Process for preparation of SERD tricyclic compounds having substituted phenyl or pyridyl moieties

Abstract

Provided herein are methods for preparing SERD tricyclic compounds having a substituted phenyl or pyridyl moiety. Provided herein are methods for preparing intermediate compounds of Formula (II) and compounds of Formula (I) useful in the treatment of cancer. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application with the application date of June 28, 2021, application number 202180046838.2, and invention name “Method for preparing SERD tricyclic compounds having a substituted phenyl or pyridyl moiety”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This case claims the benefit of U.S. Provisional Application No. 63 / 046,216, filed on June 30, 2020, which is incorporated herein by reference in its entirety and for all purposes. Technical Field

[0004] Provided herein are methods for the synthesis of GDC-9545 and intermediates involving the large-scale preparation of (R)-1-(1H-indol-3-yl)propan-2-amine and (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol. Background Art

[0005] Fused tricyclic compounds within the scope of the present disclosure containing substituted phenyl or pyridyl moieties are useful as estrogen receptor ("ER") targeting agents.

[0006] ER is a ligand-activated transcriptional regulatory protein that mediates the induction of various biological effects through its interaction with endogenous estrogens. Endogenous estrogens include 17β-estradiol and estrone. ER has been found to have two isoforms, ER-α and ER-β. Estrogen and estrogen receptors are associated with a variety of diseases or conditions, such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer, and other diseases or conditions. ER-α targeting agents have specific activity in the context of metastatic disease and acquired resistance. ER-α targeting agents are disclosed in U.S. Publication No. 2016 / 0175289.

[0007] Available methods for preparing fused tricyclic compounds (e.g., GDC-9545) comprising substituted phenyl or pyridyl moieties are disclosed in U.S. Patent No. 9,980,947 and U.S. Patent Publication No. US2020 / 0002331. However, it is well known that amplification of chemical methods can lead to unexpected situations, such as increased impurities or decreased yields. Therefore, there is a need for improved methods for synthesizing GDC-9545 that increase yield and / or reduce impurities. Compared to currently known methods, the methods of the present disclosure advantageously provide improvements in, for example, process conditions, reagent selection, complexity of required unit operations, scalability, etc. Summary of the Invention

[0008] This article provides solutions to these and more problems.

[0009] In one aspect, provided herein is a method for preparing a compound of formula (II) as described herein, comprising (a) contacting a compound of formula (III) as described herein with a sulfonic acid to form a compound of formula (IIIa) as described herein; (b) contacting the compound of formula (IIIa) with a base to form a compound of formula (IV) as described herein; hydrogenating the compound of formula (IV) to form a compound of formula (V) as described herein; and contacting the compound of formula (V) with a compound of formula (VI) as described herein, thereby synthesizing a compound of formula (II).

[0010] In another aspect, provided herein is a method for preparing a compound of formula (II) as described herein, comprising (a) contacting a compound of formula (VII) as described herein with a compound of formula (VI) as described herein to prepare a compound of formula (VIIa) as described herein; (b) contacting the compound of formula (VIIa) with an acid, thereby synthesizing a compound of formula (VIIb) as described herein; contacting the compound of formula (VIIb) with 1,1'-carbonyldiimidazole, thereby synthesizing a compound of formula (VIIc) as described herein; contacting the compound of formula (VIIc) with a compound of formula (VIII) as described herein to prepare a compound of formula (Va) as described herein; and contacting the compound of formula (Va) with a base followed by an acid, thereby preparing a compound of formula (II).

[0011] In another aspect, provided herein is a method of preparing a compound of formula (II) as described herein, comprising contacting a compound of formula (V) as described herein with a compound of formula (VI) as described herein, wherein the compound of formula (V) is prepared by: (a) contacting a compound of formula (VIIp) as described herein with a compound of formula (VIII) as described herein to produce a compound of formula (Vb) as described herein; and (b) contacting the compound of formula (Vb) with an acid to thereby prepare the compound of formula (V).

[0012] In another aspect, provided herein is a process for preparing a compound of formula (II), comprising (a) contacting alanine with a compound of formula (IX) as described herein to form a compound of formula (XI) as described herein; b) contacting the compound of formula (XI) with a chlorinating agent, a (c) contacting the compound of formula (Vc) with an organoaluminum compound to form a compound of formula (Vc) as described herein; and (c) contacting the compound of formula (Vc) with a reducing agent, thereby forming a compound of formula (II).

[0013] In another aspect, provided herein is a method for synthesizing a compound of formula (1), the method comprising contacting a compound of formula (2) (synthesized according to any of the methods described herein) with a compound of formula (10).

[0014] In one aspect, provided herein is a method for treating cancer, by administering to a patient suffering from cancer an effective amount of a compound of formula (I) synthesized according to any of the methods described herein or a pharmaceutically acceptable salt thereof.

[0015] In another aspect, provided herein is a method for treating lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer or breast cancer, by administering to a patient suffering from the cancer an effective amount of a compound of formula (I) synthesized according to any of the methods described herein or a pharmaceutically acceptable salt thereof.

[0016] In another aspect, provided herein are methods of treating breast cancer in a patient having breast cancer by administering an effective amount of a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof.

[0017] This article also covers the following projects:

[0018] 1. A method for preparing a compound of formula (II)

[0019]

[0020] or a stereoisomer or salt thereof,

[0021] R 1a and R 1b Each of which is independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, -CN, unsubstituted C 3-6 Cycloalkyl or unsubstituted C 3-6 spirocycloalkyl;

[0022] Each R 2 are independently halogen, hydroxy, -CN, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl or unsubstituted C 1-3 alkoxy;

[0023] m is 0, 1, or 2; and

[0024] n is 1, 2, or 3;

[0025] The method comprises:

[0026] (a) making a compound of formula (III)

[0027]

[0028] or a stereoisomer or salt thereof is contacted with a sulfonic acid to form a compound of formula (IIIa)

[0029]

[0030] or a stereoisomer or salt thereof;

[0031] (b) contacting the compound of formula (IIIa) or its stereoisomer or salt with a base to form a compound of formula (IV)

[0032]

[0033] or a stereoisomer or salt thereof;

[0034] (c) hydrogenating the compound of formula (IV) or a stereoisomer or salt thereof to form a compound of formula (V)

[0035]

[0036] or a stereoisomer or salt thereof; and

[0037] (d) contacting the compound of formula (V) or a stereoisomer or salt thereof with a compound of formula (VI);

[0038]

[0039] Thereby a compound of formula (II) or a stereoisomer or salt thereof is formed.

[0040] 2. The method according to item 1, wherein the compound of formula (III) is * ) compounds.

[0041] 3. The method according to item 2, wherein the formula (III * ) compound is of formula (3 * ), formula (3x * ), formula (3y * ) or formula (3z * ) compounds.

[0042] 4. The method according to item 2, wherein the formula (III * ) compound is of formula (3 * ) compounds.

[0043] 5. The method according to any one of items 1 to 4, wherein the sulfonic acid is H2SO4 or ClSO3H.

[0044] 6. The process according to any one of items 1 to 5, wherein the base is a hydroxide base.

[0045] 7. The method according to item 6, wherein the base is KOH, NaOH or LiOH.

[0046] 8. The process according to any one of items 1 to 7, wherein the hydrogenation is carried out using a catalyst containing Pd, Pt or Ni.

[0047] 9. The method according to item 8, wherein the catalyst is Pd / C, Pt / C or Raney Ni.

[0048] 10. The process according to any one of items 1 to 9, wherein the hydrogenation is carried out using catalytic transfer hydrogenation in the presence of isopropanol, formic acid, a formate salt or ammonium.

[0049] 11. A method for preparing a compound of formula (II)

[0050]

[0051] or a stereoisomer or salt thereof,

[0052] R 1a and R 1b Each of which is independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, -CN, unsubstituted C 3-6 Cycloalkyl or unsubstituted C 3-6 spirocycloalkyl;

[0053] Each R 2 are independently halogen, hydroxy, -CN, C 1-3 Alkyl or C 1-3 Halogenated alkyl, C 1-3 alkoxy;

[0054] m is 0, 1, or 2; and

[0055] n is 1, 2, or 3;

[0056] The method comprises:

[0057] (a) making a compound of formula (VII)

[0058]

[0059] or a stereoisomer or salt thereof, wherein each Z is independently C 1-3 Alkyl or phenyl, contacted with a compound of formula (VI),

[0060]

[0061] where R 1a and R 1b As described herein, the compound of formula (VIIa) is synthesized

[0062]

[0063] or a stereoisomer or salt thereof;

[0064] (b) contacting the compound of formula (VIIa) or its stereoisomer or salt with an acid to thereby synthesize the compound of formula (VIIb)

[0065]

[0066] or a stereoisomer or salt thereof;

[0067] (c) contacting the compound of formula (VIIb) or its stereoisomer or salt with 1,1'-carbonyldiimidazole to synthesize the compound of formula (VIIc)

[0068]

[0069] or a stereoisomer or salt thereof;

[0070] (d) reacting the compound of formula (VIIc) or its stereoisomer or salt with a compound of formula (VIII)

[0071]

[0072] or a salt thereof to prepare a compound of formula (Va)

[0073]

[0074] or a stereoisomer or salt thereof; and

[0075] (e) contacting the compound of formula (Va) or a stereoisomer or salt thereof with a base and then with an acid, thereby preparing the compound of formula (II) or a stereoisomer or salt thereof.

[0076] 12. A method for preparing a compound of formula (II)

[0077]

[0078] or a stereoisomer or salt thereof,

[0079] R 1a and R 1b Each of which is independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, -CN, unsubstituted C 3-6 Cycloalkyl or unsubstituted C 3-6 spirocycloalkyl;

[0080] Each R 2are independently halogen, hydroxy, -CN, C 1-3 Alkyl or C 1-3 Halogenated alkyl, C 1-3 alkoxy;

[0081] m is 0, 1, or 2; and

[0082] n is 1, 2, or 3;

[0083] The method comprises making a compound of formula (V)

[0084]

[0085] or a stereoisomer or salt thereof is contacted with a compound of formula (VI),

[0086]

[0087] The compound of formula (V) is prepared by:

[0088] (a) making a compound of formula (VIIp)

[0089]

[0090] or a stereoisomer or salt thereof, wherein each Z is independently C 1-3 Alkyl or phenyl, and a compound of formula (XII)

[0091]

[0092] or its salt to prepare a compound of formula (Vb)

[0093]

[0094] or a stereoisomer or salt thereof; and

[0095] (b) contacting the compound of formula (Vb) with an acid, thereby preparing the compound of formula (V).

[0096] 13. The method according to item 11 or 12, wherein each Z is independently C 1-4 alkyl.

[0097] 14. The method according to item 11 or 12, wherein each Z is methyl, each Z is ethyl, each Z is isopropyl, or wherein SiZ3 is Si(PhMe2) or Si(t-BuMe2).

[0098] 15. The method according to item 11 or 12, wherein each Z is ethyl.

[0099] 16. The method according to any one of items 1 to 15, wherein the compound of formula (VI) is:

[0100] including stereoisomers thereof.

[0101] 17. A method for preparing a compound of the formula

[0102]

[0103] or a stereoisomer or salt thereof,

[0104] R 1a and R 1b Each of which is independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, -CN, unsubstituted C 3-6 Cycloalkyl or unsubstituted C 3-6 spirocycloalkyl;

[0105] Each R 2 are independently halogen, hydroxy, -CN, C 1-3 Alkyl or C 1-3 Halogenated alkyl, C 1-3 alkoxy;

[0106] m is 0, 1, or 2;

[0107] n is 1, 2, or 3;

[0108] The method comprises

[0109] (a) alanine and a compound of formula (IX)

[0110]

[0111] or a stereoisomer or salt thereof to form a compound of formula (XI)

[0112]

[0113] or a stereoisomer or salt thereof;

[0114] (b) reacting a compound of formula (VIII) with a chlorinating agent, a The compound is contacted with an organoaluminum compound to form a compound of formula (Vc)

[0115]

[0116] or a stereoisomer or salt thereof; and

[0117] (c) contacting the compound of formula (Vc) or a stereoisomer or salt thereof with a reducing agent, thereby forming a compound of formula (II) or a stereoisomer or salt thereof.

[0118] 18. The method according to item 17, wherein the organoaluminum compound has the formula X3Al, wherein X is independently Cl or C 1-4 alkyl.

[0119] 19. The method according to item 17, wherein X is independently methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

[0120] 20. The process according to any one of items 17 to 19, wherein the organoaluminum compound is trimethylaluminum, triethylaluminum, triisobutylaluminum, dimethylaluminum chloride, diethylaluminum chloride or ethylaluminum dichloride.

[0121] 21. The process according to any one of items 17 to 20, wherein the organoaluminum compound is trimethylaluminum.

[0122] 22. The method according to any one of items 17 to 21, wherein the reducing agent is sodium aluminum hydride.

[0123] 23. The method according to any one of items 17 to 22, wherein the chlorinating agent is SOCl2, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, pivaloyl chloride or oxalyl chloride.

[0124] 24. The method according to item 23, wherein the chlorinating agent is oxalyl chloride.

[0125] 25. The method according to item 24, wherein the chlorinating agent is in the presence of N-formylpyrrolidine or N,N-dimethylformamide.

[0126] 26. The method according to any one of items 1 to 25, wherein R 1a and R 1b are independently hydrogen, halogen, cyano, unsubstituted C 1-3 Alkyl or cyclopropyl.

[0127] 27. The method according to any one of items 1 to 25, wherein R 1a and R 1b are independently hydrogen, halogen or methyl.

[0128] 28. The method according to any one of items 1 to 25, wherein R 1a is hydrogen and R 1b is halogen, methyl, cyano or cyclopropyl.

[0129] 29. The method according to any one of items 1 to 25, wherein R1a is hydrogen and R 1b It is a halogen.

[0130] 30. The method according to any one of items 1 to 25, wherein R 1a is hydrogen and R 1b It is a methyl group.

[0131] 31. The method according to any one of items 1 to 25, wherein R 1a is methyl and R 1b is halogen, methyl, cyano or cyclopropyl.

[0132] 32. The method according to any one of items 1 to 25, wherein R 1a is a halogen and R 1b is halogen, methyl, cyano or cyclopropyl.

[0133] 33. The method according to any one of items 1 to 25, wherein R 1a and R 1b is independently halogen or methyl.

[0134] 34. The method according to any one of items 1 to 25, wherein R 1a is a halogen and R 1b It is a methyl group.

