Ketal-protected intermediates for Sonrotoclax and methods for their preparation

Abstract

Provided herein are compounds of formula (I) bearing a ketal protecting group that are used as intermediates 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), and processes for preparing compounds of formula (I), particularly 1,5-dioxa-11-azadispiro[5.1.5.1]tetradecane.

Description

[Technical Field]

[0001] Provided herein are compounds of formula (I) bearing a ketal protecting group that are used as intermediates 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), and processes for preparing compounds of formula (I), particularly 1,5-dioxa-11-azadispiro[5.1.5.1]tetradecane. [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] In the synthesis disclosed in WO2019 / 210828, protection of the intermediate ketone as 2,2-dimethoxy-7-azaspiro[3.5]nonane hydrochloride generates impurities that cannot be fully consumed in downstream steps. There is a need to optimize the synthesis of Sonrotoclax for improved impurity removal and increased stability. [Prior art documents] [Patent documents]

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

[0004] Provided herein are 7-azaspiro[3.5]nonan-2-one compounds and derivatives thereof. In some embodiments, the 7-azaspiro[3.5]nonan-2-one compound is 2,2-diethoxy-7-azaspiro[3.5]nonane, 2,2-diisopropoxy-7-azaspiro[3.5]nonane, 1,4-dioxa-10-azadispiro[4.1.5.1]tridecane, or 1,5-dioxa-11-azadispiro[5.1.5.1]tetradecane. Also provided herein are methods for producing the 7-azaspiro[3.5]nonan-2-one compounds and derivatives thereof. Also provided herein are methods for producing Sonrotoclax from the 7-azaspiro[3.5]nonan-2-one compounds and derivatives thereof. DETAILED DESCRIPTION OF THE INVENTION

[0005] definition 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 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 and branched chain (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. The alkenyl group 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 other groups 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 term heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as 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 term also includes bridged polycyclic ring systems containing heteroatoms, such as, 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] A "heterocyclylalkyl" group is a radical of the formula: -alkyl-heterocyclyl, where alkyl and heterocyclyl are as defined above. Substituted heterocyclylalkyl groups can be substituted on the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl portions of the group. Representative heterocyclylalkyl groups include, but are not limited to, 4-ethylmorpholinyl, 4-propylmorpholinyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0019] "Halogen" means fluorine, chlorine, bromine, or iodine.

[0020] A "hydroxyalkyl" group is an alkyl group as defined above that is substituted with one or more hydroxy groups.

[0021] An "alkoxy" or "alkoxyl" group is an --O-(alkyl), where alkyl is as defined above.

[0022] An "alkoxyalkyl" group is an -(alkyl)-O-(alkyl), where alkyl is defined above.

[0023] An "amino" group is a radical of the formula: --NH.sub.2.

[0024] An "alkylamino" group is a radical of the formula: --NH-alkyl or --N(alkyl)2, where each alkyl is independently as defined above.

[0025] A "carboxy" group is a radical of the formula: --C(O)OH.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] As used herein, the term "salt(s)" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and inorganic bases, and organic acids and organic 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).

[0031] 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.

[0032] 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).

[0033] 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.

[0034] 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.

[0035] Throughout this specification and embodiments thereof, the term "Cn-m" refers to an inclusive range, where n and m are integers and refer to the number of carbon atoms. Examples include C 1-8 and C 1-6Includes:

[0036] To optimize the synthesis of Sonrotoclax and obtain a more stable intermediate, pharmaceutically acceptable alcohols, including methanol, ethanol, isopropanol, glycol, and 1,3-propanediol, were used for the ketone protection of 1-azaspiro[3.5]nonan-2-one. However, only the use of 1,3-propanediol resulted in a solid with good physical form and high purity.

[0037] Considering the poor mobility of 1,3-propanediol, reaction solvents were screened. After considering alcohols, esters, and ethers, IPAc was selected as the reaction solvent and as a solvent for dissolving hydrogen chloride due to its acceptable stability under hydrogen chloride conditions. Triethyl orthoformate was selected as the dehydrating reagent to replace trimethyl orthoformate and avoid undesired reactions.

[0038] This selection of alcohol, reaction solvent, and dehydration reagent resulted in a solid product with a purity of 99.9%. Furthermore, this product was highly stable without impurity growth when stored at 2-8°C or below for 3.5 months.

