Solid forms of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol and methods for preparing fused tricyclic compounds containing substituted phenyl or pyridinyl moieties and methods of using them

Abstract

To provide compounds useful as estrogen receptor ("ER") targeting agents, crystal forms, and methods of producing the same.SOLUTION: Provided herein are solid forms, salts, e.g., the compound B in the figure, and formulations of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, processes and synthesis thereof, and methods of their use in treatment of cancer.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This non-provisional patent application claims the benefit of U.S. Provisional Patent Application No. 62 / 687,930, filed June 21, 2018, and U.S. Provisional Patent Application No. 62 / 719,896, filed August 20, 2018, each of which is incorporated herein by reference in its entirety for all purposes.

[0002] Sequence Listing

[0002] This application incorporates by reference the sequence listing submitted with this application as a text file named P34807-WO_SL.txt, created on June 12, 2019, having a size of 16.4 kilobytes.

[0003] FIELD OF THEINVENTION

[0003] Provided herein are solid forms of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol and methods of its use in the treatment of cancer. Further described herein are methods for preparing fused tricyclic compounds containing substituted phenyl or pyridinyl moieties. [Background technology]

[0004]

[0004] Fused tricyclic compounds containing substituted phenyl or pyridinyl moieties within the scope of the present disclosure are useful as estrogen receptor ("ER") targeting agents.

[0005] ER is a ligand-activated transcriptional regulatory protein that mediates the induction of various biological effects through interaction with endogenous estrogens. Endogenous estrogens include 17β (beta)-estradiol and estrone. ER has been found to have two isoforms, ER-α (alpha) and ER-β (beta). Estrogen and estrogen receptors are involved in many 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 particular activity in the setting of metastatic disease and acquired resistance. ER-α targeting agents are disclosed in U.S. Patent Application Publication No. 2016 / 0175289.

[0006]

[0006] Useful methods for preparing fused tricyclic compounds containing substituted phenyl or pyridinyl moieties are disclosed in U.S. Patent Application Publication No. 2016 / 0175289. However, improved methods for preparing ER-α targeting agents are needed.

[0007]

[0007] There is great complexity surrounding the process and selection of solid forms of pharmaceutical compounds. Differences in the solid forms of such compounds can affect both the physical and chemical properties of a pharmaceutical compound and alter its processing, stability, bioavailability, formulation, and storage. There is no reliable predictability of the solid form and its usefulness as a crystalline solid or an amorphous solid. Crystalline solids may be useful, for example, for physical or chemical stability, and amorphous solids may be useful for enhanced dissolution and bioavailability.

[0008]

[0008] Mixtures of crystalline material result from polymorphism. It is impossible to predict in advance whether a crystalline form of a compound will exist, and even less to predict whether a crystalline form can be prepared or isolated. Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement," MRS Bulletin 31:875-879 (Currently, it is generally not possible to computationally predict the observable polymorphism of even the simplest molecules.) The number of possible solid forms results in multiple different chemical and physical properties for a pharmaceutical compound, which can greatly affect product development, stability, and marketing.

[0009]

[0009] Estrogen receptors ("ER") are ligand-activated transcriptional regulatory proteins that mediate the induction of various biological effects through interaction with endogenous estrogens. Endogenous estrogens include 17β (beta)-estradiol and estrone. ER has been found to have two isoforms, ER-α (alpha) and ER-β (beta). Estrogens and estrogen receptors are involved in many diseases or conditions, such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer, and other diseases or conditions. There is a need for novel ER-α targeted agents that are active in metastatic disease and in the setting of acquired resistance. Thus, there is a demand for cancer therapies with specific solid forms. Summary of the Invention

[0010]

[0010] Provided herein are solutions to the above-mentioned problems and other problems in the art.

[0011]

[0011] In one aspect, provided herein is a compound, namely, Compound B, named 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol tartrate, as described herein.

[0012] In another aspect, provided herein is a crystalline form of Compound B having an X-ray powder diffraction pattern including peaks at 19.32, 20.26, 21.63, 23.28, or 24.81±0.1 degrees 2θ (±0.1 degrees 2θ).

[0013] In another aspect, provided herein is a crystalline form of Compound B having an X-ray powder diffraction pattern including peaks at 11.49, 12.54, 19.16, 19.42, or 24.67±0.1 degrees 2θ (±0.1 degrees 2θ).

[0014] In another aspect, provided herein is a crystalline form of Compound B having an X-ray powder diffraction pattern substantially as shown in FIG. 10 or FIG.

[0015] In another aspect, provided herein is a crystalline form of Compound B having an X-ray powder diffraction pattern including peaks at 11.31, 15.70, 16.54, 19.10, or 22.76±0.1 degrees 2θ.

[0016] In another aspect, provided herein is a crystalline form of Compound B having an X-ray powder diffraction pattern including peaks at 12.52, 15.90, 19.66, 20.65, or 24.99±0.1 degrees 2θ.

[0017] In another aspect, provided herein is a crystalline form of Compound B having an X-ray powder diffraction pattern including peaks at 11.46, 12.51, 19.29, 19.42, or 20.23±0.1 degrees 2θ.

[0018]

[0018] In another aspect, provided herein is an amorphous solid comprising Compound A.

[0019]

[0019] Further provided herein are pharmaceutical compositions comprising Compound B or a crystalline salt thereof. Such compounds and pharmaceutical compositions can be used in the methods of treating cancer as defined herein.

[0020]

[0020] In another aspect, provided herein is a process for preparing a compound of formula (IV) as defined herein or a salt thereof. The process includes (1) reacting a reaction mixture comprising a compound of formula (I) as defined herein, an organic solvent, and thionyl chloride to form a compound of formula (IIa) as defined herein, and (2) reacting a reaction mixture comprising a compound of formula (IIa), a catalyst, an oxidizing agent, and a solvent to form a compound of formula (II) as defined herein. The process further includes reacting a reaction mixture comprising a compound of formula (II) as defined herein and a compound of formula (III) in an organic solvent to form a compound of formula (IV) as defined herein or a salt thereof.

[0021]

[0021] In another aspect, provided herein is a method for preparing a compound of formula (VIII) described herein or a pharma- ceutically acceptable salt thereof. The method includes reacting a reaction mixture comprising a compound of formula (IV) described herein, a compound of formula (V) described herein, or a compound of formula (X) described herein, and an organic solvent to form a compound of formula (VI) described herein. The method further includes reacting a reaction mixture comprising a compound of formula (VI), an organic solvent, and a compound of formula (VII) described herein or a salt thereof to form a compound of formula (VIII) or a salt thereof.

[0022]

[0022] In another aspect, provided herein is a method for preparing a compound of formula (VIII) described herein or a pharma- ceutically acceptable salt thereof, the method further comprising reacting a reaction mixture comprising a compound of formula (IX) described herein or a compound of formula (X) described herein, a compound of formula (IV) described herein, and an organic solvent to form a compound of formula (VIII) described herein or a salt thereof.

[0023]

[0023] In yet another aspect, provided herein is a process for preparing a compound of formula (IX) described herein or a salt thereof, the process comprising reacting a reaction mixture comprising a compound of formula (X) described herein, a compound of formula (VII) or a salt thereof described herein, an organic solvent, and a catalyst to form a compound of formula (XI) described herein or a salt thereof.

[0024] In yet another aspect, provided herein is a process for preparing a compound of formula (III) described herein or a salt thereof, comprising reacting a reaction mixture comprising a compound of formula (XII) described herein, compound B, and an organic solvent to form a compound of formula (XIII) described herein.

[0025] In yet another aspect, provided herein is a compound of formula (XVI) described herein.

[0026]

[0026] Further provided herein is a method for preparing a compound having formula (XX), the method comprising contacting a compound of formula (XXI) described herein with a protein transaminase to form a compound of formula (3). The compound of formula (3) is contacted with a compound of formula (II) described herein to form the compound formula (XX).

[0027]

[0027] The present embodiments can be better understood by reference to the detailed description and examples which are intended to illustrate non-limiting embodiments. [Brief description of the drawings]

[0028] [Figure 1]

[0028] Figure 2 shows the XRPD pattern for Form A of Compound B. [Diagram 2]

[0029] 1 shows the TGA and DSC patterns for Form A of Compound B. [Diagram 3]

[0030] 1 shows a PLM image for Form A of Compound B. [Figure 4]

[0031] 1 shows the XRPD pattern for Form B of Compound B. [Diagram 5]

[0032] 1 shows the TGA and DSC for Form B of Compound B. [Figure 6]

[0033] 1 shows the 13C SSNMR for Form B of Compound B. [Figure 7]

[0034] 1 shows the 19F SSNMR for Form B of Compound B. [Figure 8]

[0035] 1 is a water sorption / desorption graph for Form B of Compound B. [Figure 9]

[0036] A shows an SEM image, B shows a PLM image, and C shows the particle size distribution (PSD) of compound B form B. [Figure 10]

[0037] A shows a comparative XRPD pattern of Form C of Compound B versus Forms A and B of Compound B. Form C was found to be a mixture of Forms A and B. [Figure 11]

[0038] 1 shows the TGA and DSC for Compound B Form C. [Figure 12]

[0039] 1 shows the XRPD pattern for Form D of Compound B. [Figure 13]

[0040] 1 shows the TGA and DSC for Form D of Compound B. [Figure 14]

[0041] 1 shows the XRPD pattern for Form E of Compound B. [Figure 15]

[0042] 1 shows the TGA and DSC for Form E of Compound B. [Figure 16]

[0043] 1 shows the XRPD pattern for Form F of Compound B. [Figure 17]

[0044] 1 shows a DVS graph for Form F of Compound B. [Figure 18]

[0045] 1 shows the DSC for Form F of Compound B. [Figure 19]

[0046] 1 shows the XRPD pattern for Form G of Compound B. [Figure 20]

[0047] 1 shows the TGA and DSC for Form G of Compound B. [Figure 21]

[0048] 1 is an overlay of XRPD patterns of Form A, Form B, Form C, Form D, Form F, and Form G of Compound B. [Figure 22]

[0049] 1 shows an XRPD of compression properties for Form B of Compound B. [Figure 23]

[0050] 1 shows the 19F SSNMR of compression characteristics for Form B of Compound B. [Figure 24]

[0051] 1 shows DSC of the compression properties for Form B of Compound B. [Diagram 25]

[0052] 1 shows the phase transition pathways of Forms A, B, D, and F of Compound B. [Figure 26]

[0053] 1 shows the phase transformation pathway for obtaining form B to form F of compound B. [Figure 27A]

[0054] 1 shows the XRPD pattern for Form 1 of Compound C. [Figure 27B] 1 shows the XRPD pattern for Form 2 of Compound C. [Figure 28]

[0055] 1 shows the TGA and DSC for Form 1 of Compound C. [Figure 29]

[0056] 1 shows a PLM image for Form 1 of Compound C. [Diagram 30]

[0057] 1 shows the XRPD pattern for Form M of Compound D. [Diagram 31]

[0058] 1 shows the TGA and DSC for Form M of Compound D. [Diagram 32]

[0059] 1 shows the XRPD pattern for amorphous Form D of Compound A. [Diagram 33]

[0060] 1 shows the TGA and DSC for the amorphous form of Compound A. [Diagram 34]

[0061] 1 shows cell viability in ER+ breast cancer cell lines for Compound B compared to GDC-0810 and GDC-0927. [Diagram 35]

[0062] The effect of Compound B at 0.1 mg / kg and 1 mg / kg on tumor volume is shown compared to GDC-0927 at 100 mg / kg. [Diagram 36]

[0063] A shows a CT scan and B shows an FES-PET scan of a breast cancer patient treated with compound B. [Figure 37]

[0064] A shows a CT scan and B shows an FES-PET scan of a second breast cancer patient treated with compound B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029]

[0065] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any other methods, devices, and materials similar or equivalent to those described herein can be used in the practice of the present invention.

[0030]

[0066] The following definitions are provided to facilitate understanding of some terms used frequently herein and are not intended to limit the scope of the present disclosure. All references mentioned herein are incorporated by reference in their entirety.

[0031]

[0067] Unless otherwise specified, the terms "about" and "approximately" as used herein when referring to a dose, amount, or weight percentage of a component of a composition or dosage form means a dose, amount, or weight percentage that one of ordinary skill in the art would recognize to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percentage. The equivalent dose, amount, or weight percentage can be within 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percentage.

[0032]

[0068] Unless otherwise indicated, the terms "about" and "approximately," as used herein, when referring to a numerical value or range of values ​​(e.g., XRPD peak values) used to characterize a particular solid form described herein, indicate that the value or range of values ​​may deviate from the given value to an extent that would be deemed reasonable by one of ordinary skill in the art while still describing the solid form. In one embodiment, the value of the XRPD peak position may vary over up to ±0.1 degrees 2θ (or ±0.05 degrees 2θ) while still describing a particular XRPD peak.

[0033]

[0069] As used herein, unless otherwise specified, a "pure" crystalline material is substantially free of other crystalline or amorphous solids or other chemical compounds and contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% by weight of one or more other solid forms. Detection of other solid forms can be achieved, for example, by diffraction analysis, thermal analysis, elemental combustion analysis, and / or spectroscopic analysis. Detection of other chemical compounds can be achieved, for example, by mass spectrometry, spectroscopic analysis, thermal analysis, elemental combustion analysis, and / or chromatographic analysis.

[0034]

[0070] Unless otherwise specified, the terms "solvate" and "solvate" as used herein refer to a solid form of a substance that includes a solvent. The terms "hydrate" and "hydrate" refer to a solvate in which the solvent is water. The terms "solvate" and "solvate" as used herein can also refer to a solvate of a salt, co-crystal, or molecular complex. The terms "hydrate" and "hydrate" as used herein can also refer to a hydrate of a salt, co-crystal, or molecular complex.

[0035]

[0071] The term "pharmaceutical acceptable" refers to a diluent, excipient, or carrier in a formulation that is compatible with the other ingredient(s) of the formulation and not deleterious to the recipient thereof.

[0036]

[0072] Compound A has the structure: TIFF0007660040000001.tif47170 and refers to the compound having the name 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, including pharma- ceutically acceptable salts thereof. Compound A can be a tartrate salt as described herein (e.g., Compound B). Compound A can be a fumarate salt as described herein (e.g., Compound C). Compound A can be a malonate salt as described herein (e.g., Compound D).

[0037]

[0073] The term "solid form" refers to a physical form that is not predominantly liquid or gaseous. The solid form may be a crystalline form or a mixture thereof. In some embodiments, the solid form may be liquid crystal. In some embodiments, the solid form of Compound A is Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form 1, or Form 2, an amorphous solid, or a mixture thereof. In one embodiment, the solid form of Compound A is the tartrate salt. In another embodiment, the solid form of Compound A is the fumarate salt or a mixture thereof. The solid form may be a crystalline form as defined herein.

[0038]

[0074] The term "crystalline form" or "crystalline form" refers to a solid form that is crystalline. In some embodiments, the crystalline forms of the compounds described herein are substantially free of amorphous solids and / or other crystalline forms. In some embodiments, the crystalline forms of the compounds described herein may contain less than about 1% by weight, less than about 2% by weight, less than about 3% by weight, less than about 4% by weight, less than about 5% by weight, less than about 6% by weight, less than about 7% by weight, less than about 8% by weight, less than about 9% by weight, less than about 10% by weight, less than about 15% by weight, less than about 20% by weight, less than about 25% by weight, less than about 30% by weight, less than about 35% by weight, less than about 40% by weight, less than about 45% by weight, or less than about 50% by weight of one or more amorphous solids and / or other crystalline forms. In some embodiments, the crystalline forms described herein are pure. In some embodiments, the crystalline forms of the compounds described herein may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% pure.

[0039]

[0075] The term "amorphous" or "non-crystalline solid" refers to a solid form that is substantially non-crystalline as determined by X-ray diffraction. In particular, the term "non-crystalline solid" describes a disordered solid form, i.e., a solid form that lacks long-range crystalline order. In some embodiments, the non-crystalline solid of the compounds described herein is substantially free of other non-crystalline solids and / or other crystalline forms. In some embodiments, the non-crystalline solid can be pure. In some embodiments, the non-crystalline solid of the compounds described herein can be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% pure.

[0040]

[0076] As used herein, "treating" refers to the total or partial alleviation of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease or condition, or the slowing or halting of further progression or worsening of such symptoms, or the alleviation or eradication of the cause(s) of the disorder, disease or condition. In one embodiment, the disorder is cancer.

[0041]

[0077] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that can treat or prevent a disorder, disease or condition disclosed herein, or a symptom thereof.

[0042]

[0078] A "patient" or "subject" is defined herein to include animals such as mammals, which in one embodiment include, but are not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys, chickens, turkeys, quail, or guinea pigs, and in another embodiment, humans. In one embodiment, the subject is a human having or at risk for cancer.

[0043]

[0079] The terms "moiety" and "substituent" as used herein refer to an atom or a set of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds, thereby forming a part of a molecule.

[0044]

[0080] The term "alkyl" as used herein refers to an aliphatic straight or branched chain saturated hydrocarbon moiety having 1 to 20 carbon atoms. In certain embodiments, an alkyl has 1 to 10 carbon atoms. In certain embodiments, an alkyl has 1 to 6 carbon atoms. An alkyl group may be independently substituted with one or more substituents described herein.

[0045]

[0081] The term "substituted" as used herein refers to replacing at least one of the hydrogen atoms of 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. For example, the term "haloalkyl" refers to the fact that one or more hydrogen atoms of an alkyl (described below) are replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.). In one embodiment, "substituted" as used herein can refer to replacing at least one hydrogen atom of a compound or moiety described herein with a halogen or alkyl.

[0046]

[0082] The term "alkylene," as used herein, refers to a linear or branched, saturated divalent hydrocarbon group of 1 to 12 carbon atoms, and in another aspect 1 to 6 carbon atoms, where the alkylene group is optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.

[0047]

[0083] The term "alkoxy" as described herein refers to a group of formula -O-R', where R' is an alkyl group. The alkoxy group may be independently substituted with one or more substituents described herein. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy.

[0048]

[0084] The term "aryl" as described herein refers to a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic or tricyclic aromatic ring consisting of 5 to 16 carbon ring atoms. Bicyclic aryl ring systems include fused bicyclic rings having two fused 5-membered aryl rings (designated 5-5), having a fused 6-membered aryl ring with a fused 5-membered aryl ring (designated 5-6 and 6-5), and having two fused 6-membered aryl rings (designated 6-6). The aryl group may be substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, and azulenyl. The term "aryl" also includes partially hydrogenated derivatives of cyclic aromatic hydrocarbon moieties, provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic and each is optionally substituted.

[0049]

[0085] The term "heteroaryl" as described herein refers to an aromatic heterocyclic monocyclic, bicyclic or tricyclic ring system consisting of 5 to 16 ring atoms containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon, and in some embodiments, the monocyclic heteroaryl ring is 5-6 membered. Bicyclic heteroaryl ring systems include fused bicyclic rings having two fused 5-membered heteroaryl rings (designated 5-5), having a 6-membered heteroaryl ring fused to a 5-membered heteroaryl ring (designated 5-6 and 6-5), and having two fused 6-membered heteroaryl rings (designated 6-6). Heteroaryl groups may be substituted as defined herein. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, benzothiophenyl, indolyl, aza-indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, Includes benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, and furopyrazinyl.

[0050]

[0086] As used herein, the terms "halo," "halogen" and "halide" are used interchangeably and refer to a substituent fluorine, chlorine, bromine, or iodine.

[0051]

[0087] The term "haloalkyl" as used herein refers to an alkyl group in which one or more of the hydrogen atoms of the alkyl group are replaced by the same or different halogen atoms, particularly fluorine and / or chlorine atoms. Examples of haloalkyl include monofluoro-, difluoro- or trifluoro-methyl, ethyl or propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl or trifluoromethyl.

[0052]

[0088] The term "hydroxyalkyl," as used herein, refers to an alkyl group in which one or more of the alkyl group's hydrogen atoms have been replaced by a hydroxyl moiety. Examples include alcohols and diols.

[0053]

[0089] The term "heteroalkyl," as described herein, refers to a straight-chain or branched alkyl, as described herein, having 2 to 14 carbons, 2 to 10 carbons, or 2 to 6 carbons in the chain, one or more of which are replaced by a heteroatom selected from S, O, P, and N. Non-limiting examples of heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides.

[0054]

[0090] The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated carbocyclic moiety having a monocyclic, bicyclic (including bridged bicyclic) or tricyclic ring and 3 to 10 carbon atoms in the ring. The cycloalkyl moiety may be substituted with one or more substituents. In certain embodiments, 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). Cycloalkyl moieties of 3 to 6 carbon atoms include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially unsaturated (cycloalkenyl) derivatives thereof (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, and bicyclo[3.1.1]heptenyl. Cycloalkyl moieties can be attached in a "spirocycloalkyl" fashion, such as "spirocyclopropyl": TIFF0007660040000002.tif25170

[0055]

[0091] The term "heterocycle" or "heterocyclyl" as used herein refers to 4-, 5-, 6-, and 7-membered monocyclic, 7-, 8-, 9-, and 10-membered bicyclic (including bridged bicyclic) or 10-, 11-, 12-, 13-, 14-, and 15-membered bicyclic heterocyclic moieties that are saturated or partially unsaturated and have one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from oxygen, nitrogen, and sulfur in the ring, with the remaining ring atoms being carbon. In some embodiments, a heterocycle is a heterocycloalkyl. In certain embodiments, a heterocycle or heterocyclyl refers to a 4-, 5-, 6-, or 7-membered heterocycle. When used in reference to a ring atom of a heterocycle, the nitrogen or sulfur may be in an oxidized form, and the nitrogen may be substituted with one or more (C1-C6) alkyl or groups. A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Any of the heterocycle ring atoms may be It may be substituted with one or more of the substituents described herein. Examples of such saturated or partially unsaturated heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The term heterocycle also includes groups in which the heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

[0056]

[0092] Unless otherwise indicated, the term "hydrogen" or "hydro" refers to a hydrogen atom (-H) moiety and not H2.

[0057]

[0093] The term "organic solvent" as used herein refers to any non-aqueous polar aprotic solvent, polar protic solvent, and nonpolar solvent.

[0058]

[0094] As used herein, the term "polar organic solvent" refers to both polar aprotic solvents and polar protic solvents and does not include water.

[0059]

[0095] The term "polar aprotic solvent" as used herein refers to any polar solvent that does not have proton-donating capability. Examples include, but are not limited to, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate (e.g., isopropyl acetate), acetone, dimethylsulfoxide, N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide, and propylene carbonate.

[0060]

[0096] The term "polar protic solvent" as used herein refers to any polar solvent that has proton donating capability. Examples include, but are not limited to, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid, nitromethane, and acetic acid. Organic polar protic solvents exclude any significant amount of water.

[0061]

[0097] The term "non-polar solvent" as described herein refers to a solvent that contains bonds between atoms with similar electronegativity, such as carbon and hydrogen, such that the charge of the molecule is evenly distributed. Non-polar solvents are characterized by having a low dielectric constant. Examples include, but are not limited to, pentane, hexane, heptane, cyclopentane, methyl tert-butyl ether (MTBE), diethyl ether, toluene, benzene, 1,4-dioxane, carbon tetrachloride, chloroform, and dichloromethane (DCM). In some embodiments, non-polar solvents have a dielectric constant of less than 2, examples of which include, but are not limited to, pentane, hexane, butane, heptane. Compared to other non-polar solvents, DCM exhibits some polarity at the bond level (i.e., between carbon and chlorine), but only a small polarity at the molecular level due to symmetrical cancellation of polarity.

[0062]

[0098] The term "anti-solvent" as used herein refers to a solvent in which the referenced compound is poorly soluble and which induces precipitation or crystallization of said compound from solution.

[0063]

[0099] The term "acid catalyst" as used herein refers to an acid catalyst, such as, but not limited to, a Bronsted acid, a Lewis acid, or a Bronsted-Lowry catalyst. Non-limiting examples of acid catalysts include acetic acid, glacial acetic acid, trifluoroacetic acid, benzoic acid, pivalic acid, diphenylphosphoric acid, triflic acid, formic acid, tartaric acid, fumaric acid, malonic acid, salicylic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, naphthalenesulfonic acid, clay-based Montmorillonite K-10 and resin-based Amberlyst, and combinations thereof.

[0064]

[0100] The term "amine protecting group" as used herein refers to any known protecting group that blocks or protects amine functionality. Amine protecting groups within the scope of the present disclosure include, but are not limited to, 1-chloroethyl carbamate (ACD); 4-methoxybenzenesulfonamide; acetamide (Ac); benzylamine (Bn); benzyloxy carbamate (CBz); formamide; methyl carbamate; trifluoroacetamide; tert-butoxy carbamate (Boc); p-methoxybenzyl carbonyl (MeOZ); 9-fluorenylmethoxycarbonyl (FMOC); benzoyl (Bz); p-methoxybenzyl (PMB); 3,4-dimethoxybenzyl (DMPM); p-methoxyphenyl (PMP); tosyl (Ts); and trichloroethyl chlorocarbonate (Troc). For a description of amine protecting groups and their uses, see PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis 4, Vol. 13, No. 1, 2002, pp. 111-115, 2002, 1997, 1999, 1999, 1998, 1999, 1999, 1999, 1999, 1999, 1999, 1999, 1990, 1990, 1991, 1992, 1993, 1994, 1995, 1996, 1997, 1999, 1999, 1998, 1999, 1990, 1991, 1992, 1993, 1994, 1995, 1996, 1997, 1999, 1999, 1999, 1999, 1990, 1992, 1993, 1 th See, for example, U.S. Pat. No. 6,313,311, published 1999 by the American Society of Clinical Chemistry, vol. 14, no. 1, pp. 111-115, 2003.

[0065]

[0101] The term "aldehyde protecting group" as described herein refers to any known substituent attached to an aldehyde group that blocks or protects the carbonyl group of the aldehyde functionality. Suitable protecting groups for the aldehyde functionality include, but are not limited to, (a) cyclic acetals and ketals, (b) cyclic mono- or di-thioacetals or ketals or other derivatives such as imines, hydrazones, cyanohydrins, oximes or semicarbazones such as dialkyl or diaryl acetals or 1,3 dithianes, (c) cyclic imines such as substituted methylene derivatives or N,N'-dimethylimidazolidine. Some non-limiting examples of aldehyde protecting groups include 1,3-dithianes, 1,3-dithiolanes, diethyl acetals, dimethyl acetals, ethylene glycol acetals, neopentyl glycol acetals, trimethylsilyl cyanohydrins, and trialkyl orthoformates such as triethyl orthoformates. For a discussion of aldehyde protecting groups and their uses, see Wuts and Greene.

[0066]

[0102] As used herein, a "leaving group" refers to an atom or group of atoms that is displaced as a stable species in a chemical reaction. Suitable leaving groups are well known in the art, see, for example, March's Advanced Organic Chemistry, 5.sup.th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001 and TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991, the entire contents of each of which are incorporated herein by reference. Such leaving groups include, but are not limited to, halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyl, optionally substituted alkenylsulfonyl, optionally substituted arylsulfonyl, and diazonium moieties. Some examples of leaving groups include chloro, iodo, bromo, fluoro, methanesulfonyl (mesyl), tosyl, triflate, nitro-phenylsulfonyl (nosyl), and bromo-phenylsulfonyl (brosyl).

[0067]

[0103] "Transition metal catalysts" within the scope of the present disclosure include, but are not limited to, palladium, platinum, gold, ruthenium, rhodium, and iridium catalysts. Non-limiting examples of suitable catalysts include: (2-biphenyl)di-tert-butylphosphine gold(I) chloride ("JohnPhos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl gold(I) chloride ("XPhos AuCl"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl gold(I) bis(trifluoromethanesulfonyl)imide ("XPhos AuNTf2"), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) ("XPhos Palladacycle"), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II)-methyl-t-butyl ether adduct ("SPhos Palladacycle"), t-BuXPhos palladium(II) phenethylamine chloride ("tBuXPhos Pd G1"), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) ("Xphos Pd G2"), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) ("SPhos Pd G2"), chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) ("RuPhos Pd G2"), chloro[(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) ("CPhos-Pd-G2"), [(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate ("CPhos-Pd-G3"), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate ("tBuXPhos-Pd-G3"), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate ("RuPhos-Pd-G3"), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (" XPhos-Pd-G3"), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate ("BrettPhos-Pd-G3"), [(2-{bis[3,5-bis(trifluoromethyl)phenyl]phosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate ("JackiePhos-Pd-G3"), tert-butyl BrettPhos-Pd-G3, [tert-butyl BrettPhos-Pd(allyl)]OTf), and combinations thereof.

[0068]

[0104] "Inorganic acids" as used herein 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.

[0069]

[0105] "Organic acid" as used herein 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; pyranosidyl acids, such as glucuronic acid or galacturonic acid; alpha-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.

[0070]

[0106] "Inorganic base" as used herein refers 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.

[0071]

[0107] The term "organic base" as used herein refers to an organic compound that contains one or more nitrogen atoms and 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-methyl-morpholine (NMM), diisopropylethylamine (DIPEA), triethylamine (TEA), t-butoxide (e.g., sodium, potassium, calcium, or magnesium tert-butoxide).

[0072]

[0108] The compounds of the present disclosure may exist in the form of salts, including pharmaceutically acceptable salts and non-pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" as used herein refers to salts that retain the biological effectiveness and properties of free bases or free acids, 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 useful as intermediates for the isolation or purification of said compounds.

[0073]

[0109] Exemplary acid salts of the 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, citrate, tartrate, oleate, tannate, pantothenate, acid tartrate, ascorbate, succinate, maleate, gentianate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, sulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts. Pharmaceutically acceptable salts may include the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. A counterion can be any organic or inorganic moiety that stabilizes the charge of the parent compound. Furthermore, a pharmaceutically acceptable salt can have multiple charged atoms in its structure. When multiple charged atoms are part of a pharmaceutically acceptable salt, it can have multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions.

[0074]

[0110] Exemplary base 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; trimethamine; dicyclohexylamine; lysine; arginine; histidine; caffeine; procaine; hydrabamine; choline; betaine; ethylenediamine; glucosamine; methylglucamine; theobromine; purines; piperazine; piperidine; N-ethylpiperidine; and polyamine resins.

[0075]

[0111] The compounds of the present disclosure can also be solvated, i.e. hydrated. Solvation can occur during the manufacturing process or as a result of the hygroscopic nature of the initial anhydrous compound. As used herein, "solvate" refers to an association or complex of one or more solvent molecules with the compounds of the present invention. Non-limiting examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate (EtOAc), acetic acid (AcOH) and ethanolamine.

[0076]

[0112] Compounds that have the same molecular formula but differ in the nature or sequence of the bonds of their atoms or the structure in space of their atoms are called "isomers". Isomers that differ in the structure in space of their atoms are called "stereoisomers". Diastereomers are stereoisomers that have opposite configurations at one or more chiral centers and are not enantiomers. Stereoisomers that retain one or more asymmetric centers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when a carbon atom is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of one or more of their asymmetric centers and are 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, designated as dextrorotatory or levorotatory (i.e., (+) 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 some embodiments, the compound is at least about 90% enriched by weight in a single diastereomer or enantiomer. In other embodiments, the compound is at least about 95%, 98%, or 99% enriched by weight in a single diastereomer or enantiomer.

[0077]

[0113] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, positional isomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.

[0078]

[0114] The compounds of the present invention may contain asymmetric or chiral centers and therefore may exist in various stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present invention form part of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof (e.g., racemic mixtures). In some cases, the stereochemistry has not been determined or has been tentatively assigned. Many organic compounds exist in optically active forms, i.e., they can rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to represent the absolute configuration of the molecule about its chiral center. The prefixes d and l, or (+) and (-), are used to represent the sign of rotation of the compound of plane polarized light, with (-) or l meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer is also referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur if there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. Enantiomers can be separated from a racemic mixture by chiral separation techniques such as supercritical fluid chromatography (SFC). The assignment of configurations at the chiral centers of separated enantiomers is tentative, and the stereochemistry has not been conclusively determined, such as by X-ray crystallography data.

[0079]

[0115] As used herein, "essentially" refers to at least 90%, at least 95%, at least 98% or at least 99%.

[0080]

[0116] In the present description, if there is a discrepancy between the structure shown and the name given to the structure, the structure shown shall prevail.In addition, if the stereochemistry of a structure or a portion of a structure is not shown, for example, with bold or dotted lines, the structure or portion of the structure shall be interpreted as including all of its stereoisomers.However, in some cases where there is more than one chiral center, the structure and name are represented as a single enantiomer to help describe the relative stereochemistry.

[0081]

[0117] Unless otherwise indicated, the term "compound of formula" refers to any compound selected from the group of compounds defined by formula (including, unless otherwise indicated, pharma- ceutically acceptable salts of any such compound).

[0082]

[0118] One embodiment provided herein is a compound of formula (IV): TIFF0007660040000003.tif45170 or a salt thereof, the method comprising: (a) reacting a reaction mixture comprising a compound of formula (I), an organic solvent and thionyl chloride to form a compound of formula (IIa) according to step 1 below, and reacting a reaction mixture comprising a compound of formula (IIa), a catalyst, an oxidizing agent and a solvent to form a compound of formula (II) according to step 2 below. TIFF0007660040000004.tif43170[In the formula, R 1a and R 1b Each of the groups is independently hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, -CN, C 3-6 Cycloalkyl, or C 3-6 is a spirocycloalkyl; n is an integer of 2 or 3; and (b) reacting a reaction mixture containing a compound of formula (II) and a compound of formula (III) in an organic solvent to form a compound of formula (IV) or a salt thereof, according to Step 3 below. TIFF0007660040000005.tif65170[In the formula, B is substituted or unsubstituted indolyl, benzofuranyl, benzothiophenyl, indazolyl, aza-indolyl, benzimidazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl; R 2a and R 2b each independently represents hydrogen, halogen, -OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, -CN, C 3-6 Cycloalkyl, or C 3-6 is a spirocycloalkyl; R 3a and R 3b are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, -CN, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, Phenyl, C 3-6 Heteroaryl, or C 3-6 is a spirocycloalkyl; Asterisk is R 3a and R 3b When different, it represents a chiral center. Includes.

[0083]

[0119] In one embodiment, B is substituted indolyl, benzofuranyl, benzothiophenyl, indazolyl, aza-indolyl, benzimidazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl.

[0084]

[0120] In another embodiment, B is unsubstituted indolyl, benzofuranyl, benzothiophenyl, indazolyl, aza-indolyl, benzimidazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl.

[0085]

[0121] In one embodiment, B is substituted or unsubstituted indolyl, benzofuranyl, or benzothiophenyl. In another embodiment, B is one or more halogens or C as described herein. 1-3 In another embodiment, B is an alkyl-substituted indolyl, benzofuranyl, or benzothiophenyl. In another embodiment, B is a substituted or unsubstituted pyrrolopyridazinyl, pyrrolopyrimidinyl, or pyrrolopyrazinyl. In another embodiment, B is one or more halogens or C as described herein. 1-3 In yet another embodiment, B is a substituted or unsubstituted indolyl. In a preferred embodiment, B is an unsubstituted indolyl. In one embodiment, B is a substituted indolyl (e.g., one or more halogens or C as described herein). 1-3 In another preferred embodiment, B is substituted indolyl, which includes substitution with at least one moiety selected from the group consisting of methyl, Cl, and F. In yet another embodiment, B is benzofuranyl or substituted benzofuranyl, which includes substitution with at least one moiety selected from the group consisting of methyl, Cl, and Fl.

[0086]

[0122] B is independently fluorine, chlorine, C 1-3 Alkyl, C 1-3 Haloalkyl, -CN, -OH, C 1-3 Alkoxy and C 1-3and hydroxyalkyl. In one embodiment, B is indolyl substituted with halogen (eg, F or Cl).

[0087]

[0123] In one embodiment, R 1a and R 1b are each independently hydrogen, halogen, or C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, -CN, or C 3-6 In another embodiment, R 1a and R 1b are each independently hydrogen, -F, -Cl, -OH, -CN, -CH, -CF, -CHF, -CHF, or spirocyclopropyl. 1a and R 1b is independently F or hydrogen. In one preferred embodiment, R 1a and R 1b are each independently hydrogen, -F, or -CH3. In another preferred embodiment, R 1a and R 1b is independently at each occurrence hydrogen, -F, or cyclopropyl. In one embodiment, n is 3.

