , -C(=O)NR 1a R 1b , -OC(=O)NR 1a R 1b , -NR 1a C(=O)NR 1b R 1c , or -NR 1a C(=O)R 1b and is substituted with at least one substituent selected from R 1 is C 1-6 Alkyl or C 3-6 cycloalkyl, wherein C 1-6 Alkyl or C 3-6 Each cycloalkyl may optionally be selected from the group consisting of halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -C(=O)R 1a , -C(=O)OR 1a , -OC(=O)R 1a , -OR 1a , -SO2R 1a , -SR 1a , -NR 1a R 1b , -C(=O)NR 1aR 1b , -OC(=O)NR 1a R 1b , -NR 1a C(=O)NR 1b R 1c , or -NR 1a C(=O)R 1b is replaced by In each occurrence, R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -haloC 1-6 Alkyl, or -haloC 3-6 cycloalkyl.

[0070] Embodiment 2. A compound according to embodiment 1, each R is independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, oxo, —CN, —NO2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or two R's, together with the two oxygen atoms bonded thereto, form a 3- to 12-membered ring, which is optionally substituted with at least one substituent selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and optionally substituted with at least one substituent selected from F, Cl, Br, I, oxo, -CN, -NO2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; R 1 are each independently methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is substituted with at least one substituent selected from F, Cl, Br, I, oxo, —CN, —NO2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0071] Embodiment 3. A compound according to embodiment 1, R is, independently at each occurrence, methyl, ethyl, 1-propyl, or 2-propyl; two R's, together with the two oxygen atoms bonded to each R, form a 3-, 5-, 6-, 7-, or 8-membered ring; R 1 is methyl, ethyl, 1-propyl, or 2-propyl.

[0072] Embodiment 4. A compound according to embodiment 2, wherein two R's, together with the two oxygen atoms to which they are attached, form a ring containing three or more carbon atoms; R 1 is methyl.

[0073] Embodiment 5. The compound of embodiment 1, having the structure: [ka]

[0074] Embodiment 6. A method for preparing a compound of formula (I) according to any one of embodiments 1 to 5, said method comprising: reacting a compound of formula (II) with a compound of formula (III) in the presence of a base and a solvent to form said compound of formula (I); [ka] In the formula, X is a halogen, preferably X is F, Cl, Br, or I, and more preferably X is F.

[0075] Embodiment 7. The method of embodiment 6, wherein the base is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), me-piperidine, and N,N-diisopropylethylamine (DIPEA), or a combination thereof; Preferably, it is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or a combination thereof; More preferably, it is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0076] Embodiment 8. The method according to any one of embodiments 6 to 7, wherein the molar ratio of the base used in the reaction to the compound of formula (II) is 0.9 to 1.3; Preferably, the molar ratio of the base used in the reaction to the compound of formula (II) is about 1.

[0077] Embodiment 9. The method of any one of embodiments 6-8, wherein the solvent is selected from the group consisting of N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), 2-methyltetrahydrofuran (2-MeTHF), 4-methyl-2-pentanone (MIBK), or toluene, or a combination thereof; N-methylpyrrolidone (NMP) is preferred.

[0078] Embodiment 10. The method according to any one of embodiments 6 to 9, wherein the weight ratio of the solvent used in the reaction to the total amount of the compound of formula (II) and the compound of formula (III) is about 4 to 6; Preferably, it is about 5.

[0079] Embodiment 11. The method of any one of embodiments 6 to 10, wherein the amount of the compound of Formula (II) used in the reaction ranges from about 1.3 molar equivalents to about 1.6 molar equivalents relative to the amount of the compound of Formula (III); Preferably, it is in the range of about 1.45 molar equivalents to about 1.65 molar equivalents.

[0080] Embodiment 12. The method of any one of embodiments 6 to 11, wherein the reaction temperature range is from about 40°C to about 100°C; Preferably, the temperature is about 65°C to about 80°C. More preferably, it is about 75°C.

[0081] Embodiment 13. The method according to any one of embodiments 6 to 12, wherein the method comprises: Step 1): The compound of formula (II) is reacted with the compound of formula (III) in the presence of a base and a solvent. Step 2): After the reaction of step 1) is completed, water, AcOH, and crystal seeds of formula (I) are added to the reaction system, and after filtration, a crude product containing the compound of formula (I) is obtained. Step 3): The crude product containing the compound of formula (I) is slurried with a mixed solvent, filtered, and dried to obtain the compound of formula (I).