[0039] As used herein, compounds of formula (I) [ka] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is disclosed; wherein each occurrence of R is independently C 2-6 Alkyl or C 3-6 cycloalkyl, and the aforementioned C 2-6 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 12Aryl, 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 In each of its occurrences, R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6Alkyl, C 3-6 Cycloalkyl, -haloC 1-6 Alkyl, or -haloC 3-6 cycloalkyl.

[0040] In one embodiment of the first aspect, at each occurrence, R is each independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and each of said ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 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 In each of its occurrences, R 1a , R 1b and R 1c are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -haloC 1-6 Alkyl, or -haloC 3-6cycloalkyl; Preferably, each R is independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of said ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with at least one substituent selected from F, Cl, Br, or I; More preferably, each R is independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; Even more preferably, each R is independently ethyl, propyl (n-propyl or isopropyl), or butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl).

[0041] In another embodiment of the first aspect, two R's, together with the two oxygen atoms bonded to each, form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, said ring optionally containing one or more of the following radicals: F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 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 -NR1a C(=O)R 1b and is substituted with at least one substituent selected from In each of its occurrences, R 1a , R 1b and R 1c are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -haloC 1-6 Alkyl, or -haloC 3-6 cycloalkyl; Preferably, two R's together with the two oxygen atoms bonded to each R form a 5-, 6-, 7-, or 8-membered ring, said ring being optionally substituted with at least one substituent selected from F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; More preferably, two R's together with the two oxygen atoms bonded to each R form a 5-, 6-, 7-, or 8-membered ring, said ring being optionally substituted with at least one substituent selected from F, Cl, Br, I; Even more preferably, the two R's, together with the two oxygen atoms to which they are attached, form a 5-, 6-, 7-, or 8-membered ring.

[0042] In preferred embodiments of the above aspects, the compound is selected from the group consisting of: [ka] Preferably, the compound is [ka] is.

[0043] [ka] However, the intermediate 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azadispiro[5.1.5])-4 ... 8 .1 6 When used as an intermediate in the process for preparing methyl tetradecan-11-yl)benzoate, it can significantly increase the yield and purity.

[0044] Production method In a second aspect, disclosed herein is a method for preparing a compound of formula (I), comprising step (A): reacting a compound of formula (II) with a dehydrating reagent and a reactive alcohol in the presence of an acid and a solvent to obtain a product of formula (I). [ka]

[0045] In one embodiment of the second aspect, the reaction temperature in step (A) is about 10-80°C, preferably the process temperature is about 15-60°C, more preferably the process temperature is about 20-40°C, and even more preferably the process temperature is about 20-30°C.

[0046] In another embodiment of the second aspect, the reaction time of step (A) is about 10-20 hours, preferably, the reaction time of the process is about 12-18 hours, and more preferably, the reaction time of the process is about 16 hours.

[0047] In another embodiment of the second aspect, the reactive alcohol is selected from the group consisting of methanol, ethanol, isopropanol, glycol, ethylene glycol, 1,3-propylene glycol, 2,2-dimethylcyclopentanol, and cyclohexanol, preferably selected from ethanol, isopropanol, glycol, ethylene glycol, and 1,3-propylene glycol, more preferably 1,3-propylene glycol.

[0048] In another embodiment of the second aspect, the reactive alcohol in the reaction is in the range of about 1 molar equivalent to about 20 molar equivalents relative to the amount of the compound of Formula (II), preferably, the reactive alcohol in the reaction is in the range of about 1 molar equivalent to about 10 molar equivalents relative to the amount of the compound of Formula (II), more preferably, the reactive alcohol in the reaction is in the range of about 2 molar equivalents to about 8 molar equivalents relative to the amount of the compound of Formula (II), even more preferably, the reactive alcohol in the reaction is in the range of about 2 molar equivalents to about 4 molar equivalents relative to the amount of the compound of Formula (II), and even more preferably, the reactive alcohol in the reaction is in the range of about 3 molar equivalents relative to the amount of the compound of Formula (II).

[0049] In another embodiment of the second aspect, the dehydrating reagent is selected from the group consisting of aluminum oxide, anhydrous zinc chloride, concentrated sulfuric acid, phosphoric acid, triethyl orthoformate, sodium borohydride, and trimethyl orthoformate, preferably selected from triethyl orthoformate and trimethyl orthoformate, and more preferably triethyl orthoformate.

[0050] In another embodiment of the second aspect, the amount of the dehydrating reagent in the reaction is in the range of about 0.5 molar equivalents to about 4 molar equivalents, preferably about 0.9 to 3 molar equivalents, and more preferably about 1.3 molar equivalents, relative to the amount of the compound of formula (II).