[0088]

[0124] In one embodiment: The file is TIFF0007660040000006.tif26170.

[0089]

[0125] R 2a and R 2b are each independently hydrogen, halogen, -OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, -CN, or C 3-6 In some embodiments, R 2a and R 2b Each is hydrogen. In one embodiment, R 1a and R 1bare each independently -F or CH3, R 2a and R 2b are each independently hydrogen. In one embodiment, B is indolyl, benzofuranyl, or benzothiophenyl, and R 1a and R 1b are each independently -FCH3, R 2a and R 2b are each independently hydrogen.

[0090]

[0126] R 3a and R 3b are each independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, -CN, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, phenyl, or C 3-6 In one embodiment, R 3a and R 3b are each independently hydrogen or -CH3.

[0091]

[0127] The asterisk in formula (IV) represents R 3a and R 3b When different, they represent chiral centers. Thus, in some embodiments, R 3a and R 3b is different and is hydrogen or -CH3.

[0092]

[0128] In one embodiment, the compound of formula (I) is: TIFF0007660040000007.tif91170, including its stereoisomers.

[0093]

[0129] In certain embodiments, the compound of formula (I) is: The file is TIFF0007660040000008.tif21170.

[0094]

[0130] In another embodiment, the compound of formula (I) is: TIFF0007660040000009.tif17170, including its stereoisomers.

[0095]

[0131] In one embodiment, the compound of formula (II) is: TIFF0007660040000010.tif84170, including its stereoisomers.

[0096]

[0132] In certain embodiments, formula (II) is: The file is TIFF0007660040000011.tif33170.

[0097]

[0133] In some particular embodiments, the compound of formula (II) is: TIFF0007660040000012.tif28170, including its stereoisomers.

[0098]

[0134] In one implementation, the compound of formula (III) is: TIFF0007660040000013.tif24170, including its stereoisomers, wherein X is -NH-, -N-C1-C3 unsubstituted alkyl, -O- or -S-.

[0099]

[0135] In certain embodiments, the compound of formula (III) is: The file is TIFF0007660040000014.tif27170.

[0100]

[0136] In another particular embodiment, the compound of formula (III) is: The file is TIFF0007660040000015.tif38170.

[0101]

[0137] In one implementation, the compound of formula (IV) is: TIFF0007660040000016.tif127170 or a salt thereof, including stereoisomers thereof, wherein an asterisk indicates a chiral center.

[0102]

[0138] In certain embodiments, formula (IV) is: The file is TIFF0007660040000017.tif22170.

[0103]

[0139] In another particular embodiment, formula (IV) is: The file is TIFF0007660040000018.tif27170.

[0104]

[0140] In certain embodiments, the compound of formula (I) is: TIFF0007660040000019.tif22170, and the compound of formula (II) is TIFF0007660040000020.tif32170, and the compound of formula (III) is TIFF0007660040000021.tif38170, and the compound of formula (IV) The file is TIFF0007660040000022.tif34170.

[0105]

[0141] In step 1, a reaction mixture comprising a compound of formula (I), an organic solvent, and thionyl chloride is reacted to form a compound of formula (IIa). In one embodiment, the compound of formula (I) is compound 1. In one embodiment, the organic solvent is a non-polar solvent or a polar solvent. In one embodiment, the solvent is non-polar. Non-limiting examples of suitable non-polar solvents include pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane ("DCM"), and combinations thereof. In one embodiment, the solvent is DCM. In one embodiment, the concentration of formula (I) in the solvent can be suitably about 25 g / L, about 50 g / L, about 100 g / L, about 150 g / L, about 200 g / L, about 250 g / L, and concentrations approaching saturation at the reaction temperature, and ranges built from these concentrations, for example, about 100 g / L to about 250 g / L. The equivalent ratio of thionyl chloride to the compound of formula (I) is suitably about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.5:1 or about 2:1, and ranges built from these ratios, for example, about 1.1:1 to about 1.5:1. In one embodiment, the reaction temperature is below the reflux temperature of the reaction mixture. In one embodiment, the reaction is carried out at reflux. For example, when the solvent is DCM, the reaction temperature is suitably about 25°C to about 40°C. The reaction time is not strictly limited, and the reaction is typically continued until the conversion of formula (I) to formula (IIa) is essentially complete, for example, as determined by chromatography (e.g., TLC, GC or HPLC).

[0106]

[0142] Upon completion of the reaction, the reaction mixture can be quenched. In some such embodiments, the reaction mixture can be quenched with cold water. In such embodiments, the phases can be separated into an organic phase containing the compound of formula (IIa) and an aqueous phase. The aqueous phase can be extracted one or more times with an organic solvent to recover additional compound of formula (IIa).

[0107]

[0143] In step 2, a reaction mixture comprising a compound of formula (IIa), a catalyst, an oxidizing agent, and a solvent is reacted to form a compound of formula (II). In one embodiment, the organic phase or a combination of organic phases from step 1, comprising formula (IIa), is used as a source of formula (IIa) for step 2. In one embodiment, the catalyst is a redox active metal catalyst. Non-limiting examples of suitable catalysts include NiCl2, RuCl3, CoCl2, FeCl3, FeCl2, and MnCl2. Non-limiting examples of suitable oxidizing agents include NaIO4, NaOCl, and oxone. Suitable organic solvents include non-polar and polar solvents described in other sections of this document. In general, the oxidizing agent is in an equivalent excess relative to the compound of formula (IIa), for example, the ratio of oxidizing agent to compound of formula (IIa) can be 1.1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, or 5:1. The reaction mixture of step 2 may further comprise water. In such an embodiment, the volume ratio of water to organic solvent used in the reaction mixture of step 1 may be about 9:1, about 5:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:5 or about 1:9, and ranges built therefrom, such as about 2:1 to about 1:2. The reaction temperature of step 2 may suitably be about 25°C, about 15°C, about 5°C, about 0°C, about -5°C or about -10°C, and ranges built therefrom, such as about -10°C to about 10°C. In one embodiment, the organic phase(s) comprising formula (IIa), the catalyst, and water are mixed and cooled to the reaction temperature. The oxidizing agent is then added over a period of time while the temperature is maintained around the reaction temperature.

[0108]

[0144] Upon completion of the reaction, the reaction mixture of step 2 can be separated into an organic phase containing the compound of formula (II) in solution and an aqueous phase. In some optional embodiments, the reaction mixture can be filtered, such as through a filter aid (e.g., Celite), prior to phase separation. The aqueous phase can be extracted one or more times with an organic solvent to recover additional compound of formula (II).

[0109]

[0145] In another embodiment, the organic phase(s) of step 2 can be worked up by methods known to those skilled in the art. For example, the organic phase can be washed with a base, such as with an aqueous solution of Na2SO3. The organic phase can be optionally further dried, such as with a brine solution and / or by the addition of a solid drying agent, such as CaCl2, MgSO4 or Na2SO4. The solid drying agent can be suitably removed by filtration. In one embodiment, the solution of compound Formula (II) can be used for the next reaction. In one embodiment, compound Formula (II) can be isolated from the solution by methods known to those skilled in the art, such as by distillation, concentration, precipitation (e.g., by addition of an anti-solvent or pH adjustment) and / or crystallization. In some such embodiments, the organic phase(s) can be concentrated by distillation or stripping to reduce the volume, for example, by at least 25%, 50%, or 100%, or more. Compound Formula (II) can then be precipitated / crystallized from the solution by addition of an anti-solvent, optionally followed by further concentration. In one embodiment, the anti-solvent is a C 2 tetrahydrofuran such as pentane, hexane or heptane. 4-8 It is a non-ionic solvent. The solid of compound formula (II) can be collected by methods known to those skilled in the art, such as filtration or concentration. The solid can be dried, for example, under partial vacuum, to obtain solid compound formula (II). The yield of compound formula (II) from compound formula (I) in steps 1 and 2 is at least 60%, at least 70%, or at least 75%. In one embodiment, the compound of formula (II) is compound 2.

[0110]

[0146] In step 3, a reaction mixture comprising a compound of formula (II), a compound of formula (III), and an organic solvent is reacted to form a compound of formula (IV). In one embodiment, the organic solvent is a polar aprotic solvent. Non-limiting examples of suitable solvents include tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile ("ACN"), dimethylsulfoxide, nitromethane, and propylene carbonate. In one embodiment, the solvent is ACN. The molar ratio of compound of formula (II) to compound of formula (III) is suitably about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, or more, and ranges built from these ratios, for example, between 1:1 and 1.3:1. The concentration of compound formula (II) in the solvent is suitably about 10 g / L, about 25 g / L, about 50 g / L, about 75 g / L, about 100 g / L, about 125 g / L, about 150 g / L, and up to the concentration approaching saturation at the reaction temperature, and ranges built from these concentrations, for example, about 50 g / L to about 150 g / L. The acid catalyst can be an acid catalyst described in another section of this document. In some embodiments, the acid catalyst is sulfuric acid, p-toluenesulfonic acid (p-TsOH), or methanesulfonic acid, or a combination thereof. In one embodiment, the acid catalyst is p-toluenesulfonic acid. The equivalent ratio of the acid catalyst to the compound of formula (II) is suitably about 0.75:1, about 0.9:1, about 1:1, about 1.05:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, or more, and ranges built therefrom, such as about 1:1 to about 1.2:1. In one embodiment, the compound of formula (III) is compound 3.

[0111]

[0147] In some step 3 embodiments, compound Formula (II), compound Formula (III), an organic solvent, and a base are combined to form a mixture. The base can be suitably a mild base, non-limiting examples of which include potassium tert-butoxide, trimethylamine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, ammonium hydroxide, and combinations thereof. The mixture can be heated with stirring to a reaction temperature, typically below reflux to reflux, at a temperature of 2°C to about 30°C, and held for a sufficient time to essentially complete the formation of the reaction product comprising compound Formula (III). For ACN solvent, the reaction temperature is suitably about 65°C, about 70°C, about 75°C, or about 80°C. The reaction product mixture can then be cooled, for example, to less than 50°C, less than 40°C, or less than 30°C, and optionally filtered to remove solid impurities. The solid can be optionally washed with a solvent to recover additional reaction product. An acid (e.g., p-TsOH) and water are then added. The volume ratio of organic solvent to water can be 25:1, 15:1, 10:1, 5:1, 2:1 or 1:1, and ranges built therefrom, for example, about 15:1 to about 5:1. The mixture can be heated with stirring to a reaction temperature, typically below reflux to reflux, at a temperature of 2°C to about 20°C, and held for a sufficient time to essentially complete the formation of compound formula (IV), as determined by chromatography (e.g., TLC, GC or HPLC). Upon completion of the reaction, the reaction mixture can be quenched, for example, with cold water (e.g., below 10°C or below 5°C). The pH of the quenched reaction mixture can then be adjusted to above 7, for example, about pH 8, about pH 9, about pH 10 or about pH 11, with a base. In one embodiment, the base is an aqueous base, for example, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or ammonium hydroxide.

[0112]

[0148] Upon completion of the reaction, the reaction mixture of step 3 can be separated into an organic phase containing the compound of formula (IV) in solution and an aqueous phase. In some optional embodiments, the reaction mixture can be filtered, such as through a filter aid (e.g., Celite), prior to phase separation. The aqueous phase can be extracted one or more times with an organic solvent to recover additional compound of formula (IV). In one embodiment, the solvent is aprotic. In certain embodiments, the extracting solvent is suitably isopropyl acetate ("i-PrOAc").

[0113]

[0149] In some embodiments, the organic phase(s) of step 3 can be worked up, for example, by washing the organic phase with water. The organic phase can be optionally dried, such as with a brine solution and / or by the addition of a solid drying agent, such as CaCl2, MgSO4, or Na2SO4. The solid drying agent can be suitably removed by filtration, and the collected drying agent can be optionally washed with a solvent from which compound formula (IV) can be recovered. In such embodiments, the organic phase(s) can be concentrated by distillation or stripping under partial vacuum to form a residue of compound formula (IV). The residue of compound formula (IV) can then be dissolved in an organic solvent at a temperature below the reflux temperature. An anti-solvent, for example a non-polar organic solvent as described in another section herein, can then be added to the solution of compound formula (IV) while cooling, for example to below about 10° C., to precipitate / crystallize compound formula (IV) from the solution. The solid of compound formula (IV) can be collected by methods known to those skilled in the art, such as filtration or concentration, and optionally washed with an anti-solvent. The solid can be dried, for example, under partial vacuum, to obtain a solid compound of formula (IV). The yield of compound of formula (IV) from compound of formula (II) in step 3 is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, or at least 97%. The purity of compound of formula (IV) is at least 95%, at least 98%, or at least 99%.

[0114]

[0150] One aspect of the present disclosure is directed to a process for preparing a compound of formula (VIII) or a salt thereof: TIFF0007660040000023.tif61170This method: (a) reacting a reaction mixture comprising a compound of formula (IV), a compound of formula (V) or a compound of formula (X) and an organic solvent to form a compound of formula (VI) according to the following step 1: TIFF0007660040000024.tif65170[In the formula, B is substituted or unsubstituted indolyl, benzofuranyl, benzothiophenyl, aza-indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl; R 1a and R 1b each independently represents hydrogen, fluorine, chlorine, -OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, and -CN, C 3-6 Cycloalkyl, or C 3-6 is a spirocycloalkyl; n is an integer of 2 or 3, R 2a and R 2b each independently represents hydrogen, halogen, -OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, -CN, C 3-6 Cycloalkyl, or C 3-6 is a spirocycloalkyl; R 3a and R 3b are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, -CN, C 3-6 Cycloalkyl, C3-6 Heterocycloalkyl, Phenyl, C 3-6 Heteroaryl, or C 3-6 is a spirocycloalkyl; J is phenyl or pyridinyl; Each R 4 are independently hydrogen, halogen or C 1-3 is alkyl, s is an integer from 0 to 2, LG is a leaving group, LG and CHO are located in the para position relative to each other in J of the compound of formula (V), Pg is an aldehyde protecting group, LG and CH-PG are located in the para position relative to each other in J of the compound of formula (X), Each asterisk stands independently for R 3a and R 3b When R is different 3a and R 3b is a chiral center; and (b) reacting a reaction mixture comprising a compound of formula (VI), an organic solvent, and a compound of formula (VII) or a salt thereof to form a compound of formula (VIII) or a salt thereof, according to Step 2 below. TIFF0007660040000025.tif65170[In the formula, G is C 1-3 is alkyl, p is 0 or 1; E is a substituted or unsubstituted azetidinyl or pyrrolidinyl; Each R 5 are independently hydrogen, halogen, -OH, -CN, C 1-5 Alkoxy or C 1-5 is hydroxyalkyl, v is an integer from 1 to 5, R 6 is halogen or -CN, R 10 is hydrogen or C 1-3 is alkyl] Includes.

[0115]

[0151] B, R 1a , R 1b , n, R 2a , R 2b , R 3a , R 3b and asterisk (*) are as defined herein.

[0116]

[0152] In one preferred embodiment, J is phenyl. In another embodiment, J is pyridinyl.

[0117]

[0153] In one embodiment, each R 4 is independently hydrogen or halogen. In one preferred embodiment, each R 4 is fluorine. In one embodiment, s is 1 or 2. In one embodiment, s is 2. In one preferred embodiment, each R 4 is fluorine and s is 2.

[0118]

[0154] In one embodiment, G is methylene or ethylene.

[0119]

[0155] In one embodiment, p is 0.

[0120]

[0156] In one embodiment, each R 5 is independently hydrogen, halogen, -OH, or -CN. In a preferred embodiment, each R 5 is hydrogen. In one embodiment, v is 2. In another embodiment, v is 3. In another embodiment, v is 5. In one preferred embodiment, each R 5 is hydrogen and v is 3.

[0121]

[0157] In one preferred embodiment, R 6 is halogen. In one embodiment, R 6 is F. In another embodiment, R 6 is -CN.

[0122]

[0158] In one embodiment, R 10is hydrogen or methyl. In one preferred embodiment, R 10 is hydrogen.

[0123]

[0159] In one embodiment, E is azetidinyl.In another embodiment, E is pyrrolidinyl.

[0124]

[0160] In one embodiment, E has the structure: TIFF0007660040000026.tif23170.

[0125]

[0161] In one embodiment, E is azetidinyl of the following structure: TIFF0007660040000027.tif19170

[0126]

[0162] In one embodiment, E is of the structure: TIFF0007660040000028.tif22170[where, R 5 is H, v is 2 or 3, R 6 is a halogen].

[0127]

[0163] In one implementation, E is an azetidinyl of the following structure: TIFF0007660040000029.tif20170

[0128]

[0164] In one embodiment, formula (VIII) is an acid salt. Such acid salts can be pharmaceutically acceptable salts. In some such embodiments, formula (VIII) is a salt of a pharmaceutically acceptable acid. In some particular embodiments, formula (VIII) is a salt of a pharmaceutically acceptable organic acid. In a preferred embodiment, formula (VIII) is a pharmaceutically acceptable salt of tartaric acid. In one embodiment, the compound of formula (VIII) is compound A described herein. In another embodiment, the compound of formula (VIII) is compound A (tartrate salt) of compound A described herein. In another embodiment, formula (VIII) is a pharmaceutically acceptable salt of fumaric acid. In yet another embodiment, the compound of formula (VIII) is compound B (fumarate salt) of compound A described herein.

[0129]

[0165] In one embodiment, Formula (VIII) has any one of the following structures, or a pharma- ceutically acceptable salt thereof: TIFF0007660040000030.tif214170TIFF0007660040000031.tif213170TIFF0007660040000032.tif212170TIFF0007660040000033.tif176170 or a pharma- ceutically acceptable salt thereof (including stereoisomers thereof).

[0130]

[0166] In one embodiment, Formula (VIII) has the following structure: or a pharma- ceutically acceptable salt thereof: TIFF0007660040000034.tif57170

[0131]

[0167] In one embodiment, Formula (VIII) is of the following structure: TIFF0007660040000035.tif49170

[0132]

[0168] In one embodiment, Formula (VIII) is of the following structure: TIFF0007660040000036.tif49170

[0133]

[0169] Step 1 of the method for synthesizing a compound of formula (VIII) comprises reacting a reaction mixture comprising a compound of formula (IV), a compound of formula (V) or a compound of formula (X) and an organic solvent to form a compound of formula (VI) as defined herein. In one embodiment, LG is bromine. In a preferred embodiment, when reacting with compounds of formula (IV) and formula (V), LG and CHO are located at J in para position relative to each other. In a preferred embodiment, when reacting with compounds of formula (IV) and formula (X), LG and CH-PG are located at J in para position relative to each other.

[0134]

[0170] The compound of formula (IV) is as described herein.

[0135]

[0171] In one embodiment, the compound of formula (V) is any one of the following compounds, or a salt thereof: TIFF0007660040000037.tif98170 or a salt thereof.

[0136]

[0172] In some embodiments, formula (X) is any one of the structures of formula (V) above, or a salt thereof, except that the aldehyde (-CHO) is a protected moiety of the structure -CH-PG, where PG is an aldehyde protecting group as defined elsewhere herein.

[0137]

[0173] In some embodiments, formula (VI) has any one of the following structures: TIFF0007660040000038.tif203170TIFF0007660040000039.tif244170TIFF0007660040000040.tif236170 or a salt thereof (including stereoisomers thereof).

[0138]

[0174] In step 2 of the synthesis of a compound of formula (VIII) defined herein, the compound of formula (VII) can be any one of the following structures: TIFF0007660040000041.tif43170 or a salt thereof.

[0139]

[0175] In one embodiment, the salt is an ethane-disulfonate (eg, a salt of ethane-1,2-disulfonate).

[0140]

[0176] In one embodiment, the compound of formula (VII) has the structure TIFF0007660040000042.tif20170.

[0141]

[0177] Compound (7) can be prepared according to the examples provided herein, for example, Example 4 or Example 4a.

[0142]

[0178] In one embodiment, compound 7 is prepared according to the following scheme: TIFF0007660040000043.tif56170.

[0143]

[0179] In step 1, a reaction mixture comprising a compound of formula (IV), a compound of formula (V), or a compound of formula (X), and an organic solvent is reacted to form a compound of formula (VI). In an embodiment, the organic solvent is a polar protic solvent, a non-polar solvent, a polar aprotic solvent, or a combination thereof, as described in another section herein. In some non-limiting embodiments, the solvent is toluene. In an embodiment, the solvent is acetonitrile, methyl ethyl ketone, or methyl tetrahydrofuran. In an embodiment, the reaction mixture of step 1 further comprises an acid catalyst, as described in another section herein. In some such non-limiting embodiments, the acid catalyst is acetic acid. The molar ratio of compound (IV) to compound (V) or compound (X) is about 0.95:1 to about 1.05:1 stoichiometric amount, or in some embodiments, compound (V) or compound (X) is in slight molar excess. The acid catalyst is usually present in a stoichiometric excess, for example, in an equivalent ratio to the compound of formula (IV) of about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 2:1, or more, and ranges building therefrom, for example, from about 1.2:1 to about 1.8:1.

[0144]

[0180] In some step 1 embodiments, the reaction mixture can be heated with stirring to a reaction temperature of 2°C to about 30°C below reflux to reflux and held for a sufficient time to essentially complete the reaction to compound formula (VI), such as by chromatography (e.g., TLC, GC or HPLC). For toluene solvent, the reaction temperature is suitably about 65°C, about 70°C, about 75°C, or about 80°C. The reaction product mixture can then be cooled and optionally diluted with additional solvent. The reaction product mixture can then be quenched with a base, such as an aqueous solution of a base as described in another section herein. The organic phase of the step 1 reaction product mixture containing the compound of formula (VI) can then be isolated, and in some embodiments is worked up by methods known in the art, such as washing with water and / or a brine solution as described in another section herein, followed by isolating the product as a solid. In one embodiment, the reaction product mixture is treated with activated carbon, followed by filtration and washing the activated carbon filter cake with an optional solvent. As described in another section herein: (i) the organic phase(s) containing compound of formula (VI) can be concentrated by distillation or stripping to reduce the volume, for example, by at least 25%, 50%, 100% or more; and then (ii) compound of formula (IV) can be precipitated / crystallized from the solution by addition of an anti-solvent, optionally followed by further concentration.

[0145]

[0181] In some other Step 1 embodiments, the reaction mixture of Step 1 is heated at reflux for a time to essentially complete the reaction as determined, for example, by chromatography (e.g., TLC, GC, or HPLC). The reaction mixture is then cooled and pH adjusted with a base, such as an aqueous solution of base, to a pH at which compound of Formula (VI) precipitates from solution.

[0146]

[0182] In any of the various embodiments of step 1, the solid of compound formula (VI) can be collected by methods known to those skilled in the art, such as filtration or concentration. The solid can be dried, for example, under partial vacuum, to obtain a solid compound of formula (VI). The yield of compound formula (V) to compound formula (VI) in steps 1 and 2 is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

[0147]

[0183] In step 2, a reaction mixture comprising a compound of formula (VI), a compound of formula (VII), and an organic solvent is reacted to form a compound of formula (VIII). In some embodiments, the organic solvent described in other sections herein is a polar aprotic solvent. In some non-limiting embodiments, the solvent is ACN. The reaction mixture of step 2 may further comprise a base, such as an organic base. Non-limiting examples of organic bases include DBU, NMM, DIPEA, and TEA. In some such embodiments, the base is DBU. The reaction mixture of step 2 may further comprise a catalyst, such as a transition metal catalyst. In some embodiments, the catalyst is a Pd catalyst. The molar ratio of compound (VII) to compound (VI) is about 0.95:1, about 1:1, about 1.05:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, or about 1.5:1, and ranges built therefrom, such as about 1:1 to about 1.4:1. The base is usually present in a stoichiometric excess, for example, about 1.1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, or about 8:1, and ranges built therefrom, for example, about 3:1 to about 7:1, in an equivalent ratio to the compound of formula (VI). The reaction mixture can be heated with stirring to a reaction temperature, typically below reflux to reflux, at a temperature of 2°C to about 30°C, and held for a sufficient time to essentially complete the reaction, as determined by chromatography (e.g., TLC, GC, or HPLC). For ACN solvent, the reaction temperature is suitably about 65°C, about 70°C, about 75°C, or about 80°C.

[0148]

[0184] After completion, the reaction product mixture can be appropriately cooled and optionally diluted with an organic solvent. In one embodiment, the reaction product mixture is diluted with a non-polar solvent described in another section of this document. One non-limiting example of a suitable non-polar solvent is MTBE. The reaction product mixture of step 2 can be worked up by methods known to those skilled in the art, including water washes and brine washes. In some such non-limiting embodiments, the work up includes washing with aqueous ammonium chloride, brine and water. In some embodiments, the reaction product mixture of step 2 can be contacted with a metal scavenger known in the art, for example, but not limited to, SiliaMetS thiol. The reaction product mixture can then be filtered to remove solids before isolating compound formula (VIII) therefrom.

[0149]

[0185] In some embodiments, for example in a solvent exchange step, the reaction product mixture of step 2 can be concentrated, such as by vacuum distillation or stripping, and diluted with an organic solvent, such as an alcohol (e.g., ethanol). An acid can then be added to the diluted solution of compound formula (VIII), followed by cooling to crystallize compound formula (VIII) as an acid salt. In some particular embodiments, the acid is tartaric acid and compound formula (VIII) is the tartrate salt. In some such embodiments, the acid is (2R-3R)-tartaric acid (L-(+)-tartaric acid). In another aspect, the acid is (2S-3S)-tartaric acid (D-(-)-tartaric acid). In some such embodiments, the solvent comprises an organic solvent. The crystalline material can be collected by centrifugation or filtration, optionally washed with a solvent, and optionally dried.

[0150]

[0186] In some other embodiments, compound of formula (VIII) can be isolated from the reaction product mixture of step 2 using methods described in other sections herein, including: (i) distillation, concentration, precipitation (e.g., by addition of anti-solvent or pH adjustment) and / or crystallization; (ii) collecting the solid by centrifugation or filtration; (iii) optionally washing the collected solid; and (iv) and drying.

[0151]

[0187] The yield of compound of formula (VIII) from step 2 as a free base or an acid salt is at least 80%, at least 85%, or at least 90%.

[0152]

[0188] Another aspect of the present disclosure is directed to a method for preparing a compound of formula (VIII) or a salt thereof, wherein the compound formula (VIII) is as described in another section of this document. The method for preparing formula (VIII) according to this embodiment comprises reaction step 1 as described below: TIFF0007660040000044.tif94170.

[0153]

[0189] B, R 1a , R 1b , n, R 2a , R 2b , R 3a , R 3b , R 4 ,s,J,R. 5 ,v,R 6 , R 10 Each of the symbols, G, p, E, PG, and asterisks are described in another section of this document. The CHO moiety and the nitrogen atom connecting J and G are located in para positions relative to each other on J. The CH-PG moiety and the nitrogen atom connecting J and G are located in para positions relative to each other on J.

[0154]

[0190] In one embodiment, the compound of formula (IX) is: TIFF0007660040000045.tif49170 or a salt thereof.

[0155]

[0191] In a preferred embodiment, the compound of formula (IX) is compound (8a): In some embodiments, formula (XI) is any one of the structures of formula (IX) above, or a salt thereof, except that the aldehyde (-CHO) is a protected moiety of the structure -CH-PG, where PG is an aldehyde protecting group as defined elsewhere herein.

[0156]

[0192] In step 1, a reaction mixture comprising a compound of formula (IX) or a compound of formula (XI), a compound of formula (IV) and an organic solvent is reacted to form a compound of formula (VIII) or a salt thereof. In an embodiment, the organic solvent is a polar solvent or a polar protic solvent. The reaction mixture of step 1 further comprises an acid catalyst as described in another section of this document. In certain embodiments, the acid catalyst is tartaric acid or fumaric acid. In one embodiment, the acid catalyst is tartaric acid. In another embodiment, the acid catalyst is fumaric acid. Non-limiting examples of suitable solvents include n-butanol, isopropyl alcohol, n-propanol, i-propanol, ethanol, methanol, and combinations thereof. In some particular embodiments, the solvent is ethanol. In one embodiment, the concentration of formula (IX) in the solvent can be suitably about 25 g / L, about 50 g / L, about 100 g / L%, about 150 g / L, about 200 g / L, about 250 g / L, and concentrations approaching saturation at the reaction temperature, and ranges established from these concentrations, such as about 100 g / L to about 250 g / L. The molar ratio of formula (IX) or formula (XI) to formula (IV) is suitably about 0.25:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 0.95:1, about 1:1, about 1.05:1, about 1.1:1, about 1.2:1, and ranges established from these ratios, such as about 0.95:1 to about 1.05:1. In one embodiment, formula (IX) or formula (XI) and formula (IV) are present in approximately stoichiometric amounts. In one embodiment, the reaction temperature is below the reflux temperature of the reaction mixture. In some other embodiments, the reaction is carried out at reflux. For example, when the solvent is ethanol, the reaction temperature is suitably about 50°C to about 75°C. The reaction time is not narrowly limited, and the reaction is typically continued until the conversion of formula (IX) or formula (XI) to formula (VIII) is essentially complete, for example, as determined by chromatography (e.g., TLC, GC or HPLC).

[0157]

[0193] In one embodiment, formula (VIII) is formed as an acid salt. Suitable acids include inorganic acids and inorganic acids described in other sections of this document. In one embodiment, the acid is an organic acid. In one preferred embodiment, the acid is tartaric acid. In another embodiment, the acid is fumaric acid. In one embodiment, the free base of formula (VIII) is dissolved in a suitable solvent, such as a polar protic solvent (e.g., an alcohol such as methanol or ethanol), at elevated temperature, followed by addition of the acid. Generally, the acid is in stoichiometric excess compared to the compound formula (VIII). In some such embodiments, the temperature of the solution and / or the concentration of formula (VIII) are adjusted to keep the concentration below saturation, thereby avoiding precipitation and / or crystallization of formula (VIII). Following addition of the acid, the solution can optionally be seeded with a crystalline salt of formula (VIII) of the acid. In any of the various embodiments, the solution is cooled with stirring to form a crystalline salt of formula (VIII). The salt can then be collected by methods known to those skilled in the art, such as by filtration or concentration. In one embodiment, the salt is collected by filtration. The collected salt of Formula (VIII) can optionally be washed, such as with the dissolution solvent, and then dried, such as under partial vacuum.

[0158]

[0194] In certain embodiments, the reaction mixture of step 1, defined as the fourth synthesis of the compound of formula (VIII) above, comprises tartaric acid as an acid catalyst, crystalline tartaric acid of formula (VIII), and an alcoholic solvent (e.g., ethanol); the reaction product mixture of step 1 is diluted with the alcoholic solvent; and the resulting slurry is cooled with stirring to form crystalline tartaric acid of formula (VIII). In another embodiment, the reaction mixture of step 1 comprises fumaric acid as an acid catalyst, crystalline fumaric acid of formula (VIII), and a solvent. The yield of compound formula (VIII) as the tartrate salt of step 1 is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In such an embodiment, the reaction scheme of step 1 is as follows: TIFF0007660040000046.tif94170.

[0159]

[0195] Yet another aspect of the present disclosure is directed to a method for preparing a compound of formula (IX) or a salt thereof. The method for preparing compound formula (IX) comprises two reaction steps as shown below: TIFF0007660040000047.tif93170.

[0160]

[0196] R 4 ,s,LG,PG,R 5 ,v,R 6 , R 10 , G, p, J, and E are as described in other sections of this document.

[0161]

[0197] Aldehyde protecting groups are defined herein and non-limiting examples include 1,3-dithiane, 1,3-dithiolane, diethyl acetal, dimethyl acetal, ethylene glycol acetal, neopentyl glycol acetal, trimethylsilyl cyanohydrin, and triethylorthoformate.

[0162]

[0198] In step 1, a reaction mixture comprising a compound of formula (X), a compound of formula (VII) or a salt thereof, an organic solvent, and a catalyst is reacted to form a compound of formula (XI). In an embodiment, the solvent is a non-polar solvent described in another section of this document. Non-limiting examples of suitable solvents include pentane, hexane, heptane, cyclopentane, MTBE, diethyl ether, toluene, 2-methyltetrahydrofuran (2-MeTHF), benzene, 1,4-dioxane, carbon tetrachloride, chloroform, dichloromethane, and combinations thereof. In some embodiments, the solvent is toluene. In an embodiment, the catalyst is a transition metal catalyst described herein. In an embodiment, non-limiting examples of transition metal catalysts include palladium, platinum, gold, ruthenium, rhodium, and iridium catalysts. Non-limiting examples of suitable catalysts include JohnPhos, XPhos AuCl, XPhos AuNTf2, XPhos Palladacycle, SPhos Palladacycle, tBuXPhos Pd G1, Xphos Pd G2, SPhos Pd G2, RuPhos Pd G2, CPhos-Pd-G2, CPhos-Pd-G3, tBuXPhos-Pd-G3, RuPhos-Pd-G3, XPhos-Pd-G3, BrettPhos-Pd-G3, JackiePhos-Pd-G3, tert-Butyl BrettPhos-Pd-G3, [tert-Butyl BrettPhos-Pd(allyl)]OTf), and combinations thereof. In some embodiments, the catalyst is BrettPhos-Pd-G3. In some embodiments, the reaction mixture of step 1 further comprises an organic base as described in another section of this document. In some such embodiments, the base is tert-butoxide, such as sodium or potassium tert-butoxide. The molar ratio of the compound of formula (VII) to the compound of formula (X) is suitably about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.5:1 or about 2:1, and ranges built from these ratios, such as about 1.1:1 to about 1.5:1.

[0163]

[0199] In some step 1 embodiments, the reaction mixture can be heated with stirring to a reaction temperature of 2°C to about 30°C below reflux to reflux and held for a sufficient time to essentially complete the reaction to compound formula (XI), such as by chromatography (e.g., TLC, GC, or HPLC). For toluene solvent, the reaction temperature is suitably about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C. The reaction time is not strictly limited, and the reaction is typically continued until the conversion of formula (VII) and (X) to formula (XI) is essentially complete, such as by chromatography (e.g., TLC, GC, or HPLC). After the reaction is complete, the reaction product mixture can be appropriately quenched. In some embodiments, the reaction of step 1 can be quenched with water. When the reaction is quenched with water, the organic phase containing the compound of formula (XI) in solution can be isolated and optionally washed at least once with water. In some embodiments, the reaction product mixture from step 1 can be contacted with a metal scavenger known in the art, such as, but not limited to, SiliaMetS thiol. The reaction product mixture can then be filtered to remove solids.

[0164]

[0200] In step 2, the compound of formula (XI) is deprotected to form the compound of formula (IX) by mixing a solution of compound (XI) in an organic solvent (e.g., toluene) with an acid and water. The acid is usually present in an equivalent excess, for example an equivalent ratio of acid to compound (XI) of 1.01:1, 1.05:1, 1.1:1, 1.15:1, 1.2:1, or more. In one embodiment, the deprotection temperature is not critical and can suitably be room temperature. After deprotection, the organic phase and the aqueous phase (containing the compound of formula (IX)) are separated. The organic phase can be optionally washed with water. The aqueous phase(s) can be treated with a base, for example an inorganic base (e.g., NaOH or KOH), mixed with seed crystals of compound of formula (IX). The base can be suitably added in an equivalent excess. A slurry of crystalline compound of formula (IX) is formed by optional cooling. The solid of compound of formula (IX) can be collected by methods known to those skilled in the art, such as filtration or concentration. The solid can be dried, for example, under partial vacuum, to obtain a solid compound of formula (IX). The yield of compound of formula (XI) to compound of formula (IX) in steps 1 and 2 is at least 65%, at least 70%, at least 75%, at least 80%, or at least 85%.

[0165]

[0201] One aspect of the present disclosure is directed to a method for preparing a compound of formula (III) or a salt thereof. The method for preparing compound formula (III) comprises two reaction steps as shown below: (1) reacting a reaction mixture comprising a compound of formula (XII), compound B, and an organic solvent to form a compound of formula (XIII) according to the following step 1: TIFF0007660040000048.tif47170 [wherein PG is an amine protecting group]; and (2) deprotecting the compound of formula (XIII) to form a compound of formula (III) according to step 2 below. TIFF0007660040000049.tif42170.

