Intermediate 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) Compounds of formula (I) having carbonyl protecting groups of 2-((1H-pyrrolo [2, 3, 4])-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 processes for the preparation of compounds of formula (I), including compounds of 2-((1H-pyrrolo [2, 3, 4] triazolo [2, 3, 4] triazolo [2, 3, 4] triazolo [2, 3, 4] triazolo [2, 3, 4] triazolo [2, 3, 4] triazolo [2, 3, 4] triazolo [4, 4] The preparation method comprises the following steps: adding 4-(1, 5-dioxa-11-aza-di-spiro [5.1. 58.16] tetradecane-11-yl) methyl benzoate into a reaction kettle, and carrying out a reaction for 2-4 hours to obtain 4-(1, 5-dioxa-11-aza-di-spiro [5.1. 58.16] # imgabs0 #

Description

Technical Field

[0001] Disclosed herein are compounds of formula (I) having a carbonyl protecting group useful as intermediates for preparing 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 methods for preparing compounds of formula (I) comprising 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azadispiro[5.1.5 8 .1 6 ]tetradec-11-yl)benzoic acid methyl ester. 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] However, the method for preparing Sonrotoclax also needs to be optimized. The current yield of the reaction is relatively low, and the current intermediates are not stable enough for industrial processes. Therefore, novel reaction intermediates and methods for preparing Sonrotoclax are needed. Summary of the invention

[0004] Provided herein are compounds having formula (I), and salts, stereoisomers and derivatives thereof. Further provided herein are methods for preparing compounds of formula (I). Further provided herein are methods for preparing Sonrotoclax from compounds of formula (I). DETAILED DESCRIPTION

[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] An "alkyl" group is a saturated, partially saturated, or unsaturated straight or branched chain acyclic hydrocarbon 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(CH 3 ), -CH=C(CH 3 ) 2 、-C(CH3 )=CH 2 、-C(CH 3 )=CH(CH 3 )、-C(CH 2 CH 3 )=CH 2 、-C≡CH、-C≡C(CH 3 )、-C≡C(CH 2 CH 3 ),-CH 2 C≡CH, -CH 2 C≡C(CH 3 ) and -CH 2 C≡C(CH 7 CH 3 ) and the like. Alkyl groups 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 (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; B(OH) 2 , or O(alkyl)aminocarbonyl.

[0010] An "alkenyl" group is a straight or branched chain non-cyclic hydrocarbon having 2 to 10 carbon atoms, typically 2 to 8 carbon atoms, and including at least one carbon-carbon double bond. Representative straight and branched (C 2 C 8 )Alkenyl includes -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutenyl, -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, etc. The double bond of the alkenyl group can be unconjugated or conjugated with another unsaturated group. The 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: 2-20Alkynyl; 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, 1-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-1-oxo-4,9-diazaspiro[5.5]undecane, 2-oxo-1-oxo-3,8-diazaspiro[5.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-1-oxo-4,9-diazaspiro[5.5]undecane, 2-oxo-1-oxo-3,9-diazaspiro[5.5]undecane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-1-oxo-4,9-diazaspiro[5.5]undecane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-1-oxo-4,9-diazaspiro[5.5]undecane, 3-oxo-2,8-diazaspiro[4 ...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] A "heteroaryl" group is an aryl ring system 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] "Halogen" is fluorine, chlorine, bromine or iodine.

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

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

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

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

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

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

[0025] An "aminocarbonyl" group is a group having the formula: -C(O)N(R # ) 2 、-C(O)NH(R # ) or -C(O)NH 2 , where each R # Independently is a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl group as defined herein.

[0026] 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.

[0027] 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)NH 2 、-NHC(O)N(R # ) 2 、-NHC(O)NH(R # ), or -NH(CO)NHR # , where each alkyl group and R # Independently as defined above.

[0028] 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 (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; oxygen (=O); B(OH) 2 , O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl, 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, pyridinyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl, or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0029] 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).

[0030] 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.

[0031] 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).

[0032] 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.

[0033] 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.

[0034] Throughout this specification and the accompanying aspects, the term "C n-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 .

[0035] In the following claims and the foregoing description, unless the context requires otherwise due to express language or necessary meaning, the word "comprise" or variations such as "comprises" or "comprising" are used in an inclusive sense, i.e. specifying the presence of stated features, but not excluding the presence or addition of further features in various embodiments.