[0051] In another embodiment of the second aspect, the acid is selected from the group consisting of acetic acid, hydrochloric acid, formic acid, and ascorbic acid, preferably selected from hydrochloric acid and formic acid, more preferably hydrochloric acid.

[0052] In another embodiment of the second aspect, the acid is in the range of about 1 molar equivalent to about 5 molar equivalents relative to the amount of the compound of Formula (II), preferably in the range of about 2 to 4, and more preferably about 3.5.

[0053] In another embodiment of the second aspect, the solvent is selected from the group consisting of isopropyl acetate, ethyl acetate, hexane, heptane, dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethyl sulfoxide, and any mixture thereof, and is preferably selected from isopropyl acetate.

[0054] In another embodiment of the second aspect, the method further comprises step (B): adding the mixture to a non-polar to low polarity solvent to obtain a solid compound of formula (I).

[0055] In a preferred embodiment of the second aspect, the non-polar to low polarity solvent is selected from methyl tertiary butyl ether, EtO, hexane, cyclohexane, i-propyl ether, toluene, xylene, tetrahydrofuran, dioxane, or a mixture thereof, and preferably, the non-polar to low polarity solvent is selected from methyl tertiary butyl ether.

[0056] In a preferred embodiment of the second aspect, the mixture is aged for about 1 to 10 hours after adding the non-polar to low-polarity solvent, preferably the mixture is aged for about 3 to 7 hours, and more preferably the mixture is aged for about 6 hours.

[0057] In a preferred embodiment of the second aspect, a wet cake of the solid compound of Formula (I) is recovered from the centrifugation or filtration, and the wet cake is dried under vacuum at about 10-60°C, preferably about 15-55°C, and more preferably about 35-45°C.

[0058] In a preferred embodiment of the second aspect, the wet cake is dried for 10 to 40 hours, preferably 20 to 30 hours, more preferably 20 hours.

[0059] How Sonrotoclax is made In a third aspect, disclosed herein is the method of the second aspect, wherein the compound of formula (I) is [ka] or a salt thereof.

[0060] Provided herein is a method for making Sonrotoclax. In one embodiment, the method comprises reacting a compound of formula (I) with a compound of formula (SI): [ka] and reacting in the presence of a base wherein X is a halogen, preferably X is F, Cl, Br, or I, more preferably X is F; R 1 is C 1-6 Alkyl or C 3-6 cycloalkyl, and the aforementioned 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 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, C3-6 Cycloalkyl, -haloC 1-6 Alkyl, or -haloC 3-6 cycloalkyl) A compound of formula (SII), [ka] or a salt thereof.

[0061] In one embodiment, the base is 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).

[0062] In one embodiment, the reaction occurs between about 65°C and about 75°C, about 65°C, about 70°C, or about 75°C.

[0063] Provided herein are methods for making Sonrotoclax. In one embodiment, the method comprises reacting a compound of formula (SII) with an acid or a base to produce a compound of formula (SIII): [ka] or a salt thereof.

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

[0065] Provided herein is a method for making Sonrotoclax. In one embodiment, the method comprises reacting a compound of formula (SIII) with (S)-2-(2-isopropylphenyl)pyrrolidine, or a salt thereof, to produce a compound of formula (SIV): [ka] or a salt thereof.

[0066] In one embodiment, the reaction occurs in the presence of NaBH(OAc) 3 .

[0067] In one embodiment, the reaction occurs at less than about 30°C.

[0068] Provided herein is a method for making Sonrotoclax. In one embodiment, the method comprises reacting a compound of formula (SIV) or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide to produce Sonrotoclax, [ka] or a salt thereof.

[0069] In one embodiment, the reaction occurs in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP).

[0070] Provided herein is a method for making Sonrotoclax. In one embodiment, the method comprises reacting a compound of formula (SIV) 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, [ka] or a salt thereof.

[0071] In one embodiment, the acid is HCl or the base is NaOH.

[0072] Provided herein is a method for 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 with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide to produce Sonrotoclax, [ka] or a salt thereof.

[0073] In one embodiment, the reaction occurs in the presence of EDCI and DMAP.

[0074] In one embodiment, provided herein is 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 provided herein.

[0075] Numbered embodiments: Embodiment 1. A compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof wherein each occurrence of 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 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 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 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 3-6cycloalkyl).