[0082] Embodiment 14 The method of embodiment 13, wherein the mixed solvent comprises 2-MeTHF and n-heptane.

[0083] Embodiment 15 The method according to embodiment 14, wherein 2-MeTHF:n-heptane (v:v) is 1 to 4:1. [Example]

[0084] General Synthesis The compounds disclosed herein and their salts can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic routes.

[0085] The reaction for preparing the compounds disclosed herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.Suitable solvents can be substantially non-reactive with starting materials, intermediates, or products at the temperature at which the reaction is carried out, for example, the temperature can range from the boiling temperature of the solvent to the freezing temperature.A given reaction can be carried out in one solvent or a mixture of solvents.

[0086] The selection of an appropriate protecting group can be readily determined by one of ordinary skill in the art.

[0087] Reactions can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. Compounds can be purified by a variety of methods, including HPLC and normal phase silica chromatography. [ka]

[0088] Compounds of formula (I) can be prepared as shown in Scheme I. Nucleophilic aromatic substitution (SNAr) between compound 2 and compound 3 under the aid of a base gives compound 1. For example, [ka]

[0089] [Table 2-1] [Table 2-2]

[0090] The following examples are intended to be merely illustrative and should not be construed as limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be expected. Temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification unless otherwise indicated. Unless otherwise indicated, the reactions described below were carried out under a positive pressure of nitrogen or argon or in anhydrous solvents using drying tubes; reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven-dried and / or heat-dried.

[0091] HPLC: Waters with UV detector or equivalent. Mobile phase: A: Water with 0.01% TFA, B: Acetonitrile with 0.01% TFA. Column: Waters CORTECS C18+, 100 x 4.6 mm, 2.7 um, PN: 186007407. Gradient: Flow rate: 1.0 mL / min, Time (min) A (%) B (%) [Table 3]

[0092] Control Example: [ka] Compound C1 was prepared by the reaction between compound C2 and compound 3. However, compound C1 was found to be unstable and easy to deprotect. Therefore, it cannot be a useful intermediate for preparing Sonrotoclax.

[0093] Compound C1 was prepared as follows.

[0094] To a suspension of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.01 g, 3.49 mmol) and 2,2-dimethoxy-7-azaspiro[3.5]nonane hydrochloride (1.06 g, 4.54 mmol, prepared by the method disclosed in WO2019 / 210828) in NMP (5 mL), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 80 °C for 24 hours and cooled to 50 °C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The mixture solution was stirred at 50 °C for 6 hours and then cooled to 20 °C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried with a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). After drying, the product was obtained. MS: 451.2.

[0095] Example A1: 1,5-Dioxa-11-azadispiro[5.1.5.1]tetradecane Hydrogen Chloride [ka] tert-Butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (10.0 g, 41.8 mmol) was charged to a nitrogen-inert reactor. IPAc (20.0 mL) was added to the reactor to form a mixture. The mixture was stirred at 20-30°C for 1 hour. To this mixture, triethyl orthoformate (8.1 g, 54.7 mmol) was added, followed by 1,3-propylene glycol (10.0 g, 129.6 mmol). A 15% HCl / IPAc solution (36.0 g, 146.3 mmol) was fed to the reactor while maintaining the batch temperature at 20-30°C for approximately 20 hours. The product was examined by GC (carrier gas: helium (He)), which showed that 99.9% of 1,5-dioxa-11-azadispiro[5.1.5.1]tetradecane hydrogen chloride was obtained and the solid was well separated. GC-MS: 197.1

[0096] Example A2: 1,5-Dioxa-11-azadispiro[5.1.5.1]tetradecane Hydrogen Chloride [ka] tert-Butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (10.0 g, 41.8 mmol) was charged to a nitrogen-inert reactor. IPAc (20.0 mL) was added to the reactor to form a mixture. The mixture was stirred at 20-30°C for 1 hour. Triethyl orthoformate (8.1 g, 54.7 mmol) was added to the mixture, followed by 1,3-propylene glycol (10.0 g, 129.6 mmol). A 15% HCl / IPAc solution (36.0 g, 146.3 mmol) was fed to the reactor while maintaining the batch temperature at 20-30°C for approximately 16 hours. Upon completion of the reaction, methyl tertiary butyl ether (MTBE, 27 mL) was charged to the batch while maintaining the batch temperature at 25±5°C. The mixture was aged for approximately 6 hours, then centrifuged to collect the wet cake. The cake is washed with MTBE (27 ml). The wet cake is dried under vacuum at 40±5° C. for 20 hours to give the solid product 1,5-dioxa-11-azadispiro[5.1.5.1]tetradecane hydrochloride. 1H NMR (400MHz, d-DMSO) δ8.908(s,2H),3.722(t,4H),2.924(m,4H),1.906(s,4H),1.692(t,4H),1.554(t,2H). GC-MS:197.1