[0135] 35. The method according to any one of items 1 to 25, wherein R 1a is a halogen and R 1b It is a halogen.

[0136] 36. The method according to any one of items 1 to 25, wherein R 1a and R 1b For F.

[0137] 37. The method according to any one of items 1 to 36, wherein each R 2 are independently hydrogen, halogen, hydroxy, -CN or C 1-3 alkyl.

[0138] 38. The method according to any one of items 1 to 37, wherein m is 0.

[0139] 39. The method according to any one of items 1 to 37, wherein m is 1.

[0140] 40. The method according to any one of items 1 to 37, wherein R 2 Halogen or C 1-3 An alkyl group and m is 1.

[0141] 41. The method according to any one of items 1 to 37, wherein R 2is halogen and m is 1.

[0142] 42. The method according to any one of items 1 to 41, wherein the compound of formula (II) is:

[0143]

[0144] or a stereoisomer or salt thereof.

[0145] 43. The method according to any one of items 1 to 38, wherein the compound of formula (II) is:

[0146]

[0147] or a salt thereof.

[0148] 44. The method according to any one of items 1 to 43, wherein the compound of formula (II) is contacted with a compound of formula (X)

[0149]

[0150] or a stereoisomer or salt thereof,

[0151] Ring A is phenyl or pyridyl;

[0152] Each R 3 are independently hydrogen, halogen or C 1-3 alkyl,

[0153] R 4 is halogen or -CN; and

[0154] p is 1 or 2;

[0155] To form a compound of formula (I)

[0156]

[0157] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0158] 45. The method according to item 44, wherein the compound of formula (X) is:

[0159]

[0160]

[0161] or a salt thereof.

[0162] 46. ​​A method for synthesizing a compound having formula (1)

[0163]

[0164] or a pharmaceutically acceptable salt thereof, the method comprising:

[0165] (a) making a compound of formula (2)

[0166]

[0167] or a salt thereof,

[0168] wherein the compound of formula (2) is synthesized according to the method according to item 1, 11 or 12, and wherein the compound of formula (V) has formula (5),

[0169]

[0170] or a salt thereof and the compound of formula (VI) has formula (6),

[0171]

[0172] (b) with a compound of formula (10)

[0173]

[0174] or a salt thereof, thereby preparing the compound of formula (1) or a pharmaceutically acceptable salt thereof.

[0175] 47. The method according to item 46, wherein the compound of formula (6) is prepared by:

[0176] (a) Make equation (12a) The compound is contacted with H2SO4 to prepare Compounds;

[0177] (b) reducing the compound of formula (12b) to prepare Compounds;

[0178] (c) cyclizing the compound of formula in the presence of SOCl2 to prepare compounds; and

[0179] (d) contacting the compound of formula (12d) with FeCl 3 , NaOCl and a base to thereby prepare the compound of formula (6). DETAILED DESCRIPTION

[0180] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure pertains.See, for example, Microbiology and Molecular Biology Dictionary (Second Edition) (Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd ed, J.Wiley&Sons (New York, NY 1994)); Molecular cloning, laboratory manual (Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY1989)). Methods, equipment and materials similar to or equivalent to the methods, equipment and materials described herein can be used in the practice of the present invention.

[0181] The following definitions are provided to facilitate understanding of some terms frequently used herein and are not intended to limit the scope of the present disclosure.All references cited herein are incorporated by reference in their entirety.

[0182] As used herein, the term "alkyl" refers to a group having 1 to 20 carbon atoms (C 1-20 ) atoms. In certain embodiments, the alkyl group has 1 to 10 carbon atoms (C 1-10 ) atoms. In certain embodiments, the alkyl group has 1 to 6 carbon atoms (C 1-6 ) atoms. In certain embodiments, the alkyl group has 1 to 4 carbon atoms (C 1-4 ) atoms. In certain embodiments, the alkyl group has 1 to 3 carbon (C 1-3 ) atoms. The alkyl group may be optionally substituted independently with one or more substituents described herein.

[0183] As used herein, the term "substituted" refers to the replacement of at least one hydrogen atom in a compound or moiety with another substituent or moiety. Examples of such substituents include, but are not limited to, halogen, -OH, -CN, oxo, alkoxy, alkyl, alkylene, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, and heterocycle. In one embodiment, substituted as used herein can refer to the replacement of at least one hydrogen atom of a compound or moiety described herein with a halogen or alkyl group.

[0184] As used herein, the term "alkoxy" refers to a radical of the formula -O-R', wherein R' is an alkyl radical. The alkoxy radical may be optionally substituted independently with one or more substituents as described herein. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy.

[0185] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms, in particular fluorine and / or chlorine atoms. Examples of haloalkyl groups include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl or trifluoromethyl.

[0186] As used herein, the terms "halo" and "halogen" are interchangeable and refer to the substituents fluorine, chlorine, bromine, or iodine.

[0187] As used herein, the term "cycloalkyl" means a saturated or partially unsaturated carbocyclic moiety having monocycle, bicycle (including bridged bicycle) or tricycle and having 3 to 10 carbon atoms in the ring. The cycloalkyl moiety can optionally be substituted with one or more substituents. In a particular embodiment, the cycloalkyl contains 3 to 8 carbon atoms (i.e., (C3-C8) cycloalkyl). In other particular embodiments, the cycloalkyl contains 3 to 6 carbon atoms (i.e., (C3-C6) cycloalkyl). The example of the cycloalkyl moiety includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and its partially unsaturated (cycloalkenyl) derivatives (such as cyclopentenyl, cyclohexenyl and cycloheptenyl), bicyclo [3.1.0] hexyl, bicyclo [3.1.0] hexenyl, bicyclo [3.1.1] heptyl and bicyclo [3.1.1] heptenyl. The cycloalkyl moiety can be connected in a "spirocycloalkyl" manner, such as a "spirocyclopropyl":

[0188] As used herein, "treating" means alleviating a disease, illness, or condition, or one or more symptoms associated with a disease, illness, or condition, in whole or in part; or slowing or stopping the further progression or worsening of these symptoms; or alleviating or eliminating the cause of the disease, illness, or condition itself. In one embodiment, the disease is cancer.

[0189] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that is capable of treating or preventing a disorder, disease or condition disclosed herein, or a symptom thereof.

[0190] "Patient" or "subject" is defined herein to include animals (e.g., mammals), including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys, chickens, turkeys, quail, or guinea pigs, etc., in one embodiment, a mammal, in another embodiment, a human. In one embodiment, the subject is a human having cancer or at risk of cancer.

[0191] As used herein, the terms "moiety" and "substituent" refer to an atom or group of chemically bonded atoms that is attached to another atom or molecule through one or more chemical bonds to form a part of a molecule.

[0192] "Inorganic acid" refers to acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and combinations thereof.

[0193] "Organic acid" refers to acids such as, but not limited to, acetic acid; trifluoroacetic acid; phenylacetic acid; propionic acid; stearic acid; lactic acid; ascorbic acid; maleic acid; hydroxymaleic acid; isethionic acid; succinic acid; valeric acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; oleic acid; palmitic acid; lauric acid; pyranosidic acids such as glucuronic acid or galacturonic acid; α-hydroxy acids such as mandelic acid, citric acid, or tartaric acid; cysteine ​​sulfinic acid; amino acids such as aspartic acid, glutaric acid, or glutamic acid; aromatic acids such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid; sulfonic acids such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, or ethanesulfonic acid; cysteine ​​sulfonic acid; and combinations thereof.

[0194] The terms "inorganic base" and "hydroxide base" are used interchangeably and refer to bases such as, but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, and combinations thereof. In certain embodiments, the inorganic base is an alkali metal base (e.g., NaOH, KOH, or LiOH).

[0195] "Organic base" refers to an organic compound containing one or more nitrogen atoms and which acts as a base. Examples of organic bases include, but are not limited to, tertiary amine bases. Examples of organic bases include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene ("DBU"), N-methylmorpholine (NMM), diisopropylethylamine (DIPEA), triethylamine (TEA), tert-butoxide (e.g., sodium tert-butoxide, potassium tert-butoxide, calcium tert-butoxide, or magnesium tert-butoxide).

[0196] The compounds described herein may exist in the form of salts, including both pharmaceutically acceptable salts and non-pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the free base or free acid and are not biologically or otherwise undesirable. In addition to pharmaceutically acceptable salts, the compounds of the present disclosure may exist in the form of non-pharmaceutically acceptable salts, which may be used as intermediates for isolating or purifying the compounds.

[0197] Exemplary acid salts of compounds of the present disclosure include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, tartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Examples where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counterions.Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0198] Exemplary basic salts of the compounds of the present disclosure include, but are not limited to, inorganic salts formed from sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum cations. Organic salts formed from cations include primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; basic ion exchange resins; isopropylamine; trimethylamine; diethylamine; trimethylamine; tripropylamine; ethanolamine; 2-diethylaminoethanol; trimethylamine; dicyclohexylamine; lysine; arginine; histidine; caffeine; procaine; hydrabamine; choline; betaine; ethylenediamine; glucosamine; methylglucamine; theobromine; purines; piperazine; piperidine; N-ethylpiperidine; and polyamine resins.

[0199] Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or in the arrangement of their atoms in space are called "isomers." Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Diastereoisomers are stereoisomers that have opposite configurations at one or more chiral centers, rather than enantiomers. Stereoisomers that have one or more asymmetric centers and are non-superimposable opposites of each other are called "enantiomers." When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of one or more asymmetric centers and described by the R and S ordering rules of Cahn, Ingold, and Prelog or by the way the molecule rotates the plane of polarized light and are designated as right-handed or left-handed (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." In certain embodiments, the compound is enriched in at least about 90% by weight of a single diastereomer or enantiomer. In other embodiments, the compound is enriched in at least about 95%, 98%, or 99% by weight of a single diastereomer or enantiomer.

[0200] Certain compounds described herein and pharmaceutically acceptable salts thereof possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, regioisomers and individual isomers (eg, individual enantiomers) are intended to be encompassed within the scope of the present disclosure.

[0201] The compounds described herein and their pharmaceutically acceptable salts may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including, but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof (e.g., racemic mixtures), are intended to form part of the present invention. In some cases, stereochemistry has not yet been determined or has been provisionally specified. Many organic compounds exist in optically active forms, i.e., they are able to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l or (+) and (-) are used to specify the rotation sign of the plane polarized light of the compound, where (-) or l means that the compound is left-handed. Compounds with a (+) or d prefix are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomers. Enantiomers can be separated from a racemic mixture by chiral separation methods, such as supercritical fluid chromatography (SFC). In separated enantiomers, the designation of the configuration at the chiral center can be tentative, while stereochemistry is definitively established, for example, from x-ray crystallographic data.

[0202] Provided herein are methods for preparing compounds for treating cancer. Compounds of formula (I), including Compound 1 and Compound A, are exemplified in, for example, U.S. Patent No. 9,980,947 and U.S. Patent Publication No. US2020 / 0002331. The methods described herein improve the product purity and yield of the final product and key intermediates in its synthesis.

[0203] Provided herein are methods for preparing a compound of formula (II) or a salt thereof,

[0204]

[0205] in

[0206] R 1a and R 1b Each of which is independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, -CN, unsubstituted C 3-6 Cycloalkyl or unsubstituted C 3-6 spirocycloalkyl;

[0207] Each R 2 are independently halogen, hydroxy, -CN, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl or unsubstituted C 1-3 alkoxy;

[0208] m is 0, 1, or 2; and

[0209] n is 1, 2 or 3.

[0210] In one aspect, provided herein is a method (P1) for preparing a compound of formula (II) or a salt thereof, wherein the method comprises the following steps:

[0211] (a) making a compound of formula (III) or a salt thereof,

[0212]

[0213] contacting with a sulfonic acid to form a compound of formula (IIIa) or a salt thereof;

[0214]

[0215] (b) contacting the compound of formula (IIIa) or a salt thereof with a base to form the compound of formula (IV) or a salt thereof;

[0216]

[0217] (c) hydrogenating the compound of formula (IV) or a salt thereof to form the compound of formula (V) or a salt thereof; and

[0218]

[0219] (d) contacting the compound of formula (V) or a salt thereof with the compound of formula (VI);

[0220]

[0221] where R 1a and R 1b As described herein, the compound of formula (II) is thereby formed.

[0222] In one embodiment of method (P1) described herein, the compound of formula (III) is a salt of the formula:

[0223]

[0224] In one such embodiment, the salt is a methanesulfonic acid (MeSO 3 ) salt.

[0225] In one embodiment of method (P1) described herein, the compound of formula (III) has the following formula:

[0226]

[0227] or a stereoisomer or salt thereof.

[0228] In one embodiment of method (P1) described herein, the compound of formula (III) has the following formula:

[0229]

[0230] or a stereoisomer or salt thereof.

[0231] In one embodiment of method (P1) described herein, the compound of formula (IIIa) has the following formula:

[0232]

[0233] or a stereoisomer or salt thereof.

[0234] In one embodiment of method (P1) described herein, the compound of formula (IV) has the following formula:

[0235]

[0236] or a stereoisomer or salt thereof.

[0237] In one embodiment of method (P1) described herein, the compound of formula (IV) has the following formula:

[0238]

[0239] In one embodiment of method (P1) described herein, the acid is H2SO4 or ClSO3H. In another embodiment, the sulfonic acid is H2SO4. In yet another embodiment, the sulfonic acid is ClSO3H.

[0240] In one embodiment of the method (P1) described herein, the base is an alkali metal hydroxide base. In one embodiment, the base is a hydroxide base. In one embodiment, the base is KOH, NaOH, or LiOH. In a preferred embodiment, the base is NaOH or KOH. In one embodiment, the base is NaOH.

[0241] In one embodiment of the process (P1) described herein, the hydrogenation of step (c) is carried out using a catalyst comprising Pd, Pt, or Ni. In one such embodiment, the catalyst is Pd / C, Pt / C, or Raney nickel (Raney Ni). In another such embodiment, the catalyst is a Pd catalyst selected from the group consisting of Pd(OH)2, Pd(OAc)2, PdCl2, PdCl2(MeCN)2, Pd(dba)2, Pd2(dba)3, Pd(TFA)2, [Pd(allyl)Cl]2, [Pd(cinnamyl)Cl]2, and (η3-allyl)(η5-cyclopentadienyl)palladium(II). In one embodiment, the Pd catalyst is Pd(OH)2.