[0076] Embodiment 2. At each occurrence thereof, R is each independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and each of said ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 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 In each of its occurrences, R 1a , R 1b and R 1c are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -haloC 1-6 Alkyl, or -haloC 3-6 cycloalkyl; Preferably, each R is independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of said ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with at least one substituent selected from F, Cl, Br, or I; More preferably, each R is independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; Even more preferably, the compound of embodiment 1, wherein each R is independently ethyl, propyl (n-propyl or isopropyl), or butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl).

[0077] Embodiment 3. Two R's, together with the two oxygen atoms to which they are bonded, form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, said ring optionally containing F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 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)R1b and is substituted with at least one substituent selected from In each of its occurrences, R 1a , R 1b and R 1c are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -haloC 1-6 Alkyl, or -haloC 3-6 cycloalkyl; Preferably, two R's together with the two oxygen atoms bonded to each R form a 5-, 6-, 7-, or 8-membered ring, said ring being optionally substituted with at least one substituent selected from F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; More preferably, two R's together with the two oxygen atoms bonded to each R form a 5-, 6-, 7-, or 8-membered ring, said ring being optionally substituted with at least one substituent selected from F, Cl, Br, and I; Even more preferably, the compound of embodiment 1, wherein two R's, together with the two oxygen atoms to which they are bonded, form a 5-, 6-, 7-, or 8-membered ring.

[0078] Embodiment 4. The compound is selected from the group consisting of: [ka] Preferably, the compound is [ka] The compound of any one of embodiments 1 to 3, wherein

[0079] Embodiment 5. A method for preparing a compound of formula (I) as described in embodiment 1, comprising: step (A): reacting a compound of formula (II) with a dehydrating reagent and a reactive alcohol in the presence of an acid and a solvent to obtain the product of formula (I). [ka]

[0080] Embodiment 6. The method of embodiment 5, wherein the reaction temperature in step (A) is about 10-80°C, preferably, the method temperature is about 15-60°C, more preferably, the method temperature is about 20-40°C, and even more preferably, the method temperature is about 20-30°C.

[0081] Embodiment 7. The method of embodiment 5, wherein the reaction time of step (A) is about 10-20 hours, preferably, the reaction time of the method is about 12-18 hours, more preferably, the reaction time of the method is about 16 hours.

[0082] Embodiment 8. The method of embodiment 5, wherein the reactive alcohol is selected from the group consisting of methanol, ethanol, isopropanol, glycol, ethylene glycol, 1,3-propylene glycol, 2,2-dimethylcyclopentanol, and cyclohexanol, preferably ethanol, isopropanol, glycol, ethylene glycol, and 1,3-propylene glycol, more preferably 1,3-propylene glycol.

[0083] Embodiment 9. The method of embodiment 5, wherein the reactive alcohol in the reaction is in the range of about 1 molar equivalent to about 20 molar equivalents relative to the amount of the compound of formula (II), preferably, the reactive alcohol in the reaction is in the range of about 1 molar equivalent to about 10 molar equivalents relative to the amount of the compound of formula (II), more preferably, the reactive alcohol in the reaction is in the range of about 2 molar equivalents to about 8 molar equivalents relative to the amount of the compound of formula (II), even more preferably, the reactive alcohol in the reaction is in the range of about 2 molar equivalents to about 4 molar equivalents relative to the amount of the compound of formula (II), and even more preferably, the reactive alcohol in the reaction is in the range of about 3 molar equivalents relative to the amount of the compound of formula (II).

[0084] Embodiment 10. The method of embodiment 5, wherein the dehydrating reagent is selected from the group consisting of aluminum oxide, anhydrous zinc chloride, concentrated sulfuric acid, phosphoric acid, triethyl orthoformate, sodium borohydride, and trimethyl orthoformate, preferably selected from triethyl orthoformate and trimethyl orthoformate, more preferably triethyl orthoformate.

[0085] Embodiment 11. The method of embodiment 5, wherein the amount of the dehydrating reagent in the reaction is in the range of about 0.5 molar equivalents to about 4 molar equivalents, preferably about 0.9 to 3 molar equivalents, and more preferably about 1.3 molar equivalents, relative to the amount of the compound of formula (II).

[0086] Embodiment 12. The method of embodiment 5, wherein the acid is selected from the group consisting of acetic acid, hydrochloric acid, formic acid, and ascorbic acid, preferably selected from hydrochloric acid and formic acid, more preferably hydrochloric acid.