[0036] Provided herein are intermediates that can greatly increase the yield and purity of Sonrotoclax; and are also stable enough to provide a robust process for industry. The inventors have discovered that Sonrotoclax can be obtained in a solid state with a purity greater than 90% and a yield greater than 70%.

[0037] In one embodiment, disclosed herein is a compound having formula (I). This embodiment comprises the following aspects:

[0038] Aspect 1. A compound 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, -C 3 -C 8 Cycloalkyl, 3 to 8 membered heterocyclic group, C 6 -C 12Aryl, 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 ;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, -C 3 -C 8 Cycloalkyl, 3 to 8 membered heterocyclic group, 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 ; R 1 It is C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl or C 3-6Each of the cycloalkyl groups is optionally substituted by halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3 -C 8 Cycloalkyl, 3 to 8 membered heterocyclic group, 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 ; 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.

[0039] In particular, 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) benzoic acid methyl ester is an important intermediate for the synthesis of Sonrotoclax, and the intermediate can be prepared by reacting 1,5-dioxa-11-azabisspiro[5.1.5 8 .1 6 ] tetradecane hydrochloride and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid methyl ester. 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azabisspiro[5.1.5 8 .1 6The synthesis and method of methyl 1-tetradecane-11-yl)benzoate (Compound 1) is highly desirable because Compound 1 can meet the requirements of preparing the final product Sonrotoclax as an intermediate with high purity and high yield.

[0040] Aspect 2. The compound as described in Aspect 1, wherein R is each independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; 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, oxo, -CN, -NO 2 , methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; or The two Rs together with the two oxygen atoms to which they are attached form a 3- to 12-membered ring, which is optionally substituted with at least one substituent, wherein the methyl, 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, oxo, -CN, -NO 2 , methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; And R 1 Each is independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; the ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, oxo, -CN, -NO 2 , methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

[0041] Aspect 3. The compound as described in Aspect 1, wherein R is each independently methyl, ethyl, 1-propyl or 2-propyl; or Two R together with the two oxygen atoms to which they are attached form a 3-, 5-, 6-, 7- or 8-membered ring; R 1 It is methyl, ethyl, 1-propyl or 2-propyl.

[0042] Aspect 4. The compound according to aspect 2, wherein two R together with the two oxygen atoms to which they are attached form a ring containing 3 or more carbon atoms; and R 1 It's methyl.

[0043] Aspect 5. The compound according to aspect 1, which has the following structure:

[0044] Aspect 6. A method for preparing a compound of formula (I) as described in any one of aspects 1 to 5, the method comprising:

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

[0046] In order to optimize the synthesis of Sonrotoclax and produce a more stable intermediate of formula (II), pharmaceutically acceptable alcohols (including methanol, ethanol, isopropanol, diols and 1,3-propylene glycol) have been used for keto protection of 1-azaspiro[3.5]nonan-2-one. The inventors found that among those alcohols, only 1,3-propylene glycol produced 1,5-dioxa-11-azadispiro[5.1.5]nonan-2-one in a solid state with a good physical form and a high purity of even 99.9%. 8 .1 6 ]Tetradecane hydrochloride (Compound 2). In addition, it was found that Compound 2 in a solid state was highly stable when stored at 2°C-8°C for 3.5 months or longer, and there was no increase in impurities.

[0047] Aspect 7. The method according to aspect 6, wherein The base is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), methylpiperidine and N,N-diisopropylethylamine (DIPEA) or a combination thereof; Preferably, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or a combination thereof; More preferably, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

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

[0049] Aspect 9. The method according to any one of aspects 6 to 8, wherein The solvent is selected from the group consisting of N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), 2-methyltetrahydrofuran (2-MeTHF), 4-methyl-2-pentanone (MIBK) or toluene or a combination thereof; Preferably, N-methylpyrrolidone (NMP). In other embodiments, NMP provides better conversion and lower impurity levels.