[0242] In another embodiment of process (P1 ) described herein, the hydrogenation of step (c) is carried out using catalytic transfer hydrogenation in the presence of isopropanol, formic acid, formate or ammonium.

[0243] In another embodiment of method (P1) described herein, the compound of formula (V) has the following formula:

[0244]

[0245] or a stereoisomer or salt thereof.

[0246] In another such embodiment of the method of P1, the compound of formula (III) is a compound of formula (3*); the compound of formula (IIIa) is a compound of formula (3a); the compound of formula (IV) is a compound of formula (4); and the compound of formula (V) is a compound of formula (5).

[0247] In another such embodiment of the method of P1, the compound of formula (III) is a compound of formula (3x*); the compound of formula (IIIa) is a compound of formula (3a1); the compound of formula (IV) is a compound of formula (4a); and the compound of formula (V) is a compound of formula (5x).

[0248] In another such embodiment of the method of P1, the compound of formula (III) is a compound of formula (3y*); the compound of formula (IIIa) is a compound of formula (3a2); the compound of formula (IV) is a compound of formula (4b); and the compound of formula (V) is a compound of formula (5y).

[0249] In another such embodiment of the method of P1, the compound of formula (III) is a compound of formula (3z*); the compound of formula (IIIa) is a compound of formula (3a3); the compound of formula (IV) is a compound of formula (4c); and the compound of formula (V) is a compound of formula (5z).

[0250] Further provided herein is a process (P2) for preparing a compound of formula (II), wherein the process comprises:

[0251] (a) making a compound of formula (VII) or a stereoisomer or salt thereof,

[0252]

[0253] Wherein each Z is independently C 1-3 Alkyl or phenyl, contacted with a compound of formula (VI),

[0254]

[0255] where R 1a and R 1b As described herein, the compound of formula (VIIa) or a salt thereof is synthesized thereby;

[0256]

[0257] (b) contacting the compound of formula (VIIa) or a stereoisomer or a salt thereof with an acid, thereby synthesizing the compound of formula (VIIb) or a salt thereof;

[0258]

[0259] (c) contacting the compound of formula (VIIb) or a stereoisomer or salt thereof with 1,1'-carbonyldiimidazole, thereby synthesizing the compound of formula (VIIc) or a salt thereof;

[0260]

[0261] (d) contacting a compound of formula (VIIc) or a stereoisomer or salt thereof with a compound of formula (VIII) or a salt thereof,

[0262]

[0263] where R 2 and m as described herein, to prepare a compound of formula (Va) or a salt thereof; and

[0264]

[0265] (e) contacting the compound of formula (Va) or a stereoisomer or salt thereof with a base and then with an acid, thereby preparing the compound of formula (II) or a stereoisomer or salt thereof.

[0266] In one embodiment of the methods described herein, R 2 is halogen and m is 1. In another embodiment, R 2 is F and m is 1. In a preferred embodiment, m is 0.

[0267] In one embodiment of the method (P2) described herein, step (a) further comprises converting The compound or a stereoisomer or salt thereof is deprotected to prepare a compound of formula (VII) or a salt thereof.

[0268] In one embodiment of method (P2) described herein, the compound of formula (Va) has the formula:

[0269]

[0270] or a salt thereof.

[0271] In one embodiment of method (P2) described herein, the compound of formula (Va) has the formula:

[0272]

[0273] or a salt thereof.

[0274] In one embodiment of the method (P2) described herein, each Z is independently C 1-4 In another embodiment, each Z is methyl, each Z is ethyl, each Z is isopropyl or wherein SiZ3 is Si(PhMe2) or Si(t-BuMe2). In another embodiment, each Z is ethyl.

[0275] In one embodiment of method (P2) described herein, the compound of formula (VII) has the following formula:

[0276]

[0277] or a salt thereof.

[0278] In one embodiment of method (P2) described herein, the compound of formula (VIIa) has the following formula:

[0279]

[0280] or a salt thereof.

[0281] In one embodiment of method (P2) described herein, the compound of formula (VIIb) has the formula:

[0282]

[0283] or a salt thereof.

[0284] In one embodiment of method (P2) described herein, the compound of formula (VIIc) has the following formula:

[0285]

[0286] or a salt thereof.

[0287] In one embodiment of method (P2) described herein, the compound of formula (VIII) has the following formula:

[0288]

[0289] or a salt thereof.

[0290] In one embodiment of the method (P2) described herein, the acid of step (b) is an inorganic acid. In one such embodiment, the acid is H2SO4.

[0291] In one embodiment of method (P2) described herein, the base of step (e) is an inorganic base, such as NaOH, KOH, or LiOH. In one such embodiment, the base of step (e) is LiOH. In one embodiment of method (P2) described herein, the acid of step (e) is an inorganic acid. In one such embodiment, the acid is HCl.

[0292] In one embodiment of method (P2) described herein, step (d) further comprises a palladium catalyst. In one such embodiment, the palladium catalyst is Pd(dppf)Cl2.DCM. In one embodiment of method (P2) described herein, the acid is HCl.

[0293] In one embodiment of the method (P2) described herein, the method comprises synthesizing a compound of formula (2) or a salt thereof, the method comprising:

[0294] (a) contacting a compound of formula (7) or a salt thereof with a compound of formula (6) to prepare a compound of formula (7a) or a salt thereof;

[0295] (b) contacting the compound of formula (7a) or a salt thereof with an acid as described herein, thereby synthesizing the compound of formula (7b) or a salt thereof;

[0296] (c) contacting the compound of formula (7b) or a salt thereof with 1,1′-carbonyldiimidazole to thereby synthesize the compound of formula (7c) or a salt thereof;

[0297] (d) contacting a compound of formula (7c) or a salt thereof with a compound of formula (8) or a salt thereof in the presence of a Pd catalyst as described herein, thereby synthesizing a compound of formula (5a) or a salt thereof; and

[0298] (e) contacting the compound of formula (5a) or a salt thereof with a base described herein, and then contacting it with an acid described herein, thereby synthesizing the compound of formula (2) or a salt thereof.

[0299] Further provided herein is a process (P3) for preparing a compound of formula (II) or a salt thereof, wherein the process comprises reacting a compound of formula (V)

[0300]

[0301] or a salt thereof,

[0302] where R 2 and m as described herein, contacted with a compound of formula (VI),

[0303]

[0304] where R 1a and R 1b As described herein, and

[0305] The compound of formula (V) or its salt is prepared by the following method:

[0306] (a) making a compound of formula (VIIp)

[0307]

[0308] or a stereoisomer or salt thereof, wherein each Z is as described herein, and a compound of formula (VIII)

[0309]

[0310] or a salt thereof, thereby synthesizing a compound of formula (Vb); and

[0311]

[0312] (b) contacting the compound of formula (Vb) or a stereoisomer or a salt thereof with an acid, thereby preparing the compound of formula (V) or a salt thereof.

[0313] In one embodiment of the process (P3) described herein, each Z is ethyl. In one embodiment of the process (P3) described herein, m is 0. In one embodiment of the process (P3) described herein, the acid of step b is an inorganic acid. In one such embodiment, the acid is HCl.

[0314] In one embodiment, the compound of formula (VIIp) has the formula:

[0315]

[0316] In one embodiment of the method (P3) described herein, step (a) further comprises a palladium catalyst. In one such embodiment, the palladium catalyst is Pd(dppf)Cl2·DCM.

[0317] In one embodiment of method (P3) described herein, the compound of formula (Vb) has the formula:

[0318]

[0319] or a salt thereof.

[0320] In one embodiment of method (P3) described herein, the compound of formula (Vb) has the formula:

[0321]

[0322] or a salt thereof.

[0323] In one embodiment of methods (P1), (P2), and (P3) described herein, the compound of formula (VI) comprises the formula:

[0324] or a stereoisomer thereof.

[0325] In one embodiment of methods (P1), (P2), and (P3) described herein, the compound of formula (VI) comprises formula (6), (6a), or (6b). In one embodiment of methods (P1), (P2), and (P3) described herein, the compound of formula (VI) comprises formula (6c), (6d), or (6e). In one embodiment of methods (P1), (P2), and (P3) described herein, the compound of formula (VI) comprises formula (6f), (6g), (6h), (6i), or (6j). In one embodiment of methods (P1), (P2), and (P3) described herein, the compound of formula (VI) comprises formula (6).

[0326] The present invention also provides a method (P4) for preparing a compound of formula (II) or a salt thereof, comprising the following steps:

[0327] (a) contacting alanine with a compound of formula (IX),

[0328]

[0329] where R 1a 、R 1b and n are as described herein, to form a compound of formula (XI)

[0330]

[0331] or its salts;

[0332] (b) reacting a compound of formula (XI) or a salt thereof with (i) a chlorinating agent, (ii) Compound (wherein R 2 and (iii) an organoaluminum compound to form a compound of formula (Vc)

[0333]

[0334] or its salts; and

[0335] (c) contacting the compound of formula (Vc) or a salt thereof with a reducing agent, thereby forming the compound of formula (II) or a salt thereof.

[0336] In one embodiment of the method (P4) described herein, the organoaluminum compound has the formula X3Al, wherein X is independently Cl or C 1-4 In one such embodiment, X is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl. In another embodiment of method (P4) described herein, the organoaluminum compound is trimethylaluminum, triethylaluminum, triisobutylaluminum, dimethylaluminum chloride, diethylaluminum chloride, or ethylaluminum dichloride. In one such embodiment, the organoaluminum compound is trimethylaluminum.

[0337] In one embodiment of the method (P4) described herein, the reducing agent is sodium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum dihydride. In one such embodiment, the reducing agent is sodium aluminum hydride. In one such embodiment, the reducing agent is sodium aluminum hydride in the presence of methanol.

[0338] In one embodiment of the method (P4) described herein, the chlorinating agent is SOCl2, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, pivaloyl chloride, or oxalyl chloride. In one such embodiment, the chlorinating agent is oxalyl chloride. In another such embodiment, the chlorinating agent is oxalyl chloride in the presence of N-formylpyrrolidine or N,N-dimethylformamide.

[0339] In one embodiment of method (P4) described herein, the compound of formula (IX) has the following formula:

[0340]

[0341] or a salt thereof.

[0342] In one embodiment of method (P4) described herein, the compound of formula (Xi) has the following formula:

[0343]

[0344] or a salt thereof.

[0345] In one embodiment of process (P4) described herein, the indole of step b) has the formula:

[0346]

[0347] or a salt thereof.

[0348] In one embodiment of method (P4) described herein, the compound of formula (Vc) has the following formula:

[0349]

[0350] or a salt thereof.

[0351] In one embodiment of the methods described herein, R 1a and R 1b Each of which is independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl or unsubstituted C 1-3 Alkoxy.

[0352] In one embodiment of the methods described herein, R 1a and R 1b Each of which is independently hydrogen, halogen or unsubstituted C 1-3 alkyl.

[0353] In one embodiment of the methods described herein, R 1a and R 1b are independently hydrogen, halogen, cyano, unsubstituted C 1-3 In another embodiment of the methods described herein, R 1a and R 1b is independently hydrogen, halogen or methyl. In another embodiment of the methods described herein, R 1a is hydrogen and R 1b is halogen, methyl, cyano or cyclopropyl. In another embodiment of the methods described herein, R 1a is hydrogen and R 1b In another embodiment of the methods described herein, R 1a is hydrogen and R 1b In another embodiment of the methods described herein, R 1a is methyl and R 1b is halogen, methyl, cyano or cyclopropyl. In another embodiment of the methods described herein, R 1a is a halogen and R 1b is halogen, methyl, cyano or cyclopropyl.

[0354] In one embodiment of the methods described herein, R 1a and R 1b is independently halogen or methyl. In another embodiment of the methods described herein, R 1a is a halogen and R 1b In a preferred embodiment of the method described herein, R 1a is a halogen and R 1b In a preferred embodiment of the method described herein, R 1a and R 1b For F.

[0355] In one embodiment of the methods described herein, R 1a and R 1b Each of which is independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl or unsubstituted C 1-3 Alkoxy.

[0356] In one embodiment of the methods described herein, R 1a and R 1b Each is unsubstituted C 3-6 Cycloalkyl or unsubstituted C 3-6 In another embodiment of the methods described herein, R 2 is halogen and m is 1.

[0357] In a preferred embodiment of the methods described herein, m is 0.

[0358] In one embodiment of the methods described herein, each R 2 are independently halogen or unsubstituted C 1-3 In another embodiment of the methods described herein, R 2 Halogen or C 1-3 An alkyl group and m is 1.

[0359] In another embodiment of the methods described herein, each R 2 are independently unsubstituted C 1-3 Haloalkyl or unsubstituted C 1-3 Alkoxy.

[0360] In another embodiment of the methods described herein, n is 1 or 2. In a preferred embodiment of the methods described herein, n is 3. In one such embodiment, n is 3, wherein R 1a and R 1b In another embodiment of the methods described herein, n is 3, wherein R 1a and R 1b In another such embodiment of the methods described herein, n is 3, wherein R 1a and R 1b In another embodiment of the methods described herein, n is 3, wherein R 1a and R 1b Each of is independently hydrogen or cyclopropyl.

[0361] In one embodiment of the methods described herein, the compound of formula (II) prepared according to method P1, P2, P3 or P4 has the following formula:

[0362]

[0363] or a stereoisomer or salt thereof.

[0364] In one embodiment of the methods described herein, the compound of formula (II) or a stereoisomer or salt thereof prepared according to method P1, P2, P3 or P4 has formula (2), formula (2a) or formula (2b). In another embodiment of the methods described herein, the compound of formula (II) or a stereoisomer or salt thereof prepared according to method P1, P2, P3 or P4 has formula (2c) or (2d). In another embodiment of the methods described herein, the compound of formula (II) or a stereoisomer or salt thereof prepared according to method P1, P2, P3 or P4 has formula (2e) or (2f). In another embodiment of the methods described herein, the compound of formula (II) or a stereoisomer or salt thereof prepared according to method P1, P2, P3 or P4 has formula (2g).

[0365] In a preferred embodiment of the methods described herein, the compound of formula (II) or a stereoisomer or salt thereof prepared according to method P1, P2, P3 or P4 has the following formula:

[0366]

[0367] or a salt thereof.

[0368] In one embodiment, the compound of formula (2) is prepared according to method P1 as described herein. In another embodiment, the compound of formula (2) is prepared according to method P2 as described herein. In another embodiment, the compound of formula (2) is prepared according to method P3 as described herein. In another embodiment, the compound of formula (2) is prepared according to method P4 as described herein.