[0087] Embodiment 13. The method of embodiment 5, wherein the acid is in the range of about 1 molar equivalent to about 5 molar equivalents relative to the amount of the compound of Formula (II), preferably in the range of about 2 to 4 molar equivalents, and more preferably about 3.5 molar equivalents.

[0088] Embodiment 14. The method of embodiment 5, wherein the solvent is selected from the group consisting of isopropyl acetate, ethyl acetate, hexane, heptane, dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethyl sulfoxide, and any mixture thereof, preferably isopropyl acetate.

[0089] Embodiment 15. The method of embodiment 5, further comprising step (B): adding the mixture to a non-polar to low polarity solvent to obtain the solid compound of formula (I).

[0090] Embodiment 16. The method of embodiment 15, wherein the non-polar to low polarity solvent is selected from methyl tertiary butyl ether, Et2O, hexane, cyclohexane, i-propyl ether, toluene, xylene, tetrahydrofuran, dioxane, or a mixture thereof, preferably, the non-polar to low polarity solvent is selected from methyl tertiary butyl ether.

[0091] Embodiment 17. The method of embodiment 15, wherein the mixture is aged for about 1 to 10 hours after adding the non-polar to low-polarity solvent, preferably, the mixture is aged for about 3 to 7 hours, and more preferably, the mixture is aged for about 6 hours.

[0092] Embodiment 18. The method of embodiment 15, wherein a wet cake of the solid compound of Formula (I) is recovered from centrifugation or filtration, and the wet cake is dried under vacuum at about 10-60°C, preferably about 15-55°C, more preferably about 35-45°C.

[0093] Embodiment 19. The method of embodiment 18, wherein the wet cake is dried for 10 to 40 hours, preferably 20 to 30 hours, more preferably 20 hours.

[0094] Embodiment 20. The compound of formula (I) is [ka] or a salt thereof. [Example]

[0095] 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.

[0096] 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.

[0097] The selection of an appropriate protecting group can be readily determined by one of ordinary skill in the art.

[0098] 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]

[0099] Compounds of formula (I) can be prepared as shown in Scheme I. An acid and triethyl orthoformate assisted ketal reaction is carried out between an alcohol and compound (I) to give compound (II).

[0100] A nitrogen inert reactor is charged with Compound (I), followed by the solvent, and set to stir. Triethyl orthoformate is added to the vessel, followed by the alcohol. Acid is then fed to the vessel while maintaining the batch temperature at 25±5°C for 10-20 hours to yield Compound (II).

[0101] Post-processing Upon completion of the reaction, the batch is charged with methyl tertiary butyl ether while maintaining the batch temperature at 25±5° C. The mixture is aged for approximately 6 hours and then centrifuged to collect the wet cake. The cake is washed with methyl tertiary butyl ether.

[0102] Drying The wet cake is dried under vacuum for 20 hours at 40±5° C. Drying is considered complete when the isopropyl acetate content is 5000 ppm or less, the methyl tertiary butyl ether content is 5000 ppm or less, and the moisture content is 0.5% or less.

[0103] [Table 2]

[0104] Example 1: 2,2-Dimethoxy-7-azaspiro[3.5]nonane Hydrochloride [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. EtOH (20.0 mL) was added to the reactor to obtain a mixture. The mixture was stirred at 20-30°C for 1 hour. Triethyl orthoformate (8.1 g, 54.7 mmol) was then added to the mixture, followed by a 15% HCl / EtOH solution (36.0 g, 146.3 mmol) while maintaining the temperature at 20-30°C for 20 hours to obtain the product. The product was analyzed by GC (carrier gas: helium (He)). Purity: 74.3%. GC-MS: 213.2.

[0105] Example 2: 2,2-Diisopropoxy-7-azaspiro[3.5]nonane Hydrochloride [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. Isopropanol (20.0 mL) was added to the reactor to obtain a mixture. The mixture was stirred at 20-30°C for 1 hour. Triethyl orthoformate (8.1 g, 54.7 mmol) was then added to the mixture, followed by 15% HCl / isopropanol solution (36.0 g, 146.3 mmol), while maintaining the batch temperature at 20-30°C for approximately 20 hours to obtain the product. The product was analyzed by GC (carrier gas: helium (He)). Only 5% 2,2-diisopropoxy-7-azaspiro[3.5]nonane hydrochloride was obtained.