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

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

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

[0053] Aspect 13. A method as described in any one of aspects 6-12, comprising Step 1): reacting the compound having the formula (II) and the compound having the formula (III) in the presence of a base and a solvent; Step 2): After the reaction of step 1) is completed, water, AcOH and seed crystals having the formula (I) are added to the reaction system; after filtering, a crude product containing the compound having the formula (I) is obtained; Step 3): The crude product containing the compound of formula (I) is slurried with a mixture of solvents, filtered and dried to obtain the compound of formula (I). In an embodiment, the seed crystals having formula (I) are prepared by the following method, which comprises: Step 1-1): reacting the compound having the formula (II) and the compound having the formula (III) in the presence of a base and a solvent; Step 2-1): After the reaction of step 1) is completed, water and AcOH are added to the reaction system; after filtration, a crude product containing the compound of formula (I) is obtained; Step 3-1): The crude product containing the compound of formula (I) is slurried with a mixture of solvents, filtered and dried to obtain seed crystals of formula (I).

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

[0055] Aspect 15. The method according to aspect 14, wherein 2-MeTHF:n-heptane (v:v)=1-4:1.

[0056] Aspect 16. Provided herein is a method for preparing Sonrotoclax. In one embodiment, the method comprises reacting a compound having formula (I) with an acid or a base to provide a compound having formula (SI) or a salt thereof.

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

[0058] Aspect 17. Provided herein is a method for preparing Sonrotoclax. In one embodiment, the method comprises reacting a compound having formula (SI) with (S)-2-(2-isopropylphenyl)pyrrolidine or a salt thereof to provide a compound having formula (SII) or a salt thereof.

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

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

[0061] Aspect 18. Provided herein is a method for preparing Sonrotoclax. In one embodiment, the method comprises making a compound having formula (SII) or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide to provide Sonrotoclax or a salt thereof.

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

[0063] Aspect 19. Provided herein is a method for preparing Sonrotoclax. In one embodiment, the method comprises reacting a compound having formula (SII) 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.

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

[0065] Aspect 20. Provided herein is a method for preparing Sonrotoclax. In one embodiment, the method comprises reacting (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide to provide Sonrotoclax or a salt thereof.

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

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

[0068] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Numbered Examples: Example 1. A compound 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, -C 3 -C 8 Cycloalkyl, 3 to 8 membered heterocyclic group, 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 ;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, -C 3 -C 8 Cycloalkyl, 3 to 8 membered heterocyclic group, 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 、-NR1a 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 ; 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, -C 3 -C 8 Cycloalkyl, 3 to 8 membered heterocyclic group, 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 ; 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 as described in embodiment 1, wherein: R is each independently ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; 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, oxo, -CN, -NO 2 , methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; or The two Rs together with the two oxygen atoms to which they are attached form a 3- to 12-membered ring, which is optionally substituted with at least one substituent, wherein the methyl, 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, oxo, -CN, -NO 2 , methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; R 1 Each is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; the ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, oxo, -CN, -NO 2 , methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Embodiment 3. The compound as described in embodiment 1, wherein: R is each independently methyl, ethyl, 1-propyl or 2-propyl; or Two R together with the two oxygen atoms to which they are attached form a 3-, 5-, 6-, 7- or 8-membered ring; R 1 It is methyl, ethyl, 1-propyl or 2-propyl. Embodiment 4. The compound of embodiment 2, wherein two R together with the two oxygen atoms to which they are attached form a ring containing 3 or more carbon atoms; and R 1 It's methyl. Embodiment 5. The compound as described in Embodiment 1 has the following structure: Embodiment 6. A method for preparing a compound of formula (I) as described in any one of embodiments 1-5, comprising: reacting a compound having formula (II) and a compound having formula (III) in the presence of a base and a solvent to form the compound having formula (I); in X is halogen; preferably, X is F, Cl, Br, or I; more preferably, X is F. Embodiment 7. The method of embodiment 6, wherein the base is selected from the group consisting of: 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), methylpiperidine and N,N-diisopropylethylamine (DIPEA) or a combination thereof; Preferably, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or a combination thereof; More preferably, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Embodiment 8. The method of any one of embodiments 6-7, wherein the molar ratio of the base used in the reaction to the compound of formula (II) is 0.9-1.3; Preferably, the molar ratio of the base to the compound of formula (II) used in the reaction is about 1. Embodiment 9. The method of any one of embodiments 6-8, wherein the solvent is selected from the group consisting of: N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), 2-methyltetrahydrofuran (2-MeTHF), 4-methyl-2-pentanone (MIBK) or toluene or a combination thereof; Preferably, N-methylpyrrolidone (NMP). Embodiment 10. The method of any one of embodiments 6-9, wherein the weight ratio of the solvent used in the reaction to the sum of the compound of formula (II) and the compound of formula (III) is about 4-6; Preferably, about 5. Embodiment 11. The method of any one of embodiments 6-10, wherein the amount of the compound of formula (II) used in the reaction is in the range of about 1.3 molar equivalents to about 1.6 molar equivalents relative to the amount of the compound of formula (III); Preferably, about 1.45 molar equivalents to about 1.65 molar equivalents. Embodiment 12. The method of any one of embodiments 6-11, wherein the reaction temperature ranges from about 40°C to about 100°C; Preferably, about 65°C to about 80°C; More preferably, about 75°C. Embodiment 13. The method as described in any one of embodiments 6-12, the method comprising Step 1): reacting the compound having the formula (II) and the compound having the formula (III) in the presence of a base and a solvent; Step 2): After the reaction of step 1) is completed, water, AcOH and seed crystals having the formula (I) are added to the reaction system; after filtering, a crude product containing the compound having the formula (I) is obtained; Step 3): The crude product containing the compound of formula (I) is slurried with a mixed solvent, filtered and dried to obtain the compound of formula (I). Embodiment 14. The method as described in Embodiment 13, wherein the mixed solvent comprises 2-MeTHF and n-heptane. Embodiment 15. The method 14 as described in Embodiment 1, wherein 2-MeTHF:n-heptane (v:v)=1-4:1. Examples Universal synthesis