[0369] Further provided herein are methods for preparing compounds of formula (I)

[0370]

[0371] or a pharmaceutically acceptable salt thereof (P5):

[0372] where R 1a 、R 1b and n as described in this article,

[0373] The method comprises reacting a compound of formula (II) or a stereoisomer or salt thereof prepared according to method P1, P2, P3 or P4 as described herein with a compound of formula (X)

[0374]

[0375] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein

[0376] Ring A is phenyl or pyridyl;

[0377] Each R 3 are independently hydrogen, halogen or C 1-3 alkyl;

[0378] R 4 is halogen or -CN; and

[0379] p is 1 or 2.

[0380] In one embodiment of process (P5) described herein, the process further comprises the presence of tartaric acid.

[0381] In one embodiment of the method (P5) described herein, the compound of formula X has the following formula:

[0382]

[0383]

[0384] or a salt thereof.

[0385] In one such embodiment, the salt is the tartrate salt.

[0386] In one embodiment of method (P5) described herein, the compound of formula X, or a salt thereof, has formula (10), formula (10a), or formula (10b). In another embodiment of method (P5) described herein, the compound of formula X, or a salt thereof, has formula (10c), formula (10d), or formula (10e). In another embodiment of method (P5) described herein, the compound of formula X, or a salt thereof, has formula (10f) to (10m). In another embodiment of method (P5) described herein, the compound of formula X, or a salt thereof, has formula (10n) to (10w).

[0387] In one embodiment of method (P5) described herein, the compound of formula (I) has the following formula:

[0388]

[0389]

[0390]

[0391] or a pharmaceutically acceptable salt thereof.

[0392] In one such embodiment, the pharmaceutically acceptable salt is the tartrate salt.

[0393] In one embodiment of the method (P5) described herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof has formula (I), formula (Ia), formula (Ib) or formula (Id). In another embodiment of the method (P5) described herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof has formula (Ic) or (Ie) to (Ij). In another embodiment of the method (P5) described herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof has formula (Ik). In another embodiment of the method (P5) described herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof has formula (Il) to (In). In another embodiment of the method (P5) described herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof has formula (Io) to (It). In another embodiment of the method (P5) described herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof has formula (Iu). In another embodiment of the method (P5) described herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof has formula (Iv) to (Iy).

[0394] In one embodiment, the compound of formula (I) has the following formula:

[0395]

[0396] or a pharmaceutically acceptable salt thereof.

[0397] In another embodiment, the compound of formula (I) has the following formula:

[0398]

[0399] In another aspect, provided herein are methods for synthesizing compounds having formula (1)

[0400]

[0401] or a pharmaceutically acceptable salt thereof (P6), the method comprising:

[0402] (a) making (2) compound or a salt thereof,

[0403]

[0404] wherein the compound of formula (2) is synthesized according to method P1, P2, P3 or P4 as described herein;

[0405] (b) contacting with a compound of formula (10) or a salt thereof,

[0406]

[0407] Thus, the compound of formula (1) or a pharmaceutically acceptable salt thereof is prepared.

[0408] In a preferred embodiment of process (P6) described herein, the compound of formula (2) or a salt thereof is prepared using process P2 or P3.

[0409] In another aspect, provided herein is a method (P7) for synthesizing a compound having formula (A):

[0410]

[0411] The method includes:

[0412] (a) making a compound of formula (2)

[0413]

[0414] or a salt thereof, wherein the compound of formula (2) or a salt thereof is synthesized according to method P1, P2, P3 or P4 described herein;

[0415] (b) contacting with a compound of formula (10) or a salt thereof in the presence of tartaric acid,

[0416]

[0417] Thus, the compound of formula (A) is prepared.

[0418] In one embodiment of method (P7) described herein, step (b) comprises EtOH. In one such embodiment, the reaction occurs at about 70°C.

[0419] In one embodiment of methods (P6) and (P7) described herein, the compound of formula (2), or a salt thereof, is prepared according to method P1, P2, P3, or P4 described herein. In one embodiment of methods (P6) and (P7) described herein, the compound of formula (2), or a salt thereof, is prepared according to method P1, P2, P3, or P4 described herein. In one embodiment of methods (P6) and (P7) described herein, the compound of formula (2), or a salt thereof, is prepared according to method P2 or P3 described herein. In one embodiment of methods (P6) and (P7) described herein, the compound of formula (2), or a salt thereof, is prepared according to method P1 described herein. In another embodiment of methods (P6) and (P7) described herein, the compound of formula (2), or a salt thereof, is prepared according to method P2 described herein. In another embodiment of methods (P6) and (P7) described herein, the compound of formula (2), or a salt thereof, is prepared according to method P3 described herein. In another embodiment of methods (P6) and (P7) described herein, the compound of formula (2), or a salt thereof, is prepared according to method P4 described herein.

[0420] In one embodiment of methods (P6) and (P7) described herein, the compound of formula (6) is prepared by:

[0421] (a) Make equation (12a) The compound is contacted with H2SO4 to prepare Compounds;

[0422] (b) reducing the compound of formula (12b) to prepare Compounds;

[0423] (c) cyclizing the compound of formula in the presence of SOCl2 to prepare compounds; and

[0424] (d) contacting the compound of formula (12d) with FeCl3, NaOCl and a base to thereby prepare the compound of formula (6).

[0425] In one such embodiment, the base of step (d) is NaOH, KOH or LiOH. In one such embodiment, the base of step (d) is NaOH. In one embodiment, step (d) is performed in DCM and water.

[0426] In another embodiment of methods (P6) and (P7) described herein, the methods independently further comprise recrystallization according to the following schemes A or B:

[0427] Process A:

[0428]

[0429] Process B:

[0430]

[0431] The compounds of formula (I) and pharmaceutically acceptable salts thereof synthesized according to any of the methods described herein can be administered in an effective amount (eg, an amount as described herein) for treating cancer.

[0432] In one aspect, the present invention provides a method for treating cancer, wherein the method comprises administering to a patient suffering from cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof synthesized according to any method described herein. In one embodiment, the compound is a compound of formula (1) or formula (A).

[0433] In another aspect, provided herein is a method for treating lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer, by administering to a patient suffering from the cancer an effective amount of a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is ovarian cancer or endometrial cancer. In one embodiment, the cancer is breast cancer.

[0434] Further provided herein are methods of treating breast cancer in a patient suffering from breast cancer by administering an effective amount of a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof. In one such embodiment, the compound is compound (1) or compound (A) as described herein.

[0435] The compound of formula (I) or a pharmaceutically acceptable salt thereof synthesized according to any of the methods described herein can be used to prepare a medicament for treating breast cancer as described herein.

[0436] The methods provided herein for treating breast cancer include treatments in which the breast cancer can be hormone receptor-positive breast cancer (eg, ER+ breast cancer), HER2-positive breast cancer, HER2-negative breast cancer, or triple-negative breast cancer (TNBC).

[0437] In one embodiment, breast cancer is HER2-negative breast cancer. HER2-negative breast cancer can be defined herein as, for example, a HER2 IHC score of 0 or 1+, or an IHC score of 2+ with a negative fluorescent, chromogenic, or silver in situ hybridization test indicating the absence of HER2-gene amplification, or a HER2 / CEP17 ratio of <2.0, or as defined in local clinical guidelines. In one embodiment, breast cancer is ER+ / HER2- breast cancer. Breast cancer can be stage 0, I, II, III, or IV as understood in the art.

[0438] In another embodiment, the breast cancer is locally advanced or metastatic breast cancer (mBC).

[0439] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof synthesized according to any of the methods described herein can be administered as a component of adjuvant therapy. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof synthesized according to any of the methods described herein can be administered as a component of pre-adjuvant therapy.

[0440] The breast cancer patients described herein may be premenopausal prior to treatment with the compounds or solid forms described herein. The breast cancer patients described herein may be postmenopausal prior to treatment with the compounds or solid forms described herein.

[0441] The methods provided herein include administering to a patient an effective amount of a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, in an amount as described herein. The effective amount may be, for example, an amount of about 10 mg, 30 mg, 50 mg, 90 mg, 100 mg, 125 mg, or 250 mg. In one embodiment of the methods provided herein, the compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, is administered orally. In one embodiment, the compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, is administered as a tablet (e.g., a coated tablet or a non-coated tablet). In another embodiment, the compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, is administered as a capsule. Therefore, provided herein is a composition suitable for administration to a patient with breast cancer, wherein such a composition comprises a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg, 30 mg, 50 mg, 90 mg, 100 mg, 125 mg, or 250 mg in a tablet or capsule as described herein.

[0442] Although there is no standard treatment regimen or procedure, systemic chemotherapy is considered to be a standard of care (SOC) for mBC patients. The patient of the methods described herein may have received prior treatment with one or more anticancer agents or radiotherapy. For example, in one embodiment, the patient may have been previously treated (e.g., with 1L, 2L, 3L or more line therapy) with the following drugs: doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, albumin-bound paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparib, methotrexate, anastrozole, nab-1 ... ), exemestane, toremifene, letrozole, tamoxifen, 4-hydroxytamoxifen, raloxifene, droloxifene, trioxifene, keoxifene, flutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprolide, pegfilgrastim, filgrastim, or venetoclax.

[0443] In another embodiment, the patient may have previously been treated with an AKT inhibitor, a CDK4 / 6 inhibitor, a PARP inhibitor, or an aromatase inhibitor (e.g., 1L, 2L, 3L, or more lines of therapy). In one embodiment, the AKT inhibitor is ipatasertib (GDC-0068). In one embodiment, the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib. In some cases, the patient may have previously been treated with: (1) abemaciclib, ribociclib, or palbociclib; (2) ipatacept; (3) everolimus or fulvestrant; (4) trastuzumab bemtansine, trastuzumab, pertuzumab, or atezolizumab; or (5) alemtuzumab, bevacizumab, cetuximab, panitumumab, rituximab, tositumomab, or a combination thereof. The patient described herein may have undergone surgery prior to treatment with Compound (A) or a solid form thereof.

[0444] In one embodiment of the methods described herein, prior to administration of the combination therapy described herein, the patients described herein may have undergone surgical treatment such as, for example, breast-conserving surgery (i.e., lumpectomy, which focuses on removing the primary tumor with margins) or more extensive surgery (i.e., mastectomy, which aims to completely remove all breast tissue). In another embodiment, the patients described herein may have undergone surgical treatment after treatment with the combination therapy described herein.

[0445] Radiation therapy is also administered to the breast / chest wall and / or local lymph nodes after surgery for the purpose of killing microcancerous cells left behind after surgery. In the case of breast-conserving surgery, radiation is administered to the remaining breast tissue and sometimes to local lymph nodes (including axillary lymph nodes). In the case of mastectomy, radiation may still be administered if there are factors that predict a higher risk of local recurrence. In some embodiments of the methods provided herein, the patients described herein may have received radiation therapy prior to the administration of the combination therapy described herein. In other embodiments of the methods provided herein, the patients described herein may receive radiation therapy after the administration of the combination therapy described herein.

[0446] In another embodiment, the patient herein may be refractory to one or more anticancer therapies. For example, the patient herein may be refractory to aromatase inhibitors. In another example, the patient herein may be refractory to selective estrogen receptor degraders (SERDs), such as fulvestrant. In another example, the patient may be refractory to one or more endocrine therapies such as: clomifene, toremifene, raloxifene, anordrin, bazedoxifene, broparestrol, cyclofenil, lasofoxifene, ormeloxifene, acolbifene, elacestrant, brilanestrant, clomifenoxide, droloxifene, etacstil or ospemifene. In another embodiment, the patient may be refractory to abemaciclib, anastrozole, exemestane, fulvestrant, goserelin, letrozole, leuprolide, megestrol acetate, palbociclib, tamoxifen, or toremifene. In another example, the patient is refractory to treatment with trastuzumab eltansine, trastuzumab, pertuzumab, atezolizumab, pembrolizumab, durvalumab, avelumab, or nivolumab.

[0447] Provided herein are methods for treating ER+, HER2-1aBC or mBC in patients with such cancers. In one embodiment, the method comprises treating ER+, HER2-1aBC or mBC in patients with such cancers by administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof synthesized according to any of the methods described herein over a 28-day cycle.

[0448] Compounds of formula (I) or pharmaceutically acceptable salts thereof synthesized according to any of the methods described herein can also be used in methods comprising inhibiting ERa in a patient. Such methods comprise administering to the patient an amount of such compound.

[0449] The compound of formula (I) or its pharmaceutically acceptable salt synthesized according to any method described herein can be administered in combination with one or more anticancer agents. "Combination" administration as described herein includes sequential administration (in any order) of the compound described herein and one or more anticancer therapies and simultaneous administration. Therefore, provided herein is a method for treating breast cancer in a breast cancer patient, such method comprising administering a combination of a compound of formula (I) or its pharmaceutically acceptable salt synthesized according to any method described herein and one or more other anticancer therapies. In one embodiment, the anticancer therapy comprises doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, nab-paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparib, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxytamoxifen, raloxifene, droloxifene, troloxifene, comoxifen, flutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprorelin, peglugrastin, filgrastin, or venetoclax.

[0450] Provided herein are methods for treating breast cancer in a patient with breast cancer by administering an effective amount of a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, in combination with doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, nab-paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparib, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxytamoxifen, raloxifene, droloxifene, troloxifene, comoxifen, flutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprorelin, peglugrastin, filgrastin, or venetoclax.

[0451] In another aspect, provided herein is a method for treating breast cancer in a breast cancer patient by administering an effective amount of a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, in combination with paclitaxel, albumin-bound paclitaxel, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxytamoxifen, raloxifene, droloxifene, troloxifene, comoxifen, or venetoclax. In another aspect, provided herein is a method for treating breast cancer in a breast cancer patient by administering an effective amount of a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, in combination with fulvestrant, paclitaxel, albumin-bound paclitaxel, clomiphene, toremifene, raloxifene, anordrin, bazedoxifene, bromopastriene, cyclofenil, lasofoxifene, ormeloxifene, acolbifene, elesetron, bullistron, oxyclomiphene, droloxifene, etisul, or ospemifene.

[0452] In another aspect, provided herein is a method for treating breast cancer in a breast cancer patient by administering an effective amount of a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, in combination with a CDK4 / 6 inhibitor, a PARP inhibitor, or an aromatase inhibitor.

