Intermediate for ketal protection of Sonrotoclax and preparation method thereof

Abstract

Disclosed herein are compounds useful as intermediates for the preparation of 2-((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy)-N-((4-((((1r, 4r, 4r, 4r, 4r, 4r, 4r, 4r, 4r) The invention relates to a compound of formula (I) with a ketal protecting group of (3R, 4r)-4-hydroxy-4-methylcyclohexyl) methyl) amino)-3-nitrophenyl) sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl) pyrrolidin-1-yl)-7-azaspiro [3.5] nonane-7-yl) benzamide (Sonrotoclax), and to a method for preparing a compound of formula (I), in particular 1, 3, 4, 5, 6, 7, 8-tetrahydro-2H-pyrazolo [3, 4-b] pyridin-2-yl)-1, 3, 4-triazolo [3, 4-b] pyridin-1-yl)-1, 3, 4-triazolo [3, 4-b] pyridin-1-yl)-1, 3, 4- The invention relates to a method for preparing 2, 5-dioxa-11-aza-di-spiro [5.1. 5.1] tetradecane.

Description

Technical Field

[0001] Disclosed herein are compounds of formula (I) having a ketal protecting group useful 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 (Sonrotoclax)), and methods for preparing compounds of formula (I), particularly 1,5-dioxa-11-azadispiro[5.1.5.1]tetradecane. Background Art

[0002] International publication WO 2019 / 210828 discloses a series of Bcl-2 inhibitors, particularly 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]nonane-7-yl)benzamide (hereinafter referred to as Sonrotoclax), which selectively inhibit Bcl-2 protein for the treatment of dysregulated apoptotic diseases such as cancer, autoimmune diseases and prothrombotic disorders.

[0003] In the synthesis disclosed in WO 2019 / 210828, protection of the ketone in the intermediate as 2,2-dimethoxy-7-azaspiro[3.5]nonane hydrochloride leads to the generation of impurities that are not well removed in downstream steps. The synthesis of Sonrotoclax needs to be optimized to achieve improved impurity removal and high stability. Summary of the invention

[0004] Provided herein are 7-azaspiro[3.5]nonane-2-one compounds and derivatives thereof. In some embodiments, the 7-azaspiro[3.5]nonane-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. Further provided herein are methods for preparing 7-azaspiro[3.5]nonane-2-one compounds and derivatives thereof. Further provided herein are methods for preparing Sonrotoclax from 7-azaspiro[3.5]nonane-2-one compounds and derivatives thereof. DETAILED DESCRIPTION definition

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

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

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

[0008] As used herein and unless otherwise indicated, the terms "about" and "approximately", when used with respect to a value or range of values ​​provided to characterize a particular solid form, such as with respect to a particular temperature or temperature range, such as, for example, describing a melting, dehydration, desolvation, or glass transition temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, such as, for example, expressed in mass or percentage; or a peak position, such as, for example, in an analysis by, for example, IR or Raman spectroscopy or XRPD; indicate that the value or range of values ​​may deviate to a degree that is considered reasonable by a person of ordinary skill in the art while still describing a solid form. In certain embodiments, the terms "about" and "approximately", when used in this context, indicate that the 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 value or range of values.

[0009] "Alkyl" groups are saturated, partially saturated or unsaturated straight or branched acyclic hydrocarbons having 1 to 10 carbon atoms, typically 1 to 8 carbon atoms, or in some embodiments 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; while saturated branched alkyl groups 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(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH7CH3), etc. The alkyl group may be substituted or unsubstituted. When alkyl groups described herein are said to be "substituted," they may be substituted with any one or more of the substituents found in the exemplary compounds and examples disclosed herein, as well as the following: halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; amido; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl.

[0010] "Alkenyl" group is a straight or branched non-cyclic hydrocarbon with 2 to 10 carbon atoms, typically 2 to 8 carbon atoms, and includes at least one carbon-carbon double bond.Representative straight and branched (C2C8) alkenyl includes-vinyl ,-allyl ,-1-butenyl,-2-butenyl ,-isobutylenyl ,-1-pentenyl, 2 pentenyls,-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 octenyls etc.The double bond of alkenyl group can be unconjugated or conjugated with another unsaturated group.Alkenyl group can be unsubstituted or substituted.

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

[0012] "Cycloalkyl" group is a saturated, partially saturated or unsaturated cyclic alkyl group with 3 to 10 carbon atoms, which has a single ring or multiple condensed rings or bridged rings that can be optionally substituted by 1 to 3 alkyl groups. In certain embodiments, the cycloalkyl group has 3 to 8 ring members, and in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6 or 3 to 7. The cycloalkyl comprising more than one ring can be fused, spirocyclic or bridged, or a combination thereof. For example, such a cycloalkyl group includes a monocyclic structure, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or includes polycyclic 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, etc. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, etc. The cycloalkyl group may be substituted or unsubstituted. For example, such substituted cycloalkyl groups include cyclohexanol, etc.