[0166] [In the formula, R 2a , R 2b , R 3a , R3b , B, and asterisks are as described elsewhere in this document.]

[0167]

[0202] Non-limiting examples of amine protecting groups include ACD, Ac, Bn, CBz, trifluoroacetamide, Boc, MeOZ, FMOC, Bz, PMB, DMPM, PMP, Ts, and Troc. In one embodiment, PG is Boc.

[0168]

[0203] In one embodiment, the compound of Formula (III) has the structure The compound represented by the formula TIFF0007660040000050.tif25170 or a salt thereof.

[0169]

[0204] In some other embodiments, the compound of formula (III) is The compound represented by the formula TIFF0007660040000051.tif39170 or a salt thereof.

[0170]

[0205] In step 1, a reaction mixture comprising a compound of formula (XII), B and an organic solvent is reacted to form a compound of formula (XIII). In one embodiment, the organic solvent is a non-polar solvent or a polar solvent. In one embodiment, the solvent is non-polar. Non-limiting examples of suitable solvents include pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, DCM, and combinations thereof. In one embodiment, the solvent is DCM. In some embodiments, the concentration of B in the solvent is suitably about 10 g / L, about 25 g / L, about 50 g / L, about 75 g / L, about 100 g / L%, about 125 g / L, about 150 g / L, about 175 g / L, or about 200 g / L, and up to a concentration approaching saturation at the reaction temperature, and ranges established from these concentrations, such as about 25 g / L to about 125 g / L. The equivalent ratio of B to compound of formula (XII) is about 0.75:1, about 0.9:1, about 1:1, about 1.25:1, about 1.5:1, about 1.75:1 or about 2:1, and ranges therein, such as about 1.25:1 to about 1.75:1. The reaction mixture of step 1 may further comprise a suitable alkylating agent. Non-limiting examples of alkylating reagents include alkyllithium (e.g., methyllithium) and organomagnesium halide compounds, such as methylmagnesium chloride (e.g., in THF). The equivalent ratio of B to the alkylating reagent is suitably about 0.75:1, about 0.8:1, about 0.85:1, about 0.9:1, about 0.95:1, about 1:1, about 1.05:1, about 1.1:1, about 1.15:2, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1 or more, and ranges built therein, such as about 1.1 to about 1.3:1. In one embodiment, the reaction mixture further comprises an alkylation catalyst. In some such embodiments, the catalyst is a transition metal catalyst. In some such embodiments, the transition metal is copper. In certain embodiments, the catalyst is suitably a transition metal halide, such as copper(I) halide (e.g., CuCl).In one embodiment, the reaction temperature is about 25° C., about 20° C., about 15° C., about 10° C., about 5° C., about 0° C., about −5° C., about −10° C., about −15° C., about −20° C., about −25° C., about −30° C., about −35° C., about −40° C., about −45° C., or about −50° C., and ranges built therefrom, such as about −20° C. to about 0° C. In one embodiment, the reaction time is not strictly limited, and the reaction is typically continued until the conversion of B and compound of formula (XII) to compound of formula (XIII) is essentially complete, as determined, for example, by chromatography (e.g., TLC, GC, or HPLC).

[0171]

[0206] After the reaction is complete, the reaction can be quenched, such as by the addition of an aqueous acid. In one embodiment, the acid is an organic acid described in another section of this document, a non-limiting example of which is citric acid. The organic phase containing the compound of formula (XIII) can then be worked up to dry the compound. In some such embodiments, the quenched reaction product mixture can be separated into an organic phase containing the compound of formula (XIII) and an aqueous phase. The aqueous phase can be washed one or more times with an organic solvent such as a solvent to form a reaction mixture (e.g., two washes, each with a volume of solvent compared to the volume of the reaction mixture). The organic phases can be mixed and washed one or more times with brine (e.g., two brine washes, each with a volume of brine compared to the volume of the reaction mixture). The washed organic phase is then mixed with activated charcoal and a solid drying agent (e.g., Na2SO4) while stirring. Any activated charcoal and solid drying agent can be removed by filtration or concentration. Any collected solids can then be optionally washed with additional solvent and the compound of formula (XIII) recovered therefrom.

[0172]

[0207] In one embodiment, a solution of compound formula (XIII) can be used as the starting material for step 2. In one embodiment, solid compound formula (XIII) can be prepared. In such an embodiment, the collected solution of compound formula (XIII) in an organic solvent can be concentrated under partial vacuum to form crude compound formula (XIII). Alternatively, solid compound formula (XIII) can be precipitated / crystallized from the solution by addition of an anti-solvent, such as a non-polar solvent (e.g., 2 volumes of heptane compared to the solvent volume in the reaction mixture). The solid can be collected by filtration or concentration, and the collected solid can be washed with an anti-solvent. The solid can be dried under partial vacuum at a temperature of less than 40° C. to provide the final compound formula (XIII). The yield of compound formula (XIII) based on compound (XII) is typically at least 50%, at least 55%, at least 60%, or at least 65%. The purity (area %) by HPLC is at least 90%, at least 95%, at least 98%, or at least 99%.

[0173]

[0208] In some Step 1 embodiments, compound B, metal catalyst and alkylating agent are mixed in a first volume of solvent at a reaction temperature as indicated above. The volume of solvent is suitably about 30% to about 80% of the total volume of solvent used in Step 1. A solution of compound of formula (XII) in the remaining solvent is then added over a period of time at the reaction temperature to form a reaction mixture. The reaction mixture is then held at a temperature for a period of time to essentially complete the formation of compound of formula (XIII), followed by quenching and workup of the solution of compound of formula (XIII) or dried compound of formula (XIII).

[0174]

[0209] In step 2, compound formula (XIII) is deprotected to form compound formula (III). In any of the various embodiments, the solution of compound formula (XIII) is suitably deprotected by the addition of an acid. In one embodiment, solid compound formula (XIII) is dissolved in a polar protic solvent (e.g., methanol, ethanol, or i-propanol) as described in another section of this document. The concentration of compound formula (XIII) in the solvent is about 25 g / L, about 50 g / L, about 75 g / L, about 100 g / L, about 125 g / L, about 150 g / L, about 175 g / L, or about 200 g / L, and ranges built therefrom, such as about 50 g / L to about 150 g / L. The temperature of the acid addition is not strictly critical.

[0175]

[0210] In some step 2 embodiments, the acid described in another section herein is an inorganic acid. A non-limiting example of a suitable inorganic acid is HCl. In one embodiment, the equivalent ratio of the acid to compound of formula (XIII) is about 1.5:1, about 2.5:1, about 5:1, about 7.5:1, about 10:1, about 12.5:1, or about 15:1, and ranges built therein, such as about 5:1 to about 15:1. After the acid addition, the solution is held at a constant temperature with stirring until the deprotection of compound of formula (XIII) to form compound of formula (III) is essentially complete. In one embodiment, a solvent exchange from a polar protic solvent to a non-polar solvent (described in another section herein) or to a polar aprotic solvent (described in another section herein) can be performed. In some such embodiments, the solution of compound of formula (III) is concentrated under partial vacuum and extracted with a non-polar or polar aprotic solvent. In some such embodiments, the extraction solvent is DCM. After extraction, the pH of the aqueous phase can be adjusted to strong basicity (i.e., pH greater than 11) using a suitable base, such as aqueous sodium hydroxide. After basification, the aqueous phase can then be further extracted at least once with an extraction solvent. The organic phase(s) can then be dried, for example, with brine and / or with a solid drying agent, followed by filtration to remove any solids. The collected solids can be optionally washed to recover additional compound formula (III). The solid compound can be isolated from the solution in the organic solvent by methods known in the art. For example, the solution can be concentrated under partial vacuum and dried. Alternatively, the solution can be concentrated, followed by addition of an anti-solvent to form solid compound (III), which can be collected by filtration or concentration, washing, and drying. The yield of compound formula (III) based on compound (XIII) is typically at least 85%, at least 90%, at least 95%, or at least 97%. The purity (area %) by HPLC is at least 90%, at least 95%, or at least 96%.

[0176]

[0211] In some other step 2 embodiments, the acid is an organic acid described in another section of this document. Non-limiting examples of suitable organic acids include sulfonic acid and camphorsulfonic acid (CSA) (e.g., L-(-)-CSA). For CSA, the equivalent ratio of CSA to compound of formula (XIII) is about 1.5:1, about 2:1, about 2.5:1, about 5:1, about 7.5:1, or about 10:1, and ranges built therefrom, such as about 2:1 to about 4:1. After acid addition, the solution is heated and held at an elevated temperature (e.g., about 35°C to about 60°C) with stirring to complete the deprotection and form the acid salt of compound of formula (XIII). The solution / suspension of the acid salt is then cooled, for example, to less than about 5°C, to form a solution of the acid salt of compound of formula (XIII). The salt can be collected by filtration or concentration, and optionally washed with a solvent. The salt is then dried under partial vacuum to obtain a solid salt of the compound of formula (XIII), such as its L-(-)-CSA salt. The yield of the compound of formula (III) salt based on compound (XIII) is typically at least 85%, at least 90%, at least 92%, or at least 95%. The purity by HPLC (area %) is at least 90%, at least 95%, at least 96%, or at least 97%. The salt of compound of formula (XIII) can be dissolved in water and the pH adjusted to a value above 13, for example about 14, with a strong base to form a suspension containing the solid compound of formula (III) free base. The solid material can be collected by filtration or concentration and optionally washed with cold water. The solid can then be dried under partial vacuum to obtain the dried compound of formula (III) free base. The yield of compound of formula (III) based on compound (XIII) is typically at least 80%, at least 85%, or at least 90%. The purity by HPLC (area %) is at least 90%, at least 95%, at least 96%, or at least 97%.

[0177]

[0212] In one embodiment, the compound of formula (VIII) prepared herein is further recrystallized. In one embodiment, the recrystallization comprises recrystallizing the compound of formula (VIII) in a two-step process. The process comprises heating a slurry comprising the compound of formula (VIII) in a mixture of methanol / ethanol, diluting with methanol, and cooling the mixture. In one embodiment, the mixture of methanol / ethanol is a 95:5, 90:10, 85:15, or 80:20 methanol / ethanol mixture. In another embodiment, the mixture of ethanol / methanol is a 90:10 methanol / ethanol mixture. The mixture can be heated to a temperature > about 50°C, for example, about 55°C, 60°C, or 65°C. Cooling can be down to about room temperature. In one embodiment, cooling is performed to about 20°C, 25°C, or 30°C. The solution can be filtered and dried.

[0178]

[0213] In another embodiment, the recrystallization comprises recrystallizing the compound of formula (VIII) from MTBE. A compound of formula (VIII), such as NaOH or KOH, is added to a slurry containing the compound of formula (VIII) in MTBE. The mixture is stirred, for example, at 15° C., 20° C., 25° C., or 30° C., and is optionally filtered and diluted with ethanol.

[0179]

[0214] In some embodiments of the process for preparing a compound of Formula (III) or a salt thereof, the process further comprises preparing a compound of Formula (XII) or a salt thereof.

[0180]

[0215] The process for preparing a compound of formula (XII) comprises reaction steps 3a and 3b shown below: (1) reacting a reaction mixture comprising a compound of formula (XIV), thionyl chloride, and an organic solvent to form a compound of formula (XV) according to step 3a below. TIFF0007660040000052.tif47170 and (2) reacting a reaction mixture comprising a compound of formula (XV), a catalyst, an oxidizing agent, and an organic solvent to form a compound of formula (XII) according to step 3b below. TIFF0007660040000053.tif47170

[0181]

[0216] R 2a , R 2b , R 3a , R 3b and the nitrogen protecting group PG is as described herein.

[0182]

[0217] In step 3a, a reaction mixture comprising a compound of formula (XIV), thionyl chloride, and an organic solvent is reacted to form a compound of formula (XV). In an embodiment, the organic solvent is a non-polar solvent or a polar solvent as described in another section of this document. In an embodiment, the solvent is non-polar as described in another section of this document. Non-limiting examples of suitable solvents include pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, DCM, and combinations thereof. In some particular embodiments, the solvent is DCM. In one embodiment, the concentration of the compound of formula (XIV) in the solvent can be suitably about 10 g / L, about 25 g / L, about 50 g / L, about 75 g / L, about 100 g / L%, about 125 g / L, about 150 g / L, about 175 g / L, or about 200 g / L, and concentrations approaching saturation at the maximum reaction temperature, and ranges built from these concentrations, such as about 25 g / L to about 125 g / L. The equivalent ratio of thionyl chloride to compound of formula (XIV) is about 1:1, about 1.25:1, about 1.5:1, about 1.75:1, about 2:1, about 2.25:1, or about 2.5:1, and ranges thereof, such as about 1.25:1 to about 1.75:1. In one embodiment, the reaction temperature is about 10°C, about 5°C, about 0°C, about -5°C, or about -10°C, and ranges built therein, such as about -5°C to about 5°C. In one embodiment, the reaction time is not strictly limited, and the reaction is typically continued until the conversion of compound formula (XIV) is essentially complete, for example, as determined by chromatography (e.g., TLC, GC, or HPLC). The reaction mixture of step 3a further comprises a base, a non-limiting example of which is imidazole. In such embodiments, the equivalent ratio of the thionylation reagent to thionyl chloride is about 1:1, about 2:1, about 3:1, or about 4:1. The reaction mixture of step 3a may further comprise a base, such as an organic base described in another section of this document. In some such embodiments, the base is TEA.In such embodiments, the ratio of equivalents of base to compound of formula (XIV) is about 1.25:1, about 1.5:1, about 1.75:1, about 2:1, about 2.25:1, about 2.5:1, about 3:1, about 3.5:1, or about 4:1, and ranges therein, such as about 1.5:1 to about 2.5:1.

[0183]

[0218] In some particular step 3a embodiments, a solution of a base (e.g., imidazole) in a solvent is formed to which thionyl chloride is added with stirring while maintaining the reaction temperature. Compound of formula (XIV) in a solvent is then added with stirring while maintaining the reaction temperature, followed by addition of a base with stirring while maintaining the reaction temperature. The reaction mixture is then maintained at the reaction temperature with stirring until conversion of compound of formula (XIV) is essentially complete to form a mixture of reaction products including compound of formula (XV).

[0184]

[0219] In any of the various embodiments of step 3a, the reaction product mixture can be worked up by methods known to those skilled in the art. For example, the reaction mixture of step 3a can be quenched with cooling water (e.g., 0.25 to 2 volumes of water per volume of organic solvent in the reaction product mixture of step 3a). The organic phase containing the compound of formula (XV) in solution can be isolated, and the isolated aqueous phase can be extracted with an organic solvent to recover additional compound of formula (XV). The organic phases can be combined and washed with an aqueous acid, an aqueous base, or brine. A non-limiting example of an aqueous acid is a solution of a weak acid, such as citric acid. A non-limiting example of a base solution is a solution of a weak base, such as sodium bicarbonate.

[0185]

[0220] In step 3b, the reaction mixture comprising the compound of formula (XV) in a solution of an organic solvent is mixed with a catalyst and an oxidizing agent and reacted to form a mixture of reaction products comprising the compound of formula (XII). In one embodiment, the catalyst is a redox active metal catalyst described in another section of this document. Non-limiting examples of suitable catalysts include NiCl2, RuCl3, CoCl2, FeCl3, FeCl2, and MnCl2. Non-limiting examples of suitable oxidizing agents include NaIO4, NaOCl, and oxone. In some embodiments, the reaction mixture further comprises water. The volume ratio of water to organic solvent is suitably about 0.25:1, about 0.5:1, about 0.75:1, about 1:1, about 1.25:1, about 1.50:1, about 1.75:1, about 2:1, or about 2.5:1, and ranges built therefrom, such as about 0.5:1 to about 1.5:1. The reaction temperature is suitably from about 5° C. to about 50° C. The reaction mixture is maintained at the reaction temperature, with stirring, until conversion of compound of formula (XV) to form a mixture of reaction products including a compound of formula (XII) is essentially complete, for example as determined by chromatography (e.g., TLC, GC or HPLC).

[0186]

[0221] The reaction product mixture of step 3b can be worked up by methods known to those skilled in the art. For example, the organic phase containing the compound of formula (XII) in solution can be isolated, and the aqueous phase can be optionally filtered and then extracted with an organic solvent to recover the compound of formula (XII). The organic phase(s) can be optionally washed with a reducing agent (e.g., sodium thiosulfate) and brine. The organic phase can be dried with a solid drying agent (e.g., sodium sulfate), followed by filtration to remove the solids and optionally washing with an organic solvent. The solid compound of formula (XII) can be obtained from the solution of the organic solvent by methods known in the art. For example, the solution can be concentrated under partial vacuum to dryness. Alternatively, the solution can be concentrated, followed by the addition of an anti-solvent to form a solid compound (XII), which can be collected by filtration or concentration, washing, and drying. The yield of compound of formula (XII) based on compound (XIV) is typically at least 85%, at least 90%, or at least 92%. The purity (area %) by HPLC is at least 95%, at least 98%, or at least 99%.

[0187]

[0222] Chiral primary amines can be generated using stereospecific transaminases via asymmetric transamination of prochiral ketones or kinetic resolution of racemic amines. Transamination is a reaction equilibrium consisting of a pair of amines and ketones (donor and acceptor), and the applied reaction conditions shift the equilibrium towards the chiral target amine. In one such embodiment, the amine donor is alanine or 2-propylamine. In one embodiment, the amine acceptor is pyruvic acid or acetone.

[0188]

[0223] Thus, there is further provided a process for preparing a compound of formula (XX) or a salt thereof, wherein the conversion of chiral tryptamine comprises using an enzymatic conversion: TIFF0007660040000054.tif41170

[0189]

[0224] The method for preparing the compound of formula (XX) is to prepare a compound of formula (XXI) TIFF0007660040000055.tif34170 is contacted with a protein transaminase to produce a compound of formula (3): This includes forming TIFF0007660040000056.tif27170.

[0190]

[0225] The method further comprises the presence of one or more amine donors. In one embodiment, the amine donor is alanine or isopropylamine.

[0191]

[0226] The contacting can be carried out in a mixed aqueous organic solvent system. For example, the transaminase reaction can be carried out in an aqueous buffer with an organic co-solvent such as cyclo-hexane, methyl-cyclo-hexane, iso-octane, DMSO, acetonitrile, or acetone. Such co-solvents can be present at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50% v / v.

[0192]

[0227] Mixed organic / aqueous solvent systems (low-aqueous reaction systems) can include one or more organic solvents, including, in certain cases, small amounts of aqueous buffer. In one embodiment, the contacting is carried out in TBME, dibutyl ether, CPME, toluene, ethyl acetate, butyl acetate, isopropyl acetate, butyl butyrate, ethyl butyrate, or iso-butyl acetate, including less than 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% v / v of aqueous buffer. When carried out in an organic solvent, the transaminase can be immobilized on a solid support.

[0193]

[0228] In another embodiment, the conversion of compound (XXI) to compound (3) is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or greater than 99%. In another aspect, the conversion is greater than 90%. In another embodiment, the conversion is greater than 95%.

[0194]

[0229] Reductive amination completed by the transaminase can provide the compound of formula (3) in an enantiomeric excess (EE) of at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%. In certain cases, the transaminase converts the compound of formula (XXI) to (3) in an EE of greater than 99%.

[0195]

[0230] In one embodiment, the asymmetric transamination of a compound of formula (XXI) is carried out using the following scheme: TIFF0007660040000057.tif51170.

[0196]

[0231] The compound of formula (3) may be reacted with a compound of formula (II) as described herein: TIFF0007660040000058.tif39170 to form a compound of formula (XX).

[0197]

[0232] R 1a , R 1b and n are as described in another section of this document. 1a and R 1b is independently fluorine.

[0198]

[0233] In one embodiment, the compound of formula (XX) has the structure: The file is TIFF0007660040000059.tif24170.

[0199]

[0234] The protein transaminase can be selected from Table 6. In one such aspect, the transaminase is (R)-selective. In one embodiment, the transaminase is TA-P2-A01. In one embodiment, the protein transaminase is selected from the (S)-enantioselective transaminases of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4.

[0200]

[0235] Further provided herein is a method for enzymatically synthesizing a compound of formula (3) through kinetic resolution of a racemic amine in the presence of an amine acceptor and a transaminase. The reaction can be carried out, for example, in a mixed aqueous / organic solvent system as described herein, under conditions as described herein. In one such embodiment, the reaction is carried out in an aqueous buffer containing acetonitrile. Such kinetic resolution can provide a compound of formula (3) with an EE of at least 99%, requiring a conversion rate of greater than 50%. The kinetic resolution includes the use of an (S)-selective transaminase as described herein to carry out the kinetic resolution. In one embodiment, the transaminase is selected from Table 6.

[0201]

[0236] One embodiment of the present disclosure is a compound of formula (XVI): The target is TIFF0007660040000060.tif54170. R 4 ,s,R 10 , G, and p are as defined herein.

[0202] R 7a , R 7b , R 8a and R 8b Each of the groups is independently hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 In one embodiment, R 7a , R 7b , R 8a and R 8b Each of R is independently hydrogen, fluorine, -CH, or -CN. 7a , R 7b , R 8a and R 8b Each of is hydrogen.

[0203] y is an integer of 1 or 2; x is an integer of 1 or 2; and the sum of x and y is 2 or 3.

[0204] M is C 1-5 is alkyl; r is 0 or 1; R 9 is halogen or -CN.

[0205]

[0237] In one embodiment, M is -CHCHCH-, p is 1, and R 9 is fluorine.

[0206]

[0238] In one embodiment, M is -CHCHCH-, p is 1, and R 9 is -CN.

[0207]

[0239] In one embodiment, the compound of formula (XVI) is: TIFF0007660040000061.tif199170 or a salt thereof.

[0208]

[0240] In a particular embodiment, the compound of formula (XVI) is: The file is TIFF0007660040000062.tif41170.

[0209]

[0241] In another aspect, provided herein is a compound having the structure: The compound has the following structure: TIFF0007660040000063.tif50170.

[0210]

[0242] In another aspect, provided herein is a compound of the formula: TIFF0007660040000064.tif57170, which is carried out as set forth in Scheme A below, according to embodiments and according to the embodiments provided herein.

[0211]

[0243] Scheme A: TIFF0007660040000065.tif90170BrettPhos Pd G3 = [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0212]

[0244] Yet another embodiment of the present disclosure is a compound of the formula: TIFF0007660040000066.tif55170, which is carried out as set forth in Scheme B below, according to embodiments provided herein.

[0213]

[0245] Scheme B: TIFF0007660040000067.tif80170

[0214]

[0246] The above methods for the synthesis of compound B (e.g., Schemes A and B) can further include recrystallization according to the following Schemes C or D:

[0215]

[0247] Scheme C: TIFF0007660040000068.tif32170

[0216]

[0248] Scheme D: TIFF0007660040000069.tif33170

[0217]

[0249] In one embodiment, compounds (3) and (4) described herein, as provided in Scheme A and Scheme B, and optionally Scheme C or D above, are synthesized according to Scheme E below, as an embodiment and as provided herein.

[0218]

[0250] Scheme E: TIFF0007660040000070.tif107170

[0219]

[0251] Further provided herein is a process for preparing a compound of formula (XXIII) or a salt thereof: TIFF0007660040000071.tif63170

[0220]

[0252] B, R 1a , R 1b , n, R 2a, R 2b , R 3a , R 3b ,J.R. 4 ,s,G,R 5 ,v,R 6 , E, and asterisk are as defined herein.

[0221]

[0253] In one embodiment, the compound of formula (XXIII) is an acid salt. In such an embodiment, the compound of formula (VIII) is an acid salt. In a preferred embodiment, the compound of formula (XXIII) is a tartaric acid salt. In some embodiments, the compound of formula (XXIII) is a fumaric acid salt.

[0222]

[0254] In one embodiment, the compound of formula (XXIII) has any one of the following structures, or a tartrate salt thereof: TIFF0007660040000072.tif199170TIFF0007660040000073.tif202170TIFF0007660040000074.tif211170TIFF0007660040000075.tif109170

[0223]

[0255] In another embodiment, the compound is a fumarate salt.

[0224]

[0256] In one embodiment, the compound of Formula (XXIII) has the following structure, or a pharma- ceutically acceptable salt thereof: TIFF0007660040000076.tif57170

[0225]

[0257] The process for preparing the compound of formula (XXIII) comprises two reaction steps as shown below: TIFF0007660040000077.tif132170

[0226]

[0258] LG is as defined herein.

[0227]

[0259] The variables of formulas (IV), (V) and (VI) are as defined herein.

[0228]

[0260] In one embodiment, the compound of formula (XXIV) has any one of the following structures, or a salt thereof: TIFF0007660040000078.tif46170.

[0229]

[0261] One embodiment of the present disclosure is directed to a method for preparing a compound of formula (XXIII) or a salt thereof described herein. The method for preparing a compound of formula (XXIII) according to this embodiment comprises reaction step 1 shown below: TIFF0007660040000079.tif66170.

[0230]

[0262] B, R 1a , R 1b , n, R 2a , R 2b , R 3a , R 3b , R 4 ,s,J,R. 5 ,v,R 6 Each of , G, p, E and the asterisk is as described elsewhere herein. The CHO moiety and the nitrogen atom connecting J and G are located in the para position of J relative to each other.

[0231]

[0263] In some embodiments, the compound of formula (XXIV) is: TIFF0007660040000080.tif38170 or a salt thereof.

[0232]

[0264] One embodiment of the present disclosure is directed to a process for preparing a compound of formula (XXVII) or a salt thereof.

[0233]

[0265] The method for preparing compound of formula (XXVII) includes the reaction steps shown below: TIFF0007660040000081.tif91170.

[0234]

[0266] R 4 ,s,L.G.,R. 5 ,v,R 6 , G, p, E and PG are as defined herein.

[0235]

[0267] Further provided herein is compound A: TIFF0007660040000082.tif53170, solid forms, formulations comprising such solid forms, and methods of using such solid forms, which refer to the compound having the name 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, including pharmaceutically acceptable salts thereof.

[0236]

[0268] In one embodiment, provided herein is a solid form of Compound A. Compound A can be a free base as described herein that exists in an amorphous solid form. In another embodiment, Compound A is a crystalline solid as described herein. In yet another embodiment, Compound A is a crystalline tartrate salt having the following structure: TIFF0007660040000083.tif53170

[0237]

[0269] In another aspect, provided herein is a crystalline solid form of Compound A as a fumarate salt having the following structure: TIFF0007660040000084.tif54170

[0238]

[0270] In yet another aspect, provided herein is a solid form of a malonate salt of Compound A having the structure: TIFF0007660040000085.tif54170

[0239]

[0271] The solid forms described herein may be crystalline. In another embodiment, the solid forms are single-component solid forms. The solid forms described herein may be solvates, hydrates, anhydrates, or salts as defined herein. In one embodiment, the solid forms described herein comprise a tartrate salt. In another embodiment, the solid forms described herein comprise an anhydrate of Compound B. In another embodiment, the solid forms described herein comprise a fumarate salt. In yet another embodiment, the solid forms described herein comprise a phosphate salt or other salt.

[0240]

[0272] Without intending to be bound by any particular theory, solid forms can be characterized by physical properties such as, for example, stability, dissolution and dissolution rates, density, compressibility, hardness, morphology, shear, adhesion, solubility, hygroscopicity, electrical properties, thermal behavior, solid state reactivity, physical stability, and chemical stability, which influence the particular method (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization) of making a particular solid form suitable for manufacturing a solid dosage form. Such properties can be determined using certain analytical chemistry techniques, including solid state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis), as described herein.

[0241]

[0273] The solid forms described herein, including salt forms, crystalline forms, and amorphous solids, can be characterized by a number of methods, including, for example, single crystal X-ray diffraction, powder X-ray diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), thermogravimetric analysis (TGA), and hot stage microscopy), spectroscopy (e.g., infrared, Raman, and solid-state nuclear magnetic resonance), ultra-high performance liquid chromatography (UHPLC), and proton nuclear magnetic resonance (spectroscopy).

[0242]

[0274] Techniques for characterizing crystalline forms and amorphous solids include, for example, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy such as infrared (IR) and Raman spectroscopy, solid state and solution nuclear magnetic resonance (NMR) spectroscopy ( 1 These include NMR (including 1 H NMR and 1 F NMR), scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies.

[0243]

[0275] The purity of the solid forms provided herein can be determined by standard analytical methods, such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, ultra-performance liquid chromatography (UHPLC), and mass spectrometry (MS).

[0244]

[0276] Form A of Compound B:

[0277] In some embodiments, provided herein is a solid form of Compound B designated Form A. Form A is a crystalline solid form of Compound B. In one embodiment, Form A is an acetone solvate of Compound B. In one embodiment, Form A is a crystalline acetone solvate tartrate salt of Compound A.

[0245]

[0278] In another embodiment, Form A of Compound B is obtained by slurrying in acetone followed by evaporation. Form A can be prepared according to the methods and examples described herein.

[0246]

[0279] In one embodiment, the solid form provided herein, e.g., Form A, is a tartrate salt of Compound A (i.e., Compound B) and is crystalline as indicated by measured X-ray powder diffraction pattern (XRPD). In one embodiment, the XRPD of the solid form provided herein, e.g., Form A, is substantially as shown in FIG. In another embodiment, a solid form provided herein, e.g., Form A, has one or more characteristic XRPD peaks at about 4.64, 8.26, 9.28, 11.18, 11.49, 11.96, 12.54, 13.77, 14.22, 14.61, 15.09, 15.56, 16.01, 17.35, 18.55, 18.84, 19.32, 19.82, 20.26, 21.34, 21.63, 21.92, 22.52, 22.97, 23.28, 23.54, 23.94, 24.81, or 25.96±0.1 degrees 2θ, e.g., as shown in FIG. 1 and as found in Table 16 herein. In yet another embodiment, a solid form provided herein, e.g., Form A, has at least 3, at least 5, at least 7, or at least 10 XPRD peaks at about 4.64, 8.26, 9.28, 11.18, 11.49, 11.96, 12.54, 13.77, 14.22, 14.61, 15.09, 15.56, 16.01, 17.35, 18.55, 18.84, 19.32, 19.82, 20.26, 21.34, 21.63, 21.92, 22.52, 22.97, 23.28, 23.54, 23.94, 24.81, or 25.96 ± 0.1 degrees 2θ, e.g., as shown in FIG. 1 and as found in Table 16 herein. In yet another embodiment, the solid form described herein, such as Form A, has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or all of the characteristic XRPD peaks set forth in Table 16.

[0247]

[0280] In yet another embodiment, a solid form provided herein, e.g., Form A, has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XRPD peaks at about 12.54, 14.61, 16.01, 19.32, 20.26, 21.63, 23.28, 23.54, 23.94, or 24.81±0.1 degrees 2θ, e.g., as shown in Figure 1 and as seen in Table 16 herein. In another embodiment, a solid form provided herein, e.g., Form A, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 19.32, 20.26, 21.63, 23.28, or 24.81±0.1 degrees 2θ, e.g., as shown in Figure 1 and as seen in Table 16 herein. In another embodiment, a solid form provided herein, e.g., Form A, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 19.32, 20.26, 21.63, 23.28, or 24.81 ± 0.05 degrees 2θ, e.g., as shown in FIG. 1 and as found in Table 16 herein.

[0248]

[0281] In one embodiment, described herein is a solid form, e.g., Form A, having a TGA thermogram substantially corresponding to a representative TGA thermogram, as shown in Figure 2. In some embodiments, the crystalline form exhibits a TGA thermogram that includes a total mass loss of about 7.2% of the total mass of the sample before about 125°C.

[0249]

[0282] In another embodiment, described herein is a solid form, e.g., Form A, having a DSC thermogram substantially as shown in FIG. 2, with a desolvation event at about 124° C., a melting temperature with an onset temperature of about 164° C., and a peak maximum temperature of about 171° C.

[0250]

[0283] In another embodiment, described herein is a solid form, e.g., Form A, having a polarized microscope image as shown in FIG.

[0251]

[0284] In yet another embodiment, Form A is pure. In some embodiments, pure Form A is substantially free of other solid forms, such as amorphous solids. In some embodiments, the purity of Form A is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5%, or about 99.9% or more.

[0252]

[0285] Form B of Compound B:

[0286] In some embodiments, provided herein is a solid form of Compound B designated as Form B. Form B is a crystalline solid form of Compound B. In one embodiment, Form B is an anhydrous form of Compound B. In another embodiment, Form B is an anhydrous tartrate salt of Compound A.

[0253]

[0287] In one embodiment, Form B of Compound B is obtained by slurrying Compound B in ethyl acetate at RT for about 24 hours. In another embodiment, Form B of Compound B is obtained by slurrying Compound B in acetone:water (e.g., 90:10, 95:5, 96:4, 97:3, 99:1 v / v) for about 6 hours at about 50° C. In yet another embodiment, Form B of Compound B is obtained by slurrying Compound B in ethanol.

[0254]

[0288] In certain cases, Form B of Compound B is obtained by slurrying Compound B in a solvent system containing ≧95% acetone (e.g., ≧95:5 acetone:water). Form B of Compound B is then isolated from the slurry, for example, by centrifugation or filtration. In another embodiment, Form B of Compound B is obtained from Form A or Form F described herein. In one embodiment, Form A of Compound B is reslurried in ethanol (e.g., 100% ethanol) for 10, 12, 16, or 24 hours (e.g., overnight) to obtain Form B. In one embodiment, Form F is converted to Form D described herein in the presence of water. The mixture can then be slurried in neat ethanol (e.g., at about 50° C.) or 95:5 or 97:3 acetone:water (v / v) to form Form B. The mixture can optionally be seeded with crystals of Form B.

[0255]

[0289] Form B can be prepared according to the methods and examples described herein. Thus, provided herein is a method of preparing Form B, the method comprising slurrying Compound B in a solvent system comprising acetone or an aqueous mixture of acetone and water (e.g., 50%, 90%, 95%, 96%, 97%, 98% and 99% acetone v / v). In one embodiment, the solvent system for crystallizing Form B comprises ≧95% acetone. In one embodiment, the solvent system for Form B comprises 96:4 acetone:water. The mixture can be slurried at RT for about 120 hours. The mixture can be filtered and analyzed (e.g., XRPD) as described herein. In one embodiment, Form B is prepared according to the methods and / or examples provided herein.

[0256]

[0290] In one embodiment, the solid form provided herein, e.g., Form B, is a tartrate salt of Compound A and is crystalline as indicated by powder X-ray diffraction pattern (XRPD) measurements. In one embodiment, the XRPD of the solid form provided herein, e.g., Form B, is substantially as shown in Figure 4. In another embodiment, a solid form provided herein, e.g., Form B, has one or more characteristic XRPD peaks at about 7.68, 11.49, 12.54, 14.24, 15.30, 15.55, 16.01, 16.63, 17.37, 18.24, 19.16, 19.42, 19.89, 20.24, 21.81, 22.52, 22.99, 23.25, 23.57, 24.67, 25.07, 25.91 ± 0.1 ° 2θ, as shown, for example, in FIG. 4 and as found in Table 17 herein. In yet another embodiment, a solid form provided herein, e.g., Form B, has at least 3, at least 5, at least 7, or at least 10 characteristic XPRD peaks at approximately 7.68, 11.49, 12.54, 14.24, 15.30, 15.55, 16.01, 16.63, 17.37, 18.24, 19.16, 19.42, 19.89, 20.24, 21.81, 22.52, 22.99, 23.25, 23.57, 24.67, 25.07, 25.91 ± 0.1 ° 2θ, e.g., as shown in FIG. 4 and found in Table 17 herein. In yet another embodiment, the solid form described herein, such as Form B, has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all of the characteristic XRPD peaks shown in Table 17.

[0257]

[0291] In yet another embodiment, a solid form provided herein, e.g., Form B, has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XRPD peaks at about 11.49, 12.54, 15.30, 15.55, 19.16, 19.42, 20.24, 23.25, 24.67, or 25.91±0.1 degrees 2θ. In yet another embodiment, a solid form provided herein, e.g., Form B, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 11.49, 12.54, 19.16, 19.42, or 24.67±0.1 degrees 2θ, as shown, for example, in FIG. In yet another embodiment, a solid form provided herein, e.g., Form B, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 11.49, 12.54, 19.16, 19.42, or 24.67±0.05° 2θ, as shown, for example, in FIG.