[0453] On the other hand, provided herein is a method for treating breast cancer in a breast cancer patient, wherein the method comprises administering an effective amount of a compound of formula (I) synthesized according to any method described herein, or a pharmaceutically acceptable salt thereof, and a combination of a CDK4 / 6 inhibitor, wherein the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib. In one embodiment, the method comprises administering a combination of compound (A) and palbociclib. In another embodiment, the method comprises administering a combination of compound (A) and abemaciclib or ribociclib. On the other hand, provided herein is a kit comprising (i) a compound of formula (I) synthesized according to any method described herein, or a pharmaceutically acceptable salt thereof; (ii) a second unit dosage form of a CDK4 / 6 inhibitor (e.g., palbociclib); and a container containing each dosage form.

[0454] The dosage of abemaciclib can be 50 mg to 500 mg per day or 150 mg to 450 mg per day, and administration can be daily in a 28-day cycle or on fewer than 28 days per 28-day cycle, for example, 21 days per 28-day cycle, 14 days per 28-day cycle, or 7 days per 28-day cycle. In one embodiment, when administered orally, abemaciclib is administered once daily or, preferably, twice daily. In the case of twice-daily dosing, the doses may be separated by 4, 8, or 12 hours. Abemaciclib is administered orally at 150 mg twice daily, with each dose administered approximately 12 hours apart. In certain embodiments, the dosage of abemaciclib is administered according to the package insert.

[0455] The dose of ribociclib may be 200 mg to 1,000 mg per day; or 250 mg to 750 mg per day, and administration may be daily in a 28-day cycle or less than 28 days per 28-day cycle, such as 21 days per 28-day cycle, 14 days per 28-day cycle, or 7 days per 28-day cycle. In one embodiment, in the case of oral administration, ribociclib is administered once daily. In certain embodiments, the dose of ribociclib is administered according to the drug package insert.

[0456] The dosage of palbociclib may be 25 mg to 250 mg per day, or 50 mg to 125 mg per day, or 75 mg to 125 mg per day, or 75 mg to 100 mg per day, or 125 mg per day. Administration may be daily in a 28-day cycle or less than 28 days per 28-day cycle, such as 21 days per 28-day cycle, 14 days per 28-day cycle, or 7 days per 28-day cycle. In one embodiment, in the case of oral administration, palbociclib is administered once daily. In certain embodiments, the dosage of palbociclib is administered according to the drug package insert.

[0457] Also provided herein is a method of treating ER+, HER2-1aBC or mBC in a patient suffering from such cancer, wherein the method comprises administering to the patient a combination therapy comprising a compound of Formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, and palbociclib, wherein the combination therapy is administered over one or more 28-day cycles.

[0458] Further provided herein is a method of treating ER+, HER2-1aBC or mBC in a patient suffering from such cancer, wherein the method comprises administering to the patient a combination therapy described herein comprising a dosing regimen comprising: (i) once daily (QD) administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof synthesized according to any of the methods described herein on days 1 to 28 of the first 28-day cycle; and (ii) once daily administration of palbociclib on days 1 to 21 of the first 28-day cycle.

[0459] In one such embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof synthesized according to any of the methods described herein is administered as a fixed dose or once daily. In another such embodiment, administration is an oral form (PO), wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof synthesized according to any of the methods described herein is formulated into a tablet or capsule. In another such embodiment, such a compound is administered in an amount of about 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 30 mg, 10 mg to 100 mg, 10 mg to 50 mg, or 10 mg to 30 mg once daily. In another such embodiment, such a compound is administered in an amount of about 10, 30, 50, or 100 mg. In another such embodiment, palbociclib is administered according to the drug package insert. In a preferred embodiment, palbociclib is administered in an amount of about 125 mg.

[0460] The method for treating breast cancer provided herein may include administering the combination therapy described herein as part of a dosing regimen. In one embodiment, the dosing regimen includes one or more cycles. In another embodiment, the dosing regimen includes at least 2 cycles. In another aspect provided herein, the dosing regimen includes 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54, 60, 66 or 72 cycles. In another embodiment, the dosing regimen includes about 2 to 72, 2 to 66, 2 to 60, 2 to 54, 2 to 48, 2 to 42, 2 to 36, 2 to 30, 2 to 24, 2 to 18 or 2 to 12 cycles.

[0461] In another aspect provided herein, the methods described herein comprise administering an effective amount of a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor (AI), wherein the AI ​​is letrozole, anastrozole, exemestane, or testolactone.

[0462] On the other hand, provided herein is a method for treating breast cancer in a breast cancer patient by administering an effective amount of a compound of formula (I) synthesized according to any method described herein, or a pharmaceutically acceptable salt thereof, in combination with an immunotherapy (e.g., an antibody). In one embodiment, in one embodiment, a compound of formula (I) synthesized according to any method described herein, or a pharmaceutically acceptable salt thereof, is administered in combination with trastuzumab eltansine, trastuzumab, pertuzumab, atezolizumab, pembrolizumab, durvalumab, avelumab or nivolumab, or a combination thereof. In one embodiment, a compound of formula (I) synthesized according to any method described herein, or a pharmaceutically acceptable salt thereof, is administered in combination with a cancer immunotherapy comprising a PD-1 or PD-L1 inhibitor, wherein the cancer immunotherapy is atezolizumab, pembrolizumab or nivolumab.

[0463] Also provided herein are methods of inhibiting tumor growth or producing tumor regression in a patient described herein by administering a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof. In one such embodiment, the method comprises administering a second agent, such as palbociclib.

[0464] In one embodiment, provided herein is a method of producing or enhancing tumor regression in a patient with mBC as described herein by administering a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof. In one such embodiment, the method comprises administering a second agent, such as palbociclib.

[0465] pharmaceutical preparations

[0466] The compound of formula (I) or its pharmaceutically acceptable salt synthesized according to any method described herein can be administered in the following ways, for example, orally, intramuscularly, subcutaneously, intravenously, intradermally, transdermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subconjunctivally, intracapsularly, intramucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, intravitreally (e.g., by intravitreal injection), by eye drops, topically, transdermally, parenterally, by inhalation, by injection, by implantation, by infusion, by continuous infusion, by local perfusion directly into target cells, by catheter, by lavage, in a cream or in a lipid composition. The compound of formula (I) or its pharmaceutically acceptable salt synthesized according to any method described herein can be formulated into a pharmaceutical composition suitable for oral administration as provided herein. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof synthesized according to any of the methods described herein can be administered intramuscularly. In a preferred embodiment, the compound is compound (A).

[0467] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof synthesized according to any of the methods described herein is administered as a pharmaceutical composition that can be administered orally or parenterally to an individual. The pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof synthesized according to any of the methods described herein can be prepared into oral dosage forms, such as capsules, microcapsules, tablets (coated and non-coated tablets), granules, powders, pills or suppositories. The compound of formula (I) or a pharmaceutically acceptable salt thereof synthesized according to any of the methods described herein can be formulated for topical or parenteral use, wherein the compound is dissolved or otherwise suspended in a solution suitable for injection, suspension, syrup, cream, ointment, gel, spray, solution and emulsion. In a preferred embodiment, the compound is compound (A).

[0468] The pharmaceutical compositions described herein include one or more pharmaceutically acceptable excipients, such as, but not limited to, sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate, cellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, hydroxypropyl starch, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol (PEG), starch, sodium bicarbonate, calcium citrate, magnesium stearate, sodium lauryl sulfate, sodium benzoate, sodium bisulfite, methylparaben, propylparaben, citric acid, sodium citrate or acetic acid, polyvinylpyrrolidone, aluminum stearate), water, and cocoa butter. Such excipients are used as, for example, diluents, binders, lubricants, and disintegrants and are well known in the art.

[0469] The pharmaceutical compositions described herein comprise an effective amount of a compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof. The dosage of a compound described herein (e.g., compound (A)) can be a measure of a specific amount of the compound (e.g., a standard dose) or can be measured as a function of, for example, the patient's weight. In one embodiment, the compound described herein is administered in an amount equivalent to about 0.1, 0.5, 0.75, 1, 2, 3, 4, 5, 10, 15, 20, 30, 50, 75, 100, 200, or 250 mg / kg. In another embodiment, a compound of formula (I) (e.g., compound (A)) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.1 mg / kg to about 1 mg / kg; about 0.5 mg / kg to about 2 mg / kg; about 1 mg / kg to about 5 mg / kg; about 3 mg / kg to about 10 mg / kg; about 8 mg / kg to about 15 mg / kg; or about 15 mg / kg to about 30 mg / kg. In another embodiment, the compound of formula (I) synthesized according to any of the methods described herein, or a pharmaceutically acceptable salt thereof, is administered in an amount of less than about 100 mg / kg, less than about 50 mg / kg, less than about 30 mg / kg, less than about 10 mg / kg, or less than about 1 mg / kg.

[0470] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., Compound (A)) synthesized according to any of the methods described herein is administered in an amount of about 1, 5, 10, 20, 25, 30, 50, 60, 75, 90, 100, 120, 150, or 250 mg. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., Compound (A)) synthesized according to any of the methods described herein is administered in an amount of about 10 mg. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., Compound (A)) synthesized according to any of the methods described herein is administered in an amount of about 30 mg. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., Compound (A)) synthesized according to any of the methods described herein is administered in an amount of about 90 mg. In one embodiment, the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., Compound (A)) synthesized according to any of the methods described herein is administered once daily (QD) in the amounts described above.

[0471] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound (A)) synthesized according to any of the methods described herein is administered in an amount of about 1 mg to about 10 mg; about 10 mg to about 30 mg; about 10 mg to about 90 mg; about 30 mg to about 90 mg; or about 90 mg to about 250 mg. In one embodiment, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound (A)) synthesized according to any of the methods described herein is about 1, 10, 30, 50, 90, 100, or 150 mg. The compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound (A)) synthesized according to any of the methods described herein can be provided in a single dose (e.g., a single tablet or capsule for a given dose) or can be provided in multiple doses administered over a period of time (e.g., two or more tablets or capsules of equal doses). In one embodiment, the compound is compound (I) or compound (A).

[0472] The pharmaceutical compositions described herein can be administered once a day (QD); twice a day (BID), three times a day (TID), every other day (Q2D), every three days (Q3D), or once a week. In addition, the dosage of the pharmaceutical compositions provided herein comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound (A)) synthesized according to any of the methods described herein can be administered before meals (ac), after meals (pc), or with food. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound (A)) synthesized according to any of the methods described herein is administered QD during the treatment period (the period of time during which the drug is administered to the patient described herein), followed by a rest period (the period of time during which the drug is not administered to the patient described herein). The rest period may include the administration of an anticancer agent other than the compounds described herein. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound (A)) synthesized according to any of the methods described herein is formulated for oral administration as provided herein and is administered QD for 20 to 28 days, followed by a rest period of 3 to 10 days. In another embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof (eg, Compound (A)) synthesized according to any of the methods described herein is administered QD without a rest period.

[0473] Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound (A)) synthesized according to any of the methods described herein is formulated for oral administration. Oral administration can promote the patient's compliance with taking the compound (e.g., formulated into a pharmaceutical composition), thereby improving compliance and efficacy. Oral pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound (A)) synthesized according to any of the methods described herein include, but are not limited to, tablets (e.g., coated, non-coated, and chewable) and capsules (e.g., hard gelatin capsules, soft gelatin capsules, enteric-coated capsules, and sustained-release capsules). Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Oral pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound (A)) synthesized according to any of the methods described herein can be formulated for delayed or extended release as understood in the art.

[0474] Example

[0475] Exemplary embodiments of the invention described herein are provided below.

[0476] Example No. 1. A method for preparing a compound of formula (II)

[0477]

[0478] or a stereoisomer or salt thereof,

[0479] R 1a and R 1b Each of which is independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, -CN, unsubstituted C 3-6 Cycloalkyl or unsubstituted C 3-6 spirocycloalkyl;

[0480] Each R 2 are independently halogen, hydroxy, -CN, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl or unsubstituted C 1-3 alkoxy;

[0481] m is 0, 1, or 2; and

[0482] n is 1, 2, or 3;

[0483] The method includes:

[0484] (a) making a compound of formula (III) or a stereoisomer or salt thereof,

[0485]

[0486] contacting with a sulfonic acid to form a compound of formula (IIIa) or a stereoisomer or salt thereof;

[0487]

[0488] (b) contacting the compound of formula (IIIa) or a stereoisomer or salt thereof with a base to form the compound of formula (IV) or a stereoisomer or salt thereof;

[0489]

[0490] (c) hydrogenating the compound of formula (IV) or a stereoisomer or salt thereof to form the compound of formula (V) or a stereoisomer or salt thereof; and

[0491]

[0492] (d) contacting a compound of formula (V) or a stereoisomer or salt thereof with a compound of formula (VI);

[0493]

[0494] Thereby a compound of formula (II) or a stereoisomer or salt thereof is formed.

[0495] Embodiment 1a. The method according to embodiment 1, wherein the compound of formula (III) is a compound of formula (III*).

[0496] Embodiment 1b. The method according to embodiment 1 or 1a, wherein the compound of formula (III*) is a compound of formula (3*, 3x*, 3y* or 3z*).

[0497] Embodiment No. 2. The method of embodiment 1, 1a or 1b, wherein the sulfonic acid is H2SO4 or ClSO3H.

[0498] Embodiment No. 3. The method of embodiment 1, 1a or 1b, wherein the base is a hydroxide base.

[0499] Embodiment No. 4. The method according to embodiment 3, wherein the base is KOH, NaOH or LiOH.

[0500] Embodiment No. 5. The method according to any one of embodiments 1 to 4, wherein the hydrogenation is performed using a catalyst containing Pd, Pt, or Ni.

[0501] Embodiment No. 6. The method according to embodiment 5, wherein the catalyst is Pd / C, Pt / C or Raney nickel.

[0502] Embodiment No. 7. The method of any one of embodiments 1 to 4, wherein the hydrogenation is performed using catalytic transfer hydrogenation in the presence of isopropanol, formic acid, a formate salt, or ammonium.