[0106] Example 3: 1,4-Dioxa-10-azadispiro[4.1.5.1]tridecane 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 then added to the mixture, followed by ethylene glycol (8.2 g, 132.1 mmol). While maintaining the batch temperature at 20-30°C for approximately 20 hours, a 15% HCl / IPAc solution (36.0 g, 146.3 mmol) was added to the reactor to form the product. The product was analyzed by GC (carrier gas: helium (He)), which indicated that 99.9% 1,4-dioxa-10-azadispiro[4.1.5.1]tridecane hydrochloride was obtained. However, no solid was separated. GC-MS: 183.1

[0107] Example 4: 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

[0108] Example 5: 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. 1 H 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

[0109] Example 6: 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. It was packaged in a double-layered LDPE bag with a desiccant between the two layers, then placed in a heat-sealed aluminum foil bag and stored 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]

[0110] Example 7: 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)benzoic acid methyl ester [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 B12), which is incorporated by reference in its entirety. 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]benzoate were dissolved in NMP (5 mL). 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 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 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 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).

[0111] Example 8: 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)benzoic acid methyl ester [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).

[0112] Example 9: 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)benzoic acid methyl ester (compound 1) [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).

[0113] Example 10: 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 (compound 1) (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.

[0114] 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.

[0115] 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).

[0116] 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.

[0117] 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.

[0118] 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 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 3 N 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.

[0119] 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 selected from the following: 【Transformation 30】 Or its salt.

2. The compound 【Chemistry 31】 2. The compound of claim 1, which is: or a salt thereof.

3. The compound 【Chemistry 32】 2. The compound of claim 1, which is: or a salt thereof.

4. The compound 【Transformation 33】 or a salt thereof.

5. The compound 【Transformation 34】 or a salt thereof.

6. Compound of formula (SII) 【Chemistry 35】 or a salt thereof, comprising the steps of: 【Transformation 36】 or a salt thereof, by reacting a compound of formula (SI): 【Chemistry 37】 and reacting in the presence of a base. wherein at each occurrence, R is independently selected from 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 and the intervening carbons to which they are attached, 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 At 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; X is a halogen, preferably X is F, Cl, Br, or I, more preferably X is F; 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).

7. 7. The method of claim 6, wherein the base is 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).

8. 8. The method of claim 6 or 7, comprising reacting the compound of formula (I) with the compound of formula (SII) at a temperature of about 65°C to about 75°C, or at a temperature of about 65°C, about 70°C or about 75°C.

9. Reacting the compound of formula (SII) with an acid or a base to give a compound of formula (SIII): 【Transformation 38】 9. The method of any one of claims 6 to 8, further comprising providing a compound selected from the group consisting of methyl, methylamino ...

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

11. The compound of formula (SIII) or a salt thereof is reacted with (S)-2-(2-isopropylphenyl)pyrrolidine or a salt thereof to give a compound of formula (SIV) 【Chemistry 39】 11. The method of claim 9 or 10, further comprising providing:

12. The compound of formula (SIII) or a salt thereof is reacted with (S)-2-(2-isopropylphenyl)pyrrolidine or a salt thereof and NaBH(OAc) ３ 12. The method of claim 11, comprising reacting in the presence of

13. 13. The method according to claim 11 or 12, comprising reacting the compound of formula (SIII) or a salt thereof with (S)-2-(2-isopropylphenyl)pyrrolidine or a salt thereof at a temperature of less than about 30°C.

14. The compound of formula (SIV) or a salt thereof is reacted with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide to produce Sonrotoclax, 【Chemistry 40】 14. The method of any one of claims 11 to 13, further comprising providing a compound selected from the group consisting of methyl methylcellulose, methylcellulose, methylcellulose, methylcellulose derivatives ...

15. 15. The method of claim 14, wherein the reaction occurs in the presence of EDCI and DMAP.

16. The compound of formula (SIV) or a salt thereof is reacted with an acid or a base to obtain (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 41】 16. The method of claim 14 or 15, further comprising providing a compound selected from the group consisting of methyl, methylamino ...

17. 17. The method of claim 16, wherein the acid is HCl or the base is NaOH.

18. (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 42】 or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide to give Sonrotoclax, 【Chemistry 43】 18. The method of claim 16 or 17, further comprising providing a compound selected from the group consisting of methyl, methylamino ...

19. (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 44】 or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide in the presence of EDCI and DMAP.

20. 15. 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 of claim 14.

21. 20. 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 of claim 18.

22. 20. 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 6 to 19.

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