[0097] Example A3: Stability test of 1,5-dioxa-11-azadispiro[5.1.5.1]tetradecane hydrochloride 1,5-Dioxa-11-azadispiro[5.1.5.1]tetradecane hydrochloride (2.0 g, 8.4 mmol) was stored at 2-8°C, packaged in a double-layered LDPE bag with a desiccant between the two layers, and then placed in a heat-sealed aluminum foil bag for 3.5 months. The sample was analyzed by GC (carrier gas: N2) and HPLC (column: Waters Xselect HSS T3 (150 mm x 4.6 mm, 3.5 μm) P / N: 186004786; mobile phase: 0.05% TFA aqueous solution, ACN:MeOH = 1:1, v / v; flow rate: 1 mL / min; temperature: 30°C). The results in Table 1 indicate that the intermediate 1,5-dioxa-11-azadispiro[5.1.5.1]tetradecane hydrochloride was sufficiently stable under these conditions. [Table 1]

[0098] Example 1: NMP as solvent, DBU as base, reaction temperature: 80°C and 1.3 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate was synthesized according to the method in WO2019210828 (e.g., Example F43), which is incorporated by reference in its entirety.

[0099] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6 To a suspension of tetradecane hydrochloride (1.06 g, 4.54 mmol), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 93.17%, Yield: 83%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0100] Example 2: NMP as solvent, DBU as base, reaction temperature: 80°C and 1.45 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.18 g, 5.06 mmol), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 90.59%, Yield: 87%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0101] Example 3: NMP as solvent, DBU as base, reaction temperature: 80°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 93.91%, Yield: 86%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0102] Example 4: NMP as solvent, DBU as base, reaction temperature: 60°C and 1.60 equivalents of compound (I) (relative to the equivalents of compound (II)) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 60°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 93.83%, Yield: 82%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0103] Example 5: NMP as solvent, DBU as base, reaction temperature: 65°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 65°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 95.62%, Yield: 83%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0104] Example 6: NMP as solvent, DBU as base, reaction temperature: 70°C and 1.60 equivalents of compound (I) (relative to the equivalents of compound (II)) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 70°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 95.26%, Yield: 83%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0105] Example 7: NMP as solvent, DBU as base, reaction temperature: 75°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), followed by DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 75°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 95.25%, Yield: 81%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0106] Example 8: NMP as solvent, DBU as base, reaction temperature: 80°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 94.27%, Yield: 83%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0107] Example 9: DMSO as solvent, DBU as base, reaction temperature: 80°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 94.27%, Yield: 81%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0108] Example 10: 2-MeTHF as solvent, DBU as base, reaction temperature: 80°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), followed by DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 80.18%, Yield: 71%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0109] Example 11: MIBK as solvent, DBU as base, reaction temperature: 80°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5] in MIBK (5 mL) 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 90.91%, Yield: 78%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0110] Example 12: Toluene as solvent, DBU as base, reaction temperature: 80°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 87.31%, Yield: 76%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0111] Example 13: DMAc as solvent, DBU as base, reaction temperature: 80°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 94.36%, Yield: 83%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0112] Example 14: NMP as solvent, TMG as base, reaction temperature: 80°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), TMG (1.13 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 87.51%, Yield: 80%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0113] Example 15: NMP as solvent, DBN as base, reaction temperature: 80°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), followed by DBN (1.22 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 5.5%, Yield: ND. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0114] Example 16: NMP as solvent, DABCO as base, reaction temperature: 80°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), DABCO (1.10 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 8.9%, Yield: 5%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0115] Example 17: NMP as solvent, Me-piperidine as base, reaction temperature: 80° C. and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), Me-piperidine (0.98 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 84.38%, Yield: 70%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0116] Example 18: NMP as solvent, DIPEA as base, reaction temperature: 80°C and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3) [ka] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol), DIPEA (1.27 g, 9.85 mmol) was added. The resulting solution was stirred at 80°C for 24 hours and cooled to 50°C. The pH was adjusted to a target value of 7 with AcOH, and then water (1.5 mL) was added, followed by the addition of seeds (0.01 g). The resulting solution was stirred at 50°C for 6 hours and then cooled to 20°C. The wet cake was collected by filtration and washed with water. The resulting wet cake was slurried in a mixed solvent of 2-MeTHF (8 mL) and n-heptane (2 mL). The product was obtained after drying. Purity: 86.18%, Yield: 76%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0117] Example 19: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Sonrotoclax) Step 1: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azaspiro[5.1.5]) in DCM (2 L) 8 .1 6To a solution of methyl tetradecan-11-ylbenzoate (180 g, 0.39 mol), diluted HCl (1 M, 1.5 L) was added and stirred overnight. After the reaction was complete, the mixture was cooled to 10 °C and adjusted to pH 8-9 with aqueous NaOH (4 M) while stirring. The organic phase was separated and washed with 15% aqueous NaCl (1 L) and then with HO (1 L). After concentrating the organic phase to 500 mL, MTBE (1 L) was poured into the solution, and the system was then concentrated to 500 mL (this workup was repeated three times). The resulting system was stirred for 0.5 h. After filtration, the cake was collected and then dried under vacuum to give the title product as a white solid (152 g, yield: 96%). 1 H NMR(400MHz,DMSO-d6)δppm:11.64(s,1H),8.02(d,J=2.4Hz,1H),7.78(d,J=9.2Hz,1H),7.47(t,J=3.2Hz,1H),7.44(d,J=2.4Hz,1H),6. 83(dd,J=2.4Hz,J=9.2Hz,1H),6.43(d,J=2.4Hz,1H),6.38-6.36(m,1H),3.65(s,3H),3.24-3.21(m,4H),2.80(s,4H),1.70-1.67(m,4H). MS(ESI,m / e)[M+1] + 405.9.