[0503] Example No. 8. A method for preparing a compound of formula (II)

[0504]

[0505] or a stereoisomer or salt thereof,

[0506] R 1a and R 1b Each of which is independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, -CN, unsubstituted C 3-6 Cycloalkyl or unsubstituted C 3-6 spirocycloalkyl;

[0507] Each R 2 are independently halogen, hydroxy, -CN, C 1-3 Alkyl or C 1-3 Halogenated alkyl, C 1-3 alkoxy;

[0508] m is 0, 1, or 2; and

[0509] n is 1, 2, or 3;

[0510] The method includes:

[0511] (a) making a compound of formula (VII)

[0512]

[0513] or a stereoisomer or salt thereof, wherein each Z is independently C 1-3 Alkyl or phenyl, contacted with a compound of formula (VI),

[0514]

[0515] where R 1a and R 1b As described herein, the compound of formula (VIIa) is synthesized

[0516]

[0517] or a stereoisomer or salt thereof;

[0518] (b) contacting the compound of formula (VIIa) or its stereoisomer or salt with an acid to thereby synthesize the compound of formula (VIIb)

[0519]

[0520] or a stereoisomer or salt thereof;

[0521] (c) contacting the compound of formula (VIIb) or its stereoisomer or salt with 1,1'-carbonyldiimidazole to synthesize the compound of formula (VIIc)

[0522]

[0523] or a stereoisomer or salt thereof;

[0524] (d) contacting a compound of formula (VIIc) or a stereoisomer or salt thereof with a compound of formula (VIII) or a stereoisomer or salt thereof;

[0525]

[0526] to prepare a compound of formula (Va) or a stereoisomer or salt thereof; and

[0527]

[0528] (e) contacting the compound of formula (Va) or a stereoisomer or salt thereof with a base and then with an acid, thereby preparing the compound of formula (II) or a stereoisomer or salt thereof.

[0529] Example No. 9. A method for preparing a compound of formula (II)

[0530]

[0531] or a stereoisomer or salt thereof,

[0532] R 1a and R 1b Each of which is independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, -CN, unsubstituted C 3-6 Cycloalkyl or unsubstituted C 3-6 spirocycloalkyl;

[0533] Each R 2 are independently halogen, hydroxy, -CN, C 1-3 Alkyl or C 1-3 Halogenated alkyl, C 1-3 alkoxy;

[0534] m is 0, 1, or 2; and

[0535] n is 1, 2, or 3;

[0536] The method comprises making a compound of formula (V)

[0537]

[0538] or its stereoisomers or salts, and a compound of formula (VI)

[0539]

[0540] or a stereoisomer or salt thereof, wherein the compound of formula (V) is prepared by:

[0541] (a) making a compound of formula (VIIp)

[0542]

[0543] or a stereoisomer or salt thereof, wherein each Z is independently C 1-3 Alkyl or phenyl, and a compound of formula (XII)

[0544]

[0545] or its salt to prepare a compound of formula (Vb)

[0546]

[0547] or a stereoisomer or salt thereof; and

[0548] (b) contacting a compound of formula (Vb) or a stereoisomer or a salt thereof with an acid, thereby preparing a compound of formula (V) or a stereoisomer or a salt thereof.

[0549] Embodiment No. 10. The method according to embodiment 8 or 9, wherein each Z is independently C 1-4 alkyl.

[0550] Embodiment No. 11. The method of embodiment 8 or 9, wherein each Z is methyl, each Z is ethyl, each Z is isopropyl or wherein SiZ3 is Si(PhMe2) or Si(t-BuMe2).

[0551] Embodiment No. 12. The method of embodiment 8 or 9, wherein each Z is ethyl.

[0552] Embodiment No. 13. The method according to any one of embodiments 1 to 12, wherein the compound of formula (VI) is:

[0553] including stereoisomers thereof.

[0554] Example No. 14. A method for preparing a compound of formula (II)

[0555]

[0556] or a stereoisomer or salt thereof,

[0557] R 1a and R 1b Each of which is independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, -CN, unsubstituted C 3-6 Cycloalkyl or unsubstituted C 3-6 spirocycloalkyl;

[0558] Each R 2 are independently halogen, hydroxy, -CN, C 1-3 Alkyl or C 1-3 Halogenated alkyl, C 1-3 alkoxy;

[0559] m is 0, 1, or 2;

[0560] n is 1, 2, or 3;

[0561] The method includes

[0562] (a) alanine and a compound of formula (IX)

[0563]

[0564] or a stereoisomer or salt thereof to form a compound of formula (XI)

[0565]

[0566] or a stereoisomer or salt thereof;

[0567] (b) reacting a compound of formula (XI) or a stereoisomer or salt thereof with a chlorinating agent, a The compound is contacted with an organoaluminum compound to form a compound of formula (Vc)

[0568]

[0569] or a stereoisomer or salt thereof; and

[0570] (c) contacting the compound of formula (Vc) or a stereoisomer or salt thereof with a reducing agent, thereby forming the compound of formula (II) or a stereoisomer or salt thereof.

[0571] Embodiment No. 15. The method according to embodiment 14, wherein the organoaluminum compound has the formula X3Al, wherein X is independently Cl or C 1-4 alkyl.

[0572] Embodiment No. 16. The method of embodiment 14, wherein X is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl.

[0573] Embodiment No. 17. The method according to any one of embodiments 14 to 16, wherein the organoaluminum compound is trimethylaluminum, triethylaluminum, triisobutylaluminum, dimethylaluminum chloride, diethylaluminum chloride, or ethylaluminum dichloride.

[0574] Embodiment No. 18. The method of any one of embodiments 14 to 17, wherein the organoaluminum compound is trimethylaluminum.

[0575] Embodiment No. 19. The method according to any one of embodiments 14 to 18, wherein the reducing agent is sodium aluminum hydride.

[0576] Embodiment No. 20. The method of any one of embodiments 14 to 19, wherein the chlorinating agent is SOCl2, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, pivaloyl chloride, or oxalyl chloride.

[0577] Embodiment No. 21. The method of embodiment 20, wherein the chlorinating agent is oxalyl chloride.

[0578] Embodiment No. 22. The method according to embodiment 21, wherein the chlorinating agent is in the presence of N-formylpyrrolidine or N,N-dimethylformamide.

[0579] Embodiment No. 23. The method according to any one of embodiments 1 to 22, wherein R 1a and R 1b are independently hydrogen, halogen, cyano, unsubstituted C 1-3 Alkyl or cyclopropyl.

[0580] Embodiment No. 24. The method according to any one of embodiments 1 to 22, wherein R 1a and R 1b are independently hydrogen, halogen or methyl.

[0581] Embodiment No. 25. The method according to any one of embodiments 1 to 22, wherein R 1a is hydrogen and R 1b is halogen, methyl, cyano or cyclopropyl.

[0582] Embodiment No. 26. The method according to any one of embodiments 1 to 22, wherein R 1a is hydrogen and R1b It is a halogen.

[0583] Embodiment No. 27. The method according to any one of embodiments 1 to 22, wherein R 1a is hydrogen and R 1b It is a methyl group.

[0584] Embodiment No. 28. The method according to any one of embodiments 1 to 22, wherein R 1a is methyl and R 1b is halogen, methyl, cyano or cyclopropyl.

[0585] Embodiment No. 29. The method according to any one of embodiments 1 to 22, wherein R 1a is a halogen and R 1b is halogen, methyl, cyano or cyclopropyl.

[0586] Embodiment No. 30. The method according to any one of embodiments 1 to 22, wherein R 1a and R 1b is independently halogen or methyl.

[0587] Embodiment No. 31. The method according to any one of embodiments 1 to 22, wherein R 1a is a halogen and R 1b It is a methyl group.

[0588] Embodiment No. 32. The method according to any one of embodiments 1 to 22, wherein R 1a is a halogen and R 1b It is a halogen.

[0589] Embodiment No. 33. The method according to any one of embodiments 1 to 22, wherein R 1a and R 1b For F.

[0590] Embodiment No. 34. The method according to any one of embodiments 1 to 33, wherein each R 2 are independently hydrogen, halogen, hydroxy, -CN or C 1-3 alkyl.

[0591] Embodiment No. 35. The method according to any one of embodiments 1 to 34, wherein m is 0.

[0592] Embodiment No. 36. The method according to any one of embodiments 1 to 34, wherein m is 1.

[0593] Embodiment No. 37. The method according to any one of embodiments 1 to 34, wherein R 2 Halogen or C 1-3 An alkyl group and m is 1.

[0594] Embodiment No. 38. The method according to any one of embodiments 1 to 34, wherein R 2 is halogen and m is 1.

[0595] Embodiment No. 39. The method according to any one of embodiments 1 to 38, wherein the compound of formula (II) is:

[0596]

[0597] or a stereoisomer or salt thereof.

[0598] Embodiment No. 40. The method according to any one of embodiments 1 to 35, wherein the compound of formula (II) is:

[0599]

[0600] or a salt thereof.

[0601] Embodiment No. 41. The method according to any one of embodiments 1 to 40, wherein the compound of formula (II) or a stereoisomer or salt thereof is contacted with a compound of formula (X)

[0602]

[0603] or a stereoisomer or salt thereof:

[0604] Ring A is phenyl or pyridyl;

[0605] Each R 3 are independently hydrogen, halogen or C 1-3 alkyl,

[0606] R 4 is halogen or -CN; and

[0607] p is 1 or 2;

[0608] To form a compound of formula (I)

[0609]

[0610] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0611] Embodiment No. 42. The method according to embodiment 41, wherein the compound of formula (X) is:

[0612]

[0613]

[0614] or its salt. Example No. 43. A synthesis of a compound having formula (1)

[0615]

[0616] or a pharmaceutically acceptable salt thereof, the method comprising:

[0617] (a) making a compound of formula (2)

[0618]

[0619] or a salt thereof, wherein the compound of formula (2) is synthesized according to the method described in Example 1, 8 or 12, and wherein the compound of formula (V) or a salt thereof has formula (5),

[0620]

[0621] And the compound of formula (VI) has formula (6),

[0622]

[0623] (b) with a compound of formula (10)

[0624]

[0625] or a salt thereof, thereby preparing the compound of formula (1) or a pharmaceutically acceptable salt thereof.

[0626] Embodiment No. 44. The method according to embodiment 43, wherein the compound of formula (6) is prepared by:

[0627] (a) Make equation (12a) The compound is contacted with H2SO4 to prepare Compounds;

[0628] (b) reducing the compound of formula (12b) to prepare Compounds;

[0629] (c) cyclizing the compound of formula in the presence of SOCl2 to prepare compounds; and

[0630] (d) contacting the compound of formula (12d) with FeCl3, NaOCl and a base to thereby prepare the compound of formula (6).

[0631] The following examples are presented by way of illustration and not limitation.

[0632] Examples

[0633] Synthesis of the compounds described herein. All reagents and solvents were purchased from commercial suppliers and used without additional purification. Anhydrous solvents (dichloromethane) were used. Commercially available solvents were not further purified.

[0634] Example 1:

[0635]

[0636] Step 1: (S)-2-amino-3-(1H-indol-3-yl)propyl sulfate compound 3a

[0637] Acetonitrile and THF were charged to a reactor and the temperature was set to -5°C to 5°C. Compound 3* (1 equivalent) and ClSO3H (1.13 equivalents) were added alternately in 5 portions at -5°C to 5°C and the reaction was stirred for at least 30 minutes. The resulting suspension was filtered and the filter cake washed with THF. Compound 3* was reacted in 30g and 75kg portions.

[0638] Step 2: (S)-3-(aziridin-2-ylmethyl)-1H-indole compound 4

[0639] The THF-wet product 3a was dissolved in 3.1 equivalents of aqueous NaOH (10% w / w). Anisole (4 V relative to 3*) was added and the THF was distilled off until the temperature reached 93°C to 97°C. The biphasic reaction mixture was stirred at 93°C to 97°C for 5 hours to form aziridine 4. The phases were separated and the aqueous layer was discarded. 1 V butanol (relative to 3*) was added to the organic layer, and the organic layer was washed twice with water at 65°C to 75°C. 3 V butanol (relative to 3*) was added to the organic layer, and the solution was cooled to 20°C to 30°C and then inserted into step 3. Alternatively, after phase separation, the organic layer was washed once at 30°C.

[0640] Step 3: (R)-1-(1H-indol-3-yl)propan-2-amine compound 5

[0641]

[0642] Anisole / 1-butanol (1:1 v / v) containing compound 4 embedded from step 2 and a Pd(OH)2 / C catalyst (5% w / w relative to 3*) are suspended in anisole / 1-butanol. After inertization and changing the atmosphere to hydrogen, the temperature is set to 75°C to 85°C and a hydrogen pressure of 14 to 16 bar is applied. Hydrogenation is continued at 75°C to 85°C for about 2 hours until completion. Alternatively, a hydrogen pressure of 12 bar is applied and hydrogenation is carried out for 5 to 6 hours. The temperature is set to 20°C to 30°C and the catalyst is filtered out. The filter cake is washed with butanol and the filtrate is used for further processing.

[0643] Then the product crystallization from step 3 is α-methyltryptamine methanesulfonate, which removes the main impurities including dimer by-products. After the concentrated product solution is to remove residual water, methanesulfonic acid (1.05 equivalents, based on the total amount of amine base) is added at least 1 hour at 75 ℃ to 85 ℃. The suspension is placed at least 1 hour at 75 ℃ to 85 ℃, cooled to 20 ℃ to 30 ℃ through at least 2 hours, and finally placed at least 1 hour at 20 ℃ to 30 ℃. The suspension is filtered and the filter cake is washed with anisole / 1-butanol (1: 1-v / v). Water is added, and azeotropic distillation is performed at 90 ℃ to 100 ℃ and atmospheric pressure. The solution is then cooled to 15 ℃ to 25 ℃, and propyl alcohol is added afterwards to provide a water / propyl alcohol mixture of 4: 1-v / v. Sodium hydroxide solution (30% aqueous solution) is added to pH>11, and the suspension is placed at least 1 hour at 15 ℃ to 25 ℃. The suspension was filtered and the filter cake was washed with 4:1-v / v water / propanol, followed by washing the slurry with water.The product was dried under vacuum at 35-45°C to afford the final product as a white to pale yellow solid.

[0644] (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol compound 2

[0645]

[0646] At an internal temperature of 15°C to 25°C, compound 5 (25g, 0.14mol) was mixed with compound 6 (27.0g, 0.16mol, 1.10 equivalents) and 5 volumes of acetonitrile (relative to compound 5). The mixture was heated to an internal temperature of 75°C to 85°C. At this temperature, potassium carbonate (13.8g, 0.10mol, 0.7 equivalents) was added in 4 portions over 1 hour, and the mixture was stirred for another 2 hours. Moderate gas generation was observed. Conversion was checked. The mixture was then cooled to an internal temperature of 30°C to 40°C and filtered. The filter cake was replaced and washed with 25mL of acetonitrile, respectively. The mixture was then heated to an internal temperature of 75°C to 85°C, a solution of 1 volume of deionized water containing 29.8g (0.16mol, 1.1 equivalents) of p-toluenesulfonic acid was added over 1 hour, and the two-phase mixture was stirred for 2 hours. The integrity of the conversion was checked.

