CHK1 inhibitor synthesis method

Abstract

The present technology relates to processes, compounds, compositions and methods useful in coupling reactions. In addition, the present disclosure provides novel intermediates, compositions of matter and methods related to the Chk1 inhibitor SRA737.

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: April 6, 2021; application number: 202180027747.4).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 006,305, filed April 7, 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0004] Introduction

[0005] SRA737 is a heterocyclic small molecule and a potent checkpoint 1 inhibitor currently under clinical investigation as a chemotherapeutic agent. The structure of SRA737 is:

[0006]

[0007] SRA737 is also known by its IUPAC name: 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridinyl]amino]pyrazine-2-carbonitrile. The current conventional synthesis of SRA737 is described in U.S. Patent No. 9,663,503, which is incorporated herein by reference in its entirety.

[0008] The synthesis of SRA737 and similar heterocyclic compounds currently utilizes cross-coupling reactions that require highly loaded metal complexes as catalysts and organophosphine compounds as ligands. While these reactions are crucial for rapidly building molecular complexity, they can produce undesirable impurities in intermediates and the final active pharmaceutical ingredient (API) product, which are often difficult to purify. Furthermore, these reactions require careful preparation and often harsh reaction conditions, such as elevated temperatures and pressures, which can undesirably increase manufacturing costs.

[0009] Due to the molecular complexity of SRA737, its industrial-scale manufacturing can be a challenging process. The requirements of multi-step synthesis, purification, and waste management often result in low yields of intermediates and final products. Therefore, there is a great need for concise and easy-to-use synthetic methods for large-scale manufacturing of SRA737 and related heterocyclic small molecules. There is a high demand for improved synthetic methods for producing heterocyclic compounds (such as SRA737) on an industrial scale, with improved atom economy, waste management, and purification processes to reduce manufacturing costs. Summary of the Invention

[0010] The present disclosure provides novel compounds, compositions, and methods of making such compounds and compositions.

[0011] In some embodiments, the compounds disclosed herein are novel synthetic intermediates of SRA737. In some embodiments, the compounds are protected forms of SRA737, ie, the compounds are masked with a protecting organic group that is removed upon exposure to appropriate conditions to produce SRA737.

[0012] In some embodiments, the present disclosure provides novel compositions, compounds, and solvates that contain very low concentrations of palladium impurities.In some embodiments, the compound is an active pharmaceutical ingredient (API) compound.

[0013] In some embodiments, the present disclosure provides novel compositions, compounds, and solvates that contain very low concentrations of other organic compounds as impurities, ie, byproducts from a given reaction or cumulative reactions to a given point in the total synthesis of SRA737.

[0014] In some embodiments, the present disclosure provides novel synthetic intermediates and SRA737, or protected forms of SRA737, that are substantially free of palladium and other organic molecules as impurities.

[0015] In some embodiments, the present disclosure provides compositions of one or more compounds disclosed herein that are substantially free of palladium and other organic molecules as impurities.

[0016] In some embodiments, the present disclosure provides compositions comprising novel synthetic intermediate compounds and / or SRA737, or protected forms of SRA737, that are substantially free of palladium and other organic molecules as impurities.

[0017] In some embodiments, the compounds disclosed herein are novel solvates. In some embodiments, the compounds disclosed herein are novel dimethylformamide (DMF) solvates. In some embodiments, the compounds disclosed herein are novel crystalline solids. In some embodiments, the compounds disclosed herein are novel crystalline solids that are substantially free of palladium and other organic molecules as impurities.

[0018] In some embodiments, the present disclosure provides pharmaceutical compositions comprising one or more compounds or solvates.

[0019] In some embodiments, the present disclosure provides a kit comprising one or more compounds disclosed herein, or one or more compositions as disclosed herein.

[0020] In some embodiments, the present disclosure provides methods of administering at least one compound described herein to a subject in need of chemotherapy.

[0021] In some embodiments, the present disclosure provides methods of making the novel compounds, compositions, and solvates.

[0022] These and other embodiments are described in further detail below. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The total synthesis of SRA737 is shown.

[0024] Figure 2 Shown is the X-ray powder diffraction pattern (XRPD) of the crystalline solid form of the compound of Formula II.

[0025] Figure 3 Shown is a differential scanning calorimetry (DSC) thermogram of a crystalline solid form of the compound of Formula II.

[0026] Figure 4 Shown is the thermogravimetric analysis (TGA) of the crystalline solid form of the compound of Formula II.

[0027] Figure 5 The X-ray powder diffraction pattern (XRPD) of the crystalline solid form of the compound of Formula X is shown.

[0028] Figure 6 Shown is the X-ray powder diffraction pattern (XRPD) of the crystalline solid form of the compound of Formula VIII.

[0029] Figure 7 Shown is the X-ray powder diffraction pattern (XRPD) of a crystalline solid salt form of the compound of Formula IX.