[0013] "Aryl" groups are aromatic carbocyclic groups with 6 to 14 carbon atoms, having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthracenyl). In some embodiments, the aryl group contains 6-14 carbon atoms, in other embodiments, it contains 6 to 12 or even 6 to 10 carbon atoms in the ring portion of the group. Specific aryl groups include phenyl, biphenyl, naphthyl, etc. The aryl group can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0014] "Heterocyclyl" is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl group in which one to four ring carbon atoms are independently replaced by heteroatoms from the group consisting of O, S and N. In some embodiments, the heterocyclyl group includes 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6 or 3 to 8 ring members. The heterocyclyl group can also be bonded to other groups on any ring atom (i.e., any carbon atom or heteroatom of the heterocycle). The heterocyclyl group can be substituted or unsubstituted. The heterocyclyl group can include multiple condensed rings, including but not limited to bicyclic, tricyclic and tetracyclic, and bridged ring systems or spirocyclic systems. The heterocyclyl group includes unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-diketo) 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, but not limited to, quinuclidine. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydrofuranyl, pyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, thioxanyl, dioxy, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodisulfinyl, 1,4-dioxaspiro[4.5]decane, 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,5] undecane, homopiperazinyl, quinuclidine, indolyl (e.g., indolyl-2-one or isoindolyl-1-one), indolinyl, isoindolyl, isoindolyl, azaindolyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1 H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl , pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), imidazopyridinyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridinyl), triazolopyridinyl, isoxazolopyridinyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolyl, isoquinolyl (e.g., 3,4-dihydroisoquinolin-1(2H)-one), quinolyl, Representative non-aromatic heterocyclyl groups include oxazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thiazinyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridinyl, tetrahydropyrazolopyridinyl, tetrahydroimidazopyridinyl, tetrahydrotriazolopyridinyl, tetrahydropyrimidin-2(1H)-one, and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups do not include fused ring species containing fused aromatic groups. Examples of non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidinyl-4-one or imidazolidinyl-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, thiooxanyl, dithianyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidine-2(1H)-one. Representative substituted heterocyclyl groups may be monosubstituted with various substituents (such as those listed below), or substituted more than once (such as, but not limited to, pyridinyl or morpholinyl groups, 2, 3, 4, 5, or 6 times), or disubstituted. .

[0015] "Heteroaryl" groups are aryl ring systems having from one to four heteroatoms as ring atoms in the heteroaromatic ring system, wherein the remaining atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms, in other embodiments, it contains 6 to 9 or even 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, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, benzothienyl, furanyl, benzofuranyl, indolyl (e.g., indol-2-one or isoindolin-1-one), azaindolyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridinyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridinyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridinyl, thiapyrrolyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-one), tetrahydroquinolinyl, quinoxalinyl and quinazolinyl groups.

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

[0017] An "aralkyl" group is a group having the formula: -alkyl-aryl, wherein the alkyl and aryl are as defined above. Substituted aralkyl groups may 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 group having the following formula: -alkyl-heterocyclyl, wherein the alkyl and heterocyclyl are as defined above. The substituted heterocyclylalkyl group can be substituted at both the alkyl, heterocyclyl, or alkyl and 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" is fluorine, chlorine, bromine or iodine.

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

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

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

[0023] An "amino" group is a group having the formula: -NH2.

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

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

[0026] An "aminocarbonyl" group is a group having the formula: -C(O)N(R # )2、-C(O)NH(R # ) or -C(O)NH2, where each R # Independently is a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl group as defined herein.

[0027] An "amido" group is a group having the formula: -NHC(O)(R # ) or -N(alkyl)C(O)(R # ), wherein each alkyl group and R # Independently as defined above.

[0028] A "urea" group is a group having 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 group and R # Independently as defined above.

[0029] When groups described herein (other than alkyl groups) are referred to as "substituted", they may be substituted with any suitable substituent or substituents. Illustrative examples of substituents are those found in the exemplary compounds and examples disclosed herein, as well as halogen (chlorine, iodine, bromine, or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; amido; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be a monocyclic fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclic group, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl, or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0030] As used herein, the term "salt" 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 ed., Mack Publishing, Easton, Pa. (1990), or Remington: The Science and Practice of Pharmacy, 19th ed., Mack Publishing, Easton, Pa. (1995).

[0031] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" means one stereoisomer of a compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the 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 the compound. These compounds may have chiral centers and may exist in the form of racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms (including mixtures thereof) are included in the embodiments disclosed herein.

[0032] The use of stereoisomerically pure forms of these compounds and the use of mixtures of these forms are all encompassed in 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. Standard techniques (such as chiral columns or chiral resolving agents) can be used to asymmetrically synthesize or resolve these isomers. See, e.g., 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, New York, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions, p. 268 (ELiel, ed., Univ. of Notre Dame Press, Notre Dame, Indiana, 1972).