[0118] Step 2: (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate To a mixture of (S)-tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (50 g, 153.3 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (38.6 g, 229.9 mmol) in dioxane (500 mL) and HO (50 mL) was added CsCO (100 g, 305 mmol) and Pd(dppf)Cl (6.6 g, 7.5 mmol). The mixture was stirred at 100 °C for 8 h. TLC indicated the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE / EA (v / v) = 100 / 1 to 10 / 1) to give (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (65 g, crude). The crude product was used directly in the next step.

[0119] Step 3: (S)-tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate To a solution of (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (30 g, 104.39 mmol) in MeOH (500 mL) was added Pd / C (10 g, 10%), and the mixture was stirred at 20 °C under H (15 psi) for 12 h. TLC showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated in vacuo to give (S)-tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (60 g, crude), which was used in the next step without further purification. 1 H NMR(400MHz,CDCl3)δppm:7.39-6.90(m,4H),5.36-5.04(m,1H),3.77-3.52(m,2H),3.20-3.17( m, 1H), 2.47-2.24 (m, 1H), 1.96-1.65 (m, 3H), 1.54-1.38 (m, 2H), 1.31-1.22 (m, 8H), 1.17 (s, 7H).

[0120] Step 4: (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride To a solution of tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (55 g, 190 mmol) in DCM (50 mL) was added dropwise HCl in 1,4-dioxane (4 M, 142 mL, 570 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The resulting residue was slurried with EA (100 mL), then filtered and evaporated to dryness in vacuo to give (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride 26 g (yield: 60.4%). 1 H NMR (400 MHz, DMSO- d 6) δppm:9.93(s,1H),8.81(s,1H),7.63-7.57(m,1H),7.41-7.34(m,2H),7.32-7.24(m,1H),4.91-4.75(m,1H),3.47 -3.35(m,1H),3.31-3.25(m,1H),2.40-2.21(m,1H),2.19-1.86(m,3H),1.25(d,J=6.7Hz,3H),1.17(d,J=6.7Hz,3H). MS(ESI,m / e)[M+1] + 190.0.

[0121] Step 5: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate methyl A mixture of (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride (120 g, 0.535 mol) and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate (218 g, 0.509 mol) in DCM (2.2 L) was charged into a reactor. The temperature was controlled below 30 °C, and NaBH(OAc) (216 g, 1.018 mol) was added to the reactor in 5-6 portions. The reaction mixture was then stirred at room temperature overnight and monitored by TLC. After the starting ketone was completely consumed, the mixture was adjusted to pH 4-5 with dilute HCl acid (0.5 M). The separated organic phase was washed with H2O (600 mL x 2), then with aqueous NaHCO3 (600 mL x 2), and saturated aqueous NaCl (600 mL). The organic phase was collected, then dried over anhydrous Na2SO4, and concentrated. 256 g of an off-white solid was obtained as crude product, which was used directly in the next step. MS (ESI, m / e) [M+1] + 579.0.