[0258]

[0292] In one embodiment, described herein is a solid form, e.g., Form B, having a TGA thermogram substantially corresponding to the representative TGA thermogram shown in Figure 5. In some embodiments, the crystalline form exhibits a TGA thermogram that includes a total mass loss of approximately 3.5% of the total mass of the sample.

[0259]

[0293] In another embodiment, described herein is a solid form, e.g., Form B, having a DSC thermogram substantially as shown in Figure 5, including an endothermic event with an onset temperature of about 171°C and a peak maximum temperature of about 179°C.

[0260]

[0294] In another embodiment, described herein is a casing substantially as shown in FIG. 6 and FIG. 7, respectively. 13 C and 19 F NMR spectrum, such as form B.

[0261]

[0295] In another embodiment, described herein is a solid form, e.g., Form B, having a water sorption-desorption profile as shown in Figure 8. A solid form, e.g., Form B of Compound B, absorbs about 1.2% w / w water at about 25°C up to 90% relative humidity (RH).

[0262]

[0296] In another embodiment, described herein is a solid form having a scanning electron microscope (SEM) image and a PLM image as shown in Figures 9a and 9b, respectively, e.g., Form B. The sample contains dense spherical agglomerates.

[0263]

[0297] In another embodiment, described herein is a solid form, e.g., Form B, having a particle size distribution as shown in Figure 9c.

[0264]

[0298] In yet another embodiment, the solid form, e.g., Form B, remains substantially unchanged following compression as described herein. Figures 22, 23, and 24 show XRPDs of Form B of Compound B, respectively. 19 F SSNMR and DSC are shown comparing the compound before and after the compression described herein.

[0265]

[0299] In yet another embodiment, Form B is substantially pure. In some embodiments, pure Form B is substantially free of other solid forms, such as amorphous solids. In some embodiments, substantially pure Form B is substantially free of Form A, Form D, or Form F. In some embodiments, the purity of Form B is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5%, or about 99.9% or more.

[0266]

[0300] Form C of Compound B:

[0301] In some embodiments, provided herein is a solid form of Compound B designated Form C. Form C is a crystalline solid form of Compound B. In one embodiment, Form C is a THF solvate of Compound B.

[0267]

[0302] In one embodiment, Form C of Compound B is obtained by slurrying Compound B in THF. The mixture can then be filtered. Form C can be prepared according to the methods and examples described herein.

[0268]

[0303] In one embodiment, the solid form provided herein, e.g., Form C, is a tartrate salt of Compound A and is substantially crystalline as indicated by a measured X-ray powder diffraction pattern (XRPD). In one embodiment, the XRPD is substantially as shown in Figure 10.

[0269]

[0304] In one embodiment, described herein is a solid form, e.g., Form C, having a TGA thermogram substantially corresponding to the representative TGA thermogram shown in Figure 11. In some embodiments, the crystalline form exhibits a TGA thermogram that comprises a total mass loss of approximately 6.8% of the total mass of the sample.

[0270]

[0305] In another embodiment, described herein is a solid form, e.g., Form C, having a DSC thermogram substantially as shown in Figure 11, including an endothermic event with an onset temperature of about 118°C and a peak maximum temperature of about 125°C.

[0271]

[0306] In other embodiments, Form C is pure. In some embodiments, the purity of Form C is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5%, or about 99.9% or more.

[0272]

[0307] Form D of Compound B:

[0308] In some embodiments, provided herein is a solid form of Compound B designated Form D. Form D is a crystalline solid form of Compound B. In one embodiment, Form D is a hydrate of Compound B. In another embodiment, Form D is a monohydrate of Compound B.

[0273]

[0309] In one embodiment, Form D of Compound B is obtained by slurrying Compound B in 100% ethanol for about 48 hours. The mixture can then be filtered.

[0274]

[0310] In one embodiment, the solid form provided herein, e.g., Form D, is a tartrate salt of Compound A and is substantially crystalline as indicated by a measured X-ray powder diffraction pattern (XRPD). In another embodiment, Form D is a hydrate of Compound B. In one embodiment, the XRPD of the solid form provided herein, e.g., Form D, is substantially as shown in Figure 12. In another embodiment, a solid form provided herein, e.g., Form D, has one or more characteristic XRPD peaks at about 7.32, 10.99, 11.31, 12.18, 13.23, 13.48, 14.11, 14.66, 15.14, 15.70, 16.03, 16.21, 16.54, 17.24, 17.63, 18.11, 18.34, 19.10, 20.20, 20.58, 21.16, 21.47, 21.89, 22.76, 23.33, or 23.56±0.1 degrees 2θ, as shown, for example, in FIG. 12 and as found in Table 19. In yet another embodiment, a solid form provided herein, e.g., Form D, has at least 3, at least 5, at least 7, or at least 10 characteristic XRPD peaks at about 7.32, 10.99, 11.31, 12.18, 13.23, 13.48, 14.11, 14.66, 15.14, 15.70, 16.03, 16.21, 16.54, 17.24, 17.63, 18.11, 18.34, 19.10, 20.20, 20.58, 21.16, 21.47, 21.89, 22.76, 23.33, or 23.56 ± 0.1 degrees 2θ, e.g., as shown in FIG. 12 and seen in Table 19. In yet another embodiment, the solid forms described herein have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all of the characteristic XRPD peaks shown in Table 19.

[0275]

[0311] In yet another embodiment, a solid form provided herein, e.g., Form D, has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XRPD peaks at about 11.31, 15.70, 16.54, 19.10, 20.58, 21.16, 21.47, 21.89, 22.76, or 23.33±0.1 degrees 2θ, e.g., as shown in Figure 12. In yet another embodiment, a solid form provided herein, e.g., Form D, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 11.31, 15.70, 16.54, 19.10, or 22.76±0.1 degrees 2θ, e.g., as shown in Figure 12. In yet another embodiment, a solid form provided herein, e.g., Form D, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 11.31, 15.70, 16.54, 19.10, or 22.76±0.05° 2θ, as shown, for example, in FIG.

[0276]

[0312] In one embodiment, described herein is a solid form, e.g., Form D, having a TGA thermogram substantially corresponding to the representative TGA thermogram shown in Figure 13. In some embodiments, the crystalline form exhibits a TGA thermogram that includes a total mass loss of about 1.4% of the total mass of the sample before about 150°C.

[0277]

[0313] In another embodiment, described herein is a solid form, e.g., Form D, having a DSC thermogram substantially as shown in FIG. 13 including an endothermic event with an onset temperature of about 55° C. and a peak maximum temperature of about 82° C., followed by a second endothermic event with an onset temperature of about 165° C. and a peak maximum temperature of about 172° C.

[0278]

[0314] In yet another embodiment, Form D is pure. In some embodiments, Form D is substantially free of other solid forms, such as amorphous solids. In some embodiments, Form D is substantially free of Form A, Form B, or Form F. In some embodiments, the purity of Form D is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5%, or about 99.9% or more.

[0279]

[0315] Form E of Compound B:

[0316] In some embodiments, provided herein is a solid form of Compound B designated Form E. Form E is a solid form of Compound B. In one embodiment, Form E is a DMSO solvate of Compound B.

[0280]

[0317] In one embodiment, Form E of Compound B can be obtained by slurrying Compound B in DMSO and adding IPAc for about 24 hours. The mixture can then be filtered. Form E can be prepared according to the methods and examples described herein.

[0281]

[0318] In one embodiment, the solid form provided herein, such as Form E, is a tartrate salt of Compound A and is substantially crystalline as indicated by a measured X-ray powder diffraction pattern (XRPD). In one embodiment, the XRPD is substantially as shown in Figure 14.

[0282]

[0319] In one embodiment, described herein is a solid form, e.g., Form E, having a TGA thermogram substantially corresponding to the representative TGA thermogram shown in Figure 15. In some embodiments, the crystalline form exhibits a TGA thermogram that includes a total mass loss of approximately 8.3% of the total mass of the sample.

[0283]

[0320] In another embodiment, described herein is a solid form, e.g., Form E, having a DSC thermogram substantially as shown in FIG. 15 including an endothermic event with an onset temperature of about 126° C. and a peak maximum temperature of about 82° C., and a second endothermic event with an onset temperature of about 143° C. and a peak maximum temperature of about 147° C.

[0284]

[0321] In yet another embodiment, Form E is pure. In some embodiments, Form E is substantially free of other solid forms, such as amorphous solids. In some embodiments, the purity of Form E is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5%, or about 99.9% or more.

[0285]

[0322] Form F of Compound B:

[0323] In some embodiments, provided herein is a solid form of Compound B designated Form F. Form F is a crystalline solid form of Compound B. In one embodiment, Form F is an anhydrous form of Compound B. In another embodiment, Form F is an anhydrous tartrate salt of Compound A.

[0286]

[0324] In one embodiment, form F of compound B is obtained by slurrying compound B in 100% ethanol at RT or 50° C. for about 8, 10, 12, 15, 20, or 25 hours (e.g., overnight). In another embodiment, form F is obtained by slurrying compound B in ethanol / water (e.g., 65:35 v / v). The slurry of compound B to obtain form F includes seeding with form B described herein. The slurry can be filtered to obtain form F. Form F can also be obtained by slurrying in 100% DI water, 1:1 acetone / water, or 100% acetone at RT. The slurry of form F in neat solvent can be maintained at RT. In one embodiment, form F can be obtained from a stirred 1:1 acetone:water mixture at 5° C. In yet another embodiment, form F can be obtained by slurrying compound B in 95:5 acetone:water and 97:3 acetone:water mixtures at 50° C. for about 2 hours and cooling to RT. Form F can be prepared according to the methods and examples described herein.

[0287]

[0325] In one embodiment, the solid form provided herein, e.g., Form F, is a tartrate salt of Compound A and is substantially crystalline as indicated by a measured X-ray powder diffraction pattern (XRPD). In one embodiment, the XRPD of the solid form provided herein, e.g., Form F, is substantially as shown in Figure 16. In another embodiment, a solid form provided herein, e.g., Form F, has one or more characteristic XRPD peaks at about 3.92, 10.54, 11.72, 12.52, 14.22, 15.40, 15.54, 15.90, 16.48, 16.84, 17.29, 18.26, 18.47, 19.39, 19.66, 20.00, 20.50, 20.65, 21.16, 21.28, 21.95, 22.97, 23.49, 23.70, 23.94, 24.31, 24.67, or 24.99 ± 0.1 degrees 2θ, e.g., as shown in FIG. 16 and as found in Table 20 herein. In yet another embodiment, a solid form provided herein, e.g., Form F, has at least 3, at least 5, at least 7, or at least 10 characteristic XPRD peaks at about 3.92, 10.54, 11.72, 12.52, 14.22, 15.40, 15.54, 15.90, 16.48, 16.84, 17.29, 18.26, 18.47, 19.39, 19.66, 20.00, 20.50, 20.65, 21.16, 21.28, 21.95, 22.97, 23.49, 23.70, 23.94, 24.31, 24.67, or 24.99 ± 0.1 degrees 2θ, e.g., as shown in FIG. 16 and as found in Table 20 herein. In yet another embodiment, a solid form described herein, such as Form F, has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or all of the characteristic XRPD peaks shown in Table 20.

[0288]

[0326] In yet another embodiment, a solid form provided herein, e.g., Form F, has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XRPD peaks at about 12.52, 15.90, 19.66, 20.65, or 24.99±0.1 degrees 2θ, e.g., as shown in Figure 16. In yet another embodiment, a solid form provided herein, e.g., Form F, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 12.52, 15.90, 19.66, 20.65, or 24.99±0.1 degrees 2θ, e.g., as shown in Figure 16. In yet another embodiment, a solid form provided herein, e.g., Form F, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 12.52, 15.90, 19.66, 20.65, or 24.99±0.05 degrees 2θ, as shown, for example, in FIG.

[0289]

[0327] In one embodiment, described herein is a solid form, e.g., Form F, having a DVS isotherm graph substantially corresponding to the representative DVS isotherm graph shown in FIG.

[0290]

[0328] In another embodiment, described herein is a solid form, e.g., Form F, having a DSC thermogram substantially as shown in Figure 18, including an endothermic event with an onset temperature of about 162°C and a peak maximum temperature of about 167°C.

[0291]

[0329] In yet another embodiment, Form F is pure. In some embodiments, pure Form F is substantially free of other solid forms, such as amorphous solids. In some embodiments, the purity of Form F is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5%, or about 99.9% or more.

[0292]

[0330] Form G of Compound B

[0331] In some embodiments, provided herein is a solid form of Compound B designated Form G. Form G is a solid form of Compound B. In one embodiment, Form G is a methanol solvate of Compound B. In another embodiment, Form F is a methanol solvate tartrate salt of Compound A.

[0293]

[0332] In one embodiment, Form G of Compound B can be obtained by slurrying Compound B in methanol and slowly evaporating the methanol. The mixture can be filtered. Form G can be prepared according to the methods and examples described herein.

[0294]

[0333] In one embodiment, the solid form provided herein, e.g., Form G, is a tartrate salt of Compound A and is substantially crystalline as indicated by a measured X-ray powder diffraction pattern (XRPD). In one embodiment, the XRPD of the solid form provided herein, e.g., Form G, is substantially as shown in Figure 19. In another embodiment, a solid form provided herein, e.g., Form G, has one or more characteristic XRPD peaks at about 7.65, 11.46, 12.51, 15.27, 15.51, 16.00, 17.34, 18.21, 19.11, 19.29, 19.42, 19.84, 20.23, 21.31, 21.57, 21.79, 22.49, 22.97, 23.22, 24.65, 25.04, or 25.88±0.1 degrees 2θ, e.g., as shown in FIG. 19 and found in Table 21 herein. In yet another embodiment, a solid form provided herein, e.g., Form G, has at least 3, at least 5, at least 7, or at least 10 characteristic XPRD peaks at about 7.65, 11.46, 12.51, 15.27, 15.51, 16.00, 17.34, 18.21, 19.11, 19.29, 19.42, 19.84, 20.23, 21.31, 21.57, 21.79, 22.49, 22.97, 23.22, 24.65, 25.04, or 25.88±0.1 degrees 2θ, e.g., as shown in FIG. 19 and found in Table 21 herein. In yet another embodiment, a solid form described herein, such as Form G, has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, or all of the characteristic XRPD peaks shown in Table 21.

[0295]

[0334] In yet another embodiment, a solid form provided herein, e.g., Form G, has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XRPD peaks at about 11.46, 12.51, 15.27, 16.00, 19.29, 19.42, 20.23, 22.49, 22.97, or 24.65±0.1 degrees 2θ, e.g., as shown in Figure 19. In yet another embodiment, a solid form provided herein, e.g., Form G, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 11.46, 12.51, 19.29, 19.42, or 20.23±0.1 degrees 2θ, e.g., as shown in Figure 19. In yet another embodiment, a solid form provided herein, e.g., Form G, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 11.46, 12.51, 19.29, 19.42, or 20.23±0.05° 2θ, as shown, for example, in FIG.

[0296]

[0335] In one embodiment, described herein is a solid form, e.g., Form G, having a TGA thermogram substantially corresponding to the representative TGA thermogram shown in Figure 20. In some embodiments, the crystalline form exhibits a TGA thermogram that includes a total mass loss of approximately 2% of the total mass of the sample.

[0297]

[0336] In another embodiment, described herein is a solid form, e.g., Form G, having a DSC thermogram substantially as shown in Figure 20, including an endothermic event with an onset temperature of about 173°C and a peak maximum temperature of about 178°C.

[0298]

[0337] In yet another embodiment, Form G is pure. In some embodiments, pure Form G is substantially free of other solid forms, such as amorphous solids. In some embodiments, pure Form G is substantially free of Form B, Form D, or Form E. In some embodiments, the purity of Form G is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5%, or about 99.9% or more.

[0299]

[0338] Compound C, Form 1

[0339] In some embodiments, provided herein is a solid form of Compound C, designated Form 1. Form 1 is a crystalline solid form of Compound C.

[0300]

[0340] In one embodiment, Compound C Form 1 is obtained by slurrying Compound C in about 3:1 ratio of isoamyl alcohol / water at about 55° C. for about 1.5 hours. The mixture liquid is then evaporated under nitrogen flow and reduced pressure. In another embodiment, Compound C Form 1 is obtained by slurrying Compound C in about 3:8 ratio of ethanol / heptane at RT. In yet another embodiment, Compound C Form 1 is obtained by slurrying Compound C in about 1:1 ratio of ethanol / heptane at RT. Form 1 can be prepared according to the methods and examples described herein.

[0301]

[0341] In one embodiment, the solid form provided herein, e.g., Form 1, is a fumarate salt of Compound A and is substantially crystalline as shown by measured X-ray powder diffraction pattern (XRPD). In one embodiment, the XRPD is substantially as shown in Figure 27a. In another embodiment, the solid form provided herein, e.g., Form 1, has one or more characteristic XRPD peaks at about 7.58, 10.59, 11.44, 11.84, 12.5, 14.44, 15.45, 15.78, 16.09, 17.55, 18.92, 19.69, 19.86, 20.23, 21.35, 22.04, 23.16, 23.89, 24.23, 24.67, 25.23, or 25.93±0.1° 2θ, e.g., as shown in Figure 27a and in Table 36 herein. In yet another embodiment, a solid form provided herein, e.g., Form 1, has at least 3, at least 5, at least 7, or at least 10 characteristic XPRD peaks at about 7.58, 10.59, 11.44, 11.84, 12.5, 14.44, 15.45, 15.78, 16.09, 17.55, 18.92, 19.69, 19.86, 20.23, 21.35, 22.04, 23.16, 23.89, 24.23, 24.67, 25.23, or 25.93 ± 0.1 ° 2θ, e.g., as shown in FIG. 27a and found in Table 36 herein. In yet another embodiment, a solid form described herein, such as Form 1, has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, or all of the characteristic XRPD peaks shown in Table 36.

[0302]

[0342] In yet another embodiment, a solid form provided herein, e.g., Form 1, has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XRPD peaks at about 10.59, 15.45, 15.78, 16.09, 18.92, 19.69, 19.86, 21.35, 23.16, or 24.23±0.1° 2θ, as shown, for example, in Figure 27a. In yet another embodiment, a solid form provided herein, e.g., Form 1, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 16.09, 18.92, 19.69, 19.86, or 23.16±0.1° 2θ, as shown, for example, in Figure 27a. In yet another embodiment, a solid form provided herein, e.g., Form 1, has characteristic XRPD peaks of 1, 2, 3, 4, or 5 at approximately 16.09, 18.92, 19.69, 19.86, or 23.16±0.05° 2θ, as shown, for example, in FIG. 27a.

[0303]

[0343] In one embodiment, described herein is a solid form, e.g., Form 1, having a TGA thermogram substantially corresponding to the representative TGA thermogram shown in Figure 28. In some embodiments, the crystalline form exhibits a TGA thermogram that includes a total mass loss of approximately 2% of the total mass of the sample.

[0304]

[0344] In another embodiment, described herein is a solid form, e.g., Form 1, having a DSC thermogram substantially as shown in Figure 28, including an endothermic event with an onset temperature of about 167°C and a peak maximum temperature of about 172°C.

[0305]

[0345] In yet another embodiment, Form 1 is pure. In some embodiments, pure Form 1 is substantially free of other solid forms, such as amorphous solids. In some embodiments, the purity of Form 1 is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5%, or about 99.9% or more.

[0306]

[0346] In another embodiment, described herein is a solid form, such as Form 1, having a PLM image as shown in FIG.

[0307]

[0347] Compound C, Form 2

[0348] In some embodiments, provided herein is a solid form of Compound C, designated Form 2. Form 2 is a crystalline solid form of Compound C.

[0308]

[0349] In one embodiment, the solid form provided herein, e.g., Form 2, is a fumarate salt of Compound A and is substantially crystalline as indicated by a measured X-ray powder diffraction pattern (XRPD). In one embodiment, the XRPD is substantially as shown in Figure 27b. In another embodiment, the solid form provided herein, e.g., Form 2, has one or more characteristic XRPD peaks at about 11.52, 11.87, 15.55, 16.04, 16.51, 17.32, 18.36, 19.00, 19.43, 19.87, 20.24, 21.35, 22.03, 23.23, 23.91, 25.43, or 26.03±0.1° 2θ, e.g., as shown in Figure 27b and found in Table 37 herein. In yet another embodiment, a solid form provided herein, e.g., Form 2, has at least 3, at least 5, at least 7, or at least 10 characteristic XPRD peaks at about 11.52, 11.87, 15.55, 16.04, 16.51, 17.32, 18.36, 19.00, 19.43, 19.87, 20.24, 21.35, 22.03, 23.23, 23.91, 25.43, or 26.03±0.1° 2θ, e.g., as shown in FIG. 27b and found in Table 37 herein. In yet another embodiment, the solid form described herein, such as Form 1, has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all of the characteristic XRPD peaks shown in Table 37 herein.

[0309]

[0350] In yet another embodiment, a solid form provided herein, e.g., Form 1, has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XRPD peaks at about 11.87, 15.55, 16.04, 16.51, 17.32, 19.43, 19.87, 20.24, 23.23, or 23.91±0.1° 2θ, as shown, for example, in Figure 27b. In yet another embodiment, a solid form provided herein, e.g., Form 1, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 15.55, 19.43, 19.87, 20.24, or 23.23±0.1° 2θ, as shown, for example, in Figure 27b. In yet another embodiment, a solid form provided herein, e.g., Form 1, has 1, 2, 3, 4, or 5 characteristic XRPD peaks at about 15.55, 19.43, 19.87, 20.24, or 23.23±0.05° 2θ, as shown, for example, in FIG. 27b.

[0310]

[0351] Amorphous Form of Free Base Compound A

[0352] In some embodiments, provided herein are amorphous solid forms of free base Compound A.

[0311]

[0353] In one embodiment, the amorphous solid form of free base Compound A is as indicated by a measured X-ray powder diffraction pattern (XRPD). In one embodiment, the XRPD is substantially as shown in FIG.

[0312]

[0354] In one embodiment, described herein is an amorphous solid form of free base Compound A having a TGA thermogram substantially corresponding to the representative TGA and DSC thermograms shown in Figure 33. In some embodiments, the amorphous form exhibits a TGA thermogram that comprises a total mass loss of approximately 9.3% of the total mass of the sample.

[0313]

[0355] In yet another embodiment, the amorphous solid form of Compound A is pure. In some embodiments, the pure amorphous solid form of Compound A is substantially free of other solid forms, such as crystalline solids described herein. In some embodiments, the purity is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5%, or about 99.9% or more.

[0314] Pharmaceutical Compositions

[0356] The compounds described herein can be administered, for example, orally, intramuscularly, subcutaneously, intradermally, transdermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subconjunctivally, intravesically, intramucosally, intrapericardially, intraumbilical, intraocular, intraorbitally, intravitreally (e.g., by intravitreal injection), by eye drop, topically, transdermally, parenterally, by inhalation, by injection, by implantation, by infusion, by continuous infusion, by direct local perfusion of target cells, by catheter, by lavage, in a cream, or in a lipid composition. The compounds described herein can be formulated into pharmaceutical compositions provided herein suitable for oral administration. In another embodiment, the compounds described herein can be administered intramuscularly.

[0315]

[0357] In one embodiment, the compounds described herein are administered to a subject as a pharmaceutical composition that can be administered orally or parenterally.The pharmaceutical compositions of the compounds described herein can be prepared as oral dosage forms such as capsules, microcapsules, tablets (coated and uncoated tablets), granules, powders, pills, or suppositories.The compounds described herein can be formulated for topical or parenteral use, where the compounds are dissolved or otherwise suspended in a solution suitable for injection, suspension, syrup, cream, ointment, gel, spray, solution, and emulsion.

[0316]

[0358] The pharmaceutical compositions described herein may include one or more pharma- ceutically acceptable additives, such as, but not limited to, sucrose, starch, mannitol, sorbitol, glucose, sorbitol, calcium or calcium phosphate, talc, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylstarch, 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 acetate, polyvinylpyrrolidone, aluminum stearate), water, and cocoa butter.For example, the use of such additives as diluents, binders, lubricants, and disintegrants is well known in the art.

[0317]

[0359] The pharmaceutical compositions described herein include an effective amount of a compound described herein (e.g., Compound A, Compound B, Compound C, Compound D, or a solid form thereof). The dose of the compounds described herein can be a measure of a specific amount of the compound (e.g., a standard dose) or can be measured, for example, as a function of the patient's body weight. In one embodiment, the compounds described herein are 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, the compounds described herein are 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 yet another embodiment, the compounds described herein are 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.

[0318]

[0360] In one embodiment, the compound 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 described herein is administered in an amount of about 10 mg. In yet another embodiment, the compound described herein is administered in an amount of about 30 mg. In yet another embodiment, the compound described herein is administered in an amount of about 90 mg. In one embodiment, the pharmaceutical composition comprising the compound described herein is administered once daily (QD) in the above-mentioned prescribed amount. The compound can be Compound B, or a solid form thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, or Form G). In another embodiment, the compound is a solid form of Compound B (e.g., Form B, Form D, or Form F). In one embodiment, the compound is Compound C, or Form 1 or Form 2 of Compound C. In another embodiment, the compound is Compound D, or a solid form described herein.

[0319]

[0361] In another embodiment, the compound 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 compound administered is Compound B in an amount of about 1, 10, 30, 50, 90, 100, or 150 mg. The dose of the compound described herein can be provided as a single dose (e.g., a single tablet or capsule of a given dosage amount) or as multiple doses (e.g., two or more tablets or capsules equal to a dosage amount) given over a period of time. The compound can be Compound B, or a solid form thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, or Form G). In another embodiment, the compound is a solid form of Compound B (e.g., Form B, Form D, or Form F). In one embodiment, the compound is Compound C or Form 1 or Form 2 of Compound C. In another embodiment, the compound is Compound D or a solid form described herein.

[0320]

[0362] 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 third day (Q3D), or once a week. Furthermore, doses of the pharmaceutical compositions provided herein that include the compounds described herein can be administered before a meal (ac), after a meal (pc), or during a meal. In one embodiment, the compounds described herein are administered QD during a treatment period (a period during which a drug is administered to a patient described herein), followed by a rest period (a period during which a drug is not administered to a patient described herein). The rest period can include administration of an anticancer agent other than the compounds described herein. In one embodiment, the compounds described herein are formulated for oral administration as provided herein and are administered QD for 20-28 days, followed by a rest period of 3-10 days. In another embodiment, the compounds are administered QD without a rest period.

[0321]

[0363] Preferably, the compounds described herein are formulated for oral administration. Oral administration can facilitate patient compliance in taking the compounds (e.g., formulated as pharmaceutical compositions), thereby increasing compliance and efficacy. Oral pharmaceutical compositions comprising the compounds described herein include, but are not limited to, tablets (e.g., coated, uncoated and chewable) and capsules (e.g., hard gelatin capsules, soft gelatin capsules, enteric capsules, and sustained release capsules). Tablets can be prepared by direct compression, wet granulation, or dry granulation. Oral pharmaceutical compositions comprising the compounds described herein can be formulated as understood in the art for sustained or extended release. In one embodiment, compound B or a solid form (e.g., Form B, Form D, or Form F) described herein is formulated as a tablet or capsule for oral administration in the amount specified herein.

[0322]

[0364] Further provided herein is a compound of the formula: The compound has the following structure: TIFF0007660040000086.tif144170.

[0323]

[0365] Compounds M1, M2, M3, M4 can be considered metabolites and / or degradants of compound B, including the solid forms described herein. In certain cases, such compounds can be found in compositions described herein that have been stored for a period of time at about 50%, 55%, 60%, 65%, 70%, 75%, 80% or more relative humidity (RH). Such compounds can also be found at elevated temperatures of about 30°C, 35°C, 40°C, 45°C, or about 50°C. In one embodiment, compounds M1, M2, M3, or M4 can be found in compositions described herein that contain less than about 30 mg of compound B or a solid form. In certain cases, such compounds can be found in compositions that contain uncoated tablets as described herein.

[0324]

[0366] In some embodiments, the compositions described herein comprise Compound B or a solid form of Compound B (e.g., Form A, Form B, Form C, Form D, Form E, Form F, or Form G). The compositions described herein comprise less than 0.01%, 0.02%, 0.03%, 0.04, 0.05, 0.1, 0.15, 0.75, 0.2, 0.225, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1% w / w of one or more of M1, M2, M3, or M4. In one embodiment, the compositions described herein comprise less than about 0.5% w / w of one or more of M1, M2, M3, or M4.

[0325] Cancer Treatment Methods

[0367] The compounds and solid forms described herein can be administered in an effective amount (e.g., the amounts described herein) to treat cancer. It is understood that the methods described herein also include treatment with a pharmaceutical composition described herein that includes a compound described herein (e.g., Compound B or a solid form thereof) and one or more pharma- ceutically acceptable excipients.

[0326]

[0368] In one embodiment, provided herein is a method of treating cancer by administering to a patient having cancer an effective amount of Compound B described herein. In one embodiment, Compound B is a solid form described herein (e.g., Form A, Form B, Form C, Form D, Form E, Form F, or Form G).

[0327]

[0369] In another embodiment provided herein, Form A of Compound B can be administered as described herein to treat a patient having a cancer as defined herein.

[0328]

[0370] In another embodiment provided herein, Form B of Compound B can be administered as described herein for a patient having a cancer as defined herein.

[0329]

[0371] In another embodiment provided herein, Form C of Compound B can be administered as described herein for patients with cancer as defined herein.

[0330]

[0372] In another embodiment provided herein, Form D of Compound B can be administered as described herein for patients with cancer as defined herein.

[0331]

[0373] In another embodiment provided herein, Form E of Compound B can be administered as described herein for patients with cancer as defined herein.

[0332]

[0374] In another embodiment provided herein, Form F of Compound B can be administered as described herein for patients with cancer as defined herein.

[0333]

[0375] In another embodiment provided herein, Form G of compound B can be administered as described herein to treat a patient having lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer, as defined herein.

[0334]

[0376] In another aspect provided herein, an amorphous non-crystalline form of Compound A or Compound B can be administered as described herein to treat a patient having lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer, as defined herein.

[0335]

[0377] 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 an effective amount of Compound B or a solid form described herein to a patient having said cancer. In one embodiment, the cancer is ovarian cancer or endometrial cancer. In one embodiment, the cancer is breast cancer. In one embodiment of such a method, Compound B is a solid form described herein (e.g., Form A, Form B, Form C, Form D, Form E, Form F, or Form G).

[0336]

[0378] In a further aspect, Form A of Compound B can be administered as described herein to treat patients with lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer, as defined herein.

[0337]

[0379] In a further aspect, Form B of Compound B can be administered as described herein to treat patients with lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer, as defined herein.

[0338]

[0380] In a further aspect, Form C of Compound B can be administered as described herein to treat patients with lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer, as defined herein.

[0339]

[0381] In a further aspect, Form D of Compound B can be administered as described herein to treat patients with lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer as defined herein.

[0340]

[0382] In a further aspect, Form E of Compound B can be administered as described herein to treat patients with lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer, as defined herein.

[0341]

[0383] In a further aspect, Form F of Compound B can be administered as described herein to treat patients with lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer as defined herein.

[0342]

[0384] In a further aspect, Form G of Compound B can be administered as described herein to treat patients with lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer, as defined herein.

[0343]

[0385] In a further aspect, an amorphous non-crystalline form of Compound A or Compound B can be administered as described herein to treat a patient having lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer, as defined herein.

[0344]

[0386] Further provided herein is a method of treating breast cancer in a patient having breast cancer by administering an effective amount of Compound B or a solid form of Compound B described herein. One embodiment is a method of treating breast cancer in such a patient by administering an effective amount of a solid form of Compound B described herein. In one embodiment, the method comprises administering to a patient having breast cancer an effective amount of Form B of Compound B described herein, thereby treating breast cancer in the patient. In one embodiment, the method comprises administering to a patient having breast cancer an effective amount of pure Compound B (e.g., substantially free of other solid forms described herein, e.g., substantially free of Form D and / or Form F) to treat breast cancer in the patient. In another embodiment, the method comprises administering to a patient having breast cancer an effective amount of Form D of Compound B described herein, thereby treating breast cancer in the patient. In another embodiment, the method comprises administering to a patient having breast cancer an effective amount of Form F of Compound B described herein, thereby treating breast cancer in the patient. In yet another embodiment, the method comprises administering to a patient having breast cancer an effective amount of Form A of Compound B as described herein, thereby treating breast cancer in the patient. In yet another embodiment, the method comprises administering to a patient having breast cancer an effective amount of Form C of Compound B as described herein, thereby treating breast cancer in the patient. In yet another embodiment, the method comprises administering to a patient having breast cancer an effective amount of Form E of Compound B as described herein, thereby treating breast cancer in the patient. In yet another embodiment, the method comprises administering to a patient having breast cancer an effective amount of Form G of Compound B as described herein, thereby treating breast cancer in the patient. In yet another embodiment, the method comprises administering to a patient having breast cancer an effective amount of the amorphous non-crystalline form of Compound B as described herein, thereby treating breast cancer in the patient.

[0345]

[0387] A compound described herein (e.g., Compound B or a solid form thereof described herein) can be used in the manufacture of a medicament for use in treating breast cancer as described herein.

[0346]

[0388] The methods of treating breast cancer provided herein include treatments where the breast cancer can be hormone receptor positive breast cancer (e.g., ER+ breast cancer), HER2 positive breast cancer, HER2 negative breast cancer, or triple negative breast cancer (TNBC).

[0347]

[0389] In one embodiment, breast cancer is HER2-negative breast cancer.HER2-negative breast cancer can be defined here as, for example, HER2 IHC score of 0 or 1+, or IHC score of 2+ with negative fluorescence, chromogenic, or silver in situ hybridization test showing absence of HER2-gene amplification, or HER2 / CEP17 ratio <2.0, or 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.

[0348]

[0390] In another embodiment, the breast cancer is locally advanced or metastatic breast cancer (mBC).

[0349]

[0391] In one embodiment, Compound B or a solid form thereof (e.g., Form B, Form D, or Form F) can be administered as a component of adjuvant therapy. In another embodiment, Compound B or a solid form thereof (e.g., Form B, Form D, or Form F) can be administered as a component of neoadjuvant therapy.

[0350]

[0392] The breast cancer patients described herein can be premenopausal prior to treatment with a compound or solid form described herein. The breast cancer patients described herein can be postmenopausal prior to treatment with a compound or solid form described herein.

[0351]

[0393] The methods provided herein include administering to a patient an effective amount of Compound B or a solid form thereof as described herein, in an amount as defined herein. The effective amount can 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, Compound B or a solid form thereof as described herein is administered orally. In one embodiment, Compound B or a solid form thereof is administered as a tablet (e.g., a coated or uncoated tablet). In another embodiment, Compound B or a solid form thereof is administered as a capsule. Accordingly, provided herein are compositions suitable for administration to breast cancer patients, such compositions comprising Compound B or a solid form thereof as described herein 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 defined herein. When administered according to the methods provided herein, Compound B or a solid form thereof can be pure as described herein.

[0352]

[0394] The patient in the above method may have previously been treated with one or more anti-cancer drugs or radiation therapy. For example, in one embodiment, the patient has had prior treatment (e.g., in 1L, 2L, 3L or more line therapy) with doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, albumin-bound paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparib, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxy tamoxifen, raloxifene, droloxifene, trioxyphene, keoxifene, ftutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprolide, pegfilgrastim, filgrastim, or venetoclax.

[0353]

[0395] In another embodiment, the patient may have been previously treated with an AKT inhibitor, a CDK4 / 6 inhibitor, a PARP inhibitor, or an aromatase inhibitor (e.g., in 1L, 2L, 3L or higher line therapy). In one embodiment, the AKT inhibitor is ipatasertib (GDC-0068). In one embodiment, the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib. In certain cases, the patient may have been previously treated with: (1) abemaciclib, ribociclib, or palbociclib; (2) ipatasertib; (3) everolimus or fulvestrant; (4)-trastuzumab emtansine, trastuzumab, pertuzumab, or atezolizumab; or (5) alemtuzumab, bevacizumab, cetuximab, panitumumab, rituximab, tositumomab, or combinations thereof. The patients described herein may have undergone surgery prior to treatment with Compound B or a solid form thereof.