[0033] It should also be noted that the compound may include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In certain embodiments, the compound is isolated as an E or Z isomer. In other embodiments, the compound is a mixture of E and Z isomers.

[0034] As used herein and unless otherwise indicated, "atropisomers" refers to stereoisomers resulting from hindered rotation about a single bond axis, where the energy barrier to rotation is high enough to allow separation of the individual rotamers.

[0035] Throughout this specification and the accompanying aspects, the term "Cn-m" indicates a range including endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 and C 1-6 .

[0036] In order to optimize the synthesis of Sonrotoclax and produce more stable intermediates, pharmaceutically acceptable alcohols (including methanol, ethanol, isopropanol, diols and 1,3-propylene glycol) were used for ketone protection of 1-azaspiro[3.5]nonan-2-one. However, only when 1,3-propylene glycol was used could a solid with good physical form and high purity be obtained.

[0037] Considering the poor fluidity of 1,3-propylene glycol, the reaction solvent was screened. After considering alcohols, esters, and ethers, IPAc was selected as the reaction solvent and the solvent for dissolving hydrogen chloride due to its acceptable stability under hydrogen chloride conditions. Triethyl orthoformate was selected as the dehydrating agent to replace trimethyl orthoformate to avoid adverse reactions.

[0038] The alcohol, reaction solvent and dehydrating agent were selected to produce a solid product with a purity of 99.9%. In addition, the product was highly stable when stored at 2°C-8°C for 3.5 months with no increase in impurities.

[0039] In a first aspect, disclosed herein are compounds having formula (I), or a salt thereof, or a stereoisomer thereof, in At each occurrence, R is independently C 2-6 Alkyl or C 3-6 Cycloalkyl, the C 2-6 Alkyl or C 3-6 Each of the cycloalkyl groups is optionally substituted by halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12Aryl, 5- to 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 ;or The two Rs together with the two oxygen atoms to which they are attached form a 5- to 12-membered ring, which is optionally substituted with at least one substituent selected from the group consisting of halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 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 ; At each occurrence, R 1a , R 1b and R 1c are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -halogenated C 1-6 Alkyl or -halogenated C 3-6 Cycloalkyl.

[0040] In one embodiment of the first aspect, at each occurrence, R is independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; each of the ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with at least one substituent 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- to 8-membered heterocyclyl, phenyl, 5- to 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 ; At each occurrence, R 1a , R 1b and R 1c are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -halogenated C 1-6 Alkyl or -halogenated C 3-6 Cycloalkyl; Preferably, each R is independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; each of the ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with at least one substituent selected from the group consisting of 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, isobutyl, tert-butyl).

[0041] In another embodiment of the first aspect, two R together with the two oxygen atoms to which they are attached form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring optionally substituted with at least one substituent 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- to 8-membered heterocyclyl, phenyl, 5- to 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 ; At each occurrence, R 1a , R 1b and R 1c are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -halogenated C 1-6 Alkyl or -halogenated C 3-6 Cycloalkyl; Preferably, two R together with the two oxygen atoms to which they are attached form a 5-, 6-, 7- or 8-membered ring, which is optionally substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; More preferably, two R together with the two oxygen atoms to which they are attached form a 5-, 6-, 7- or 8-membered ring, which is optionally substituted with at least one substituent selected from the group consisting of: F, Cl, Br, I; Even more preferably, two R 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: Preferably the compound is

[0043] when In the preparation of Sonrotoclax, especially in the preparation of the intermediate 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azabisspiro[5.1.5 8 .1 6 When used as an intermediate in the process for preparing methyl benzoate of tetradecane-11-yl) benzoate, it can greatly improve the yield and purity. Preparation method

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

[0045] In one embodiment of the second aspect, the reaction temperature of step (A) is about 10°C-80°C; preferably, the temperature of the method is about 15°C-60°C; more preferably, the temperature of the method is about 20°C-40°C; even more preferably, the temperature of the method is about 20°C-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 method is about 12-18 hours; more preferably, the reaction time of the method is about 16 hours.

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

[0048] In another embodiment of the second aspect, the amount of the reactant alcohol in the reaction relative to the compound of formula (II) ranges from about 1 molar equivalent to about 20 molar equivalents; preferably, the amount of the reactant alcohol in the reaction relative to the compound of formula (II) ranges from about 1 molar equivalent to about 10 molar equivalents; more preferably, the amount of the reactant alcohol in the reaction relative to the compound of formula (II) ranges from about 2 molar equivalents to about 8 molar equivalents; even more preferably, the amount of the reactant alcohol in the reaction relative to the compound of formula (II) ranges from about 2 molar equivalents to about 4 molar equivalents; even more preferably, the amount of the reactant alcohol in the reaction relative to the compound of formula (II) ranges from about 3 molar equivalents.