[0122] Step 6: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid To a solution of (S)-methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (105 g, 181.7 mmol) in THF (525 mL) and MeOH (525 mL) was added aqueous NaOH (3.5 M). The mixture was stirred at room temperature overnight. After the THF and MeOH were removed in vacuo, 3.5 L of water was added to the residue. The resulting mixture was adjusted to pH 5-6 with 3N HCl acid while stirring at room temperature. The precipitate was filtered and evaporated to dryness to give the product as a white solid (102.4 g, yield: 99%). 1 H NMR (400 MHz, DMSO- d6) δppm:12.13(s,1H),11.58(s,1H),7.95(s,1H),7.67(d,J=8.0Hz,1H),7.5 6-7.40(m,2H),7.35(s,1H),7.27-7.04(m,3H),6.68(d,J=8.0Hz,1H),6.32( s,2H),3.62(s,1H),3.32-3.26(m,1H),3.10-3.04(m,4H),2.35-2.30(m,1H) ,2.9-2.15(m,1H),1.74-1.64(m,4H),1.52-1.37(m,6H),1.28-1.06(m,6H). MS(ESI,m / e)[M+1] + 564.9.

[0123] Step 7: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Sonrotoclax) A mixture of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (44 g, 78 mmol), 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (26.8 g, 78 mmol), TEA (15.7 g, 156 mmol), EDCI (19.4 g, 101 mmol), and DMAP (19 g, 156 mmol) in anhydrous DCM (880 mL) was stirred at room temperature overnight. The reaction was monitored by HPLC. After complete consumption of the (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid starting material, the reaction mixture was heated to about 35° C. and N 1 ,N 117.2 g (195 mmol) of 1,2-dimethylethane-1,2-diamine was added in one portion. The reaction mixture was stirred for an additional 12 h. The mixture was washed twice with 10 wt% aqueous AcOH (300 mL × 2) and then with saturated aqueous NaHCO3 (300 mL × 2). The organic layer was collected and concentrated to approximately 90 mL. 22 g of silica gel was added and stirred for 2 h. After filtration, 180 mL of EA was added to the refluxing filtrate and stirred for an additional 5 h. After cooling the mixture to room temperature, the precipitate was filtered, and the wet cake was washed twice with EA (180 mL). After drying under vacuum at 80-90 °C, the desired compound was obtained (48 g, yield: 69.5%). 1 H NMR (DMSO- d 6) δppm:11.65(s,1H),11.11(br,1H),8.58-8.39(m,2H),8.00(d,J=2.8Hz,1H),7.74(d,J=8. 8Hz,1H),7.57-7.37(m,4H),7.30-7.10(m,3H),7.00(d,J=9.2Hz,1H),6.65(d,J=1.2Hz,1H),6 .35(s,1H),6.17(s,1H),4.24(s,1H),3.39-3.20(m,5H),3.04-2.88(m,4H),2.23(s,1H),1.9 4-1.47(m,11H),1.44-1.26(m,7H),1.19(d,J=8.0Hz,3H),1.14(d,J=8.0Hz,3H),1.10(s,4H). MS(ESI, m / e)[M+1] + 889.9.