[0647] The mixture was then cooled to an internal temperature of 0°C to 10°C and quenched with 8 volumes of pure water over 10 minutes. The pH was adjusted to 9 by adding 3.5 volumes of saturated sodium carbonate solution at an internal temperature of 0°C to 10°C. The mixture was then stirred at an internal temperature of 0°C to 10°C for 30 minutes. Slight gas evolution was observed. The mixture was then warmed to an internal temperature of 15°C to 25°C, and the pH was readjusted to 9 using sodium carbonate solution. The mixture was then extracted twice with 5 volumes of isopropyl acetate at an internal temperature of 15°C to 25°C, and the combined organic phases were washed with 5 volumes of deionized water to remove residual salts. The product remained in the organic phase. After the organic phase was concentrated to approximately 5 volumes at an internal temperature of 35°C to 45°C and a pressure of 200 to 300 mbar, 16 volumes of methanol were added in parallel with the distillation. After approximately 17 volumes of distillate had been distilled, the completeness of the solvent exchange was checked. Three volumes of pure water were then added at an internal temperature of 35°C to 45°C over a period of at least 1 hour, and the brown solution crystallized. Monitor crystallization. After crystallization begins, add another 5 volumes of purified water at an internal temperature of 35 to 45°C over a period of at least 1 hour, cool the suspension to an internal temperature of 0 to 10°C over at least 2 hours, and stir at this temperature for at least 1 hour. Collect the wet product by filtration, slurry-wash twice with 2 volumes of purified water, and dry under vacuum at an internal temperature of 55 to 65°C.

[0648] Example 2:

[0649]

[0650] Step 1: (R)-5-(Trimethylsilyl)pent-4-yn-2-amine compound 7

[0651]

[0652] Starting material (R)-(5-(trimethylsilyl)pent-4-yn-2-yl)t-butyl carbamate (28.6 g, 91.4A%, 84 wt%, 94.2 mmol, 1.0 equivalent) was dissolved in DCM (140 mL, 5 volumes) and EA (28 mL, 1 volume). The solution was cooled to 0 ° C, and TFA (64.4 g, 565.2 mmol, 6.0 equivalents) was then added dropwise at 0 to 5 ° C. After the addition was complete, the mixture was warmed to ambient temperature and stirred for another 16 hours. The reaction mixture was concentrated under vacuum at 38 ° C for 1 hour to provide approximately 80.5 g of crude compound 7 (approximately 51 w%), 89% yield (corrected). The crude product was used in the next step without further purification.

[0653] Step 2: (R)-2,2-Difluoro-3-((5-(trimethylsilyl)pent-4-yn-2-yl)amino)propyl hydrogen sulfate compound 7a

[0654]

[0655] Toluene (70mL x 3) is added to the crude compound. 7 (about 67.0g, 88.6mmol, 1.0 equivalent). The resulting solution is concentrated in vacuo at 38°C for 30 minutes to provide about 37.6g of crude material. The crude material is dissolved in MeCN / toluene (210mL, 10 volumes). The mixture is stirred at 45 to 50°C. K2CO3 (30.5g, 221.5mmol, 2.5 equivalents) is added to the mixture in batches. Compound 6 (15.8g, 93.0mmol, 1.05 equivalents) is added. After the addition is complete, the mixture is heated to 75 to 80°C and stirred for another 4 hours.

[0656] 10% citric acid (about 500 mL) was added to adjust the pH to 3-4, and the mixture was extracted with EtOAc (200 mL x 2). The combined organic phases were washed with brine (200 mL) and then dried over Na2SO4. The filter cake was filtered and washed with EA, and the combined filtrates and washings were concentrated under vacuum at 38°C for 30 minutes to provide a crude product (about 26.0 g, 69.4 wt%).

[0657] The crude material was stirred in EtOAc / n-heptane (2 vol:2 vol, 100 mL) at 0-5° C. for 1 hour. The filter cake was filtered and washed with EtOAc / n-heptane (1:1, 2 vol, approximately 50 mL), and the filter cake was dried under vacuum at 38° C. for 2 hours and then dried under high vacuum to provide 15.1 g of compound 7a as a light yellow solid, 50% corrected over three steps.

[0658] Step 3: (R)-2,2-Difluoro-3-((5-(trimethylsilyl)pent-4-yn-2-yl)amino)propan-1-ol Compound 7b

[0659]

[0660] Compound 7a (0754144, 26.0 g, 79.0 mmol, 1.0 eq) was dissolved in THF (260 mL, 10 vol.), and then H2O (17.0 g, 948.0 mmol, 12.0 eq) was added. H2SO4 (7.75 g, 79.0 mmol, 1.0 eq) was added dropwise. The reaction mixture was stirred at 20-25°C for 16 hours.

[0661] Na2CO3 (solid, 5.3 g, 1.5 eq) was added, and the resulting mixture was stirred at about 25°C for 10 minutes. Na2SO4 (15.0 g) was added. The suspension was filtered and the filter cake was washed with THF (30 mL). The filtrate was concentrated in vacuo to provide 19.4 g of compound 7b as a gray jelly in 98% isolated yield.

[0662] Step 4: 5,5-difluoro-3-(5-(trimethylsilyl)pent-4-yn-2-yl)-1,3-oxazin-2-one compound 7c

[0663]

[0664] Compound 7b (3.5 g, 14.0 mmol, 1.0 eq) was dissolved in THF (35 mL, 10 vol) under N₂. CDI (2.64 g, 15.4 mmol, 1.1 eq) and DMAP (175 mg, 1.4 mmol, 0.1 eq) were added. The reaction mixture was heated to reflux and stirred for 16 h. The mixture was diluted with EtOAc and then washed with saturated NH₄Cl solution (50 mL x 2).

[0665] After phase separation, the organic phase was washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated in vacuo to obtain about 5.0 g of crude product. The crude product was purified by column (n-heptane / EA=1:0 to 20:1) to provide about 3.4 g of compound 7c with a yield of 90% (uncorrected).

[0666] Step 5: (R)-5,5-difluoro-3-(1-(2-(trimethylsilyl)-1H-indol-3-yl)propan-2-yl)-1,3- Oxazine-2-one compound 5a

[0667]

[0668] Compound 7c (400 mg, 1.45 mmol, 1.0 eq) was dissolved in DMF (8.0 mL, 20 vol) under N2. Na2CO3 (307 mg, 2.9 mmol, 2.0 eq), LiCl (60 mg, 1.45 mmol, 1.0 eq), Pd(dppf)Cl2 (88 mg, 0.12 mmol, 8 mol%), and 2-bromoaniline (300 mg, 1.74 mmol, 1.2 eq) were quickly added. The reaction mixture was purged with N2 4-5 times, then heated to 100°C and stirred for 3 hours. IPC1.

[0669] The reaction mixture was gradually cooled to approximately 25° C. EA (50 mL) and brine (50 mL) were added and the two phases were separated. The aqueous phase was extracted with EA (50 mL), the organic phase was then dried over Na SO and the filtrate was concentrated to dryness. The crude product was purified by column to provide approximately 320 mg of compound 5a (92A% purity) in approximately 60% yield (uncorrected).

[0670] Step 6: (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol Compound 2

[0671]

[0672] Crude product 5a (50 mg, 0.14 mmol, 1 eq), LiOH.HO (15.4 mg, 0.35 mmol, 2.5 eq) and HO (0.5 mL) / EtOH (0.5 mL) were added to a vial (10 mL). The resulting mixture was heated to 50 to 55 ° C and stirred for 2 hours. Aqueous HCl (6 N, 0.5 mL) was added to the above mixture, and the resulting mixture was stirred for 1 hour. The mixture was cooled to about 20 ° C. Filtered and the filter cake was dried under high vacuum at 35 to 40 ° C for 1 hour to provide about 38 mg of crude product (about 80A%), 100% yield.

[0673] Example 3:

[0674]

[0675] Step 1: (4R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2-oxide

[0676] To a solution of imidazole (437 g, 6.4 mol, 1.5 equiv) in DCM (5.5 L, 7.5 vol) was added dropwise SOCl (763 g, 6.4 mol, 1.5 equiv) at -5 to 0 ° C under N2 over a period of 2 hours. The reaction mixture was stirred at -5 to 0 ° C for 0.5 hours. The starting material (R)-tert-butyl (1-hydroxypropan-2-yl)carbamate (740 g, 4.3 mol, 1.0 equiv) was added dropwise in DCM (5.5 L, 7.5 vol) at -5 to 0 ° C over 2 hours. The reaction mixture was stirred at -2 to 0 ° C for 0.5 hours. Et3N (865 g, 8.6 mol, 2 equiv) was added dropwise at -5 to 0 ° C, and the mixture was stirred for 2 hours.

[0677] When the reaction is complete, water (6 L) is added at 0°C to 20°C and the two phases are separated. The aqueous layer is extracted with DCM (5 L). The combined organic phases are washed with 10 w% citric acid (5 L), aqueous NaHCO (5 L), and brine (5 L). The organic phase is cooled to 0°C to 10°C.

[0678] Step 2: (R)-tert-Butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

[0679] HO (13 L) and RuCl .xHO (9.6 g) were added sequentially, followed by oxone (4.0 kg, 6.4 mol, 1.5 eq). The reaction mixture was gradually warmed to 30° C. to 33° C. and stirred for 4 hours. The reaction mixture was filtered through 500 g of celite, and the filter cake was washed with DCM (5 L) and the two phases were separated (filtrate).

[0680] The aqueous phase was then extracted with DCM, and the combined organic phases were washed with saturated Na2S2O3 (5 L x 3) and brine (5 L x 2), then dried over Na2SO4 (1 kg). Filtered, the filter cake was washed with DCM (3 L), and the combined filtrate and washings were concentrated under vacuum at 30°C to provide approximately 850 g of (R)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide, which was 98 wt% by qNMR, in approximately 85% isolated yield.

[0681] Step 3: tert-Butyl (R)-(5-(triethylsilyl)pent-4-yn-2-yl)carbamate

[0682]

[0683] Triethyl(ethynyl)silane (92.6 g, 0.66 mol, 1.3 eq) was dissolved in THF (150 mL), and the solution was cooled to -5°C to 0°C. n-BuLi (265 mL, 2.5 M, 1.3 eq) was added dropwise over 1 hour. The reaction mixture was stirred at -5°C to 0°C for 30 minutes.

[0684] Under N2, (R)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (120 g, 0.51 mol, 1.0 eq) was dissolved in THF (600 mL). The reaction mixture was cooled to -10°C to 0°C. Refined TESC2Li (approximately 500 mL, 0.66 mol, 1.3 eq) was added dropwise at -10°C to 0°C over 1 hour. The reaction mixture was stirred at -5°C to 0°C for 2 hours.

[0685] The reaction was quenched with saturated NH4Cl (300 mL) at -10°C to 0°C. The mixture was separated and the aqueous phase was extracted with EtOAc (approximately 500 mL x 2). The organic phases were combined and washed with brine (500 mL x 2). The organic phase was dried over Na2SO4 (approximately 30 g) and then filtered.

[0686] The filter cake is rinsed with EtOAc (about 50mL×2). The filtrate is concentrated under vacuum at 35°C for about 2 hours to provide about 180g of crude (R)-(5-(triethylsilyl)pent-4-alkynes-2-yl)t-butyl carbamate. Crude (R)-(5-(triethylsilyl)pent-4-alkynes-2-yl)t-butyl carbamate is passed through a column (silica gel, 200-300 mesh, 6w) and purified with EtOAc / normal heptane (0-10%). The desired portion of about 14L is collected. After 35-40°C of vacuum concentration, about 105g of pure (R)-(5-(triethylsilyl)pent-4-alkynes-2-yl)t-butyl carbamate (compound 7p) is obtained, with 98A% in 70% isolated yield.

[0687] Step 4: (R)-1-(1H-indol-3-yl)propan-2-amine compound 5

[0688]

[0689] Step 4a: (R)-tert-Butyl(1-(2-(triethylsilyl)-1H-indol-3-yl)propan-2-yl)carbamate

[0690] Under N2, Na2CO3 (4.5 g, 42 mmol, 2.5 eq), Pd2(dba)3 (0.77 g, 0.84 mmol, 0.05 eq), P(tBu)HBF4 (0.48 g, 1.68 mmol, 0.1 eq), 2-bromoaniline (4.3 g, 25.2 mmol, 1.5 eq) and compound 7p (6.27 g, 16.8 mmol, 1.0 eq) were charged into Me-THF (50 mL, 10 vol). The reaction mixture was purged with N2 4 to 5 times, heated to reflux and stirred for 24 h. The reaction mixture was cooled to about 25°C and 100 mL of DCM and 100 mL of H2O were added.

[0691] The two phases were separated and the aqueous phase was extracted with DCM (approximately 50 mL). The combined organic phases were washed with H2O (50 mL) and brine (50 mL) and dried over Na2SO4 (5 g). The mixture was filtered and the filter cake was washed with DCM. The combined washings and filtrate were concentrated under vacuum at 35 to 40°C to provide 24.1 g of crude product (20.4 w%), 75% yield (corrected).

[0692] Step 4b: (R)-1-(1H-indol-3-yl)propan-2-amine compound 5

[0693] The crude compound (20.4 w%) dissolved in DCM (50 mL) was washed four times with approximately 30 mL of 1 M HCl solution. The organic phase was charged to a flask and HCl gas was bubbled through at room temperature (approximately 20° C.) for 1 hour. Approximately 30 mL of water was added, the two phases separated, and the aqueous phase was extracted with DCM (15 mL x 2). The aqueous solution was adjusted to pH 7-8 with solid NaOH and then extracted with DCM (10 mL).

[0694] A solution of NaOH (1.5 g) in water (4 mL) was added dropwise to the above aqueous solution under stirring at room temperature (about 20° C.). The aqueous phase was extracted with DCM (50 mL), and the organic phase was concentrated under vacuum at 35° to provide 2.0 g of compound 5 with 96A% in 90% isolated yield (uncorrected).

[0695] Compound 2 can be prepared from step 2 according to the method of Example 1 described herein.