[0049] In another embodiment of the second aspect, the dehydrating agent 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 is triethyl orthoformate.

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

[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; and more preferably is hydrochloric acid.

[0052] In another embodiment of the second aspect, the amount of the acid relative to the compound of formula (II) ranges from about 1 molar equivalent to about 5 molar equivalents; preferably ranges from about 2 to 4, 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; preferably selected from isopropyl acetate.

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

[0055] In a preferred embodiment of the second aspect, the non-polar to low-polarity solvent is selected from methyl tert-butyl ether, Et2O, hexane, cyclohexane, isopropyl ether, toluene, xylene, tetrahydrofuran, dioxane or a mixture thereof; preferably, the non-polar to low-polarity solvent is selected from methyl tert-butyl ether.

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

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

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

[0059] In a third aspect, the present invention discloses a method as described in the second aspect, wherein the compound having formula (I) is or a salt thereof.

[0060] Provided herein is a method for preparing Sonrotoclax. In one embodiment, the method comprises reacting a compound having formula (I) with a compound having formula (SI): In the presence of a base, wherein X is halogen; preferably, X is F, Cl, Br, or I; more preferably, X is F; and R 1 It is C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl or C 3-6 Each of the cycloalkyl groups is optionally substituted by halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -NO2, -C(=O)R 1a 、-C(=O)OR 1a 、-OC(=O)R 1a 、-OR 1a 、-SO2R1a 、-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 ; At each occurrence, R 1a , R 1b and R 1c are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -halogenated C 1-6 Alkyl or -halogenated C 3-6 Cycloalkyl, To provide a compound having formula (SII) 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, or at about 65°C, about 70°C, or about 75°C.

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

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

[0065] Provided herein are methods for preparing Sonrotoclax. In one embodiment, the method comprises reacting a compound having formula (SIII) with (S)-2-(2-isopropylphenyl)pyrrolidine or a salt thereof to provide a compound having formula (SIV) 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 are methods for preparing Sonrotoclax. In one embodiment, the method comprises reacting a compound having formula (SIV) or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide to provide Sonrotoclax 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 are methods for preparing Sonrotoclax. In one embodiment, the method comprises reacting a compound having formula (SIV) or a salt thereof with an acid or a base to provide (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.