[0354]

[0396] In another embodiment, the patient herein may be refractory to one or more anti-cancer therapies. For example, the patient herein is refractory to an aromatase inhibitor. In another example, the patient herein is refractory to a selective estrogen receptor degrader (SERD), such as fulvestrant. In yet another example, the patient herein is refractory to one or more endocrine therapies, such as clomiphene, toremifene, raloxifene, anodrine, bazedoxifene, broparestol, cyclophenyl, lasofoxifene, ormeloxifene, acolbifene, elacestrant, brilanestrant, clomifenoxide, droloxifene, etacstil, or ospemifene. In another embodiment, the patient herein is refractory to abemaciclib, anastrozole, exemestane, fulvestrant, goserelin, letrozole, leuprorelin, megestrol, palbociclib, tamoxifen, or toremifene. In another example, the patient is refractory to treatment with trastuzumab emtansine, trastuzumab, pertuzumab, atezolizumab, pembrolizumab, durvalumab, avelumab, or nivolumab.

[0355]

[0397] The compounds described herein can also be used in methods that involve inhibiting ER alpha in a patient. Such methods include administering to the patient an amount of a compound described herein (e.g., Compound A or Compound B, including solid forms thereof described herein).

[0356] Combination therapy

[0398] The compounds and solid forms described herein can be administered in combination with one or more anti-cancer agents. The administration of "combination" as described herein includes sequential administration (in any order) and simultaneous administration of the compounds described herein with one or more anti-cancer therapies. Thus, provided herein is a method of treating breast cancer in a patient having breast cancer, such method comprising administering compound B or solid forms described herein in combination with one or more additional anti-cancer therapies. In one embodiment, the anticancer therapy comprises doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, albumin-bound paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparib, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxy tamoxifen, raloxifene, droloxifene, trioxyphene, keoxifene, ftutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprolide, pegfilgrastim, filgrastim, or venetoclax.

[0357]

[0399] In one embodiment, provided herein is a method of treating breast cancer in a patient having breast cancer by administering an effective amount of Compound B or a solid form described herein in combination with doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, albumin-bound paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparib, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxy tamoxifen, raloxifene, droloxifene, trioxyphene, keoxifene, ftutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprolide, pegfilgrastim, filgrastim, or venetoclax.

[0358]

[0400] In another aspect, provided herein is a method of treating breast cancer in a patient with breast cancer by administering an effective amount of Compound B or a solid form described herein in combination with paclitaxel, albumin-bound paclitaxel, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxy tamoxifen, raloxifene, droloxifene, trioxyphene, keoxifene, or venetoclax. In yet another aspect, provided herein is a method of treating breast cancer in a patient having breast cancer by administering an effective amount of Compound B or a solid form described herein in combination with fulvestrant, paclitaxel, albumin-bound paclitaxel, clomiphene, toremifene, raloxifene, anodrin, bazedoxifene, proparestrol, cyclophene, lasofoxifene, ormeloxifene, acolbifene, elacestrant, brilanestrant, clomifenoxide, droloxifene, etacstil, or ospemifene.

[0359]

[0401] In yet another aspect, provided herein is a method of treating breast cancer in a patient having breast cancer by administering an effective amount of Compound B or a solid form described herein in combination with a CDK4 / 6 inhibitor, a PARP inhibitor, or an aromatase inhibitor.

[0360]

[0402] In a further aspect, provided herein is a method of treating breast cancer in a patient having breast cancer as described herein, the method comprising administering an effective amount of compound B or a solid form as described herein in combination with a CDK4 / 6 inhibitor that is abemaciclib, ribociclib, or palbociclib. In a preferred embodiment, the method comprises administering compound B or a solid form as described herein in combination with palbociclib. In yet another embodiment, the method comprises administering compound B or a solid form as described herein in combination with abemaciclib or ribociclib. In another aspect, provided herein is a kit comprising: (i) a unit dosage form of compound B or a solid form thereof; (ii) a second unit dosage form of a CDK4 / 6 inhibitor (e.g., palbociclib); and a container containing each dosage form.

[0361]

[0403] The dose of abemaciclib can be 50mg to 500mg daily, or 150mg to 450mg daily, and administration can be daily in a 28-day cycle, or less than 28 days in a 28-day cycle, such as 21 days in a 28-day cycle, or 14 days in a 28-day cycle, or 7 days in a 28-day cycle. In one embodiment, abemaciclib is administered once a day, or preferably on the indicated schedule if administration is oral. If administered twice a day, it can be administered 4 hours, 8 hours, or 12 hours apart. In some embodiments, abemaciclib is administered at 150mg per dose, with each dose administered about 12 hours apart. In some embodiments, the dose of abemaciclib is administered according to the package insert.

[0362]

[0404] The dose of ribociclib can be 200mg to 1,000mg daily; or 250mg to 750mg daily, and administration can be daily in a 28-day cycle, or less than 28 days in a 28-day cycle, such as 21 days in a 28-day cycle, or 14 days in a 28-day cycle, or 7 days in a 28-day cycle. In one embodiment, ribociclib is administered once a day when administration is oral. In some embodiments, the dose of ribociclib is administered according to the package insert.

[0363]

[0405] The dose of palbociclib can be 25mg to 250mg daily, or 50mg to 125mg daily, or 75mg to 125mg daily, or 75mg to 100mg daily, or 125mg daily. Administration can be daily in a 28-day cycle, or less than 28 days in a 28-day cycle, such as 21 days in a 28-day cycle, or 14 days in a 28-day cycle, or 7 days in a 28-day cycle. In one embodiment, palbociclib is administered once a day when administration is oral. In some embodiments, the dose of palbociclib is administered according to the package insert.

[0364]

[0406] In another aspect provided herein, the methods described herein include administering an effective amount of Compound B or a solid form described herein in combination with an aromatase inhibitor (AI) that is letrozole, anastrozole, exemestane, or testolactone.

[0365]

[0407] In yet another aspect, provided herein is a method of treating breast cancer in a patient having breast cancer by administering an effective amount of compound B or a solid form described herein in combination with a cancer immunotherapy (e.g., an antibody). In one embodiment, compound B or a solid form described herein is administered in combination with trastuzumab emtansine, trastuzumab, pertuzumab, atezolizumab, pembrolizumab, durvalumab, avelumab, or nivolumab, or a combination thereof. In one embodiment, compound B or a solid form described herein is administered in combination with a cancer immunotherapy comprising a PD-1 or PD-L1 inhibitor, and the cancer immunotherapy is atezolizumab, pembrolizumab, or nivolumab.

[0366]

[0408] Administration of a compound described herein (e.g., Compound B or a solid form described herein) results in a patient having adverse events (AEs) characterized as Grade 2 or less. In one embodiment, a patient administered Compound B or a solid form described herein has an AE of Grade 2 or less. EXAMPLES

[0367]

[0409] The following examples are offered by way of illustration and not by way of limitation.

[0368]

[0410] All reagents and solvents used in the synthesis of compounds described herein were purchased from commercial suppliers and used without further purification. Anhydrous solvents (dichloromethane) were utilized. Commercially available solvents were not further purified.

[0369]

[0411] All reactions were carried out in screw-cap vials equipped with Teflon septa under a nitrogen atmosphere.

[0370]

[0412] Flash column chromatography was performed using a Teledyne Isco CombiFlash with pre-packed RediSepRf gold-silica cartridges. (R) It was carried out using an Rf instrument.

[0371]

[0413] Unless otherwise indicated, yields reported are for isolated material and are corrected for residual solvent.

[0372]

[0414] The compound is 1 H NMR, 13 Characterized by one or more of C NMR, melting point and HRMS, and HPLC analysis (e.g., to check purity).

[0373]

[0415] 1 H, and 13 C nuclear magnetic resonance spectra were recorded on a Bruker 400 MHz instrument at room temperature. All 1 1 H NMR spectra were measured in parts per million (ppm) relative to the residual chloroform signal (7.26 ppm) or dimethylsulfoxide (2.50 ppm) in deuterated solvents. 1 H NMR data are reported as follows: chemical shift, multiplicity (br=broad signal, overlap=overlap, s=singlet, d=doublet, t=triplet, q=quartet, p=pentet, m=multiplet), coupling constants and integration. All 13 C NMR spectra are reported in ppm relative to deuterated chloroform (77.06 ppm) or deuterated dimethylsulfoxide (39.53 ppm) and are given in full unless otherwise stated. 1 H decoupling. HPLC analyses were performed on an Agilent 1260 Infinity HPLC system equipped with a UV detector at 220 nm using an Ace Super C18 column. Melting points were obtained using a Buchi B-540 Melting Point Apparatus and are uncorrected. High resolution mass spectrometry (HRMS) data were obtained on a Thermo Scientific Orbitrap Fusion mass spectrometer.

[0374]

[0416] Examples 1-3: Alkylation of indoles

[0375]

[0417] The alkylation of indole was carried out by the sequence of Boc protection (Example 1), sulfamide formation (Example 2), and indole alkylation (Example 3).

[0376]

[0418] Example 1: Boc protection

[0419] Example 1: Boc Protection General Reaction Scheme.

[0377]

[0420] The Boc protection can be carried out according to the following general reaction scheme: A and R B correspond to the various functional groups in the protection reactions of Example 1 below, where the asterisks represent chiral centers] were carried out according to: TIFF0007660040000087.tif24170

[0378]

[0421] Example 1A: Preparation of tert-butyl (S)-(2-hydroxy-1-(4-methoxyphenyl)ethyl)carbamate: TIFF0007660040000088.tif25170

[0379]

[0422] General Reaction Scheme 1 above was carried out as follows: To a slurry of (S)-2-amino-2-(4-methoxyphenyl)ethan-1-ol hydrochloride (1.04 g, 5.10 mmol, 100 mol%) in THF (4.4 mL) was added Boc2O (1.21 mL, 5.61 mmol, 110 mol%), NaHCO3 (451 mg, 5.10 mmol, 100 mol%), and water (4.4 mL) at rt. The solution was stirred at rt for 18 h and extracted with iPrOAc (20 mL x 2). The organic layer was washed with saturated brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give the product without further purification. The reported yield of Example 1A is 1 Corrected based on residual solvent from H NMR. The reaction gave tert-butyl (S)-(2-hydroxy-1-(4-methoxyphenyl)ethyl)carbamate (1.36 g, 100% yield) as a white solid. mp: 139.0-139.9 °C; FTIR (neat, cm-1 ) 3370, 2984, 2837, 1681, 1613, 1512, 1461; 1 H NMR(400MHz,CDCl3):δ 7.24-7.20(m,2H), 6.92-6.86(m,2H), 5.10(d,J=7.2Hz,1H), 4.72(br,1H), 3.82(t,J=5.6Hz,2H), 3.80(s,3H), 2.35(br,1H), 1.43(s,9H); 13 C NMR (100MHz, CDCl3): δ 159.1, 156.2, 131.6, 127.7, 114.2, 80.0, 66.8, 56.4, 55.3, 28.4.

[0380]

[0423] Example 1B: Preparation of tert-butyl (R)-(1-cyclopropyl-2-hydroxyethyl)carbamate: TIFF0007660040000089.tif17170

[0381]

[0424] The general reaction scheme of Example 1A above was carried out with (R)-2-amino-2-cyclopropylethan-1-ol (1.16 g, 11.5 mmol, 100 mol%) to give tert-butyl (R)-(1-cyclopropyl-2-hydroxyethyl)carbamate (2.31 g, 100% yield) as a white solid. mp: 70.0-70.8 °C; FTIR (neat, cm -1 ) 3358, 2974, 2937, 1682, 1521, 1366; 1 H NMR(400MHz,CDCl3):δ 4.80(br,1H), 3.80(ddd,J=10.8, 6.8, 3.2Hz,1H), 3.67(ddd,J=10.8, 6.0, 4.8Hz,1H), 2.94(dtd,J=9.6, 6.4, 3 .2Hz,1H), 2.81(br,1H), 1.45(s,9H), 0.85(dtt,J=9.6, 8.0, 4.8Hz,1H), 0.60-0.47(m,2H), 0.44-0.25(m,2H); 13 C NMR (100MHz, CDCl3): δ 156.6, 79.7, 66.3, 57.9, 28.4, 13.0, 3.3, 2.9.

[0382]

[0425] Example 1C: Preparation of tert-butyl ((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate: TIFF0007660040000090.tif18170

[0383]

[0426] The general reaction scheme of Example 1A above was carried out with (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (5.15 g, 34.5 mmol, 100 mol%) to give tert-butyl ((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate (8.61 g, 100% yield) as a white solid. mp: 67.3-68.4 °C; FTIR (neat, cm -1 )3428, 3350, 2983, 2933, 1688, 1509; 1 H NMR(400MHz,CDCl3):δ 7.31-7.26(m,1H), 7.26-7.18(m,3H), 5.17(br,1H), 5.05(br,1H), 4.57(ddd,J=7.2, 4.8, 2.0Hz,1 H), 3.12(dd,J=16.8, 5.2Hz,1H), 2.91(dd,J=16.8, 2.4Hz,1H), 2.31(d,J=4.8Hz,1H), 1.50(s,9H); 13 C NMR (100MHz, CDCl3): δ 156.3, 140.9, 139.9, 128.2, 127.1, 125.3, 124.5, 79.9, 73.6, 58.9, 39.4, 28.4.

[0384]

[0427] Example 1D: Preparation of tert-butyl (S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate: TIFF0007660040000091.tif22170

[0385]

[0428] The general reaction scheme of Example 1A above was carried out with (S)-2-amino-2-(3-fluorophenyl)ethan-1-ol (1.36 g, 8.73 mmol, 100 mol%) to give tert-butyl (S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate (2.23 g, 100% yield) as a white solid. mp: 106.5-107.9 °C; FTIR (neat, cm -1 ) 3251, 3059, 2977, 2901, 1671, 1587, 1543; 1 H NMR(400MHz,CDCl3):δ 7.33(ddd,J=7.6, 7.6, 6.0Hz,1H), 7.12-7.07(m,1H), 7.05-6.95(m,2H), 5 .24(br,1H), 4.77(br,1H), 3.93-3.77(m,2H), 2.02(br,1H), 1.44(s,9H); 13 C NMR(100MHz,CDCl3):δ 163.0(d, 1 J CF =246Hz), 156.0, 142.5, 130.2(d, 3 J CF =9Hz), 122.2(d, 4 J CF =3Hz), 114.5(d, 2 J CF =21Hz), 113.6(d, 2 J CF =21Hz), 80.2, 66.2, 56.3, 28.3; 19 F NMR (CDCl3, 376MHz): δ-112.4.

[0386]

[0429] Example 1E: Preparation of (S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate TIFF0007660040000092.tif23170

[0387]

[0430] The general reaction scheme of Example 1A above was carried out with (S)-2-amino-2-(3-(trifluoromethyl)phenyl)ethan-1-ol hydrochloride (1.00 g, 4.12 mmol, 100 mol%) to give (S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate (1.26 g, 100% yield) as a white solid. mp: 50.3-52.5° C.; FTIR (neat, cm -1 ) 3368, 3254, 2979, 2939, 1691, 1510, 1453, 1333; 1 H NMR(400MHz,CDCl3):δ 7.59-7.54(m,2H), 7.53-7.45(m,2H), 5.31(d,J=6.4Hz,1H), 4.83(br,1H), 3.9 2(ddd,J=11.2, 6.8, 4.0Hz,1H), 3.88-3.79(m,1H), 1.94(br,1H), 1.43(s,9H); 13 C NMR (100MHz, CDCl3): δ 156.1, 141.1, 130.9(q, 2 J CF =32Hz), 130.1, 129.0, 124.3(q, 3 J CF =4Hz), 124.1(q, 1 J CF =270Hz), 123.4(q, 3 J CF =4Hz), 80.3, 65.8, 56.3, 28.2; 19 F NMR (CDCl3, 376 MHz): δ-62.6. Example 2: Formation of sulfamidate

[0388]

[0431] Example 2: General reaction scheme for sulfamidate formation

[0432] The formation of sulfamidates can be carried out according to the following general reaction scheme: A and R B correspond to the various functional groups in the reaction of Example 2 below, where an asterisk represents a chiral center] was carried out according to: TIFF0007660040000093.tif34170.

[0389]

[0433] Example 2A: Preparation of tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide: TIFF0007660040000094.tif20170

[0390]

[0434] General Reaction Scheme 2 above was carried out as follows: To a cold (-40°C) solution of SOCl2 (10.9 mL, 149 mmol, 250 mol%) in CHCl2 (60.0 mL) was added a solution of tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate (15.0 g, 59.7 mmol, 100 mol%) in CHCl2 (60.0 mL) at -40°C over 60 min. Pyridine (25.3 mL, 313 mmol, 525 mol%) was then added to the reaction mixture at -40°C over 30 min. The reaction mixture was stirred at -40°C for 2 h, solvent switched to CHCl2 / iPrOAc (1:1), and filtered. The filtrate was washed with saturated brine solution (20 mL), dried (NaSO4), filtered, and concentrated under reduced pressure. The residue was dissolved in CH3CN (60.0 mL) at 0 °C. NaIO4 (14.0 g, 65.7 mmol, 110 mol%), RuCl3 (61.9 mg, 0.298 mmol, 0.5 mol%), and water (60.0 mL) were added to the reaction mixture at 0 °C and stirred for 15 min. The reaction mixture was heated to room temperature, stirred at room temperature for 2 h, extracted with iPrOAc (20 mL), washed with saturated NaHCO3 solution (15 mL), saturated brine solution (15 mL), dried (Na2SO4), filtered, and purified by chromatography on SiO2. The specific gradient used for each sample is included in the characterization data. All reported yields are 1 Corrected based on residual solvent from H NMR. Reaction 2A gave tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (18.7 g, 56% yield) as a white solid. Column gradient: 0 to 5% CH3OH in CH2Cl2. mp: 134.4-135.0 °C; FTIR (neat, cm -1) 3261, 2979, 2903, 1712, 1673, 1540; 1 H NMR (400MHz, CDCl3): δ 7.38-7.20(m,5H), 4.49-4.40(m,2H), 4.35-4.28(m,1H), 3.37(dd,J=14.0, 4.0Hz,1H), 2.98-2.87(m,1H), 1.56(s,9H); 13 C NMR (100MHz, CDCl3): δ 148.5, 135.2, 129.5, 129.1, 127.5, 85.6, 68.8, 58.6, 37.9, 28.0.

[0391]

[0435] Example 2B: Preparation of tert-butyl (S)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide: TIFF0007660040000095.tif22170

[0392]

[0436] The general reaction scheme of Example 2A above was carried out with tert-butyl (S)-(2-hydroxy-1-phenylethyl)carbamate (10.0 g, 42.1 mmol, 100 mol%) to give the compound tert-butyl (S)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5.23 g, 42% yield) as a white solid. Column gradient: 0 to 5% CHOH in CH2Cl2. mp: 144.3-145.0 °C; FTIR (neat, cm -1 )2976, 1722, 1458, 1377; 1 H NMR (400MHz, CDCl3): δ 7.44-7.35(m,5H), 5.28(dd,J=6.4, 4.0Hz,1H), 4.87(dd,J=9.2, 6.4Hz,1H), 4.39(dd,J=9.2, 4.4Hz,1H), 1.42(s,9H); 13 C NMR (100MHz, CDCl3): δ 148.3, 137.0, 129.2, 129.1, 126.2, 85.5, 71.8, 60.8, 27.8.

[0393]

[0437] Example 2C: Preparation of tert-butyl (S)-4-(4-methoxyphenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide: TIFF0007660040000096.tif25170

[0394]

[0438] The general reaction scheme of Example 2A above was carried out with tert-butyl (S)-(2-hydroxy-1-(4-methoxyphenyl)ethyl)carbamate (1.45 g, 5.42 mmol, 100 mol%) to give the compound tert-butyl (S)-4-(4-methoxyphenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.05 g, 59% yield) as a white solid. Column gradient: 0 to 5% CHOH in CH2Cl2. mp: 151.6-153.0 °C; FTIR (neat, cm -1 ) 2979, 2933, 2838, 1721, 1636, 1510, 1457; 1 H NMR(400MHz,CDCl3):δ 7.37-7.32(m,2H), 6.95-6.90(m,2H), 5.24(dd,J=6.8, 4.4Hz,1H), 4.84(dd ,J=9.2, 6.8Hz,1H), 4.39(dd,J=9.2, 4.4Hz,1H), 3.82(s,3H), 1.44(s,9H); 13 C NMR (100MHz, CDCl3): δ 160.2, 148.3, 128.9, 127.7, 114.6, 85.5, 72.0, 60.5, 55.4, 27.9.

[0395]

[0439] Example 2D: Preparation of tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide: TIFF0007660040000097.tif19170

[0396]

[0440] The general reaction scheme of Example 2A above was carried out with tert-butyl (R)-(1-hydroxypropan-2-yl)carbamate (5.00 g, 28.5 mmol, 100 mol%) to give the compound tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (3.85 g, 57% yield) as a white solid. Column gradient: 0 to 5% CHOH in CH2Cl2. FTIR (neat, cm -1 )3245, 2982, 1719, 1402, 1329; 1 H NMR (400MHz, CDCl3): δ 4.66(dd,J=9.2, 6.0Hz,1H), 4.41(qdd, J=6.4, 6.0, 2.8Hz,1H), 4.19(dd,J=9.2, 2.8Hz,1H), 1.54(s,9H), 1.50(d,J=6.4Hz,3H); 13 C NMR (100MHz, CDCl3): δ 148.5, 85.4, 71.4, 53.8, 28.0, 18.3.

[0397]

[0441] Example 2E: Preparation of tert-butyl (R)-4-isopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide: TIFF0007660040000098.tif20170

[0398]

[0442] The general reaction scheme of Example 2A above was carried out with tert-butyl (R)-(1-hydroxy-3-methylbutan-2-yl)carbamate (5.00 g, 24.6 mmol, 100 mol%) to give the compound tert-butyl (R)-4-isopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (3.93 g, 60% yield) as a white solid. Column gradient: 0 to 5% CHOH in CH2Cl2. mp: 104.8-105.8 °C; 1H NMR(400MHz,CDCl3):δ 4.55(dd,J=9.6, 6.4Hz,1H), 4.38(dd,J=9.6, 2.0Hz,1H), 4.17(ddd,J=6.4, 5.2, 1.6Hz,1H), 2.24(qqd,J=6.8, 6.8, 5.2Hz,1H), 1.53(s,9H), 1.00(d,J=6.8Hz,3H), 0.95(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ 149.1, 85.3, 67.0, 62.0, 30.0, 27.9, 18.0, 16.4.

[0399]

[0443] Example 2F: Preparation of tert-butyl (R)-4-cyclopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide: TIFF0007660040000099.tif18170

[0400]

[0444] The general reaction scheme of Example 2A above was carried out with tert-butyl (R)-(1-cyclopropyl-2-hydroxyethyl)carbamate (2.31 g, 11.5 mmol, 100 mol%) to give tert-butyl (R)-4-cyclopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.36 g, 45% yield) as a white solid. Column gradient: 0 to 5% CHOH in CH2Cl2. mp: 52.7-55.7 °C; FTIR (neat, cm -1 ) 2977, 1734, 1460, 1363; 1 H NMR(400MHz,CDCl3):δ 4.64(dd,J=9.2, 6.0Hz,1H), 4.40(dd,J=8.8, 2.0Hz,1H), 3.77(ddd,J=9.2, 6.0, 2.0Hz,1H) , 1.54(s,9H), 1.35-1.23(m,1H), 0.74-0.65(m,2H), 0.63-0.54(m,1H), 0.29-0.20(m,1H); 13 C NMR (100MHz, CDCl3): δ 148.9, 85.3, 71.1, 61.6, 27.9, 14.3, 4.4, 1.7.

[0401]

[0445] Example 2G: Preparation of tert-butyl (3aR,8aS)-8,8a-dihydroindeno[1,2-d][1,2,3]oxathiazole-3(3aH)-carboxylate 2,2-dioxide: TIFF0007660040000100.tif20170

[0402]

[0446] The general reaction scheme of Example 2A above was carried out with tert-butyl ((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate (9.12 g, 36.6 mmol, 100 mol%) to give tert-butyl (3aR,8aS)-8,8a-dihydroindeno[1,2-d][1,2,3]oxathiazole-3(3aH)-carboxylate 2,2-dioxide (7.50 g, 66% yield) as a white solid. Column gradient: 0 to 5% CHOH in CH2Cl2. mp: 134.2-135.0 °C; FTIR (neat, cm -1 ) 2988, 2937, 1732, 1462, 1375; 1 H NMR(400MHz,CDCl3):δ 7.62-7.57(m,1H), 7.39-7.24(m,3H), 5.71(d,J=5.6Hz,1H), 5.50(dt,J=6.0, 3.2Hz,1H), 3.38(d,J=3.2Hz,1H), 1.62(s,9H); 13 C NMR (100MHz, CDCl3): δ 149.6, 138.4, 137.9, 129.9, 128.4, 126.2, 125.2, 85.7, 82.2, 65.0, 36.5, 28.0.

[0403]

[0447] Example 2H: Preparation of tert-butyl (S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide: TIFF0007660040000101.tif19170

[0404]

[0448] The general reaction scheme of Example 2A above was carried out with tert-butyl (S)-(2-hydroxypropyl)carbamate (6.25 g, 35.7 mmol, 100 mol%) to give the compound tert-butyl (S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (6.10 g, 72% yield) as a white solid. Column gradient: 0 to 5% CHOH in CH2Cl2. mp: 116.9-118.2 °C; FTIR (neat, cm -1 ) 3370, 2956, 2938, 2837, 1681, 1512, 1461, 1366; 1 H NMR (400MHz, CDCl3): δ 5.00-4.90(m,1H), 4.06(dd,J=9.6, 5.6Hz,1H), 3.63(dd,J=9.6, 9.2Hz,1H), 1.56(d,J=6.4Hz,3H), 1.53(s,9H); 13 C NMR (100MHz, CDCl3): δ 148.6, 85.3, 76.2, 51.7, 27.9, 18.0.

[0405]

[0449] Example 2I: Preparation of tert-butyl (S)-4-(3-fluorophenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide: TIFF0007660040000102.tif21170

[0406]

[0450] The general reaction scheme of Example 2A above was carried out with tert-butyl (S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate (1.45 g, 5.68 mmol, 100 mol%) to give tert-butyl (S)-4-(3-fluorophenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.702 g, 39% yield) as a white solid. Column gradient: 0 to 50% iPrOAc in heptane. mp: 112.9-114.3 °C; FTIR (neat, cm -1 ) 2976, 1722, 1636, 1594, 1458; 1H NMR(400MHz,CDCl3):δ 7.44-7.36(m,1H), 7.24-7.18(m,1H), 7.17-7.11(m,1H), 7.11-7.05(m,1H), 5.28(dd,J =6.8, 3.6Hz,1H), 4.88(dd,J=9.2, 6.8Hz,1H), 4.39(dd,J=9.2, 3.6Hz,1H), 1.47(s,9H); 13 C NMR(100MHz,CDCl3):δ 163.2(d, 1 J CF =246Hz), 148.2, 139.6(d, 3 J CF =7Hz), 131.1(d, 3 J CF =8Hz), 121.8(d, 4 J CF =3Hz), 116.2(d, 2 J CF =21Hz), 113.4(d, 2 J CF =22Hz), 86.0, 71.6, 60.2(d, 4 J CF = 3Hz), 27.9; 19 F NMR (CDCl3, 376MHz): δ-111.0.

[0407]

[0451] Example 2J: Preparation of tert-butyl (S)-4-(3-(trifluoromethyl)phenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide: TIFF0007660040000103.tif24170

[0408]

[0452] The general reaction scheme of Example 2A above was carried out with tert-butyl (S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate (1.00 g, 3.28 mmol, 100 mol%) to give tert-butyl (S)-4-(3-(trifluoromethyl)phenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.528 g, 44% yield) as a white solid. Column gradient: 0 to 50% iPrOAc in heptane. mp: 92.0-92.6 °C; FTIR (neat, cm -1 ) 2989, 1720, 1463, 1373, 1325; 1 H NMR(400MHz,CDCl3):δ 7.70-7.61(m,3H), 7.61-7.55(m,1H), 5.35(dd,J=6.8, 4.0Hz,1H), 4.92(dd,J=9.2, 6.8Hz,1H), 4.41(dd,J=9.2, 3.6Hz,1H), 1.46(s,9H); 13 C NMR (100MHz, CDCl3): δ 148.2, 138.2, 131.8(q, 2 J CF =32Hz), 130.1, 129.4, 126.1(q, 3 J CF =4Hz), 123.7(q, 1 J CF =270Hz), 123.4(q, 3 J CF =4Hz), 86.2, 71.4, 60.2, 27.8; 19 F NMR (CDCl3, 376MHz): δ-62.8.

[0409]

[0453] Example 2K: Preparation of tert-butyl (S)-4-phenyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide: TIFF0007660040000104.tif26170

[0410]

[0454] The general reaction scheme of Example 2A above was carried out with tert-butyl (S)-(3-hydroxy-1-phenylpropyl)carbamate (2.00 g, 7.96 mmol, 100 mol%) to give tert-butyl (S)-4-phenyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (1.26 g, 51% yield) as a white solid. Column gradient: 0 to 50% iPrOAc. mp: 128.6-129.9 °C; FTIR (neat, cm -1 )2986, 1727, 1449, 1367; 1 H NMR (400 MHz, DMSO-d6) (mixture of 94:6 rotamers): δ 7.48-7.35(m,4H), 7.35-7.23(m,1H), 5.65(dd,J=4.4, 4.4Hz,0.94H), 5.53(dd,J=11.2, 4.4Hz,0.06H), 4.70(ddd,J=10.4, 7.2, 2.8Hz,0.94H), 4 .51(ddd,J=8.8, 4.4, 4.4Hz,0.06H), 4.40(ddd,J=10.4, 10.4, 6.8Hz,1H) , 2.80-2.68(m,1H), 2.66-2.56(m,1H), 1.41(s,8.46H), 1.12(s,0.54H); 13 C NMR (100MHz, DMSO-d6) (rotamer): δ 155.1, 143.0, 128.4 (128.6), 127.0 (127.3), 126.3 (125.4), 78.1 (84.3), 73.6 (70.9), 50.5 (60.0), 36.0, 28.2 (27.4).

[0411]

[0455] Example 3: Alkylation of Indoles

[0456] Chiral tryptamines are frequently encountered in pharmacology due to their important biological activities in the central nervous system. In addition, chiral tryptamine moieties serve as synthetic precursors for many medicamentously important indole alkaloids and are found in numerous biologically active natural products and pharmaceuticals.

[0412]

[0457] In particular, stereocontrolled syntheses of tetrahydro-β-carboline-containing compounds such as those described here often rely on the diastereoselective Pictetb-Spengler reaction, which in turn requires enantiomerically pure tryptamine as starting material. The latter is generally prepared non-stereoselectively via a multi-step sequence involving hazardous nitroalkane reagents. Thus, the development of a simple regioselective alkylation approach involving readily available unprotected indoles as nucleophiles and chiral amine-derived electrophiles, such as chiral aziridines and cyclic sulfamidates, provided convenient access to these valuable chiral scaffolds.

[0413]

[0458] Aziridine electrophiles are reacted with C under Lewis acid conditions. 3 however, this method is only applicable to the synthesis of β-substituted tryptamines since substitution occurs preferentially at the more highly substituted carbon. As discovered here, lower caprates of indoles in conjunction with chiral cyclic sulfamidates successfully provided practical access to both α- and β-substituted chiral tryptamines with high regioselectivity.

[0414]

[0459] Reactions with chiral aziridines as electrophiles always yielded mixtures of α- and β-substituted tryptamines, whereas reactions with cyclic sulfamidates as electrophiles were found to react cleanly to displace the CO bond.

[0415]

[0460] When Grignard reagents are used as bases, C 3In contrast to previous literature findings suggesting preferential alkylation at the 1-position, initial attempts were in lower than expected yields and poor site selectivity. Without wishing to be bound by any particular theory, soft indole nucleophiles were tried, as they are more amenable to reaction as carbon-centered nucleophiles. Various additives were investigated, including Cu,Zn salts. Interestingly, mixed halide systems such as MeMgCl with CuBr or CuI, or MeMgBr with CuCl, were much less efficient than the chloride-only systems. Other copper salts such as CuCl2, CuCN, CuTC, or Cu(SCN) were also inferior to CuCl. TIFF0007660040000105.tif178170

[0416]

[0461] Catalytic amounts of CuCl were not tolerated, resulting in a significant decrease in yield and selectivity. Notably, a reversal of regioselectivity was observed when zinc halides were used instead of CuCl (see above). This was also the case when MeLi was used as the base instead of MeMgCl. The use of other Grignard reagents was well tolerated. The effect of reaction temperature was evaluated, demonstrating that the substitution reaction is optimally performed around -20 °C. Below -30 °C, a significant decrease in regioselectivity was observed, likely due to incomplete caprate salt formation.

[0417]

[0462] Cu-mediated indole alkylation is carried out on indole nucleophiles as well as on C 3 A variety of substitutions were tolerated both on the cyclic sulfamic acid affording the -alkylated indole products in moderate to good yields and excellent regioselectivity. For example, indoles bearing electron donating or electron withdrawing substituents participated in both directions in the reaction (exemplary compounds 6b-6g above), and sterically demanding substrates also worked reasonably well (exemplary compounds 6h and 6i above).

[0418]

[0463] On the other hand, it appears that azaindoles may be poor substrates. Under standard reaction conditions, 6-azaindole, although with comparable regioselectivity, provided only 8% of the alkylation product (see, for example, exemplary compound 6j above). Other azaindoles, such as indazole and 7-azaindole, were unable to produce the desired alkylation product.

[0419]

[0464] A variety of sulfamidates were tested in the reaction with success. Both aryl- and alkyl-substituted sulfamidates, prepared in a two-step sequence from the corresponding amino alcohols, were smoothly converted to their respective α-substituted chiral tryptamines. Similarly, six-membered cyclic sulfamidates were also successfully alkylated to produce homologated tryptamines in good yields and regioselectivities. This alkylation process can also be applied to gain access to β-substituted, and α,β-disubstituted tryptamines (see exemplary compounds 6s and 6t above). In such cases, the indole nucleophile was added to the corresponding cyclic sulfamidate with inversion of stereochemistry at the carbon-bearing oxygen with complete stereospecificity. The utility of this alkylation process has been demonstrated as provided herein.

[0420]

[0465] Example 3: Indole Alkylation General Reaction Scheme

[0466] Indole alkylation was carried out according to the following general reaction scheme: A and R B correspond to the various functional groups in the reaction of Example 3 below, where the asterisks represent chiral centers]: TIFF0007660040000106.tif41170.

[0421]

[0467] Example 3A: Preparation of tert-butyl (R)-(1-(1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate: TIFF0007660040000107.tif30170

[0422]

[0468] General Reaction Scheme 3 above was carried out as follows: To a cold (0° C.) mixture of indole (280 mg, 2.39 mmol, 150 mol%) and CuCl (193 mg, 1.95 mmol, 130 mol%) in (3.0 mL) was added MeMgCl (3.0 M in THF, 0.65 mL, 1.95 mmol, 130 mol%) at 0° C. over 10 min. The reaction mixture was stirred at 0° C. for 1 h and cooled to −20° C. A solution of tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (500 mg, 1.60 mmol, 100 mol%) in CHCl (2.0 mL) was added to the reaction mixture at −20° C. over 30 min. The reaction mixture was then stirred at -20°C for 18 h, quenched with 10% aqueous citric acid (5.0 mL) at 0°C, filtered, extracted with CHCl (10.0 mL x 2), washed with saturated brine (20.0 mL x 2), dried (NaSO), filtered, and purified by chromatography on SiO. The specific gradient used for each sample is included in the characterization data. All reported yields are 1 Corrected based on residual solvent from H NMR. Reaction 3A gave tert-butyl (R)-(1-(1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (424 mg, 76% yield) as a white solid. 3 / N 1 The ratio was 97:3. Column gradient: 0 to 50% iPrOAc in heptane. mp: 152.1-153.2 °C; FTIR (neat, cm -1 )3418, 3402, 3376, 2974, 2911, 1684, 1522; 1H NMR (400 MHz, DMSO-d6) (85:15 mixture of rotamers): δ 10.78(br,1H), 7.46(d,J=8.0Hz,1H), 7.32(d,J=8.0Hz,1H), 7.28-7.21( m,2H), 7.19-7.10(m,4H), 7.05(ddd,J=8.4, 7.2, 1.2Hz,1H), 6.95(ddd,J =8.0, 6.8, 1.2Hz,1H), 6.76(d,J=8.4Hz,0.85H), 6.34(d,J=9.2Hz,0.15H) ), 3.97-3.83(m,1H), 2.90-2.65(m,4H), 1.29(s,7.65H), 1.12(s,1.35H); 13 C NMR (100MHz, DMSO-d6) (rotamer): δ 155.1, 139.6, 136.1, 129.0, 128.0, 127.5, 125.8, 123.2, 120.8, 118.3, 118.1, 111.4, 111.3, 77.3, 52.6, 39.9, 30.4, 28.2 (27.8).