[0069] 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.

[0070] 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.

[0071] The selection of appropriate protecting groups can be readily determined by one skilled in the art.

[0072] 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

[0073] Compounds of formula (I) can be prepared as shown in Scheme 1. Nucleophilic aromatic substitution reaction (SNAr) between compound 2 and compound 3 with the aid of a base gives compound 1. For example:

[0074] abbreviation

[0075] The following examples are intended to be purely exemplary and should not be considered to be limiting in any way. Although efforts have been made to ensure the accuracy of the numbers (e.g., amount, temperature, etc.) used, some experimental errors and deviations should be considered. Unless otherwise stated, temperatures are expressed in degrees Celsius. Reagents are purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and unless otherwise stated, can be used without further purification. Unless otherwise stated, the reactions described below are carried out with drying tubes under a positive pressure of nitrogen or argon or in anhydrous solvents; Reaction flasks are equipped with rubber septa for introducing substrates and reagents via syringes; and glassware is oven dried and / or heated and dried.

[0076] HPLC: Waters with UV detector or equivalent. Mobile phase: A: water containing 0.01% TFA, B: acetonitrile containing 0.01% TFA. Column: Waters CORTECS C18+, 100*4.6mm, 2.7um, PN: 186007407. Gradient method: Flow rate: 1.0mL / min; Time (min) A (%) B (%) Time (min) A(％) B(％) 0 80 20 19 55 45 31 10 90 31.1 80 20 36 80 20

[0077] Comparison example:

[0078] Compound C1 was prepared by the reaction between Compound C2 and Compound 3. However, it was found that Compound C1 was unstable and it was easily deprotected. Therefore, it could not be used as a useful intermediate for the preparation of Sonrotoclax.

[0079] Compound C1 was prepared as follows.

[0080] Subsequently, DBU (1.50 g, 9.85 mmol) was added to a suspension of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.01 g, 3.49 mmol) and 2,2-dimethoxy-7-azaspiro[3.5]nonane hydrochloride (1.06 g, 4.54 mmol, prepared by the method disclosed in WO 2019 / 210828) in NMP (5 mL). The resulting solution was stirred at 80 ° C for 24 h and cooled to 50 ° C. The pH value was adjusted to a 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 filtration and washed 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. MS: 451.2.

[0081] Example A1: 1,5-Dioxa-11-azadispiro[5.1.5.1]tetradecane hydrochloride

[0082] 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

[0083] Example A2: 1,5-Dioxa-11-azadispiro[5.1.5.1]tetradecane hydrochloride

[0084] 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

[0085] Example A3: Stability test of 1,5-dioxa-11-azadispiro[5.1.5.1]tetradecane hydrochloride

[0086] 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.

[0087] Table 1

[0088] Example 1: NMP as solvent, DBU as base, reaction temperature: 80°C, and 1.3 equivalents of compound 2 (relative to the equivalents of compound 3)

[0089] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate was synthesized according to the method in WO 2019210828 (which is incorporated by reference in its entirety) (eg, Example F43).