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

[0072] Provided herein is a method for preparing Sonrotoclax. In one embodiment, the method comprises making (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 to provide Sonrotoclax 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 Sonrotoclax is prepared according to the method provided herein. Numbered Examples: Example 1. A compound having formula (I), or a salt thereof, or a stereoisomer thereof, in At each of its occurrences, R is independently C 2-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 2-6 Alkyl or C 3-6 Each of the cycloalkyl groups is optionally substituted by halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 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 ;or The two Rs together with the two oxygen atoms to which they are attached form a 5- to 12-membered ring, which is optionally substituted with at least one substituent selected from the group consisting of halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 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 1cor -NR 1a C(=O)R 1b ; At each occurrence, R 1a , R 1b and R 1c are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -halogenated C 1-6 Alkyl or -halogenated C 3-6 Cycloalkyl. Embodiment 2. The compound of embodiment 1, wherein at each occurrence, 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 is optionally substituted with at least one substituent 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- to 8-membered heterocyclyl, phenyl, 5- to 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 ; At each occurrence, R 1a , R 1b and R 1c are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -halogenated C 1-6 Alkyl or -halogenated C 3-6 Cycloalkyl; Preferably, each R is independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; each of the ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with at least one substituent selected from the group consisting of 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, isobutyl, tert-butyl). Embodiment 3. A compound as described in Embodiment 1, wherein two R together with the two oxygen atoms to which they are attached form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which is optionally substituted with at least one substituent 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- to 8-membered heterocyclyl, phenyl, 5- to 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 ; At each occurrence, R 1a , R 1b and R 1c are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -halogenated C 1-6 Alkyl or -halogenated C 3-6 Cycloalkyl; Preferably, two R together with the two oxygen atoms to which they are attached form a 5-, 6-, 7- or 8-membered ring, which is optionally substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; More preferably, two R together with the two oxygen atoms to which they are attached form a 5-, 6-, 7- or 8-membered ring, which is optionally substituted with at least one substituent selected from the group consisting of: F, Cl, Br, I; Even more preferably, two R together with the two oxygen atoms to which they are attached form a 5-, 6-, 7- or 8-membered ring. Embodiment 4. The compound of any one of embodiments 1-3, wherein the compound is selected from the group consisting of: Preferably the compound is Example 5. A method for preparing a compound of formula (I) as described in Example 1, the method comprising step (A): reacting a compound of formula (II) with a dehydrating agent and a reactant alcohol in the presence of an acid and a solvent to obtain a product of formula (I) Embodiment 6. The method as described in Embodiment 5, wherein the reaction temperature of step (A) is about 10 ℃-80 ℃; preferably, the temperature of the method is about 15 ℃-60 ℃; more preferably, the temperature of the method is about 20 ℃-40 ℃; even more preferably, the temperature of the method is about 20 ℃-30 ℃. Embodiment 7. The method as described in 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. Embodiment 8. The method of embodiment 5, wherein the reactant 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; and more preferably 1,3-propylene glycol. Embodiment 9. The method as described in Embodiment 5, wherein the amount of the reactant alcohol in the reaction relative to the amount of the compound having formula (II) ranges from about 1 molar equivalent to about 20 molar equivalents; preferably, the amount of the reactant alcohol in the reaction relative to the amount of the compound having formula (II) ranges from about 1 molar equivalent to about 10 molar equivalents; more preferably, the amount of the reactant alcohol in the reaction relative to the amount of the compound having formula (II) ranges from about 2 molar equivalents to about 8 molar equivalents; even more preferably, the amount of the reactant alcohol in the reaction relative to the amount of the compound having formula (II) ranges from about 2 molar equivalents to about 4 molar equivalents; even more preferably, the amount of the reactant alcohol in the reaction relative to the amount of the compound having formula (II) ranges from about 3 molar equivalents. Embodiment 10. The method as described in embodiment 5, wherein the dehydrating agent 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. Embodiment 11. The method as described in Embodiment 5, wherein the amount of the dehydrating agent in the reaction relative to the compound of formula (II) ranges from about 0.5 molar equivalents to about 4 molar equivalents; preferably ranges from about 0.9 to 3; more preferably is about 1.3. 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; and more preferably is hydrochloric acid. Embodiment 13. The method of embodiment 5, wherein the amount of the acid relative to the amount of the compound of formula (II) ranges from about 1 molar equivalent to about 5 molar equivalents; preferably ranges from about 2 to 4, more preferably about 3.5. 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 selected from isopropyl acetate. Embodiment 15. The method as described in embodiment 5, further comprising Step (B): A non-polar to low-polarity solvent is added to the mixture to obtain a solid compound having formula (I). Embodiment 16. The method as described in Embodiment 15, wherein the non-polar to low polar solvent is selected from methyl tert-butyl ether, Et2O, hexane, cyclohexane, isopropyl ether, toluene, xylene, tetrahydrofuran, dioxane or a mixture thereof; preferably, the non-polar to low polar solvent is selected from methyl tert-butyl ether. Embodiment 17. The method of embodiment 15, wherein after adding the non-polar to low polarity solvent, the mixture is aged for about 1-10 hours, preferably the mixture is aged for about 3-7 hours; more preferably, the mixture is aged for about 6 hours. Embodiment 18. The method of embodiment 15, wherein a wet cake of a solid compound having formula (I) is collected from centrifugation or filtration, and the wet cake is dried under vacuum at about 10°C-60°C, preferably at about 15°C-55°C, more preferably at about 35°C-45°C. Embodiment 19. The method of embodiment 18, wherein the wet cake is dried for 10-40 hours, preferably 20-30 hours, more preferably 20 hours. Embodiment 20. The method of any one of embodiments 5-19, wherein the compound of formula (I) is or a salt thereof. Examples Universal synthesis

[0075] The compounds disclosed herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0076] The reaction for preparing the compounds disclosed herein can be carried out in a suitable solvent that can be easily selected by a technician in the field of organic synthesis. Suitable solvents can be substantially non-reactive with starting materials, intermediates or products at a temperature (e.g., a temperature that can range from the boiling temperature of the solvent to the freezing temperature) for carrying out the reaction. A given reaction can be carried out in a mixture of one solvent or multiple solvents.

[0077] The selection of appropriate protecting groups can be readily determined by one skilled in the art.

[0078] The reaction can be monitored according to any suitable method known in the art (e.g., NMR, UV, HPLC, LC-MS, and TLC). The compounds can be purified by a variety of methods including HPLC and normal phase silica gel chromatography. Scheme I

[0079] Compounds of formula (I) can be prepared as shown in Scheme I. Ketal reaction between alcohol and compound (I) with the aid of acid and triethyl orthoformate affords compound (II).