[0423]

[0469] Example 3B: Preparation of tert-butyl (S)-(2-(1H-indol-3-yl)-1-phenylethyl)carbamate: TIFF0007660040000108.tif30170

[0424]

[0470] The general reaction of Example 3A was carried out between indole (294 mg, 2.51 mmol, 150 mol%) and tert-butyl (S)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (500 mg, 1.67 mmol, 100 mol%) to give tert-butyl (S)-(2-(1H-indol-3-yl)-1-phenylethyl)carbamate (398 mg, 71% yield) as a white solid. 3 / N 1 The ratio was 97:3. Column gradient: 0 to 50% iPrOAc in heptane. mp: 134.6-135.2 °C; FTIR (neat, cm -1 )3416, 3401, 3371, 2980, 2909, 1683, 1524; 1H NMR (400 MHz, DMSO-d6) (85:15 mixture of rotamers): δ 10.74(br,1H), 7.54(d,J=7.6Hz,1H), 7.41(d,J=8.4Hz,1H), 7.38-7.25(m,5H), 7.20(dd,J=6.8, 7.2Hz,1H), 7.06(dd,J=7.6, 7.2Hz,1H), 7.02(s, 1H), 6.98(dd,J=7.6, 7.2Hz,1H), 4.89-4.74(m,1H), 3.08(dd,J=14.8, 8. 8Hz,1H), 2.99(dd,J=14.4, 6.0Hz,1H), 1.31(s,7.65H), 1.08(s,1.35H); 13 C NMR (100MHz, DMSO-d6): δ 155.0, 144.5, 136.0, 128.0, 127.3, 126.5, 126.4, 123.2, 120.8, 118.3, 118.2, 111.3, 111.3, 77.6, 55.0, 32.8, 28.2.

[0425]

[0471] Example 3C: Preparation of tert-butyl (S)-(2-(1H-indol-3-yl)-1-(4-methoxyphenyl)ethyl)carbamate: TIFF0007660040000109.tif45170

[0426]

[0472] The general reaction of Example 3A was carried out between indole (264 mg, 2.25 mmol, 150 mol%) and tert-butyl (S)-4-(4-methoxyphenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (495 mg, 1.50 mmol, 100 mol%) to give tert-butyl (S)-(2-(1H-indol-3-yl)-1-(4-methoxyphenyl)ethyl)carbamate (378 mg, 69% yield) as a white solid. 3 / N 1 The ratio was 98:2. Column gradient: 0 to 50% iPrOAc in heptane. mp: 173.3-176.5 °C; FTIR (neat, cm -1 )3402, 3326, 2979, 2925, 2904, 1690, 1611, 1506; 1H NMR (400 MHz, DMSO-d6) (85:15 mixture of rotamers): δ 10.72(br,1H), 7.54(d,J=8.0Hz,1H), 7.39-7.28(m,2H), 7.24(d,J=8.8Hz,2H), 7.05(ddd,J=8.4, 7.2, 1.2Hz,1H), 7.02-6.94(m,2H), 6.84(d ,J=8.4Hz,2H), 4.88-4.57(m,1H), 3.72(s,3H), 3.06(dd,J=14.8, 8.4Hz,1H), 2.96(dd,J=14.8, 6.4Hz,1H), 1.31(s,7.65H), 1.11(s,1.35H); 13 C NMR(100MHz,DMSO-d6):δ 157.9, 154.9, 136.4, 136.0, 127.5, 127.3, 123.2, 120.7, 118.3, 118.1, 113.4, 111.4, 111.2, 77.5, 55.0, 54.4, 32.8, 28.2.

[0427]

[0473] Example 3D: Preparation of tert-butyl (R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate: TIFF0007660040000110.tif28170

[0428]

[0474] The general reaction of Example 3A was carried out between indole (370 mg, 3.16 mmol, 150 mol%) and tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (500 mg, 2.11 mmol, 100 mol%) to give tert-butyl (R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate (406 mg, 70% yield) as a white solid. 3 / N 1 The ratio was 99:1. Column gradient: 0 to 50% iPrOAc in heptane. mp: 82.2-84.3 °C; FTIR (neat, cm -1 )3416, 3401, 3366, 2974, 2963, 1684, 1524; 1H NMR (400MHz, DMSO-d6): δ 10.77(br,1H), 7.56(d,J=7.6Hz,1H), 7.33(ddd,J=8.0, 1.2, 0.8Hz,1H), 7. 10(d,J=2.4Hz,1H), 7.05(ddd,J=8.0, 6.8, 1.2Hz,1H), 6.97(ddd,J=8.0, 6. 8, 1.2Hz, 1H), 6.71 (d, J=8.4Hz, 1H), 3.82-3.66 (m, 1H), 2.87 (dd, J=14.0, 6 .0Hz,1H), 2.65(dd,J=14.0, 7.6Hz,1H), 1.38(s,9H), 1.01(d,J=6.8Hz,3H); 13 C NMR (100MHz, DMSO-d6): δ 155.0, 136.1, 127.5, 123.1, 120.7, 118.4, 118.1, 111.6, 111.2, 77.3, 46.8, 32.2, 28.3, 20.1.

[0429]

[0475] Example 3E: Preparation of tert-butyl (R)-(1-(1H-indol-3-yl)-3-methylbutan-2-yl)carbamate: TIFF0007660040000111.tif32170

[0430]

[0476] The general reaction of Example 3A was carried out between indole (331 mg, 2.83 mmol, 150 mol%) and tert-butyl (R)-4-isopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (500 mg, 1.88 mmol, 100 mol%) to give tert-butyl (R)-(1-(1H-indol-3-yl)-3-methylbutan-2-yl)carbamate (335 mg, 59% yield) as a white solid. 3 / N 1 The ratio was 94:6. Column gradient: 0 to 50% iPrOAc in heptane. mp: 145.1-146.9 °C; FTIR (neat, cm -1 )3417, 3402, 3362, 2978, 1686, 1526; 1H NMR (400MHz, DMSO-d6) (85:15 mixture of rotamers): δ 10.72(br,1H), 7.51(d,J=8.0Hz,1H), 7.31(ddd,J=8.0, 1.2, 0.8Hz,1H), 7.07(d,J=2.0Hz,1 H), 7.04(ddd,J=8.0, 6.8, 1.2Hz,1H), 6.96(ddd,J=8.0, 6.8, 1.2Hz,1H), 6.59(d,J=9.2Hz,0 .85H), 6.15(d,J=10.0Hz,0.15H), 3.64-3.53(m,1H), 2.80(dd,J=14.8, 5.2Hz,1H), 2.68(dd ,J=14.8, 8.8Hz,1H), 1.77-1.65(m,1H), 1.32(s,7.65H), 1.12(s,1.35H), 0.95-0.82(m,6H); 13 C NMR (100MHz, DMSO-d6): δ 155.6, 136.1, 127.5, 122.7, 120.7, 118.3, 118.0, 112.0, 111.2, 77.1, 55.6, 31.4, 28.3, 27.1, 19.4, 17.7.

[0431]

[0477] Example 3F: Preparation of tert-butyl (S)-(1-cyclopropyl-2-(1H-indol-3-yl)ethyl)carbamate: TIFF0007660040000112.tif34170

[0432]

[0478] The general reaction of Example 3A was carried out between indole (264 mg, 2.25 mmol, 150 mol%) and tert-butyl (R)-4-cyclopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (395 mg, 1.50 mmol, 100 mol%) to give tert-butyl (S)-(1-cyclopropyl-2-(1H-indol-3-yl)ethyl)carbamate (292 mg, 65% yield) as a white solid. 3 / N 1 The ratio was 99:1. Column gradient: 0 to 50% iPrOAc in heptane. mp: 128.8-130.5 °C; FTIR (neat, cm -1)3414, 3400, 3362, 2981, 2937, 1683, 1525; 1 H NMR (400 MHz, DMSO-d6) (mixture of 9:1 rotamers): δ 10.73 (br, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.31 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.04 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.95 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.66 (d, J = 8.4 Hz, 0.9H), 6.26 ( s,0.1H), 3.30-3.18(m,1H), 2.91(dd,J=14.4, 5.6Hz,1H), 2.85(dd,J=14.4, 8.0Hz,1H), 1.33(s,8 .1H), 1.17(s,0.9H), 0.96-0.83(m,1H), 0.42-0.32(m,1H), 0.32-0.24(m,2H), 0.15-0.01(m,1H); 13 C NMR (100MHz, DMSO-d6): δ 155.3, 136.0, 127.7, 122.9, 120.6, 118.4, 118.0, 111.6, 111.2, 77.2, 54.2, 30.4, 28.2, 16.0, 3.0, 1.9.

[0433]

[0479] Example 3G: Preparation of tert-butyl ((1S,2S)-2-(1H-indol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate: TIFF0007660040000113.tif40170

[0434]

[0480] The general reaction of Example 3A was carried out between indole (282 mg, 2.41 mmol, 150 mol%) and tert-butyl (3aR,8aS)-8,8a-dihydroindeno[1,2-d][1,2,3]oxathiazole-3(3aH)-carboxylate 2,2-dioxide (500 mg, 1.61 mmol, 100 mol%) to give tert-butyl ((1S,2S)-2-(1H-indol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (304 mg, 54% yield) as a white solid. 3 / N1 The ratio was 95:5. Column gradient: 0 to 50% iPrOAc in heptane. mp: 155.7-157.1 °C; FTIR (neat, cm -1 )3387, 3351, 2980, 2938, 1691, 1500; 1 H NMR (400 MHz, DMSO-d6) (mixture of 87:13 rotamers): 10.85 (br, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42-7.32 (m, 2H), 7.30-7.20 (m, 4H), 7.17 (dd, J = 8.0, 4.0 Hz, 1H), 7.07 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.97 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 5.18 ( dd,J=9.2, 9.2Hz,1H), 3.69(dd,J=18.4, 9.6Hz,0.87H), 3.64-3.53(m,0.13H), 3.37(dd,J=15.2, 8.0Hz,0.87H), 3.30-3.23(m,0.13H), 3.13-3.04(m,0.13H), 2.99(dd,J=15.2, 10.4Hz,0.87H), 1.38(s,7.83H), 1.12(s,1.17H); 13 C NMR (100MHz, DMSO-d6) (rotamer): δ 155.9, 144.5, 141.3, 136.6, 127.2, 127.1, 126.4, 124.4, 123.3, 121.7, 120.9, 119.1, 118.2, 115.5, 111.4, 77.7, 60.8, 44.0, 37.2, 28.2 (27.7).

[0435]

[0481] Example 3H: Preparation of tert-butyl (S)-(2-(1H-indol-3-yl)propyl)carbamate: TIFF0007660040000114.tif27170

[0436]

[0482] The general reaction of Example 3A was carried out between indole (264 mg, 2.25 mmol, 150 mol%) and tert-butyl (S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (356 mg, 1.50 mmol, 100 mol%) to give tert-butyl (S)-(2-(1H-indol-3-yl)propyl)carbamate (319 mg, 78% yield) as a colorless liquid. 3 / N 1 The ratio was 93:7. Column gradient: 0 to 50% iPrOAc in heptane. FTIR (neat, cm -1 )3412, 3327, 2971, 2930, 1685, 1508, 1456; 1 H NMR (400MHz, DMSO-d6) (9:1 mixture of rotamers): δ 10.78(br,1H), 7.58(d,J=7.6Hz,1H), 7.33(ddd,J=8.0, 1.2, 0.8Hz,1H), 7.10(d,J=2.0H) z,1H), 7.05(ddd,J=8.0, 6.8, 1.2Hz,1H), 6.96(ddd,J=8.0, 6.8, 1.2Hz,1H), 6.86(dd,J=6 .0, 6.0Hz, 0.9H), 6.51 (s, 0.1H), 3.29 (ddd, J=13.2, 5.6, 5.6Hz, 1H), 3.18-3.05 (m, 1H), 2.97(ddd,J=13.2, 8.8, 6.0Hz,1H), 1.41(s,0.9H), 1.38(s,8.1H), 1.25(d,J=6.8Hz,3H); 13 C NMR (100MHz, DMSO-d6) (rotamer): δ 155.7, 136.4, 126.6, 121.0, 120.8, 118.6, 118.1, 117.9, 111.4, 77.4, 46.8, 30.9, 28.3 (28.2), 18.4 (18.2).

[0437]

[0483] Example 3I: Preparation of tert-butyl (R)-(1-(3-fluorophenyl)-2-(1H-indol-3-yl)ethyl)carbamate: TIFF0007660040000115.tif43170

[0438]

[0484] The general reaction of Example 3A was carried out between indole (263 mg, 2.25 mmol, 150 mol%) and tert-butyl (S)-4-(3-fluorophenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (475 mg, 1.50 mmol, 100 mol%) to give tert-butyl (R)-(1-(3-fluorophenyl)-2-(1H-indol-3-yl)ethyl)carbamate (382 mg, 72% yield) as a white solid. 3 / N 1 The ratio was 99:1. Column gradient: 0 to 50% iPrOAc in heptane. mp: 148.6-151.2 °C; FTIR (neat, cm -1 )3414, 3398, 3363, 3055, 2981, 1682, 1591, 1527; 1 H NMR (400MHz, DMSO-d6) (9:1 mixture of rotamers): δ 10.75(br,1H), 7.53(d,J=7.6Hz,1H), 7.44(d,J=8.4Hz,1H), 7.37-7.26(m,2H), 7.20-7.11(m,2H), 7.08-6.93(m, 4H), 4.85-4.65(m,1H), 3.06(dd,J=14.4, 8.4Hz,1H), 2.98(dd,J=14.4, 6.4Hz,1H), 1.30(s,8.1H), 1.08(s,0.9H); 13 C NMR(100MHz,DMSO-d6):δ 162.2(d, 1 J CF =243Hz), 155.0, 147.5(d, 3 J CF =7Hz), 136.0, 129.9(d, 3 J CF =8Hz), 127.2, 123.3, 122.6, 120.8, 118.3, 118.2, 113.3(d, 2 J CF =21Hz), 113.0(d, 2 J CF =21Hz), 111.3, 111.0, 77.8, 54.7, 32.5, 28.2; 19 F NMR (DMSO-d6, 376MHz): δ-113.6.

[0439]

[0485] Example 3J: Preparation of tert-butyl (R)-(2-(1H-indol-3-yl)-1-(3-(trifluoromethyl)phenyl)ethyl)carbamate: TIFF0007660040000116.tif43170

[0440]

[0486] The general reaction of Example 3A was carried out between indole (176 mg, 1.50 mmol, 150 mol%) and tert-butyl (S)-4-(3-(trifluoromethyl)phenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (368 mg, 1.00 mmol, 100 mol%) to give tert-butyl (R)-(2-(1H-indol-3-yl)-1-(3-(trifluoromethyl)phenyl)ethyl)carbamate (320 mg, 79% yield) as a white solid. 3 / N 1 The ratio was 98:2. Column gradient: 0 to 50% iPrOAc in heptane. mp: 99.3-101.4 °C; FTIR (neat, cm -1 )3414, 3399, 3361, 2982, 2936, 1683, 1523; 1 H NMR (400MHz, DMSO-d6) (88:12 mixture of rotamers): δ 10.76(br,1H), 7.80-7.45(m,6H), 7.31(d,J=8.0Hz,1H), 7.08-7.00(m,2H), 6.96(ddd,J=8.0, 7.2, 1.2Hz,1H) , 5.11-4.69(m,1H), 3.09(dd,J=14.4, 8.4Hz,1H), 3.00(dd,J=14.4, 6.4Hz,1H), 1.30(s,7.9H), 1.07(s,1.1H); 13 C NMR (100MHz, DMSO-d6): δ 155.1, 145.8, 136.1, 130.8, 129.0, 128.9(q, 2 J CF =32Hz), 127.3, 124.4(q, 1 J CF =270Hz), 123.3(q, 3 J CF=4Hz), 123.0, 122.8(q, 3 J CF =4Hz), 120.8, 118.3, 118.2, 111.3, 110.8, 77.9, 55.0, 32.5, 28.2; 19 F NMR (DMSO-d6, 376MHz): δ-61.0.

[0441]

[0487] Example 3K: Preparation of tert-butyl (S)-(3-(1H-indol-3-yl)-1-phenylpropyl)carbamate: TIFF0007660040000117.tif34170

[0442]

[0488] The general reaction of Example 3A was carried out between indole (264 mg, 2.25 mmol, 150 mol%) and tert-butyl (S)-4-phenyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (470 mg, 1.50 mmol, 100 mol%) to give tert-butyl (S)-(3-(1H-indol-3-yl)-1-phenylpropyl)carbamate (401 mg, 73% yield) as a white solid. 3 / N 1 The ratio was 98:2. Column gradient: 0 to 50% iPrOAc in heptane. mp: 121.7-123.2 °C; FTIR (neat, cm -1 )3390, 2979, 2929, 2859, 1681, 1507, 1457, 1364; 1 H NMR (400 MHz, CDCl3) (mixture of 80:20 rotamers): δ 8.04 (br, 0.2H), 7.96 (br, 0.8H), 7.66 (d, J = 8.0 Hz, 0.2H), 7.52 (d, J = 8.0 Hz, 0.8H), 7.40-7.22 (m, 6H), 7.22-7.15 (m, 1H), 7.15-7.06 (m, 1H), 7.00 (br, 1H). ), 4.88(br,0.8H), 4.75(br,1H), 4.53(br,0.2H), 3.52-3.35(m,0.4H), 3.32 -3.20(m,0.4H), 2.87-2.67(m,1.6H), 2.16(d,J=8.8Hz,1.6H), 1.42(s,9H);13 C NMR (100MHz, DMSO-d6) (rotamer): δ 155.4(156.2), 143.0, 136.4(136.6), 128.6, 127.3, 127.2, 126.4, 121.8(122.0), 121.5(120.8), 11 9.0 (119.2), 118.7, 115.3, 111.2 (111.3), 79.5, 54.7 (46.7), 37.2 (31.6), 28.4 (29.7), 21.9 (18.7).

[0443]

[0489] Example 3L: Preparation of tert-butyl (R)-(1-(5-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate: TIFF0007660040000118.tif31170

[0444]

[0490] The general reaction of Example 3A was carried out between 5-methyl-1H-indole (295 mg, 2.25 mmol, 150 mol%) and tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg, 1.50 mmol, 100 mol%) to give tert-butyl (R)-(1-(5-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (401 mg, 73% yield) as a white solid. 3 / N 1 The ratio was 92:8. Column gradient: 0 to 50% iPrOAc in heptane. mp: 123.0-123.8 °C; FTIR (neat, cm -1 )3413, 3368, 2974, 2927, 1685, 1524; 1H NMR (400MHz, DMSO-d6) (85:15 mixture of rotamers): δ 10.63(br,1H), 7.30-7.13(m,7H), 7.07(d,J=2.0Hz,1H), 6.87(dd,J=8.4, 1.6Hz,1H), 6.74(d,J=8.8Hz,0.85H) , 6.34(d,J=7.6Hz,0.15H), 3.96-3.80(m,1H), 2.86-2.64(m,4H), 2.36(s,3H), 1.30(s,7.65H), 1.16(s,1.35H); 13 C NMR (100MHz, DMSO-d6) (rotamer): δ 155.1, 139.6, 134.5, 129.1, 128.0, 127.7, 126.4, 125.8, 123.2, 122.3, 117.9, 111.0, 110.9, 77.2, 52.7, 40.0, 30.2, 28.2 (27.8), 21.3.

[0445]

[0491] Example 3M: Preparation of tert-butyl (R)-(1-(7-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate: TIFF0007660040000119.tif32170

[0446]

[0492] The general reaction of Example 3A was carried out between 7-methyl-1H-indole (295 mg, 2.25 mmol, 150 mol%) and tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg, 1.50 mmol, 100 mol%) to give tert-butyl (R)-(1-(7-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (371 mg, 68% yield) as a white solid. 3 / N 1 The ratio was 97:3. Column gradient: 0 to 50% iPrOAc in heptane. mp: 124.4-125.9 °C; FTIR (neat, cm -1 )3417, 3407, 3370, 2974, 2926, 1683, 1524; 1H NMR (400MHz, DMSO-d6) (85:15 mixture of rotamers): δ 10.75 (br d, J=2.0Hz,1H), 7.34-7.21(m,3H), 7.21-7.09(m,4H), 6.90-6.83(m,2H), 6.74(d,J=8.8Hz,0.85H), 6.34 (d,J=7.6Hz,0.15H), 3.98-3.84(m,1H), 2.91-2.65(m,4H), 2.44(s,3H), 1.31(s,7.65H), 1.14(s,1.35H); 13 C NMR (100MHz, DMSO-d6) (rotamer): δ 155.2, 139.6, 135.7, 129.0, 128.0, 127.2, 125.8, 122.9, 121.3, 120.3, 118.4, 115.9, 111.9, 77.3, 52.6, 39.9, 30.5, 28.2 (27.8), 16.7.

[0447]

[0493] Example 3N: Preparation of tert-butyl (R)-(1-(5-chloro-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate: TIFF0007660040000120.tif30170

[0448]

[0494] The general reaction of Example 3A was carried out between 5-chloro-1H-indole (341 mg, 2.25 mmol, 150 mol%) and tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg, 1.50 mmol, 100 mol%) to give tert-butyl (R)-(1-(5-chloro-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (345 mg, 60% yield) as a white solid. 3 / N 1 The ratio was 96:4. Column gradient: 0 to 50% iPrOAc in heptane. mp: 70.5-73.9 °C; FTIR (neat, cm -1 )3417, 3368, 2980, 2928, 1684, 1518; 1H NMR (400MHz, DMSO-d6) (85:15 mixture of rotamers): δ 10.99(br,1H), 7.49(d,J=2.0Hz,1H), 7.34(d,J=8.8Hz,1H), 7.30-7.22(m,2H), 7.22-7.13(m,4H), 7.04(dd,J=8.4, 2.0Hz,1H ), 6.77(d,J=8.8Hz,0.85H), 6.34(d,J=8.8Hz,0.15H), 3.90-3.76(m,1H), 2.83-2.62(m,4H), 1.27(s,7.65H), 1.10(s,1.35H); 13 C NMR (100MHz, DMSO-d6) (rotamer): δ 155.1, 139.5, 134.6, 129.0, 128.8, 128.0, 125.8, 125.2, 122.9, 120.6, 117.7, 112.8, 111.5, 77.2, 52.9, 40.0, 30.1, 28.2 (27.7).

[0449]

[0495] Example 3O: Preparation of tert-butyl (R)-(1-phenyl-3-(5-(trifluoromethyl)-1H-indol-3-yl)propan-2-yl)carbamate: TIFF0007660040000121.tif31170

[0450]

[0496] The general reaction of Example 3A was carried out between 5-(trifluoromethyl)-1H-indole (417 mg, 2.25 mmol, 150 mol%) and tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg, 1.50 mmol, 100 mol%) to give tert-butyl (R)-(1-phenyl-3-(5-(trifluoromethyl)-1H-indol-3-yl)propan-2-yl)carbamate (297 mg, 47% yield) as a white solid. 3 / N 1 The ratio was 96:4. Column gradient: 0 to 50% iPrOAc in heptane. mp: 130.9-131.8 °C; FTIR (neat, cm -1 )3417, 3368, 2980, 2929, 1684, 1519;1 H NMR (400MHz, DMSO-d6) (85:15 mixture of rotamers): 11.26(br,1H), 7.84(s,1H), 7.50(d,J=8.4Hz,1H), 7.37-7.22(m,4H), 7.22-7.10(m,3H), 6.80(d, J=8.8Hz,0.85H), 6.36(d,J=9.2Hz,0.15H), 3.99-3.77(m,1H), 2.86(d,J=6.8Hz,2H), 2.76(d,J=6.8Hz,2H), 1.22(s,7.65H), 1.04(s,1.35H); 13 C NMR (100MHz, DMSO-d6) (rotamer): δ 155.1 (154.6), 139.5, 137.6 (137.7), 129.1, 128.0, 126.9, 125.8, 125.7 (q, 1 J CF =269Hz), 125.6, 119.1(q, 2 J CF =32Hz), 117.1(q, 3 J CF =4Hz), 116.1(q, 3 J CF =4Hz), 112.9, 111.9, 77.2, 53.0(53.7), 40.3(41.0), 29.9(30.9), 28.1(27.6); 19 F NMR (DMSO-d6, 376MHz): δ-58.1.

[0451]

[0497] Example 3P: Preparation of tert-butyl (R)-(1-(5-methoxy-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate: TIFF0007660040000122.tif30170

[0452]

[0498] The general reaction of Example 3A was carried out between 5-methoxy-1H-indole (331 mg, 2.25 mmol, 150 mol%) and tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg, 1.50 mmol, 100 mol%) to give tert-butyl (R)-(1-(5-methoxy-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (523 mg, 92% yield) as a white solid. 3 / N 1 The ratio was 97:3. Column gradient: 0 to 50% iPrOAc in heptane. mp: 123.2-123.9 °C; FTIR (neat, cm -1 ) 3368, 2975, 2933, 1692, 1680, 1516; 1 H NMR (400 MHz, DMSO-d6) (85:15 mixture of rotamers): δ 10.60(s,1H), 7.32-7.24(m,2H), 7.24-7.13(m,4H), 7.08(d,J=2.4Hz,1H), 6.91(d,J=2.4Hz,0.85H), 6.83(br,0.15H), 6.77(d,J=8.8Hz,0.85 H), 6.70(dd,J=8.8, 2.4Hz,1H), 6.34(d,J=9.2Hz,0.15H), 3.94-3.80(m ,1H), 3.72(s,3H), 2.85-2.65(m,4H), 1.29(s,7.65H), 1.13(s,1.35H); 13 C NMR (100MHz, DMSO-d6) (rotamer): δ 155.2, 152.9, 139.6, 131.3, 129.1, 128.0, 127.8, 125.8, 123.8, 111.9, 111.3, 110.8, 100.3, 77.3, 55.3, 52.8, 40.2, 30.2, 28.2 (27.8).

[0453]

[0499] Example 3Q: Preparation of tert-butyl (R)-(1-phenyl-3-(5-phenyl-1H-indol-3-yl)propan-2-yl)carbamate: TIFF0007660040000123.tif28170

[0454]

[0500] The general reaction of Example 3A was carried out between 5-phenyl-1H-indole (435 mg, 2.25 mmol, 150 mol%) and tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg, 1.50 mmol, 100 mol%) to give tert-butyl (R)-(1-phenyl-3-(5-phenyl-1H-indol-3-yl)propan-2-yl)carbamate (523 mg, 82% yield) as a white solid. 3 / N 1 The ratio was 97:3. Column gradient: 0 to 50% iPrOAc in heptane. mp: 68.9-70.8 °C; FTIR (neat, cm -1 )3427, 3411, 3392, 3310, 2977, 2929, 1715, 1696, 1506; 1 H NMR (400MHz, DMSO-d6) (85:15 mixture of rotamers): δ 10.85(br,1H), 7.70(s,1H), 7.67-7.60(m,2H), 7.48-7.33(m,4H), 7.32-7.24(m,3H), 7.23-7.15(m,4H), 6.80(d,J=8.8Hz,0.8 5H), 6.39(d,J=9.2Hz,0.15H), 4.03-3.84(m,1H), 2.87(d,J=.8Hz,2H), 2.77(d,J=6.8Hz,2H), 1.24(s,7.65H), 1.09(s,1.35H); 13 C NMR (100MHz, DMSO-d6) (rotamer): δ 155.1, 142.0, 139.6, 135.8, 130.7, 129.1, 128.6, 128.1, 128.0, 126.6, 126.0, 125.8, 124.0, 120.1, 116.6, 112.2, 111.6, 77.2, 53.1, 40.4, 30.1, 28.2 (27.8).

[0455]

[0501] Example 3R: Preparation of tert-butyl (R)-(1-(2-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate: TIFF0007660040000124.tif30170

[0456]

[0502] The general reaction of Example 3A was carried out between 2-methyl-1H-indole (295 mg, 2.25 mmol, 150 mol%) and tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg, 1.50 mmol, 100 mol%) to give tert-butyl (R)-(1-(2-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (386 mg, 71% yield) as a white solid. 3 / N 1 The ratio was 99:1. Column gradient: 0 to 50% iPrOAc in heptane. mp: 117.6-119.0 °C; FTIR (neat, cm -1 )3440, 3385, 2984, 2930, 1684, 1524; 1 H NMR (400MHz, DMSO-d6) (83:17 mixture of rotamers): δ 10.67(br,1H), 7.39(d,J=7.6Hz,0.83H), 7.33(d,J=8.0Hz,0.17H), 7.28-7.18(m,3H) ), 7.18-7.07(m,3H), 6.96(ddd,J=8.0, 7.2, 1.2Hz,1H), 6.90(ddd,J=8.0, 8.0, 1.2Hz, 1H), 6.73(d,J=8.8Hz,0.83H), 6.30(d,J=8.8Hz,0.17H), 3.94-3.74(m,1H), 2.85(dd, J=14.0, 6.4Hz,1H), 2.75-2.62(m,3H), 2.32(s,3H), 1.27(s,7.47H), 1.04(s,1.53H); 13 C NMR (100 MHz, DMSO-d6) (rotamers): 155.1, 139.8, 135.2, 132.4, 128.9, 128.7, 128.0, 125.7, 119.8, 118.0, 117.5, 110.2, 107.4, 77.2, 53.4, 39.4, 29.9, 28.2 (27.7), 11.4.

[0457]

[0503] Example 3S: Preparation of tert-butyl (R)-(1-phenyl-3-(2-phenyl-1H-indol-3-yl)propan-2-yl)carbamate: TIFF0007660040000125.tif29170

[0458]

[0504] The general reaction of Example 3A was carried out between 2-phenyl-1H-indole (435 mg, 2.25 mmol, 150 mol%) and tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg, 1.50 mmol, 100 mol%) to give tert-butyl (R)-(1-phenyl-3-(2-phenyl-1H-indol-3-yl)propan-2-yl)carbamate (324 mg, 51% yield) as a white solid. 3 / N 1 The ratio was 98:2. Column gradient: 0 to 50% iPrOAc in heptane. mp: 178.5-178.8 °C; FTIR (neat, cm -1 )3380, 3354, 3376, 2981, 2932, 1683, 1508; 1 H NMR (400MHz, DMSO-d6) (82:18 mixture of rotamers): δ 11.14(s,1H), 7.69(d,J=7.6Hz,1H), 7.60(d,J=7.2Hz,2H), 7.44(dd,J=7.2, 7.2Hz,2H) , 7.35(dd,J=7.2, 7.2Hz,2H), 7.21(dd,J=7.2, 7.2Hz,2H), 7.17-6.97(m,5H), 6.79(d,J= 9.2Hz,0.82H), 6.38(d,J=9.6Hz,0.18H), 4.15-3.90(m,1H), 3.06(dd,J=14.0, 6.8Hz,1H ), 2.96(dd,J=14.4, 7.2Hz,1H), 2.64(d,J=6.8Hz,2H), 1.21(s,7.40H), 0.97(s,1.60H); 13C NMR (100MHz, DMSO-d6) (rotamer): δ 155.0, 139.5, 136.0, 134.7, 133.0, 129.2, 128.9, 128.6, 128.0, 127.8, 127. 1, 125.8, 121.3, 119.2, 118.5, 111.0, 109.2, 77.2, 53.4, 40.2, 28.1 (27.6).

[0459]

[0505] Example 3T: Preparation of tert-butyl (R)-(1-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propan-2-yl)carbamate: TIFF0007660040000126.tif30170

[0460]

[0506] The general reaction of Example 3A was carried out between 1H-pyrrolo[2,3-c]pyridine (266 mg, 2.25 mmol, 150 mol%) and tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg, 1.50 mmol, 100 mol%) to give tert-butyl (R)-(1-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propan-2-yl)carbamate (40 mg, 8% yield) as a white solid. 3 / N 1 The ratio was 98:2. Column gradient: 0 to 50% iPrOAc in heptane. mp: 196.2-197.0 °C; FTIR (neat, cm -1 )3360, 2978, 2931, 1685, 1625, 1524; 1H NMR (400MHz, CDCl3) (90:10 mixture of rotamers): δ 8.56(br,1H), 8.28(s,1H), 7.57(d,J=6.4Hz,1H), 7.38-7.31(m,2H), 7.30-7.25(m, 2H), 7.25-7.20(m,2H), 6.70(br,1H), 5.44(br,0.10H), 5.24(d,J=5.6Hz,0.90H), 4. 52(dd,J=13.2, 8.4Hz,1H), 4.36(dd,J=13.6, 4.8Hz,1H), 4.26-4.14(m,1H), 3.00(dd ,J=14.0, 7.6Hz,1H), 2.91(dd,J=14.0, 6.8Hz,1H), 1.27(s,8.10H), 1.11(s,0.90H).

[0461]

[0507] Example 4

[0508] Preparation of azetidinyl-amines

[0509] Compounds of formula (VII) were prepared according to the following general scheme: TIFF0007660040000127.tif38170.

[0462]

[0510] R 5 ,v,R 6 , and R 10 is as described herein.

[0463]

[0511] Example 4A:

[0512] Preparation of 1-(3-fluoropropyl)azetidin-3-amine ethane-1,2-disulfonate

[0513] 1-(3-fluoropropyl)azetidin-3-amineethane-1,2-disulfonate was prepared according to the following reaction scheme: TIFF0007660040000128.tif41170.

[0464]

[0514] tert-Butyl azetidin-3-ylcarbamate hydrochloride (109.7 kg, 1.0 eq.) was dissolved in MTBE (793.4 kg) and 1-bromo-3-fluoropropane (82.3 kg) was added. MTBE (14 kg) and water (530 kg) were added followed by LiOH·H2O (66.0 kg) at 15-25 °C, followed by stirring at 50-60 °C. After completion of the reaction, the organic phase was separated and then mixed with 1,2-ethanedisulfonic acid dihydrate aqueous solution (247.8 kg) at 0-5 °C. The resulting mixture was stirred for 30 minutes at 15-20 °C. The aqueous phase was separated and 1,2-ethanedisulfonic acid dihydrate (56.85 kg) was added to the organic phase. The resulting mixture was stirred at 35-40 °C for 5 hours until deprotection was complete. MeOH (884.1 kg) was then added at 35-40° C., and the mixture was stirred for 2 h at 35-40° C. After cooling to room temperature, the reaction mixture was stirred for 4 h. The solid was collected by filtration and rinsed with aqueous MeOH. The washed solid was dried under reduced pressure at 35-42° C. to give 106.8 kg of 1-(3-fluoropropyl)azetidin-3-amineethane-1,2-disulfonate (63% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.92(s,0.7H), 9.63(s,0.3H), 8.35(s,3H), 4.52(dt,J=47.1, 5.6Hz,2H), 4.43-4.08(m,5H), 3.36(s,3H), 2.74(s,4H), 2.06-1.77(m,2H).