[0696] Example 4: 2,2-Difluoromalonate compound 12b

[0697]

[0698] 2 kg of compound 12a was filled into a PTFE bottom reactor and 2.1 kg of concentrated sulfuric acid was added. The mixture was then stirred and heated at 45 to 55 ° C for about 4 hours (a 30% NaOH aqueous solution was used as a scrubber to absorb the HF produced during the reaction). The mixture was then added dropwise to ice water (5 kg / 5 kg). The quenching temperature was maintained at 0 ° C. The organic phase was separated and the aqueous layer was extracted once with DCM (2 L, 1 V). The organic layers were combined and the DCM was removed under vacuum. The crude sample was purified by vacuum distillation. The main portion of compound 12b was collected at 62 to 66 ° C / 20 mmHg. 1 H NMR (400MHz, CDCl3): δ = 3.89ppm (s, 6H); 13 C NMR (100MHz, CDCl3): δ = 53.95ppm (-CH3), 105.98ppm (-CF2-, 1 J CF 259.1Hz),160.94ppm(-CO-, 2 J CF 30.9Hz); 19 F NMR (188MHz, CDCl3): δ=-112.05ppm (s, 2F).

[0699] Example 5:

[0700]

[0701] Step 1:

[0702]

[0703] A round-bottom flask equipped with a magnetic stirrer was charged with alanine (100 g, 1.122 mol, 1.00 equiv) and methanol (150 ml). To the resulting suspension was added sodium methoxide (30 w % in methanol, 1.235 mol, 1.10 equiv) over 2 minutes. The transfer line was flushed with methanol (10 ml). The reaction was stirred until completely dissolved and methyl 2,2,3,3-tetrafluoro-3-methoxypropionate (173 ml, 1.235 mol, 1.10 equiv) was added over 3 minutes. Stirring was continued for 20 minutes, and the reaction mixture was then evaporated under reduced pressure to produce a yellow, transparent oil. The oil was diluted with water, and then a 2M aqueous HCl solution (75 ml, 0.15 mol, 0.13 equiv) was added, resulting in a pH of approximately 7.

[0704] The solution was transferred to an addition funnel and the flask was charged with 105.0 g of concentrated aqueous HCl (37%) (89 ml, 1.066 mol, 0.95 eq). The contents of the addition funnel were added to the aqueous HCl solution at ambient temperature over 30 minutes with stirring. As the product suspension thickened, water was added during the addition to provide magnetic stirring. The white suspension was stirred at ambient temperature for 1 hour before filtration. The filter cake was washed with WBI and dried overnight at 10 mbar / 70°C. Yield: 266 g (95.9% yield) of the product as a white solid. 1 H NMR (600MHz, CDCl3): δ6.98–6.77(m,1H),4.74–4.65(m,1H),3.71(s,3H),1.56(d,J=7.2Hz,3H); 13 C NMR (151MHz, CDCl3): δ175.6, 158.8, 117.4, 108.0, 51.5, 48.3, 17.8.

[0705] Step 2:

[0706]

[0707] To a 1000 ml sulfated flask equipped with a mechanical stirrer, addition funnel, and argon bubbler was added indole (338.3 mmol, 1.045 eq.) and toluene (120 ml). The mixture was cooled in an ice bath and trimethylaluminum (2 M in toluene, 161.8 ml, 323.7 mmol., 1.04 eq.) was added over 15 minutes at an internal temperature of <14°C and stirred at <25°C until a white suspension formed after the addition was complete.

[0708] A 350 ml sulfated flask equipped with a mechanical stirrer, addition funnel, and argon bubbler was equipped. The flask was charged with compound 11 (323.7 mmol, 1.0 equiv), followed by toluene (80 ml) and N-formylpyrrolidine (1.15 ml, 12.1 mmol, 0.037 equiv). Oxalyl chloride (29.2 ml, 333.4 mmol, 1.03 equiv) was added over 40 minutes at 25° C. while stirring. The resulting green / yellow cloudy solution (approximately 145 ml) was stirred for 25 minutes until gas evolution ceased, and the contents were transferred to an addition funnel.

[0709] The indole dimethylaluminum suspension prepared above was cooled to -30 to -40°C and the acid chloride solution was added under stirring over 10 to 15 minutes so that the temperature of the mixture did not exceed -30°C. After the addition was complete, trimethylaluminum (2M in toluene, 194ml, 388mmol, 1.2 equivalents) was added between -30 and -40°C over 23 minutes, and the resulting dark solution was stirred at this temperature for 2 hours. Trimethylaluminum (2M in toluene, 20ml, 40mmol, 0.12 equivalents) was added and stirring was continued for 2 hours. Over 15 minutes, the reaction mixture was cannulated into a 1000 ml flask containing triamtanol (181ml 1651mmol.5.1 equivalents) at <15°C. The resulting product suspension was stirred at 25°C and heated to 65°C. Heptane (160ml) was added and the mixture was stirred at 65°C for 3 minutes. The mixture was cooled to 40° C. and 900 g of n-propanol (31.8 ml, mmol, eq.) were added within 20 min. The mixture was cooled to 10° C. and stirred for 10 min.

[0710] The mixture was cannulated onto a filter with an argon stream flowing over it. After filtration, the filter cake was compressed and the mother liquor (-150 ml) was briefly aspirated. The filter cake was washed with toluene (80 ml) and the remaining mother liquor was pushed out with heptane (80 ml). The filter cake was dried for 15 minutes (66.9 g) and dried under reduced pressure at 50° C. to yield 65.4 g (58.3% yield) of the product (98% purity) as an orange solid. 1H NMR(600MHz,DMSO-d6):δ12.07(br s,1H),9.31(d,J=7.2Hz,1H),8.42(d,J=3.2Hz,1H),8.19–8.15(m,1H),7.50–7.47(m,1H),7 .25–7.22(m,1H),7.22–7.18(m,1H),5.28–5.20(m,1H),3.65(s,3H),1.41(d,J=7.2Hz,3H); 13 C NMR (151MHz, DMSO-d6): δ192.3,157.8,136.5,134.0,125.7,123.0,121.9,121.3,117.5,113.1,112.2,108.0,51.7,51.2,18.0.

[0711] Step 3:

[0712]

[0713] A 100 ml Easymax reactor equipped with a mechanical stirrer and an argon bubbler was charged with sodium aluminum hydride, and THF (35 ml) was added at 25°C. The mixture was stirred for 15 minutes, after which a methanol solution (7.04 ml, 173.3 mmol, 123 equiv) in THF (10 ml) was added over 30 minutes at <45°C T. The resulting off-white suspension was stirred for 5 minutes, after which a solution of (R)-N-(1-(1H-indol-3-yl)-1-oxopropan-2-yl)-2,2,3,3-tetrafluoro-3-methoxypropionamide (14.44 mmol, 1.00 equiv, compound 5c)) in THF (20 ml) was added over 30 minutes at <35°C. The resulting pale yellow suspension was heated to 45°C over 30 minutes and stirred for 19 hours.

[0714] Sodium sulfate (36.1 mmol, 2.50 equiv) was added to the reaction mixture, followed by the addition of a solution of water (6.50 ml, 361 mmol, 25.0 equiv) in THF (13.5 ml) over 20 minutes with stirring at 400 rpm, allowing the temperature to rise. The resulting light grey suspension was heated to reflux and the solvent was partially exchanged with toluene (50 ml) at ambient pressure and constant volume. After the exchange was complete, the suspension was cooled to 25° C. over 50 minutes, filtered, and the filter cake was washed with ethyl acetate (20 ml).

[0715] 10% aqueous sulfuric acid (6.0 ml, 6.54 mmol, 0.45 eq) was added until the resulting aqueous phase had a pH of 2.1. The organic phase was washed with water (8 ml), and the water was acidified with a few drops of 10% aqueous sulfuric acid until a pH of 2.1 was reached. The combined aqueous phases were washed with two separate portions of ethyl acetate (20 ml) and once with heptane (20 ml). 2M aqueous NaOH (7.22 ml, 14.44 mmol, 1.00 eq) was added to the aqueous phase until a pH of 5.3 was reached. After stirring for 5 minutes, the addition of NaOH was continued for at least 2 hours until the pH of the resulting pale yellow suspension remained constant at pH 6.5 for at least 30 minutes. The suspension was cooled to 4°C, stirred for 1 hour, filtered, and the filter cake was compacted and washed with cold water (5 ml) and cold water / MeOH = 10 / 1 (5 ml). The filter cake was dried under reduced pressure overnight to give an off-white solid (2.685 g, 69.3% yield, 99.3% purity). 1 H NMR (600MHz, CDCl3): δ8.06 (br s,1H),7.58(dd,J=7.9,0.9Hz,1H),7.38(dt,J=8.2,0.9Hz,1H),7.21(ddd,J=8.1,7.1,1.1Hz,1H),7.13(ddd,J=7.9,7.0,1.0Hz ,1H),7.03(d,J=2.3Hz,1H),3.93–3.74(m,2H),3.26–3.15(m,1H),3.15–3.02(m,2H),2.95–2.78(m,2H),1.17(d,J=6.3Hz,3H); 13 C NMR(101MHz, CDCl3)δ=136.41,127.58,122.88,122.57,122.23,120.46,119.51,118.84,118 .03,112.62,111.28,65.12(t,J=31.7Hz,1C),53.46,50.59(t,J=29.0Hz,1C),32.85,20.39.

[0716] Example 6:

[0717]

[0718] An inertized reactor was charged with compound 10 (25.0 g, 91.8 mmol, 1.00 equiv), and compound 2 (30.8 g, 114.8 mmol, 1.25 equiv) was added, followed by L-(+)-tartaric acid (20.67 g, 137.7 mmol, 1.50 equiv). Ethanol was added and the reaction mixture was heated to 69-72°C. Stirring was continued for approximately 2 hours, after which seed crystals of compound A (308.8 mg) were added. The mixture was stirred for approximately 46 hours.

[0719] EtOH (95.8 mL) was added and stirred for 15 minutes. The mixture was cooled to 15 to 25 ° C over about 1 hour and stirred at this temperature for about 2 hours. The suspension was filtered, the reactor was rinsed with EtOH (95.8 mL) using a spray ball, and the filter cake was washed with two portions of EtOH. The filter cake was dried under vacuum at 50 ° C. Compound A was isolated as a light brown powder with a yield of about 80%.

Claims

1. A method for preparing a compound of the formula or a stereoisomer or salt thereof, R 1a and R 1b Each of which is independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, -CN, unsubstituted C 3-6 Cycloalkyl or unsubstituted C 3-6 spirocycloalkyl; Each R 2 are independently halogen, hydroxy, -CN, C 1-3 Alkyl or C 1-3 Halogenated alkyl, C 1-3 alkoxy; m is 0, 1, or 2; n is 1, 2, or 3; The method comprises (a) alanine and a compound of formula (IX) or a stereoisomer or salt thereof to form a compound of formula (XI) or a stereoisomer or salt thereof; (b) reacting a compound of formula (VIII) with a chlorinating agent, a The compound is contacted with an organoaluminum compound to form a compound of formula (Vc) or a stereoisomer or salt thereof; and (c) contacting the compound of formula (Vc) or a stereoisomer or salt thereof with a reducing agent, thereby forming a compound of formula (II) or a stereoisomer or salt thereof.

2. The method of claim 1, wherein the organoaluminum compound has the formula X3Al, wherein X is independently Cl or C 1-4 alkyl.

3. The method of claim 1, wherein X is independently methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

4. The method according to any one of claims 1 to 3, wherein the organoaluminum compound is trimethylaluminum, triethylaluminum, triisobutylaluminum, dimethylaluminum chloride, diethylaluminum chloride or ethylaluminum dichloride.

5. The method according to any one of claims 1 to 4, wherein the organoaluminum compound is trimethylaluminum.

6. The method according to any one of claims 1 to 5, wherein the reducing agent is sodium aluminum hydride.

7. The method according to any one of claims 1 to 6, wherein the chlorinating agent is SOCl 2 , methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, pivaloyl chloride or oxalyl chloride.

8. The method according to claim 7, wherein the chlorinating agent is oxalyl chloride.

9. The method according to claim 8, wherein the chlorinating agent is in the presence of N-formylpyrrolidine or N,N-dimethylformamide.

10. The method according to any one of claims 1 to 9, wherein R 1a and R 1b are independently hydrogen, halogen, cyano, unsubstituted C 1-3 Alkyl or cyclopropyl.

11. The method according to any one of claims 1 to 9, wherein R 1a and R 1b are independently hydrogen, halogen or methyl.

12. The method according to any one of claims 1 to 9, wherein R 1a is hydrogen and R 1b is halogen, methyl, cyano or cyclopropyl.

13. The method according to any one of claims 1 to 9, wherein R 1a is hydrogen and R 1b It is a halogen.

14. The method according to any one of claims 1 to 9, wherein R 1a is hydrogen and R 1b It is a methyl group.

15. The method according to any one of claims 1 to 9, wherein R 1a is methyl and R 1b is halogen, methyl, cyano or cyclopropyl.

16. The method according to any one of claims 1 to 9, wherein R 1a is a halogen and R 1b is halogen, methyl, cyano or cyclopropyl.

17. The method according to any one of claims 1 to 9, wherein R 1a and R 1b is independently halogen or methyl.

18. The method according to any one of claims 1 to 9, wherein R 1a is a halogen and R 1b It is a methyl group.

19. The method according to any one of claims 1 to 9, wherein R 1a is a halogen and R 1b It is a halogen.

20. The method according to any one of claims 1 to 9, wherein R 1a and R 1b For F.

21. The method according to any one of claims 1 to 20, wherein each R 2 are independently hydrogen, halogen, hydroxy, -CN or C 1-3 alkyl.

22. The method according to any one of claims 1 to 21, wherein m is 0.

23. The method according to any one of claims 1 to 21, wherein m is 1.

24. The method according to any one of claims 1 to 21, wherein R 2 Halogen or C 1-3 An alkyl group and m is 1.

25. The method according to any one of claims 1 to 21, wherein R 2 is halogen and m is 1.

26. The method according to any one of claims 1 to 25, wherein the compound of formula (II) is: or a stereoisomer or salt thereof.

27. The method according to any one of claims 1 to 22, wherein the compound of formula (II) is: or a salt thereof.

28. The method according to any one of claims 1 to 27, wherein the compound of formula (II) is contacted with a compound of formula (X) or a stereoisomer or salt thereof, Ring A is phenyl or pyridyl; Each R 3 are independently hydrogen, halogen or C 1-3 alkyl, R 4 is halogen or -CN; and p is 1 or 2; To form a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

29. The method according to claim 28, wherein the compound of formula (X) is: or a salt thereof.

Images