[0080] Add compound (I) to a nitrogen inerted reactor followed by solvent and set to stir. Add triethyl orthoformate to the vessel followed by alcohol. Feed the acid to the vessel while maintaining the batch temperature at 25°C ± 5°C for 10-20 hours to obtain compound (II). Post-processing

[0081] After the reaction was complete, methyl tert-butyl ether was added to the batch while maintaining the batch temperature at 25°C ± 5°C. The mixture was aged for approximately 6 hours and then centrifuged to collect the wet cake. The filter cake was washed with methyl tert-butyl ether. dry

[0082] The wet cake was dried under vacuum at 40°C ± 5°C for 20 h. Drying was considered complete when isopropyl acetate ≤ 5000 ppm; methyl tert-butyl ether ≤ 5000 ppm; and water content ≤ 0.5%. abbreviation

[0084] Example 1: 2,2-diethoxy-7-azaspiro[3.5]nonane hydrochloride

[0085] 2-Oxo-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (10.0 g, 41.8 mmol) was added to a nitrogen inerted reactor. EtOH (20.0 ml) was added to the reactor to obtain a mixture. The mixture was stirred at 20°C-30°C for 1 h. Triethyl orthoformate (8.1 g, 54.7 mmol) was added to the mixture, followed by 15% HCl / EtOH solution (36.0 g, 146.3 mmol), while the temperature was maintained at 20°C-30°C for 20 hours to produce the product. The product was tested by GC (carrier gas: helium (He)). Purity: 74.3%. GC-MS: 213.2.

[0086] Example 2: 2,2-Diisopropoxy-7-azaspiro[3.5]nonane hydrochloride

[0087] 2-Oxo-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (10.0 g, 41.8 mmol) was added to a nitrogen inerted reactor. Isopropanol (20.0 ml) was added to the reactor to obtain a mixture. The mixture was stirred at 20°C-30°C for 1 h. Triethyl orthoformate (8.1 g, 54.7 mmol) was added to the mixture, followed by 15% HCl / isopropanol solution (36.0 g, 146.3 mmol), while the batch temperature was maintained at 20°C-30°C for approximately 20 hours to produce the product. The product was tested by GC (carrier gas: helium (He)). Only 5% of 2,2-diisopropoxy-7-azaspiro [3.5] nonane hydrochloride was obtained.

[0088] Example 3: 1,4-Dioxa-10-azadispiro[4.1.5.1]tridecane hydrochloride

[0089] Tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (10.0 g, 41.8 mmol) was added to a nitrogen inerted reactor. IPAc (20.0 ml) was added to the reactor to obtain a mixture. The mixture was stirred at 20°C-30°C for 1 h. Triethyl orthoformate (8.1 g, 54.7 mmol) was added to the mixture, followed by ethylene glycol (8.2 g, 132.1 mmol). 15% HCl / IPAc solution (36.0 g, 146.3 mmol) was fed to the reactor while the batch temperature was at 20°C-30°C for approximately 20 hours to produce the product. The product was tested by GC (carrier gas: helium (He)), which showed that 99.9% of 1,4-dioxa-10-azabispiro[4.1.5.1]tridecane hydrochloride was obtained. However, no solid was isolated. GC-MS: 183.1

[0090] Example 4: 1,5-Dioxa-11-azadispiro[5.1.5.1]tetradecane hydrochloride

[0091] Tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (10.0 g, 41.8 mmol) was added to a nitrogen inerted reactor. IPAc (20.0 ml) was added to the reactor to obtain a mixture. The mixture was stirred at 20°C-30°C for 1 h. 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). 15% HCl / IPAc solution (36.0 g, 146.3 mmol) was fed to the reactor while maintaining the batch temperature at 20°C-30°C for approximately 20 hours. The product was tested by GC (carrier gas: helium (He)), which showed that 99.9% of 1,5-dioxa-11-azabispiro[5.1.5.1]tetradecane hydrochloride was obtained and the solid was well separated. GC-MS: 197.1

[0092] Example 5: 1,5-Dioxa-11-azadispiro[5.1.5.1]tetradecane hydrochloride

[0093] 2-Oxo-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (10.0 g, 41.8 mmol) was added to a nitrogen inerted reactor. IPAc (20.0 ml) was added to the reactor to obtain a mixture. The mixture was stirred at 20°C-30°C for 1 h. 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). 15% HCl / IPAc solution (36.0 g, 146.3 mmol) was fed into the reactor while maintaining the batch temperature at 20°C-30°C for approximately 16 hours. After the reaction was complete, methyl tert-butyl ether (MTBE, 27 ml) was added to the batch while maintaining the batch temperature at 25±5°C. The mixture was aged for approximately 6 hours and then centrifuged to collect the wet cake. The cake was washed with MTBE (27 ml). The wet cake was dried at 40°C ± 5°C under vacuum for 20 h to obtain a 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

[0094] Example 6: Stability test of 1,5-dioxa-11-azadispiro[5.1.5.1]tetradecane hydrochloride 1,5-dioxa-11-azabisspiro[5.1.5.1]tetradecane hydrochloride (2.0 g, 8.4 mmol) was stored at 2°C-8°C and packed in a double-layer LDPE bag (with a desiccant between the two layers) in a heat-sealed aluminum foil bag for 3.5 months. The sample was tested by GC (carrier gas: N2) and HPLC (column: Waters Xselect HSS T3 (150 mm*4.6 mm, 3.5 um) P / N: 186004786; mobile phase: 0.05% TFA in water, ACN:MeOH=1:1, v / v; flow rate: 1 ml / min; temperature: 30°C). The results in Table 1 show that the intermediate 1,5-dioxa-11-azabisspiro[5.1.5.1]tetradecane hydrochloride is sufficiently stable under this condition. Table 1