[0465]

[0515] Example 4B:

[0516] Preparation of 1-(3-fluoropropyl)azetidin-3-amineethane-1,2-disulfonate via strain release chemistry TIFF0007660040000129.tif26170

[0466]

[0517] Preparation of 2,3-dibromopropan-1-amine hydrobromide (3)

[0518] 1 (20.0 g, 1.0 equiv., 50 wt % in water) was added to a solution of K2CO3 (29.55 g, 1.0 equiv.) in water (100 mL) and Boc2O (93.32 g, 2.0 equiv.) in EtOAc (100 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 15 h. The organic layer was separated and solvent exchanged to EtOH (100 mL) to give a solution of 2 in EtOH. It was then added to a cold (0 °C) solution of Br2 (71.74 g, 2.1 equiv.) in EtOH (60 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 16 h, filtered, washed with MTBE (60 mL), and dried under reduced pressure at 40 °C for 15 h to give 3 as a colorless solid (43.01 g, 66%): 1 H NMR(400MHz,CD3OD)δ 4.55-4.47(m,1H), 4.01(dd,J=10.9, 4.6Hz,1H), 3.86(dd,J=10.9, 8.7Hz,1H), 3.71(dd,J=13.9, 3.2Hz,1H), 3.39-3.33(m,1H).

[0467]

[0519] Preparation of N,N-dibenzylazetidin-3-amine ethane-1,1 disulfonate TIFF0007660040000130.tif72170

[0468]

[0520] To a solution of Bn2NH (33.12 g, 1.0 equiv.) in THF (330 mL), iPrMgCl·LiCl (1.3 M in THF, 130 mL, 1.0 equiv.) was added at 20 °C and stirred at 20 °C for 5 h to give a solution of Bn2NMgCl–LiCl in THF. A separate reactor was charged with 3 (50.0 g, 1.0 equiv.) in THF (500 mL) and cooled to -60 °C. n-BuLi (201 mL, 2.5 M solution in n-hexane, 3.0 equiv.) was added to the suspension at -60 °C and stirred at -60 °C for 2 h to give a solution of 4 in THF. The Bn2NMgCl–LiCl solution was added to 4 at -60 °C, warmed to 20 °C, and stirred at 20 °C for 12 h to give a solution of 5 in THF. The reaction mixture was cooled to 0° C., a solution of Boc2O (73.28 g, 2.0 equiv.) in THF (200 mL) was added at 0° C., stirred at 20° C. for 2 h, cooled to 0° C., and quenched with a solution of AcOH (20.16 g, 2.0 equiv.) in H2O (383 mL). The organic layer was washed with 5% Na2SO4 (150 mL). The combined aqueous layers were back-extracted with MTBE (100 mL×2) to give a solution of 6. A solution of ethanedisulfonic acid (40.0 g, 1.5 equiv.) in MeOH (225 mL) was added to this solution at 20° C. and stirred at 40° C. for 20 h. The slurry was filtered, washed with THF (100 mL), and dried under vacuum (40° C.) for 20 h to give 7 (69.21 g, 75% yield) as a white solid: 1 H NMR(400MHz,D2O)δ 7.57-7.44(m,10H), 4.66(t,J=8.2Hz,1H), 4.36(s,4H), 4.10-3.95(m,4H), 3.22(s,4H). MS([M+H] + ), C 17 H 21 Calculated N2: 253.17, measured: 253.00.

[0469]

[0521] Preparation of N,N-dibenzyl-1-(3-fluoropropyl)azetidin-3-amine (8) TIFF0007660040000131.tif37170

[0470]

[0522] To a solution of 7 (40.0 g, 1.0 equiv.) in MTBE (200 mL) and HO (200 mL) was added 1-bromo-3-fluoropropane (17.20 g, 1.5 equiv.) and LiOH·HO (15.18 g, 4.0 equiv.). The reaction mixture was heated to 55° C., stirred at 55° C. for 20 h, and cooled to 20° C. The organic layer was separated and washed with 5% Na2SO4 (120 mL×2). 8 was obtained by concentration of the MTBE solution under reduced pressure as a white solid (22.3 g, 83% yield): 1 H NMR(400MHz,DMSO-d6)δ 7.35-7.22(m,10H), 4.45(t,J=6.0Hz,1H), 4.33(t,J=6.0Hz,1H), 3.45-3.39(m,4H ), 3.28-3.17(m,3H), 2.67-2.56(m,2H), 2.35(t,J=7.0Hz,2H), 1.64-1.48(m,2H). MS([M+H] + ), C 20 H 26 Calculated FN2: 313.21, actual measurement: 313.10.

[0471]

[0523] Preparation of 1-(3-fluoropropyl)azetidin-3-amine ethane-1,2-disulfonate TIFF0007660040000132.tif40170

[0472]

[0524] To a solution of 8 (2.00 g, 1.0 equiv) in MeOH (20.0 mL) was added a solution of ethanedisulfonic acid dihydrate (1.23 g, 1.0 equiv) in HO (10.0 mL) at 0 °C. The reaction mixture was heated to 30 °C and passed through a charcoal cartridge. The reaction mixture was then charged with Pd / C (0.40 g, 0.20 equiv), stirred with 40 psi H at 45 °C, filtered, concentrated to 5 mL, charged with MeOH (20.0 mL), stirred at 20 °C for 3 h, filtered, and washed with MeOH (2 mL) to give the title compound (1.36 g, 93% yield) as a white solid: 1H NMR(400MHz,D2O)δ 4.70-4.57(m,3H), 4.57-4.31(m,4H), 3.51(t,J=7.2Hz,2H), 3.24(s,4H), 2.11-1.97(m,2H); 19 F NMR (376 MHz, DO) δ-219.59.

[0473]

[0525] Example 5

[0526] Preparation of (R)-1-(1H-indol-3-yl)propan-2-amine TIFF0007660040000133.tif59170

[0474]

[0527] To a solution of imidazole (102.8 g, 1.51 mol, 1.5 equiv) in DCM (1.33 L) was added SOCl2 (179.3 g, 1.51 mol, 1.5 equiv) dropwise at -5 to 0 °C under N2 over 30 min. The reaction mixture was stirred at -5 to 0 °C for 0.5 h. tert-Butyl (R)-(1-hydroxypropan-2-yl)carbamate (Boc-alaninol) (177.7 g, 1.01 mol, 1.0 equiv) in DCM (1.33 L, 7.5 vol.) was added dropwise at -5 to 0 °C over 1 h. The reaction mixture was stirred at -2 to 0 °C for 0.5 h followed by the dropwise addition of triethylamine (204 g, 2.02 mol, 2 equiv) at -5 to 0 °C. The resulting mixture was stirred for 0.5 h or until N-Boc-alanineol was completely consumed as determined by GC analysis. Water was added to the reaction mixture (1.3 L) at 0-20 °C. The phases were separated and the aqueous phase was extracted with DCM (1.3 L). The organic phases were combined and washed successfully with 10 w% citric acid (1.3 L), aq. NaHCO3 (1.3 L), and brine (1 L). The organic phase was cooled to 0-10 °C and subsequently washed with water (3.1 L) and RuCl. 3·xH2O (2.66 g) was added, followed by oxone (927.1 g, 1.51 mol, 1.5 equiv). The reaction mixture was gradually warmed to 22° C. and held for 3.5 h or until the sulfamidite intermediate was completely consumed as determined by GC analysis. The phases were separated and the aqueous phase was filtered through a pad of Celite (50 g) followed by rinsing with DCM (1.3 L). The filtrate was extracted with DCM (1.3 L) and the organic phases were combined and then washed with saturated Na2S2O3 (1.3 L) and brine (1 L×2). The organic phase was dried over Na2SO4 (50 g) then filtered and rinsed with DCM (200 mL). The combined filtrate and washings were concentrated under reduced pressure at 30° C. for 1 h and then further concentrated under high vacuum to give 220 g of tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide in 91.8% isolated yield (corrected) over two steps, >99 wt %. 1 H NMR (400MHz, CDCl3): δ 4.66 (dd, J=9.2, 6.0Hz, 1H), 4.41 (qdd, J=6.4, 6.0, 2.8Hz, 1H), 4.19 (dd, J=9.2, 2.8Hz, 1H), 1.54 (s, 9H), 1.50 (d, J = 6.4Hz, 3H).

[0475]

[0528] Other oxidation reactions were carried out generally following the previous procedure, varying the oxidant, catalyst, and solvent. The results are shown below.

[0529] The results are shown in Table 1. In the table, "Exp." refers to the experiment number, "Product" refers to tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide, "SM" refers to Boc-alanineol starting material, "LC A%" refers to area % purity by liquid chromatography, and "ND" refers to not detected. The reaction temperatures for experiments 1 and 3-9 were 0-25°C, and the reaction temperature for experiment 2 was 0-40°C. The reaction times for experiments 1-4 and 7 were 4 hours, those for experiments 5 and 6 were 8 hours, and those for experiments 8 and 9 were 18 hours.

[0476] Table 1: Oxidizing agent, catalyst, conditions and yield JPEG0007660040000134.jpg126170

[0477]

[0530] To a mixture of indole (7.4 g, 63.2 mmol, 1.5 equiv) and CuCl (5.4 g, 54.7 mmol, 1.3 equiv) in DCM (60 ml) was added MeMgCl (3.0 M in THF, 18.7 mL, 56 mmol, 1.33 equiv) over 10 min under N2 at −15° C. The resulting light yellow mixture was stirred at −20° C. for 10 min, then a solution of tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (10.0 g, 42.1 mmol, 1.0 equiv) in DCM (40 ml) was added dropwise over 30 min at −10° C. under N2. The mixture was added dropwise at -10°C for 2 hours or until the reaction was complete as judged by TLC (PE / EA=5 / 1, disappearance of tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide) or by GC. The reaction was quenched by adding 10% citric acid (100 mL) while maintaining an internal temperature <5°C. The phases were separated and the aqueous phase was extracted with DCM (100 mL x 2). The organic phases were combined and washed with brine (100 mL x 2), followed by addition of activated charcoal (5 g) and Na2SO4 (10 g) to the organic phase. The resulting mixture was stirred at room temperature for 30 minutes and then filtered. The cake was washed with DCM (50 mL x 2). The filtrate and washings were combined and concentrated under reduced pressure at 30° C. to give crude tert-butyl (R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate (16.9 g, 40.9 LCA%). Heptane (200 ml) was added to the crude tert-butyl (R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate and the mixture was stirred at room temperature for 1 h, during which time an off-white solid gradually precipitated. The solid was collected by filtration and the cake was washed with heptane (17 mL×3). The solid was dried under high vacuum at 25° C. to give 7.0 g of tert-butyl (R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate (25.5 mmol, 97 A%, 99 wt%). 1H NMR (400MHz, DMSO-d6) δ 10.76(s,1H), 7.55(d,J=7.9Hz,1H), 7.32(dt,J=8.1, 1.0Hz,1H), 7.09(d ,J=2.3Hz,1H), 7.05(ddd,J=8.2, 7.0, 1.2Hz,1H), 6.96(ddd,J=8.0, 6.9, 1 .1Hz,1H), 6.71(d,J=8.0Hz,1H), 3.76-3.69(m,1H), 2.86(dd,J=13.9, 5.8 Hz,1H), 2.64(dd,J=14.1, 7.7Hz,1H), 1.37(s,9H), 1.00(d,J=6.6Hz,3H).

[0478]

[0531] Other indole alkylation reactions were carried out generally following the procedure just described, varying the copper catalyst species and stoichiometry of the Grignard reagent.

[0532] These results are reported in Table 2. In the table, "Exp." refers to the experiment number, "CuX" refers to the copper catalyst species, "eq." refers to equivalents, "Prod" refers to tert-butyl (R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate, "N1" refers to the by-product of indoleamine alkylation, "BA" refers to the bis-alkyl by-product, "AY" refers to the LC assay yield, "A%" refers to the area % purity by liquid chromatography, and "ND" refers to not detected.

[0479] Table 2: Indoles, alkylations, reaction conditions and yields JPEG0007660040000135.jpg57170

[0480]

[0533] Other indole alkylation reactions were carried out generally following the procedure above, varying the reaction temperature. The results are shown below.

[0534] These are reported in Table 3, where "Exp." refers to the experiment number, "G temp" refers to the Grignard reagent addition temperature in °C, "S temp" refers to the sulfamidate addition temperature in °C, "Prod" refers to tert-butyl (R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate, "N1" refers to the by-product where the indole amine is alkylated, "BA" refers to the bis-alkyl by-product, "AY" refers to the LC assay yield, and "A%" refers to the area % purity by liquid chromatography.

[0481] Table 3: Variable temperature indole alkylation experiments JPEG0007660040000136.jpg81170

[0482]

[0535] To a solution of tert-butyl (R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate (0.5 g, 1.8 mmol, 92 A%) in MeOH (5 mL, 10 vol.) was added HCl in MeOH (10 M, 1.8 mL, 18 mmol) dropwise at 0 °C under N2 atmosphere over a period of 10 min. The resulting solution was stirred at 0 °C for 2 h and then at 25-30 °C for 1 h. The solution was concentrated under reduced pressure at 30 °C, diluted with water (10 mL) and extracted with DCM (10 mL x 2). The pH of the aqueous phase was adjusted to ∼13 using 1 M aq. NaOH at 0-10 °C and then extracted with DCM (20 mL x 4). The organic phase was dried over Na2SO4 (10 g). The drying agent was filtered and the cake was washed with DCM (10 mL). The combined filtrate and washings were concentrated under reduced pressure at 30° C. to give 0.31 g of crude (R)-1-(1H-indol-3-yl)propan-2-amine in 97% isolated yield with 95.8 LCA% and 99.2% ee purity. 1H NMR:400MHz(CDCl3):δ 1.20(d,J=6,3H), 1.56(s,br,2H), 2.69(dd,J=14,8,1H), 2.91(dd,J=14,4,1H), 3.30-3.33(m,1H) , 7.05(s,1H), 7.14(t,J=7, 1H), 7.22(t,J=7, 1H), 7.38(d,J=8, 1H), 7.64(d,J=8, 1H), 8.27(s,1H).

[0483]

[0536] Example 6

[0537] Preparation of (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol TIFF0007660040000137.tif56170.

[0484]

[0538] To a solution of 2,2-difluoropropane-1,3-diol (51 kg, 90 wt%, 409.5 mol, 1 eq.) in DCM (332 kg, 5 vol.) was added thionyl chloride (58.4 kg, 491.4 mol, 1.2 eq.) over 2 h at 20-25° C. The reaction mixture was heated to 30-35° C., stirred for 2 h, and ice water (255 kg) was added to quench the reaction. The phases were separated and the aqueous phase was extracted with DCM. The organic phases were combined and washed with water. To the crude organic phase, water (255 kg) and FeCl3 (1.6 kg) were added and the biphasic mixture was cooled to −3° C. Then bleach [NaClO (8.1 wt%), 680 kg, 1556 mol, 3.8 eq.] was added dropwise over a period of 5 h at −5 to 1° C. and the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was filtered through Celite. The phases were separated and the aqueous phase was extracted with DCM. The organic phases were combined and washed with an aqueous solution of Na2SO3 and brine, then dried over Na2SO4. The drying agent was filtered off and the filtrate was concentrated to about 100 L. Heptane (80 kg) was added to the resulting suspension and the mixture was further concentrated to about 100 L. The solid was collected by filtration and dried under reduced pressure to give 52.01 kg of 5,5-difluoro-1,3,2-dioxathiane 2,2-dioxide as off-white crystals (72% yield, two steps from 2,2-difluoropropane-1,3-diol). 1 H NMR (400MHz, DMSO-d6) δ 5.14 (t, J=10.8Hz, 1H).

[0485]

[0539] A variety of other catalysts were evaluated for the preparation of 5,5-difluoro-1,3,2-dioxathiane 2,2-dioxide generally following the procedure just described. The results are given below.

[0540] The results are reported in Table 4, where "Exp." refers to the experiment number, "Diol" refers to 2,2-difluoropropane-1,3-diol, "Prod" refers to 90 wt.% 5,5-difluoro-1,3,2-dioxathiane 2,2-dioxide, and "Yield" refers to the assay yield. Each reaction was quenched with 5 volumes of water.

[0486] Table 4: Conditions for the preparation of 5,5-difluoro-1,3,2-dioxathiane 2,2-dioxide JPEG0007660040000138.jpg107170

[0487]

[0541] A 2 L flask was charged with (R)-1-(1H-indol-3-yl)propan-2-amine (99 wt%, 100 g, 568.2 mmol, 1 equiv), 5,5-difluoro-1,3,2-dioxathiane 2,2-dioxide (97.9 wt%, 108 g, 608 mmol, 1.07 equiv), K2CO3 (55 g, 398 mmol, 0.7 equiv), and acetonitrile (1 L, 10 vol.). The resulting mixture was heated to 80° C. and stirred for 4 h. The reaction was cooled to 35° C. and filtered. The cake was washed with acetonitrile (100 mL×2) and the filtrate was added to a mixture of p-TsOH monohydrate (119 g, 625.6 mmol, 1.1 equiv) and water (100 mL, 1 vol). The resulting biphasic mixture was heated to 80° C. and stirred for 3 h. The mixture was then poured into 1 L of ice water and the pH of the mixture was adjusted to 9 with saturated Na2CO3 (350 mL) at <5° C. The phases were separated and the aqueous was extracted with i-PrOAc (500 mL×2). The organic phases were combined and washed with water (500 mL) and brine (500 mL×2) and then dried over Na2SO4 (30 g). The drying agent was filtered off and the cake was washed with i-PrOAc (100 mL×2). The filtrate and washings were combined and concentrated under reduced pressure at 40° C. The residue was dissolved in i-PrOAc (200 mL) and heated to 60° C. Heptane (800 mL) was added dropwise at 60° C. and the resulting mixture was then stirred for 10 min. The mixture was slowly cooled to 30-35° C. over 2 h and then further cooled to 0° C. After stirring for 10 minutes, the solid was collected by filtration and the cake was washed with heptane (100 mL x 2). The solid thus obtained was dried under reduced pressure at 45°C to obtain (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol (155 g, 99.2 LCA%, 96 wt%, 97.6% isolated yield). 1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H), 7.51(dd,J=7.9, 1.2Hz,1H), 7.33(dt,J=8.2, 1.0Hz,1H), 7.13(d,J= 2.3Hz,1H), 7.05(ddd,J=8.2, 6.9, 1.3Hz,1H), 6.96(ddd,J=8.0, 6.9, 1.2Hz,1H), 5 .35(t,J=6.3Hz,1H), 3.61(td, J=13.8, 5.2Hz,2H), 3.03-2.91(m,3H), 2.83(dd,J= 14.0, 5.7Hz, 1H), 2.59 (dd, J = 14.0, 7.2Hz, 1H), 1.69 (s, 1H), 0.96 (d, J = 6.2Hz, 3H).

[0488]

[0542] Example 7

[0543] Preparation of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (2R,3R)-2,3-dihydroxysuccinate TIFF0007660040000139.tif110170.

[0489]

[0544] In step 1, a flask equipped with a stirrer was mixed with 4-bromo-2,6-difluorobenzaldehyde (131.79 g, 596.35 mmol), (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol (160 g, 596.35 mmol), acetic acid (51.26 mL, 894.52 mmol), and toluene. The reaction was heated to 75° C., held overnight, cooled, and then diluted with toluene. The resulting solution was then quenched with aqueous potassium carbonate, washed with brine and water, and treated with activated charcoal. Following filtration, the solution was concentrated and crystallized from toluene / heptane to give 3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol in 81% yield as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.59(s,1H), 7.45-7.36(m,3H), 7.20(d,J=8.1Hz,1H), 7.05-6.92(m,2H), 5.29(t,J=6.1Hz,1H), 5.21(s,1H), 3.71-3.55(m, 1H), 3.53-3.38(m,2H), 3.17(q,J=15.2Hz,1H), 2.89(ddd,J=15.3, 4.8, 1.5Hz,1H), 2.71-2.55(m,2H), 1.08(d,J=6.5Hz,3H). MS([M+H]+),C 21 H 19 Calculated for BrF4N2O: 470.06; measured: 470.80.

[0490]

[0545] Alternatively, 4-bromo-2,6-difluorobenzaldehyde (67.2 g, 304 mmol), (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol (80.0 g, 298 mmol), acetic acid (25.6 mL, 447 mmol), and methanol were mixed in a stirred flask. The mixture was refluxed for 24 hours and then cooled. A solid was precipitated from the resulting solution by addition of an aqueous solution of potassium carbonate. The resulting slurry was filtered and washed to give 3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol in 97% yield as a pale yellow solid.

[0491]

[0546] In steps 2 and 3, 3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (100 g, 212.2 mmol), 1-(3-fluoropropyl)azetidin-3-amineethane-1,2-disulfonate (82.09 g, 254.6 mmol), acetonitrile, DBU (1061 mmol 161.5 g 159.4 mL) were mixed in a stirred flask followed by the addition of Pd-175 (5.304 mmol 4.144 g). The reaction was heated to 75° C. for 2 hours, cooled, concentrated, and then diluted with methyl tert-butyl ether. The resulting solution was worked up with an aqueous solution of ammonium chloride, brine, and water, then stripped with SiliaMetS thiol. Following filtration, the solution was concentrated, diluted with ethanol, and crystallized with tartaric acid to give 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (2R,3R)-2,3-dihydroxysuccinate in 90% yield as a yellow solid following filtration and washing. 1 H NMR(400MHz,DMSO-d6)δ 10.52(s,1H), 7.38(dd,J=7.5, 1.3Hz,1H), 7.21-7.16(m,1H), 7.02-6.90(m,2H), 6.82(d,J=6.9 Hz,1H), 6.18-6.08(m,2H), 5.07(s,1H), 4.53(t,J=5.8Hz,1H), 4.42(t,J=5.9Hz,1H), 4.18(s,2 H), 4.14-4.05(m,1H), 3.93(ddt,J=9.1, 7.0, 3.5Hz,2H), 3.74-3.60(m,1H), 3.51-3.32(m,2H), 3.21-3.02(m,3H), 2.88-2.73(m,3H), 2.70-2.51(m,2H), 1.83-1.66(m,2H), 1.09-1.05(m,3H). MS([M+H]+),C 27 H 31Calculated for F5N4O: 522.24, actual measured: 523.00.

[0492]

[0547] Example 8

[0548] Preparation of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (2R,3R)-2,3-dihydroxysuccinate TIFF0007660040000140.tif109170.

[0493]

[0549] In step 1-4, a reactor was charged with 4-bromo-2,6-difluorobenzaldehyde (75.0 g, 0.339 mol, 100 mol%), p-toluenesulfonic acid monohydrate (162 mg, 0.000849 mol, 0.250 mol%), and toluene (225 mL). Triethyl orthoformate (55.4 g, 62.1 mL, 0.373 mol, 110 mol%) was charged at rt over 15 min, the mixture was stirred at rt for 1 h, and the mixture was distilled to obtain a toluene solution of 5-bromo-2-(diethoxymethyl)-1,3-difluorobenzene. A separate reactor was charged with 1-(3-fluoropropyl)azetidin-3-amine 2-(trioxidanylthio)ethane-1-sulfonate (131.3 g, 0.407 mol, 120 mol%), and acetonitrile (656 mL). DBU (124.0 g, 122.8 mL, 0.814 mol, 240 mol%) was charged at rt over 15 min, the mixture was stirred at rt for 2 h, distilled with toluene, and filtered to give a toluene solution of 1-(3-fluoropropyl)azetidin-3-amine. This was charged to a toluene solution of 5-bromo-2-(diethoxymethyl)-1,3-difluorobenzene along with NaOtBu (39.14 g, 0.407 mol, 120 mol%). The mixture was sparged, charged with BrettPhos Pd G3 (3.076 g, 0.00309 mol, 1.00 mol%), sparged, heated at 60° C. for 18 h, cooled, quenched with water, and washed twice with water. Siliamets thiol (20.0 g) was charged and the mixture was heated to 50 C for 2 h, cooled and filtered to give a toluene solution of N-(4-(diethoxymethyl)-3,5-difluorophenyl)-1-(3-fluoropropyl)azetidin-3-amine. Acetic acid (21.4 mL, 0.373 mol, 110 mol%) and water (300 mL) were added and the mixture was held at rt for 2 h. The aqueous phase was separated, treated with aqueous NaOH (50 wt%, 21.5 mL, 0.407 mol, 120 mol%) and seeded with 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldehyde (923 mg, 0.00339 mol, 1.00 mol%).The resulting solid was filtered, washed with water and dried to give 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldehyde (77.9 g, 84.3% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 10.05(dd,J=1.2Hz,1H), 6.05-5.97(m,2H), 5.03(d,J=6.4Hz,1H), 4.54(t,J=6.0Hz,1H), 4.42(t,J=6.0Hz,1H ), 4.14-4.03(m,1H), 3.70(td, J=6.8, 1.6Hz,2H), 2.99-2.93(m,2H), 2.59(t,J=7.2Hz,2H), 1.83-1.66(m,2H). MS:C 13 H 15 F3N2O[M+H] + Calculated value = 273.1, actual value = 273.0.

[0494]

[0550] In step 5, the reactor was charged with (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol (6.60 kg, 24.60 mol, 100 mol%), 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldehyde (6.70 kg, 24.60 mol, 100 mol%), L-tartaric acid (5.54 kg, 36.90 mol, 150 mol%), and ethanol (39.6 L). The reaction mixture was heated at 70° C. for 2 hours, seeded with 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (2R,3R)-2,3-dihydroxysuccinate (0.0827 kg, 0.123 mol, 0.5 mol%), stirred at 70° C. for 2 days, quenched with ethanol (26.4 L), cooled, and filtered to collect the solid. The solid was washed with ethanol and dried under reduced pressure to give 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (2R,3R)-2,3-dihydroxysuccinate (12.7 kg, 78% yield) as an off-white solid.

[0495]

[0551] Various acids other than tartaric acid, as well as comparative examples using tartaric acid, were evaluated for the ring closure reaction of step 5, generally following the procedure immediately above. The results were as follows:

[0552] The results are reported in Table 5, where "Exp." refers to the experiment number and "Conv" refers to the conversion to the fused tricyclic ring structure. The tartrate salt substantially increased the final yield. Furthermore, the tartrate salt minimized the presence of oligomer by-products formed during the synthesis, thereby increasing the purity of the product and reducing epimerization of the final compound product.

[0496] Table 5: Acids tested for ring closure of compound A JPEG0007660040000141.jpg79170

[0497]

[0553] Example 9:

[0554] Recrystallization of Compound B TIFF0007660040000142.tif42170

[0498]

[0555] A 250 mL reactor was charged with a mixture of crude compound B (4.00 g, 5.95 mmol) and EtOH (10.0 mL) in MeOH (90.0 mL). The slurry was heated to 60° C. until homogenous. Compound B seeds (200 mg, 0.297 mmol, 5 mol%) were added to the solution. The slurry was diluted with EtOH, cooled to 25° C. over 1 h, held at 25° C. for 1 h, filtered, and dried to give compound B (3.83 g, 91% yield) as an off-white solid.

[0499]

[0556] Example 10:

[0557] Recrystallization of compound B: TIFF0007660040000143.tif47170

[0500]

[0558] Example 10A: A 30 L reactor was charged with crude compound B (1.26 kg, 1.88 mol, 100 mol%) and MTBE (6.30 L, 5.00 mL / g). A solution of NaOH (154 g, 3.85 mol, 205 mol%) in water (6.30 L, 5.00 mL / g) was added to the slurry. The reaction mixture was stirred at 20° C. for 30 min. The upper organic layer was washed twice with water (2.53 L, 2.00 mL / g), passed through a charcoal cartridge, and distilled with EtOH to give a solution of the free base of compound B in EtOH.

[0501]

[0559] Example 10B: A 20 L reactor was charged with L-tartaric acid (296 g, 1.97 mol, 105 mol%), EtOH (2.52 L, 2.00 mL / g) and heated to 70° C. 20% of the compound B free base solution was transferred into the 20 L reactor. Compound B seeds (25.2 g, 0.0375 mol, 2 mol%) were added to the solution. The remainder of the compound B free base solution was transferred into the 20 L reactor over 1 hour, aged at 70° C. for 30 minutes, cooled to 20° C. over 5 hours, aged at 20° C. for a minimum of 2 hours, filtered, washed three times with EtOH (2.52 L, 2.00 mL / g), and dried to give compound B (1.12 kg, 89%) as an off-white solid.

[0502]

[0560] Example 11:

[0561] The compounds provided herein have been characterized by mass spectrometry and / or NMR techniques as understood in the art. The compounds of the examples have the stereochemistry assigned unless otherwise specified.

[0503]

[0562] Compound (M1) TIFF0007660040000144.tif63170Determined m / z: 672.64.

[0504]

[0563] Compound (M2) TIFF0007660040000145.tif62170Determined m / z: 672.64.

[0505]

[0564] Compound (M3) TIFF0007660040000146.tif46170Determined m / z: 652.63

[0506]

[0565] Compound (M4) TIFF0007660040000147.tif45170Determined m / z: 540.57 (stereomeric mixture).

[0507]

[0566] Example 12:

[0567] Enzymatic conversion:

[0568] Screening of transaminases in the kinetic decomposition mode of rac.alpha-methyltryptamine revealed enzymes that possessed sufficient (R)-enantioselectivity for the asymmetric reductive amination approach and sufficient (S)-enantioselectivity for the kinetic decomposition approach. Exemplary transaminases are

[0569] Listed in Table 6.

[0508] Table 6: Enantioselective Transaminases (TA): TIFF0007660040000148.tif72170

[0509]

[0570] Asymmetric reduction applying transaminase TA-P2-A07 was carried out on a 5 g scale using buffer; isopropylamine and organic cosolvents such as DMSO or acetonitrile. Compound (XXI) was converted to compound (3) described herein in greater than 95% after 1 day with an enantiomeric excess (EE) of greater than 99%.

[0510]

[0571] Reductive amination was also carried out in organic solvents containing small amounts of buffer and isopropylamine where transaminase TA-P2-A07 was immobilized on a solid support. Compound (XXI) was converted to compound (3) after 4 weeks with an EE of over 99% and a degree of conversion of over 95%. The organic solvent allowed for higher substrate loadings of up to 5% [w / w].

[0511]

[0572] Kinetic resolution was carried out in buffers containing pyruvate and organic cosolvents such as acetonitrile in the presence of transaminase ATA12 in (1) whole cells; (2) cell-free lysates or (3) crude lyophilizates. Enantiomeric excesses >99% were achieved. Conversion to compound (3) was achieved to a degree of 50% or greater. The undesired enantiomer was depleted by oxidative deamination to the ketone.

[0512]

[0573] Identification of selected TA sequences: TIFF0007660040000149.tif117170TIFF0007660040000150.tif116170TIFF0007660040000151.tif123170TIFF0007660040000152.tif116170Residues in bold and underlined correspond to mutations in the native sequence.

[0513]

[0574] Example 13:

[0575] Free Base, Salt, and Polymorphic Properties of Compound A

[0576] Abbreviation; TIFF0007660040000153.tif102170

[0514]

[0577] Free Base Polymorph Screening A 96-well plate automated high-throughput screen (HTS) using a Symyx CM2 system (Freeslate Inc., CA) was performed to identify possible polymorphs of the free base of Compound A. Compound A was dispensed into each well (8 mg / well) using an automated powder dispensing accessory, followed by the addition of 800 μl of solvent (neat or mixture) and stirring the slurry for 2 hours at 50° C. Compound A was first dispensed into a slurry plate using ethyl acetate (for the tartrate salt) or MIBK (for the fumarate salt) to maintain the solid form. From this master plate, the supernatant was filtered and dispensed into three separate plates, followed by evaporation, precipitation by addition of antisolvent, and controlled cooling at 50-20° C. for 8-10 hours. In all cases, the residual solvent was evaporated or siphoned off and the solids were examined by polarized light microscopy and XRPD.

[0515]

[0578] Example 14:

[0579] Screening of salts According to the approximate solubility data of the free base and the list of desired acids, five solvent systems were used for screening. First, approximately 20 mg of the free base amorphous compound was dispersed in 0.5 mL of the selected solvent in a glass vial, and then the corresponding acid was added at a ratio of 1:1 of molar charge. For two basic functional groups, an extra molar ratio of 2:1 (acid / free base) was tried for HCl. The mixtures were stirred at RT overnight. The resulting solids were analyzed by XRPD. The clear solutions obtained after stirring were stirred at 5° C. for 2 days, then 0.5 mL of H2O was added to each of the clear solutions in ACN / H2O (19:1, v / v), and 0.5 mL of n-heptane was added to each of the clear solutions in the other solvent systems, followed by stirring at 5° C. for about 3 days, and the final clear solutions were transferred to slow evaporation at RT to identify as many crystalline hits as possible.

[0516]

[0580] Through the initial screening,

[0581] Hits were identified with crystalline forms as shown in Table 7. The tartrate and fumarate salts were further scaled up to 50 mg-1.5 g scale for further characterization. Different solvent systems and conditions were tested, allowing a) thorough characterization of the different polymorphs obtained as hits in the screening and b) identification of conditions that suppress and control cis epimer formation. Epimer content varied from <1%-22% in different free base lots.

[0517] Table 7: Screening of salts of Compound A and hits in crystalline form TIFF0007660040000154.tif108170

[0518]

[0582] method:

[0583] Ambient powder X-ray diffraction measurements (XRPD) XRPD patterns were collected using a PANalytical Empyrean powder X-ray diffractometer (PANalytical Inc., Lelyweg, Netherlands). Powder samples were loaded into a zero-background silicon holder and run in reflector mode (Bragg Brentano geometry). The instrument was equipped with a Cu Kα source with tube voltage and tube current of 45 kV and 40 mA, respectively. Data were collected at ambient temperatures from 3.0 to 40.0° 2θ using a step size of 0.0263° at a rotation speed of 8 sec. The entrance beam path was equipped with a 0.02° Soller slit, a fixed 1° anti-scatter slit, a 10 mm fixed entrance beam mask, and a programmable divergence slit in auto mode. A beam knife for linear detection was used. The diffracted beam was equipped with a 0.02° Soller slit, a programmable anti-scatter slit in auto mode, and a nickel K-β filter. A PIXcel 1D detector was used in scanning line detector (1D) mode. Data were analyzed using commercially available software (JADE®, version 9, Materials Data Inc., Livermore, CA).

[0519]

[0584] Water Sorption Analysis Approximately 5-6 mg of powder sample was placed in the sample pan of an automated water sorption analyzer (Q5000SA, TA instruments, New Castle, Del.) at 25° C. and a nitrogen flow rate of 200 mL / min. Samples were first "dried" at 0% RH for a total of 400 minutes (60° C., followed by 25° C.), then the RH was gradually increased from 0-90% in 10% increments over RH 0-90%, with a dwell time of 200 minutes for each RH. This was followed by a gradual decrease in RH to 0% RH in 10% increments using the same protocol.

[0520]

[0585] Differential Scanning Calorimetry (DSC) Approximately 3-8 mg of powder sample was measured using a DSC Q2000 equipped with a refrigerated cooling accessory. TM The samples were analyzed using a non-hermetically sealed pan (Tzero TMThe cells were loaded into a 100-mL aluminum pan and heated typically from 0-200° C. at 10° C. / min under a purge of dry nitrogen. The instrument was calibrated using sapphire (baseline) and indium (temperature and cell constant). Data were analyzed using commercially available software (Universal Analysis 2000, version 4.7A, TA Instruments).

[0521]

[0586] Thermogravimetric Analysis (TGA) In a thermogravimetric analyzer (Discovery TGA, TA instruments), 3-5 mg samples of Compound A were heated in an open aluminum pan from RT to 350° C. at a heating rate of 10° C. / min under a dry nitrogen purge. Temperature calibration was performed using Alumel® and nickel. Standard weights of 100 mg and 1 gm were used for weight calibration.

[0522]

[0587] Polarized Light Microscopy (PLM) Samples were dispersed in silicone oil and observed under a cross-polarizer on a video-intensified Leica DM 4000B microscope equipped with a high-resolution CCD camera and a motorized stage (Clemex Technologies Inc., Longueuil, Quebec, Canada) at 200X magnification. Photomicrographs were acquired using Clemex Vision PE software (Clemex Technologies Inc., Longueuil, Quebec, Canada).

[0523]

[0588] Scanning Electron Microscopy (SEM) Powder samples were sputter coated onto SEM stubs and then analyzed using a benchtop Phenom SEM (Nanoscience Instruments, Inc., AZ). Micrographs were acquired at different magnifications.