[0090] 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 (1.06 g, 4.54 mmol) in NMP (5 mL) was added DBU (1.50 g, 9.85 mmol). The resulting solution was stirred at 80 ° 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: 93.17%, yield: 83%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0091] Example 2: NMP as solvent, DBU as base, reaction temperature: 80°C, and 1.45 equivalents of compound 2 (relative to the equivalents of compound 3)

[0092] 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 (1.18 g, 5.06 mmol) in NMP (5 mL) was added DBU (1.50 g, 9.85 mmol). The resulting solution was stirred at 80 ° 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: 90.59%, yield: 87%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0093] Example 3: NMP as solvent, DBU as base, reaction temperature: 80°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0094] 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 80 ° 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: 93.91%, yield: 86%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0095] Example 4: NMP as solvent, DBU as base, reaction temperature: 60°C, and 1.60 equivalents of compound (I) (relative to the equivalent of compound (II))

[0096] 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 60 ° 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: 93.83%, yield: 82%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0097] Example 5: NMP as solvent, DBU as base, reaction temperature: 65°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[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 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).

[0099] Example 6: NMP as solvent, DBU as base, reaction temperature: 70°C, and 1.60 equivalents of compound (I) (relative to the equivalent of compound (II))

[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 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).

[0101] Example 7: NMP as solvent, DBU as base, reaction temperature: 75°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0102] 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).

[0103] Example 8: NMP as solvent, DBU as base, reaction temperature: 80°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0104] 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 80 ° 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: 94.27%, yield: 83%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0105] Example 9: DMSO as solvent, DBU as base, reaction temperature: 80°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0106] 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 DMSO (5 mL) was added DBU (1.50 g, 9.85 mmol). The resulting solution was stirred at 80 ° 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: 94.27%, yield: 81%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0107] Example 10: 2-MeTHF as solvent, DBU as base, reaction temperature: 80°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0108] 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 2-MeTHF (5 mL), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 80 ° 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: 80.18%, yield: 71%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0109] Example 11: MIBK as solvent, DBU as base, reaction temperature: 80°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0110] 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 MIBK (5 mL), DBU (1.50 g, 9.85 mmol) was added. The resulting solution was stirred at 80 ° 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: 90.91%, yield: 78%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0111] Example 12: Toluene as solvent, DBU as base, reaction temperature: 80°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0112] 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 toluene (5 mL) was added DBU (1.50 g, 9.85 mmol). The resulting solution was stirred at 80 ° 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: 87.31%, yield: 76%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0113] Example 13: DMAc as solvent, DBU as base, reaction temperature: 80°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0114] 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 DMAc (5 mL) was added DBU (1.50 g, 9.85 mmol). The resulting solution was stirred at 80 ° 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: 94.36%, yield: 83%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0115] Example 14: NMP as solvent, TMG as base, reaction temperature: 80°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0116] 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 TMG (1.13 g, 9.85 mmol). The resulting solution was stirred at 80 ° 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: 87.51%, yield: 80%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0117] Example 15: NMP as solvent, DBN as base, reaction temperature: 80°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0118] 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), DBN (1.22 g, 9.85 mmol) was added. The resulting solution was stirred at 80 ° 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: 5.5%, yield: ND1H NMR (400 MHz, DMSO-d6) δ11.63 (s, 1H), 8.0 (d, 1H), 7.76 (d, 1H), 7.48 (t, 1H), 7.42 (d, 1H), 6.79 (dd, 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).

[0119] Example 16: NMP as solvent, DABCO as base, reaction temperature: 80°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0120] 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 DABCO (1.10 g, 9.85 mmol). The resulting solution was stirred at 80 ° 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: 8.9%, yield: 5%. 1HNMR(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( dd,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).

[0121] Example 17: NMP as solvent, methylpiperidine as base, reaction temperature: 80°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0122] 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 methyl piperidine (0.98 g, 9.85 mmol). The resulting solution was stirred at 80 ° 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: 84.38%, yield: 70%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0123] Example 18: NMP as solvent, DIPEA as base, reaction temperature: 80°C, and 1.60 equivalents of compound 2 (relative to the equivalents of compound 3)

[0124] 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 DIPEA (1.27 g, 9.85 mmol). The resulting solution was stirred at 80 ° 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: 86.18%, yield: 76%. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.0(d,1H),7.76(d,1H),7.48(t,1H),7.42(d,1H),6.79(d d,1H),6.38-6.40(m,2H),3.72(t,4H),3.65(s,3H),3.16(t,4H),1.95(s,1H),1.52-1.57(m,6H).