[0095] Example 7: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azabispiro[5.1.5 8 .1 6 ]tetradec-11-yl)benzoic acid methyl ester

[0096] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid methyl ester was synthesized according to the method in WO 2019210828 (which is incorporated by reference in its entirety) (e.g., Example B12). Subsequently, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid methyl ester (1.00 g, 3.49 mmol) and 1,5-dioxa-11-azadispiro[5.1.5 8 .1 6]To a suspension of tetradecane hydrochloride (1.30 g, 5.58 mmol) in NMP (5 mL) was added DBU (1.50 g, 9.85 mmol). The resulting solution was stirred at 65 ° C for 24 h and cooled to 50 ° C. The pH value was adjusted to the target value of 7 with AcOH, and then water (1.5 mL) was added, followed by seed crystals (0.01 g). The mixed solution was stirred at 50 ° C for 6 h and then cooled to 20 ° C. The wet cake was collected by filtering and washing with water. The obtained wet cake was slurried with 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).

[0097] Example 8: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azabispiro[5.1.5 8 .1 6 ]tetradec-11-yl)benzoic acid methyl ester

[0098] Subsequently, 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 (1.30 g, 5.58 mmol) in NMP (5 mL) was added DBU (1.50 g, 9.85 mmol). The resulting solution was stirred at 70 ° C for 24 h and cooled to 50 ° C. The pH value was adjusted to the target value of 7 with AcOH, and then water (1.5 mL) was added, followed by seed crystals (0.01 g). The mixed solution was stirred at 50 ° C for 6 h and then cooled to 20 ° C. The wet cake was collected by filtering and washing with water. The obtained wet cake was slurried with 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).

[0099] Example 9: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azabispiro[5.1.5 8 .1 6 ]Tetradec-11-yl)benzoic acid methyl ester (Compound 1)

[0100] Subsequently, 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 (1.30 g, 5.58 mmol) in NMP (5 mL) was added DBU (1.50 g, 9.85 mmol). The resulting solution was stirred at 75 ° C for 24 h and cooled to 50 ° C. The pH value was adjusted to the target value of 7 with AcOH, and then water (1.5 mL) was added, followed by seed crystals (0.01 g). The mixed solution was stirred at 50 ° C for 6 h and then cooled to 20 ° C. The wet cake was collected by filtering and washing with water. The obtained wet cake was slurried with 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).

[0101] 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)

[0102] Step 1: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate

[0103] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azabispiro[5.1.5 8 .1 6]Tetradecane-11-yl) methyl benzoate (Compound 1) (180g, 0.39mol) was added dilute HCl (1M, 1.5L) to a solution in DCM (2L) and stirred overnight. After the reaction was completed, the mixture was cooled to 10 ° C, and adjusted to pH=8-9 with aqueous NaOH solution (4M) under stirring. The organic phase was separated and washed with 15% aqueous NaCl (1L), and then washed with H2O (1L). After the organic phase was concentrated to 500mL, MTBE (1L) was poured into the solution, and the system was then concentrated to 500mL (repeated this treatment 3 times). The resulting system was stirred for 0.5 hours. After filtration, the filter cake was collected and then dried in a vacuum to obtain the title product (152g, yield: 96%) as a white solid. 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.

[0104] Step 2: (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate

[0105] 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 H2O (50 mL) was added Cs2CO3 (100 g, 305 mmol) and Pd(dppf)Cl2 (6.6 g, 7.5 mmol). The mixture was stirred at 100 °C for 8 hours. TLC showed that the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 100 / 1 to 10 / 1) to obtain (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.

[0106] Step 3: (S)-tert-Butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate

[0107] 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 hours. 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).

[0108] Step 4: (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride

[0109] 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 dried in vacuo to give (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride 26 g (yield: 60.4%). 1 H NMR(400MHz,DMSO-d6)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.

[0110] Step 5: (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

[0111] A mixture of (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride (120 g, 0.535 mole) and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonane-7-yl)benzoic acid methyl ester (218 g, 0.509 mole) in DCM (2.2 L) was charged into a reactor. The temperature was controlled to be below 30 ° C, and NaBH(OAc)3 (216 g, 1.018 mole) was added to the reactor in 5-6 portions. The reaction mixture was then stirred at room temperature and monitored by TLC. After the starting material ketone was completely consumed, the mixture was adjusted to pH=4-5 with dilute HCl (0.5 M). The separated organic phase was washed with H2O (600 mL×2), then with aqueous NaHCO3 (600 mL×2), and saturated aqueous NaCl (600 mL). The organic phase was collected, then dried over anhydrous Na2SO4, and concentrated. 256 g of off-white solid was obtained as a crude product, which was used directly in the next step. MS (ESI, m / e) [M+1] + 579.0.