[0524]

[0589] Particle size distribution (PSD) Particle size analysis was performed using a Malvern Mastersizer 2000 instrument (Malvern Instruments Ltd., Malvern, UK) equipped with a Hydros 2000SM wet dispersion attachment. ~40 mg of API was weighed into a vial and 1 mL of 0.1% Span 85 in heptane was added. The vial was sonicated for 10 s and approximately 0.5 mL was added to the sampler at a stirring speed of 1500 rpm and PSD was performed at 10-20% obscuration. Due to the presence of large clusters in the sample that quickly settled out of suspension, the dispersant was changed to 0.2% Span 85 in heptane to stabilize the suspension. Two external sonications followed by two 5-min durations were applied to break up the clusters and PLM images were acquired before and after sonication. To ensure homogeneity, an aliquot was mixed in the sampler for 2 min before data collection. The instrument was rinsed twice with isopropyl alcohol (IPA) and once with heptane before being filled with 0.1% Span 85 in heptane for each sample. After the last sample run, the instrument was rinsed once with IPA. Replicate data with 5 minutes of sonication are reported.

[0525]

[0590] BET Surface Area Analysis Surface area measurements were performed using a Micromeritics ASAP 2460 (Micromeritics Instrument Corp., GA) equipped with a Micromeritics Smart VacPrep attachment. 500 mg-1 g samples were weighed into empty ASAP 2460 tubes, placed in the Smart VacPrep, degassed under ambient conditions for 24 hours, and then exposed to krypton gas adsorption at 25° C. and 100 mm Hg holding pressure. Eleven measurements were made over a relative pressure range of 0.050-0.300, and the data was analyzed using MicroActive software supplied by the vendor.

[0526]

[0591] Solid-state Nuclear Magnetic Resonance Spectroscopy (SSNMR) All 13C (@8 kHz spinning speed) SSNMR experiments were performed using a 500 MHz Bruker instrument (Bruker BioSpin GmbH, Karlsruhe, Germany). 13 C data were acquired using a CP / TOSS sequence. 1-2K scans were collected for signal averaging. A contact time of 2 ms and a recycle delay of 5 seconds were used. A 64-s array of spinal cord was used for decoupling with a pulse length of 5.3 microseconds. A 2.9 microsecond recycle delay was used. 1 H A 90 degree pulse length was used. All 19 F (@14 kHz spinning speed) SSNMR experiments were performed using a 500 Mhz Bruker instrument. 19 F data were acquired using CP and direct polarization sequences. Scans from 64-256K were collected for signal averaging. A contact time of 750 ms and a recycle delay of 7 s were used. A 3.54 μs 1 H 90 degree pulse length was used.

[0527]

[0592] Example 15:

[0593] Preliminary Characterization of Compound A Free Base Compound A free base was found to be amorphous. Starting material free base Compound A was characterized by XRPD, TGA and mDSC prior to screening. As shown by the characterization results in Figures 32 and 33, starting material Compound A was amorphous with a weight loss of 9.3% up to 220°C in TGA and no substantial glass transition signal in mDSC. A white solid of free base Compound A was obtained by anti-solvent addition, which was shaken in MeOH / H2O (3:20, v / v) and air-dried for ∼7 days.

[0528]

[0594] Polymorphism Screening The solubility of free base Compound A was estimated in 16 solvents at RT.

[0595] Table 8.) Polymorph screening experiments were performed using different solution crystallization or solid phase transition methods. The methods used and the crystal forms identified are summarized in Table 9.

[0529] Table 8: Approximate solubility of free base Compound A TIFF0007660040000155.tif63170

[0530]

[0596] Table 9: Summary of polymorphism screening of free base Compound A TIFF0007660040000156.tif52170

[0531]

[0597] Solid Vapor Diffusion Solid vapor diffusion experiments were performed using 13 different solvents. For each experiment, approximately 15 mg of starting material was weighed into a 3 mL vial and placed in a 20 mL vial containing 2 mL of the corresponding volatile solvent. The 20 mL vials were sealed with caps and kept at RT for 11 days to allow the solvent vapor to interact with the solid samples. The isolated solids were examined by XRPD.

[0598] As summarized in Table 10, only oil or amorphous forms were obtained.

[0532]

[0598] Table 10: Summary of solid vapor diffusion experiments TIFF0007660040000157.tif98170

[0533]

[0599] Slurry conversion at RT Slurry conversion experiments were performed in different solvent systems at RT. Approximately 40 mg of starting material was suspended in 0.3 mL of solvent in a 1.5 mL glass vial. After stirring, all clear solutions were transferred to 5° C., followed by slow evaporation at RT for 3 days. The results showed that only amorphous, gel or oil was obtained.

[0534]

[0600] Table 11: Summary of slurry conversion experiments for free base Compound A TIFF0007660040000158.tif181170* No slow evaporation was performed **The solid was centrifuged and stirred at RT for 4 days before being analyzed by XRPD. N / A: No solid was obtained

[0535]

[0601] Antisolvent addition A total of 15 antisolvent addition experiments were performed. Approximately 30 mg of starting material was weighed into a 20 mL glass vial and dissolved in 0.15 mL of the corresponding solvent at RT. The antisolvent was added stepwise and the sample was magnetically stirred until a precipitate appeared or the total amount of antisolvent reached 12 mL. The precipitate was isolated for XRPD analysis. If no solids were observed, the clear solution was magnetically stirred overnight at 5° C. and then evaporated at RT.

[0602] The results in Table 12 showed that only amorphous or gel forms were produced.

[0536] Table 12: Summary of antisolvent addition experiments for free base Compound A TIFF0007660040000159.tif103170

[0537]

[0603] Liquid vapor diffusion 14 conditions (

[0604] Liquid vapor diffusion experiments were carried out under Table 13). Approximately 30 mg of starting material was weighed into each 3 mL glass vial. The corresponding solvent was added to obtain a solution. The vial was sealed in a 20 mL glass vial with 3 mL of the corresponding anti-solvent and kept at RT, allowing the vapor to interact with the solution for approximately 11 days. The precipitate was isolated for XRPD analysis. The clear solution was transferred to evaporation at RT.

[0538] Table 13: Summary of liquid vapor diffusion experiments for free base Compound A TIFF0007660040000160.tif97170

[0539]

[0605] Slow evaporation Slow evaporation experiments were carried out under 12 conditions. In each experiment, approximately 20 mg of starting material was weighed into a 3 mL glass vial, followed by adding the corresponding solvent or solvent mixture to obtain a clear solution. The vial was then covered with parafilm with 3-4 pinholes and kept at 4 °C to allow the solution to evaporate slowly.

[0606] Only gel was obtained, as summarized in Table 14.

[0540] Table 14: Summary of slow evaporation experiments for free base Compound A TIFF0007660040000161.tif100170

[0541]

[0607]

[0608]

[0608] Table 15 summarizes the morphologies obtained via the manual screening described herein.

[0542] Table 15: Polymorphism of Compound A TIFF0007660040000162.tif115170

[0543]

[0609] Example 16:

[0610] Characterization of Compound B Form A Compound B Form A was prepared on a 200 mg scale via solution reactive crystallization in acetone as evidenced by XRPD (Figure 1). Approximately 7.2% weight loss was observed by 125°C in TGA and DSC results showed one endotherm at 124.3°C (onset temperature) as shown in Figures 2a and 2b. 1 H NMR showed that the molar ratio was 0.98 (acid / free base) with 5.6% acetone (0.69 molar ratio to free base) detected. To further identify Form A, heating experiments were performed. No change in morphology was observed after heating Form A to 90 °C, but after heating to 140 °C, the sample turned amorphous. A significant amount of acetone (4.5%) was still observed after heating the Form A sample to 90 °C. The Form A sample consisted mainly of fine particles and some aggregates (Figure 3). Based on the collected data, Form A of Compound B is an acetone solvate, with solvent loss occurring concomitantly with melting.

[0544]

[0611] Table 16: Representative XRPD peaks for Compound B Form A: JPEG0007660040000163.jpg209170

[0545]

[0612] Preparation of Compound B Form A Approximately 57.5 mg of tartaric acid was weighed into a 5 mL glass vial and 2.0 mL of acetone was added to obtain a clear solution. The clear acid solution was added in a 1:1 molar ratio to 2.0 mL of a stock solution of the free base in acetone (~100 mg / mL) in a 5 mL vial and stirred at RT. Approximately 1 mg of Compound B Form A seeds were added and the solution became cloudy. The sample was stirred overnight before the XRPD measurement described herein. The pattern was compatible with Compound B Form A. The suspension was then stirred at RT for an additional 24 hours and the cake was dried at 50° C. for 1.5 hours. Yield: 170.4 mg, ~65.3% yield.

[0546]

[0613] Example 17:

[0614] Characterization of Compound B Form B. Compound B Form B was prepared on a 200 mg scale via solution reactive crystallization in EtOAc as evidenced by XRPD (FIG. 4). As shown in FIG. 5a and FIG. 5b, limited weight loss of about 1.3% was observed by TGA up to 140° C., and DSC results showed a melting endotherm peak at 156.7° C. (onset temperature). The stoichiometry was determined to be 1.08 (acid / free base), 1 1.4% EtOAc (0.11 molar ratio to the free base) was detected by H NMR. Based on the collected characterization data, Compound B Form B is anhydrous.

[0547]

[0615] Solid state characterization data indicates that Form B is substantially crystalline (XRPD) and TGA indicates the presence of some surface solvent at ∼163°C with early onset of weight loss from RT-100°C indicating the presence of some ∼2% surface solvent. The onset of melting is at 163°C, followed by a shallow endotherm (evaporation of residual solvent). Based on the derived weight loss curve, a very rapid weight loss (2.4% w / w) was detected by 100°C, which can be attributed to surface solvent. The total weight loss, including melting, is 3.5% w / w. Form B was found to be slightly hygroscopic with a moisture uptake of 1.2% w / w at 90% RH and 25°C, as shown by the water sorption-desorption profile in Figure 8. 13 C (Figure 6) and 19F SSNMR spectrum (Figure 7) further indicated the formation of Form B. SEM (Figure 9a, 500X magnification) and PLM (Figure 9b, 200X magnification) images of compound B show that Form B is composed of dense spherical aggregates.

[0548]

[0616] Table 17: Representative XRPD peaks for compound B form B: JPEG0007660040000164.jpg163170

[0549]

[0617] Preliminary stress stability analysis of Compound B Form B. XRPD patterns of Compound A salts (fumarate and tartrate) exposed to 40°C / 75% RH under open conditions for 1 month. The solid form did not change under these conditions.

[0550]

[0618] Although no correlation was observed between the epimer content, which ranged from 0.56-0.72%, and the solid-state properties of the different salt forms, SSNMR, XRPD and DSC data indicate that a mixture of forms may be obtained from the fumarate salt, given the variability in structural data and melting points with changing crystallization conditions, and that control of morphology in either salt requires a significant amount of downstream effort. The tartrate salt was exposed to 40°C / 75% RH for 1 month and at 0.18% lacked the impurity found in the fumarate sample.

[0551]

[0619] Compression Analysis of Compound B Form B Figures 22, 23, and 24 show the effect of compression on Compound B tartrate Form B. A 250 mg compression of neat Compound B Form B was analyzed. Both SSNMR and XRPD (Figures 23 and 22, respectively) show that the form does not change under compression. 19 A decrease in T1 relaxation time was observed upon compression due to the onset of disorder, which is consistent with the results of the compression of Compound B Form B in Figure 23. 19 It was very small, as evident from the F SSNMR spectrum. 19 F T1 relaxation values ​​for neat and compressed compound B form B

[0620] The data are included in Table 18. As can be seen in the DSC thermogram (Figure 24), compression did not affect the melting point of Compound B Form B. Comparative XRPD collected before and after exposure to accelerated stability conditions of 30°C / 65% RH and 40°C / 75% RH for up to 6 months (open) demonstrated that Compound A Form B remains unchanged upon exposure to these conditions.

[0552] Table 18: Compound B Form B 19 F T1 relaxation time TIFF0007660040000165.tif33170

[0553]

[0621] XRPD of 1 Month Stability Sample The XRPD of Compound B Form B exposed to 40° C. / 75% RH for 1 month shows that Compound B Form B remains unchanged under stress stability conditions including elevated temperature and humidity.

[0554]

[0622] Preparation of Compound B Form B Approximately 58.0 mg of tartaric acid was weighed into a 5 mL glass vial and 2.0 mL of EtOAc was added. The acid remained undissolved. Approximately 2.0 mL of the free base stock solution in EtOAc (~100 mg / mL) was added to a 5 mL vial in a 1:1 molar ratio and the solution was stirred at RT. Approximately 1 mg of Form B seeds were added and the solution remained clear. The solution was stirred overnight and sampled by XRPD. The pattern was compatible with Compound B Form B. The suspension was stirred at 50°C for an additional 2 days. The suspension was centrifuged and the cake was dried at 50°C for 2 hours. Yield: 144.5 mg, ~56.1% yield.

[0555]

[0623] Example 18:

[0624] Preparation of Compound B Form C Form C was prepared on a 200 mg scale via solution reactive crystallization in THF as evidenced by XRPD (Figure 10). As shown in Figures 11a and 11b, a weight loss of 6.8% was observed by 130°C in TGA and DSC showed one endotherm at 118.1°C (onset temperature). The stoichiometry was determined to be 1.02 (acid / free base) and 9.7%.

[0556]

[0625] Preparation of Compound B Form C: Approximately 56.9 mg of tartaric acid was added to a 3 mL glass vial and 1.0 mL of THF was added to obtain a clear solution. The clear acid solution was added to 2.0 mL of the free base stock solution in THF (~100 mg / mL) in a 1:1 molar ratio and stirred at RT. Approximately 1 mg of Form C seeds was added, causing the solution to become slightly cloudy. The suspension was stirred overnight and sampled by XRPD. The pattern was compatible with Form C. The suspension was stirred for an additional 24 hours at RT and the cake was dried at 50° C. for 1.5 hours. Yield: The suspension was centrifuged to collect the solid. Yield: 161.4 mg, ~62.7% yield.

[0557]

[0626] Example 19:

[0627] Preparation of Compound B Form D A sample of Form D was obtained via fast evaporation in MeOH / DCM and via slurry in H2O at RT, respectively. The XRPD pattern of Form D is shown in Figure 12. The TGA and DSC results of a sample of Form D are shown in Figures 13a and 13b, respectively, and show a 3.5% weight loss before 150°C and an endotherm at 73.0°C before melting / decomposition at 163.9°C (onset temperature). After heating Form D to 150°C, cooling to 30°C under nitrogen protection, and then exposing to ambient conditions, a morphological change to Form F was observed. 1 No significant amounts of process solvents MeOH or DCM were detected by H NMR, and the stoichiometry of L-tartaric acid to free base was determined to be 1.0. Form D is a hydrate.

[0558]

[0628] To evaluate the physical stability of Form D under various humidities, DVS data of Form D samples were collected at 25° C. after the samples were equilibrated at ambient humidity (80% RH). In the DVS study of Form D, a platform from 20% RH (2.25% water uptake) to 80% RH (2.72% water uptake) was observed during desorption, suggesting that dehydration of hydrous Form D occurs when the associated humidity value is below 20%. Furthermore, the theoretical water content of a monohydrate is 2.6%. Therefore, Form D is likely to be a monohydrate.

[0559]

[0629] Table 19: Representative XRPD peaks for compound B form D: JPEG0007660040000166.jpg189170

[0560]

[0630] Example 20:

[0631] Preparation of Compound B Form E Form E was obtained by DMSO mediated crystallization by adding IPAc to the DMSO solution and its XRPD is shown in Table 14. The TGA and DSC curves (Figures 15a and 15b, respectively) showed a weight loss of 8.3% before 140° C. and an endotherm at 126.3° C. before dissolution / decomposition at 142.6° C. (onset temperature). 1 The H NMR spectrum showed 0.7 equivalents of DMSO (~9.4 wt%) and no significant amount of IPAc was detected. The stoichiometry of L-tartaric acid to free base was determined to be 1.0. Form E is a DMSO solvate.

[0561]

[0632] Example 21:

[0633] Preparation of Compound B Form F Form F was obtained by heating a sample of Form D to 150° C., cooling to 30° C. under nitrogen protection, and exposing to ambient conditions. The XRPD pattern of Form F is shown in Figure 16. DSC analysis (Figure 18) showed that Form F is crystalline and has an endothermic peak at 164.2° C. (onset body temperature). 1 1 H NMR determined the stoichiometry of L-tartaric acid to free base to be 1.0, with no significant solvent signal detected.

[0562]

[0634] Table 20: Representative XRPD peaks for compound B form F: JPEG0007660040000167.jpg202170

[0563]

[0635] To further characterize Form F, variable temperature XRPD (VT-XRPD) was performed on Form D. In this case, the temperature was increased to 150° C. and returned to 30° C. under nitrogen protection. Under these conditions, Form F was observed following dehydration of the Form D sample at elevated temperatures, indicating that Form F is anhydrous.

[0564]

[0636] To assess the physical stability of Form F at various humidities, dynamic vapor sorption (DVS) data for Form F was collected at 25° C. after equilibrating the samples at ambient humidity (80% RH). Approximately 1.9% water uptake was observed by 80% RH, suggesting that Form F is slightly hygroscopic.

[0565]

[0637] Preparation of Compound B Form G Form G was obtained by slow evaporation in MeOH at RT. The XRPD of Form G is shown in Figure 19. The TGA and DSC results are shown in Figures 20a and 20b, respectively, and demonstrated a 3.3% weight loss before 150°C and a melting / decomposition peak at 170.4°C (onset temperature). 1 The H NMR spectrum showed 0.49 equivalents of MeOH (equivalent to ~3.0 wt%). The stoichiometry of L-tartaric acid to free base was determined to be 1.0. Form G is a MeOH solvate.

[0566]

[0638] Table 21: Representative XRPD peaks of compound B form G; JPEG0007660040000168.jpg161170

[0567]

[0639] Example 22:

[0640] Polymorph Screening of L-Tartrate Salt Compound B Form B material solubility was estimated in 20 solvents at RT.

[0641] Table 22) Approximately 2 mg of solid was added to a 3 mL glass vial. Solvents from Tables 6-7 were then added stepwise into the vial until the solid dissolved or a total volume of 1 mL was reached. The results in Table 22 were used to guide solvent selection in polymorph screening. Polymorph screening experiments were performed using different solution crystallization or solid phase transition methods. The methods utilized and the crystalline forms identified are summarized in Table 23.

[0568] Table 22: Solubility of Compound B TIFF0007660040000169.tif73170

[0569]

[0642] Table 23: Summary of polymorphism screening TIFF0007660040000170.tif57170

[0570]

[0643] Example 23:

[0644] Anti-solvent addition A total of 14 anti-solvent addition experiments were performed. For each experiment, approximately 15 mg of compound B form B was weighed into a 20 mL glass vial, followed by the addition of 0.3-1.0 mL of the corresponding solvent. The mixture was then magnetically stirred at a speed of 500 RPM to obtain a clear solution at RT. The corresponding anti-solvent was then added to the solution to induce precipitation or until the total amount of anti-solvent reached 10.0 mL. The clear solution was transferred to a slurry at 5° C. If no precipitation occurred, the solution was then transferred to fast evaporation at RT. The solid was isolated for XRPD analysis. The results, summarized in Table 24, indicated that compound B forms B, D, and E were obtained.

[0571]

[0645] Table 24: Summary of antisolvent addition experiments TIFF0007660040000171.tif99170* Stir at 5°C to obtain a solid. **Solid was obtained by fast evaporation at RT N / A: No solid was obtained

[0572]

[0646] Example 24:

[0647] Slurry conversion at RT Slurry conversion experiments were performed in different solvent systems at RT. For each experiment, about 20 mg of compound B form B was suspended in 0.3 mL of the corresponding solvent in a 1.5 mL glass vial. After the suspension was magnetically stirred at RT for 17 days, the remaining solid was isolated for XRPD analysis. The results summarized in Table 25 showed that compound B forms B, D, and G were obtained.

[0573]

[0648] Table 25: Summary of slurry conversion experiments at RT TIFF0007660040000172.tif140170*After stirring for 17 days, the sample was subjected to heating and cooling.

[0574]

[0649] Example 25:

[0650] Slurry conversion at elevated temperatures Slurry conversion experiments were performed in different solvent systems at 50° C. and 70° C. For each experiment, approximately 20 mg of compound B Form B was suspended in 0.3 mL of the corresponding solvent in a 1.5 mL glass vial. After the suspension was magnetically stirred at 50° C. and 70° C. for 17 days, the remaining solid was isolated for XRPD analysis. The results, summarized in Table 26, showed that compound B Form B was obtained.

[0575]

[0651] Table 26: Summary of slurry conversion experiments at elevated temperatures TIFF0007660040000173.tif123170

[0576]

[0652] Example 26:

[0653] Slow Evaporation Slow evaporation experiments were performed under 9 conditions. For each experiment, approximately 15 mg of compound B form B was weighed into a 3 mL glass vial, followed by adding the corresponding solvent or solvent mixture to obtain a clear solution. The vial was then covered with parafilm with 3-4 pinholes and kept at RT to allow the solution to slowly evaporate. The isolated solid was examined by XRPD. As summarized, compound B form G was produced.

[0577]

[0654] Table 27: Summary of slow evaporation experiments TIFF0007660040000174.tif78170

[0578]

[0655] Example 27:

[0656] Solid Vapor Diffusion Solid vapor diffusion experiments were performed using 11 solvents. For each experiment, approximately 15 mg of compound B form B was weighed into a 3 mL vial, which was placed into a 20 mL vial containing 4 mL of the corresponding solvent. The 20 mL vial was sealed with a cap and kept at RT for 14 days to allow the solvent vapor to interact with the solid sample. The isolated solid was examined by XRPD. The results, summarized in Table 28, showed that compound B form B was obtained.

[0579]

[0657] Table 28: Summary of solid vapor diffusion experiments TIFF0007660040000175.tif105170

[0580]

[0658] Example 28:

[0659] Liquid Vapor Diffusion Twelve liquid vapor diffusion experiments were performed. For each experiment, approximately 15 mg of compound B form B was dissolved in 0.5-1.0 mL of the corresponding solvent to obtain a clear solution in a 3 mL vial. This solution was then placed in a 20 mL vial containing 4 mL of the corresponding anti-solvent. The 20 mL vial was sealed with a cap and kept at RT, allowing sufficient time for the solvent vapor to interact with the solution. The solid was isolated for XRPD analysis. The results, summarized in Table 29, showed that a mixture of compound B form B and forms B+G / B+D was obtained.

[0581]

[0660] Table 29: Summary of liquid vapor diffusion experiments TIFF0007660040000176.tif97170N / A: No solid was obtained

[0582]

[0661] Example 29:

[0662] Slow cooling Slow cooling experiments were performed in 10 solvent systems. For each experiment, approximately 20 mg of compound B form B was suspended in 1.0 mL of the corresponding solvent in a 3 mL glass vial at RT. The suspension was transferred to a slurry at 50 °C using a magnetic stirrer at a speed of 500 RPM. The sample was equilibrated at 50 °C for 2 hours and filtered using a 0.45 μm nylon membrane. The filtrate was then slowly cooled from 50 °C to 5 °C at a rate of 0.1 °C / min. The summarized results showed that no solids were observed.

[0583]

[0663] Table 30: Summary of annealing experiments TIFF0007660040000177.tif86170

[0584]

[0664] Example 30:

[0665] Phase Transitions Crystallization of compound B from solvents such as ethyl acetate, ethanol, acetone, or their aqueous mixtures can produce anhydrous form B, anhydrous form F, monohydrate form D, and one more acetone solvate form A. The XRPD patterns of these four solid forms are shown in Figure 21. Therefore, it was important to know the physical stability of these forms to determine the complete phase transition landscape and control the crystallization to obtain the desired form B. Due to the close melting points of forms F and B (onset temperature of 160-164°C for form F vs. 166-175°C for form B), competitive slurry cross-linking experiments at RT required time for form conversion and gave a mixture of both forms. As a result, equilibrium solubility studies of both forms in ethanol at 25, 35, and 50°C over a period of 17 hours were performed to determine their thermodynamic stability relationship.

[0585]

[0666] Form F was found to have higher solubility at these three temperatures, confirming that form B is the thermodynamically stable form from 25-50 °C. Van't Hoff plots of solubility versus temperature for forms B and F showed that the two anhydrides are enantiomerically related with a transition temperature at ~19 °C. For hydrate-anhydride stability, form B exhibited a higher water activity (a w )a w It was found that hydrate form D remained stable at a < 0.2 (RT), above which hydrate form D was stable. However, form B remained stable at a of 0.4 (RT) in slurry cross-linking experiments up to 36 days. w This indicates that the hydrate is kinetically stable up to the critical temperature a w Although the value is low, it suggests that there is a significant kinetic barrier for the conversion of form B to form D.

[0586]

[0667] Slurry and crystallization samples Form B + Form A

[0668] (1) mixtures of Form A / acetone solvate and Form B, and (2) 1:1 mixtures of Compound B lot containing Form B were made and added to 100% acetone and aqueous mixtures of acetone in water (90% acetone, 95, 96, 97, 98 and 99% acetone v / v). The samples were slurried for 120 hours at RT, filtered and then analyzed by XRPD.

[0587]

[0669] Form F

[0670] Form F was slurried overnight in 100% ethanol at RT and 50° C. One of the suspensions was seeded with Form B at RT and the other was not. The stirred suspension at 50° C. was seeded with Form B. The samples were filtered and analyzed by XRPD. Samples of Form F were slurried separately in 100% DI water, 1:1 acetone / water and 100% acetone at RT. The slurry of Form F in neat solvent was kept at RT while a solution of Form F was obtained in a 1:1 acetone:water mixture and thus stirred at 5° C. for cooling crystallization / precipitation. After 24 hours, all samples were filtered and analyzed by XRPD. Form F was also slurried in 95:5 acetone:water and 97:3 acetone:water mixtures at 50° C. for 2 hours, after which the slurry was cooled to RT, filtered and analyzed by XRPD. Finally, Form F was recrystallized from 95:5 acetone:water seeded with Form B at 50°C.

[0588]

[0671] Form D

[0672] Form D was slurried in 100% ethanol for 48 hours at RT, after which the sample was filtered and analyzed by XRPD.

[0589]

[0673] result

[0674] Development of a calorimetric method to estimate purity. Switching from ethanol to acetone / water as the cr...

Claims

1. Compound B, Form A 20. A crystalline form comprising:

2. 2. The crystalline form of claim 1, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at an additional 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 at 4.64, 8.26, 9.28, 11.18, 11.49, 11.96, 12.54, 13.77, 14.22, 14.61, 15.09, 15.56, 16.01, 17.35, 18.55, 18.84, 19.82, 21.34, 21.92, 22.52, 22.97, 23.54, 23.94, or 25.96 (±0.1° 2θ).

3. 2. The crystalline form of claim 1, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern comprising characteristic X-ray powder diffraction peaks using CuKα radiation at 4.64, 8.26, 9.28, 11.18, 11.49, 11.96, 12.54, 13.77, 14.22, 14.61, 15.09, 15.56, 16.01, 17.35, 18.55, 18.84, 19.82, 21.34, 21.92, 22.52, 22.97, 23.54, 23.94, or 25.96 (±0.1° 2θ) in an additional 10 or more.

4. 2. The crystalline form of claim 1, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at: 4.64, 8.26, 9.28, 11.18, 11.49, 11.96, 12.54, 13.77, 14.22, 14.61, 15.09, 15.56, 16.01, 17.35, 18.55, 18.84, 19.32, 19.82, 20.26, 21.34, 21.63, 21.92, 22.52, 22.97, 23.28, 23.54, 23.94, 24.81, and 25.96 (±0.1° 2θ).

5. Compound B, Form B 20. A crystalline form comprising:

6. 6. The crystalline form of claim 5, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern comprising characteristic X-ray powder diffraction peaks using CuKα radiation at an additional 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 at 7.68, 14.24, 15.30, 15.55, 16.01, 16.63, 17.37, 18.24, 19.89, 20.24, 21.81, 22.52, 22.99, 23.25, 23.57, 25.07, or 25.91 (±0.1° 2θ).

7. 6. The crystalline form of claim 5, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern comprising characteristic X-ray powder diffraction peaks using CuKα radiation at an additional 10 or more of the following positions: 7.68, 14.24, 15.30, 15.55, 16.01, 16.63, 17.37, 18.24, 19.89, 20.24, 21.81, 22.52, 22.99, 23.25, 23.57, 25.07, or 25.91 (±0.1° 2θ).

8. 6. The crystalline form of claim 5, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at: 7.68, 11.49, 12.54, 14.24, 15.30, 15.55, 16.01, 16.63, 17.37, 18.24, 19.16, 19.42, 19.89, 20.24, 21.81, 22.52, 22.99, 23.25, 23.57, 24.67, 25.07, and 25.91 (±0.1° 2θ).

9. Compound B, Form D 4. A crystalline form comprising:

10. 10. The crystalline form of claim 9, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern comprising characteristic X-ray powder diffraction peaks using CuKα radiation at an additional 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 at 7.32, 10.99, 12.18, 13.23, 13.48, 14.11, 14.66, 15.14, 16.03, 16.2, 17.24, 17.63, 18.11, 18.34, 20.20, 20.58, 21.16, 21.47, 21.89, 22.76, 23.33, or 23.56 (±0.1° 2θ).

11. 10. The crystalline form of claim 9, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern comprising characteristic X-ray powder diffraction peaks using CuKα radiation at an additional 10 or more at: 7.32, 10.99, 12.18, 13.23, 13.48, 14.11, 14.66, 15.14, 16.03, 16.21, 17.24, 17.63, 18.11, 18.34, 20.20, 20.58, 21.16, 21.47, 21.89, 23.33, or 23.56 (±0.1° 2θ).

12. 10. The crystalline form of claim 9, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at: 7.32, 10.99, 11.31, 12.18, 13.23, 13.48, 14.11, 14.66, 15.14, 15.70, 16.03, 16.21, 16.54, 17.24, 17.63, 18.11, 18.34, 19.10, 20.20, 20.58, 21.16, 21.47, 21.89, 22.76, 23.33, and 23.56 (±0.1° 2θ).

13. Compound B, Form F 4. A crystalline form comprising:

14. 14. The crystalline form of claim 13, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern comprising characteristic X-ray powder diffraction peaks using CuKα radiation at an additional 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 at 3.92, 10.54, 11.72, 14.22, 15.40, 15.54, 16.48, 16.84, 17.29, 18.26, 18.47, 19.39, 20.00, 20.50, 21.16, 21.28, 21.95, 22.97, 23.49, 23.70, 23.94, 24.31, or 24.67 (±0.1° 2θ).

15. 14. The crystalline form of claim 13, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern comprising characteristic X-ray powder diffraction peaks using CuKα radiation at an additional 10 or more of the following: 3.92, 10.54, 11.72, 14.22, 15.40, 15.54, 16.48, 16.84, 17.29, 18.26, 18.47, 19.39, 20.00, 20.50, 21.16, 21.28, 21.95, 22.97, 23.49, 23.70, 23.94, 24.31, or 24.67 (±0.1° 2θ).

16. 14. The crystalline form of claim 13, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at: 3.92, 10.54, 11.72, 12.52, 14.22, 15.40, 15.54, 15.90, 16.48, 16.84, 17.29, 18.26, 18.47, 19.39, 19.66, 20.00, 20.50, 20.65, 21.16, 21.28, 21.95, 22.97, 23.49, 23.70, 23.94, 24.31, 24.67, and 24.99 (±0.1° 2θ).

17. Compound B, Form G 42. A crystalline form comprising:

18. 18. The crystalline form of claim 17, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern comprising characteristic X-ray powder diffraction peaks using CuKα radiation at an additional 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 at 7.65, 15.27, 15.51, 16.00, 17.34, 18.21, 19.11, 19.84, 21.31, 21.57, 21.79, 22.49, 22.97, 23.22, 24.65, 25.04, or 25.88 (±0.1° 2θ).

19. 18. The crystalline form of claim 17, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern comprising characteristic X-ray powder diffraction peaks using CuKα radiation at an additional 10 or more of the following positions: 7.65, 15.27, 15.51, 16.00, 17.34, 18.21, 19.11, 19.84, 21.31, 21.57, 21.79, 22.49, 22.97, 23.22, 24.65, 25.04, or 25.88 (±0.1° 2θ).

20. 18. The crystalline form of claim 17, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at: 7.65, 11.46, 12.51, 15.27, 15.51, 16.00, 17.34, 18.21, 19.11, 19.29, 19.42, 19.84, 20.23, 21.31, 21.57, 21.79, 22.49, 22.97, 23.22, 24.65, 25.04, and 25.88 (±0.1° 2θ).

21. 21. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 20 and at least one pharma- ceutically acceptable excipient.

22. 22. A medicament for treating lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer in a patient, comprising an effective amount of a crystalline form of any one of claims 1 to 20 or a pharmaceutical composition of claim 21.

23. 22. A medicament for treating breast cancer in a patient comprising an effective amount of a crystalline form of any one of claims 1 to 20 or a pharmaceutical composition of claim 21.

24. The pharmaceutical composition of claim 23, wherein the breast cancer is hormone receptor positive breast cancer, HER2 positive breast cancer, HER2 negative breast cancer, or triple negative breast cancer (TNBC).

25. The pharmaceutical composition of claim 24, wherein the breast cancer is hormone receptor positive breast cancer.

26. The pharmaceutical agent according to claim 25, wherein the breast cancer is TNBC.

27. The pharmaceutical agent of claim 25, wherein the hormone receptor positive breast cancer is HER2 negative.

28. The pharmaceutical composition of claim 23, wherein the breast cancer is metastatic breast cancer.

29. The pharmaceutical composition of claim 23, wherein the breast cancer is locally advanced breast cancer.

30. 30. A medicament according to any one of claims 23 to 29, wherein compound B is administered as a component of adjuvant therapy.

31. 30. The method of any one of claims 23 to 29, wherein compound B is administered as a component of neoadjuvant therapy.

32. The pharmaceutical composition of any one of claims 22 to 31, wherein the patient has a history of treatment with one or more anticancer agents or radiation therapy.

33. Patients were treated with doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, albumin-bound paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparib, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxytryptamine, cyclophosphamide ... The pharmaceutical composition of claim 32, which has a history of treatment with one or more anticancer drugs selected from the group consisting of tamoxifen, raloxifene, droloxifene, trioxyphene, ketoxifene, flutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprolide, pegfilgrastim, filgrastim, and venetoclax, or combinations thereof.

34. 33. The pharmaceutical composition of claim 32, wherein the patient has been previously treated with one or more anticancer agents selected from the group consisting of abemaciclib, ribociclib, palbociclib, ipatasertib, everolimus, fulvestrant, trastuzumab, emtansine, trastuzumab, pertuzumab, atezolizumab, alemtuzumab, bevacizumab, cetuximab, panitumumab, rituximab, tositumomab, or combinations thereof.

35. The pharmaceutical agent of any one of claims 22 to 34, wherein the patient has a cancer that is refractory to treatment with one or more endocrine therapies selected from the group consisting of abemaciclib, anastrozole, exemestane, fulvestrant, goserelin, letrozole, leuprorelin, megestrol, palbociclib, tamoxifen, toremifene, trastuzumab emtansine, trastuzumab, pertuzumab, atezolizumab, pembrolizumab, durvalumab, avelumab, and nivolumab, or combinations thereof.

36. 36. The method of any one of claims 22 to 35, wherein the patient has undergone surgery prior to treatment with the compound.

37. The pharmaceutical agent according to any one of claims 22 to 36, which is administered in combination with one or more of radiation therapy, hormone therapy, cancer immunotherapy or anticancer agents.

38. The pharmaceutical agent of claim 37, wherein the anticancer agent comprises one or more of an AKT inhibitor, a CDK4 / 6 inhibitor, a PARP inhibitor, and an aromatase inhibitor.

39. The pharmaceutical composition of claim 37, wherein the anticancer drug is abemaciclib, ribociclib, or palbociclib.

40. The pharmaceutical composition of claim 37, wherein the anticancer drug is letrozole, anastrozole, exemestane or testolactone.

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