Claims

1. A compound having the following structure: 【Chemistry 40】 Or its salt.

2. A compound of formula (SI), 【Chemistry 41】 or a salt thereof, comprising: Compounds of formula (I) 【Chemistry 42】 or a salt thereof, with an acid or base, wherein R at each occurrence is independently selected from the group consisting of C ２－６ Alkyl or C ３－６ cycloalkyl, ２－６ Alkyl or C ３－６ Each cycloalkyl is optionally selected from halogen, —C １－８ Alkyl, —C ２－８ Alkenyl, -C ２－８ Alkynyl, —C ３ ~C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ ~C １２ Aryl, 5- to 12-membered heteroaryl, oxo, —CN, —NO ２ , -C(=O)R １ａ , -C(=O)OR １ａ , —OC(═O)R １ａ , -OR １ａ , -SO ２ R １ａ , -SR １ａ , -NR １ａ R １ｂ , —C(═O)NR １ａ R １ｂ , -OC(=O)NR １ａ R １ｂ , -NR １ａ C(=O)NR １ｂ R １ｃ , or -NR １ａ C(=O)R １ｂ is replaced by, or Two R's, together with the two oxygen atoms bonded to each, form a 5- to 12-membered ring, which may optionally contain halogen, -C １－８ Alkyl, —C ２－８ Alkenyl, -C ２－８ Alkynyl, —C ３ ~C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ ~C １２ Aryl, 5- to 12-membered heteroaryl, oxo, —CN, —NO ２ , -C(=O)R １ａ , -C(=O)OR １ａ , —OC(═O)R １ａ , -OR １ａ , -SO ２ R １ａ , -SR １ａ , -NR １ａ R １ｂ , —C(═O)NR １ａ R １ｂ , -OC(=O)NR １ａ R １ｂ , -NR １ａ C(=O)NR １ｂ R １ｃ , or -NR １ａ C(=O)R １ｂ and is substituted with at least one substituent selected from R １ is C １－６ Alkyl or C ３－６ cycloalkyl, １－６ Alkyl or C ３－６ Each cycloalkyl is optionally selected from halogen, —C １－８ Alkyl, —C ２－８ Alkenyl, -C ２－８ Alkynyl, —C ３ ~C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ ~C １２ Aryl, 5- to 12-membered heteroaryl, oxo, —CN, —NO ２ , -C(=O)R １ａ , -C(=O)OR １ａ , —OC(═O)R １ａ , -OR １ａ , -SO ２ R １ａ , -SR １ａ , -NR １ａ R １ｂ , —C(═O)NR １ａ R １ｂ , -OC(=O)NR １ａ R １ｂ , -NR １ａ C(=O)NR １ｂ R １ｃ , or -NR １ａ C(=O)R １ｂ is replaced by In each occurrence, R １ａ , R １ｂ , and R １ｃ are each independently hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, -haloC １－６ Alkyl, or -haloC ３－６ cycloalkyl).

3. 3. The method of claim 2, wherein the acid is HCl or the base is NaOH.

4. The compound of formula (SI) is reacted with (S)-2-(2-isopropylphenyl)pyrrolidine, or a salt thereof, to give a compound of formula (SII) 【Chemistry 43】 4. The method of claim 2 or 3, further comprising providing a compound selected from the group consisting of methyl methylcellulose, ...

5. The compound of formula (SI) is reacted with (S)-2-(2-isopropylphenyl)pyrrolidine or a salt thereof and NaBH(OAc) ３ 5. The method of claim 4, comprising reacting in the presence of

6. 6. The method of claim 4 or 5, comprising reacting the compound of formula (SI) with (S)-2-(2-isopropylphenyl)pyrrolidine or a salt thereof at a temperature below about 30°C.

7. The compound of formula (SII) 【Chemistry 44】 or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide to give Sonrotoclax, 【Chemistry 45】 The method of any one of claims 4 to 6, further comprising providing a salt.

8. 8. The method of claim 7, further comprising reacting the compound of formula (SII) or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide in the presence of EDCI and DMAP.

9. reacting the compound of formula (SII) or a salt thereof with an acid or a base to produce (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid, 【Chemistry 46】 7. The method of any one of claims 4 to 6, further comprising providing a compound selected from the group consisting of methyl methylcellulose, ...

10. 10. The method of claim 9, wherein the acid is HCl or the base is NaOH.

11. (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid, 【Chemistry 47】 or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide to give Sonrotoclax, 【Chemistry 48】 11. The method of claim 9 or 10, further comprising providing:

12. 12. The method of claim 11, comprising reacting (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid, or a salt thereof, with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide in the presence of EDCI and DMAP.

13. 9. A method for preparing a pharmaceutical composition comprising Sonrotoclax, the method comprising mixing Sonrotoclax with a pharmaceutically acceptable excipient, wherein the Sonrotoclax is prepared according to the method of claim 7 or 8.

14. 12. A method for preparing a pharmaceutical composition comprising Sonrotoclax, the method comprising mixing Sonrotoclax with a pharmaceutically acceptable excipient, wherein the Sonrotoclax is prepared according to the method of any one of claims 9 to 11.

15. 13. A pharmaceutical composition comprising sonrotoclax or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the sonrotoclax is prepared according to the method of any one of claims 2 to 12.

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