[0112] 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

[0113] 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]nonane-7-yl)benzoate (105 g, 181.7 mmol) in THF (525 mL) and MeOH (525 mL) was added aqueous NaOH (3.5 M). It was stirred at room temperature overnight. After THF and MeOH were removed in vacuo, 3.5 L of water was added to the residue. At room temperature, with stirring, the resulting mixture was adjusted to pH=5-6 with 3N HCl. The precipitate was filtered and dried in vacuo to give the product as a white solid (102.4 g, yield: 99%). 1H NMR (400MHz, DMSO-d6) δppm: 12.13 (s, 1H), 11.58 (s, 1H), 7.95 (s, 1H), 7.67 (d, J = 8.0Hz, 1H), 7.56-7.40 (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.

[0114] 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)

[0115] 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 overnight at room temperature. The reaction was monitored by HPLC. After the starting material (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 was completely consumed, the reaction mixture was heated to about 35° C. and N 1 ,N 1-dimethylethane-1,2-diamine (17.2g, 195mmol). The reaction was stirred for another 12 hours. The mixture was washed twice with 10wt% aqueous AcOH solution (300mL×2), and then washed with saturated aqueous NaHCO3 (300mL×2). The organic layer was collected and concentrated to about 90mL. 22g silica gel was added and stirred for 2 hours. After filtering, 180mL EA was added to the filtrate under reflux and further stirred for 5 hours. After the mixture was cooled to room temperature, the precipitate was filtered, and the wet cake was then washed twice with EA (180mL). At 80°C-90°C, after drying in vacuum, the desired compound (48g, yield: 69.5%) was obtained. 1 H NMR(DMSO-d6)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 .94-1.47(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: or a salt thereof.

2. The compound of claim 1, wherein the compound is or a salt thereof.

3. The compound of claim 1, wherein the compound is or a salt thereof.

4. The compound of claim 1, wherein the compound is or a salt thereof.

5. The compound of claim 1, wherein the compound is or a salt thereof.

6. A method for preparing a compound of formula (SII) or a salt thereof, The method comprises subjecting a compound having formula (I): or a salt thereof and a compound having formula (SI): In the presence of a base, in At each of its occurrences, R is independently C 2-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 2-6 Alkyl or C 3-6 Each of the cycloalkyl groups is optionally substituted by halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 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 ;or The two R's together with the two oxygen atoms to which they are attached and the intervening carbon form a 5- to 12-membered ring, which is optionally substituted with at least one substituent selected from the group consisting of halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 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 ; At each occurrence, R 1a , R 1b and R 1c are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -halogenated C 1-6 Alkyl or -halogenated C 3-6 Cycloalkyl; X is halogen; preferably, X is F, Cl, Br, or I; more preferably, X is F; and R 1 It is C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl or C 3-6 Each of the cycloalkyl groups is optionally substituted by halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 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 ; At each occurrence, R 1a , R 1b and R 1c are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -halogenated C 1-6 Alkyl or -halogenated C 3-6 Cycloalkyl.

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

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

9. The method of any one of claims 6-8, further comprising reacting the compound of formula (SII) with an acid or a base to provide a compound of formula (SIII) or a salt thereof.

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

11. The method of claim 9 or 10, further comprising reacting the compound of formula (SIII) or a salt thereof with (S)-2-(2-isopropylphenyl)pyrrolidine or a salt thereof to provide a compound of formula (SIV) or a salt thereof.

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

13. The process of 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 below about 30°C.

14. The method of any one of claims 11-13, further comprising reacting the compound of formula (SIV) or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide to provide Sonrotoclax or a salt thereof.

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

16. The method of claim 14 or 15, further comprising reacting the compound of formula (SIV) or a salt thereof with an acid or a base to provide (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.

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

18. The method of claim 16 or 17, further comprising making (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 to provide Sonrotoclax or a salt thereof.

19. The method of any one of claims 16 to 18, 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 is reacted with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide in the presence of EDCI and DMAP.

20. A method for preparing a pharmaceutical composition comprising Sonrotoclax, the method comprising mixing Sonrotoclax with a pharmaceutically acceptable excipient, wherein Sonrotoclax is prepared according to the method of claim 14.

21. A method for preparing a pharmaceutical composition comprising Sonrotoclax, the method comprising mixing Sonrotoclax with a pharmaceutically acceptable excipient, wherein Sonrotoclax is prepared according to the method of claim 18.

22. A pharmaceutical composition comprising Sonrotoclax or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein Sonrotoclax is prepared by the method of any one of claims 6 to 19.

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