[0125] Example 19: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Sonrotoclax)

[0126] Step 1: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate

[0127] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azabispiro[5.1.5 8 .1 6 To a solution of methyl benzoate (180 g, 0.39 mol) in DCM (2 L) was added dilute HCl acid (1 M, 1.5 L) and stirred overnight. After the reaction was complete, the mixture was cooled to 10 ° C and adjusted to pH = 8-9 with aqueous NaOH solution (4 M) under stirring. The organic phase was separated and washed with 15% aqueous NaCl (1 L), then washed with H 2The mixture was stirred for 0.5 hours at room temperature for 1 hr. After filtration, the filter cake was collected and then dried in vacuo to obtain the title product (152 g, yield: 96%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )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.

[0128] Step 2: (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate

[0129] To a solution of tert-butyl (S)-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 H 2 Cs 2 CO 3 (100 g, 305 mmol) and Pd(dppf)Cl 2 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)-2-(2-(prop-1-ene-2-yl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (65g, crude product). The crude product was used directly in the next step.

[0130] Step 3: (S)-tert-Butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate

[0131] 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 stirred at 20 °C under H 2 The mixture was stirred at 400 rpm for 12 hours under 40 psi. TLC showed that 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 product), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 )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).

[0132] Step 4: (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride

[0133] 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 (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.

[0134] 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

[0135] A mixture of (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride (120 g, 0.535 mole) 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 mole) in DCM (2.2 L) was charged into the reactor. The temperature was controlled below 30°C and NaBH(OAc) was added. 3 (216 g, 1.018 mol) 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 H 2 O (600 mL × 2), and then washed with aqueous NaHCO 3 (600 mL × 2), saturated aqueous NaCl (600 mL). The organic phase was collected and then washed with anhydrous Na 2 SO 4 Dry and concentrate. Obtain 256 g of off-white solid as crude product, which is used directly in the next step. MS (ESI, m / e) [M+1] + 579.0.

[0136] 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

[0137] 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%). 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),7.56-7.40(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.

[0138] 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)

[0139] 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 (17.2 g, 195 mmol). The reaction was stirred for another 12 h. The mixture was washed twice with 10 wt% aqueous AcOH solution (300 mL x 2) and then with saturated aqueous NaHCO 3The mixture was stirred for 2 hours at 4 ℃ for 1 h. The mixture was stirred for 5 hours at 4 ℃ for 1 h. ... 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=8.8 Hz,1H),7.57-7.37(m,4H),7.30-7.10(m,3H),7.00(d,J=9.2Hz,1H),6.65(d,J=1.2Hz,1H),6 .35(s,1H),6.17(s,1H),4.24(s,1H),3.39-3.20(m,5H),3.04-2.88(m,4H),2.23(s,1H),1.9 4-1.47(m,11H),1.44-1.26(m,7H),1.19(d,J=8.0Hz,3H),1.14(d,J=8.0Hz,3H),1.10(s,4H). MS(ESI,m / e)[M+1] + 889.9.

Claims

1. A compound having the following structure: or a salt thereof.

2. A method for providing a compound of formula (SI) or a salt thereof, The method comprises subjecting a compound having formula (I) to or its salts react with an acid or a base, wherein 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 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 1c or -NR 1a C(=O)R 1b ; 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.

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

4. The method of claim 2 or 3, further comprising reacting the compound of formula (SI) with (S)-2-(2-isopropylphenyl)pyrrolidine or a salt thereof to provide a compound of formula (SII) or a salt thereof.

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

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

7. The method of any one of claims 4 to 6, further comprising subjecting the compound of formula (SII) to or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide to provide Sonrotoclax or a salt thereof.

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

9. The method of any one of claims 4-6, further comprising reacting the compound of formula (SII) 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]nonane-7-yl)benzoic acid or a salt thereof.

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

11. The method according to claim 9 or 10, 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.

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

13. 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 7 or 8.

14. 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 any one of claims 9 to 11.

15. 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 2 to 12.

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