[0030] Figure 8 Shown is a differential scanning calorimetry (DSC) thermogram of a crystalline solid form of a salt of the compound of Formula IX. Detailed description

[0031] definition

[0032] Various terms used in the patent specification and claims herein are defined as follows. All technical and scientific terms not defined herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0033] "LvG" or "leaving group" has the meaning commonly associated with it in synthetic organic chemistry and refers to an atom or organic group that can be displaced from a molecule by a nucleophile by cleavage of a covalent bond. Exemplary leaving groups include, but are not limited to, F, Cl, Br, I, OTs (-OSO2C6H4CH3), OMs (-OSO2CH3), ONs (SO2C6H4NO2), OTf (-OSO2CF3), N2 + 、H2O+ , carbonates (-OCO2R), esters (-OCOR), acids (-OCOH) and anhydrides (-OCO2COR).

[0034] By "substantially purified or free of impurities" is meant a mixture in which a small organic molecule of interest greatly outweighs the amount of minerals, metals and / or other small organic molecules that act as impurities, and in which at least 95% by dry weight, such as at least 96%, at least 97%, at least 98%, at least 99% or at least 99.5% by dry weight, is the small organic molecule of interest.

[0035] Should be understood that during some procedures as herein described, it may be necessary to protect certain reactive groups or substituents (such as amino). Any convenient protection and deprotection method and chemical substance can be used in combination with this type of reactive group or substituent." amino protecting group " refers to an organic group that can be covalently linked to a reactive amino group to block undesirable reaction and can use a deprotection method to selectively remove from the amino group. The selection and use of protecting groups and the reaction conditions for installing and removing protecting groups include Greene's Protective Groups in Organic Synthesis, the 4th edition, John Wiley & Sons, New York, those described in 2007, the disclosure of which is incorporated herein by reference in its entirety. Exemplary amino protecting groups include but are not limited to TMS, TBDMS, TBDPS, Ms, Ns, Tf, Fmoc, Boc, Cbz, Troc, Alloc, acetyl (including acetamide where R = methyl or trifluoroacetamide where R = trifluoromethyl), hydroxylamine Tr or trityl (-C(Ph)3), benzylidene hydrazine (where R can also be C(O)R'), benzoyl (-C(O)Ph), benzyl (-CH2Ph), allyl, vinyl, Bu t and Piv.

[0036] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, such as 1 to 12 carbon atoms. This term includes, for example, straight-chain and branched hydrocarbon groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-) and neopentyl ((CH3)3CCH2-). xAlkyl refers to an alkyl group having x number of carbon atoms.

[0037] "Alkenyl" refers to a straight or branched hydrocarbon group having 1 to 12 carbon atoms, preferably 2 to 4 carbon atoms, and having at least 1, preferably 1 to 2, sites of unsaturation (>C=C<). Examples of such groups are vinyl, allyl, and but-3-en-1-yl. This term includes both cis and trans isomers or mixtures of these isomers. x Alkenyl refers to an alkenyl group having x number of carbon atoms.

[0038] "Alkynyl" refers to a straight or branched monovalent hydrocarbon radical having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and having at least 1, preferably 1 to 2, sites of acetylenic (-C≡C-) unsaturation. Examples of such alkynyl radicals include ethynyl (-C≡CH) and propargyl (-CH2C≡CH). x Alkynyl refers to an alkynyl group having x number of carbon atoms.

[0039] "Substituted alkyl" refers to an alkyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl) ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein the substituents are defined herein.

[0040] In some embodiments, substituted alkyl groups include haloalkyl groups, particularly halomethyl groups such as trifluoromethyl, difluoromethyl, fluoromethyl, and the like.

[0041] "Alkylaryl" refers to an alkyl group of 1 to 8, preferably 1 to 5 or more preferably 1 to 3 carbon atoms in length and particularly substituted with an aryl group on any carbon along the chain.

[0042] "Alkenylaryl" refers to an alkenyl or alkene group of 1 to 8, preferably 1 to 5, or more preferably 1 to 3 carbon atoms in length and substituted with an aryl group, particularly at any carbon along the chain. The aryl group may or may not include heteroatoms.

[0043] "Alkynylaryl" refers to an alkynyl or alkyne group of 1 to 8, preferably 1 to 5, or more preferably 1 to 3 carbon atoms in length and substituted with an aryl group, particularly at any carbon along the chain. The aryl group may or may not include heteroatoms.

[0044] "Cycloalkyl" or "cycloalkyl" refers to a saturated or partially saturated, but non-aromatic, group having 3 to 10 ring carbon atoms and no heteroatoms. Cycloalkyl encompasses monocyclic ring systems.

[0045] "Ar" and / or "aryl" refers to any aromatic group. Such a group must be cyclic and contain no heteroatoms.

[0046] "Alkoxy" refers to the group -O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, and n-pentoxy.

[0047] "Substituted alkoxy" refers to the group -O-(substituted alkyl), wherein substituted alkyl is defined herein. Preferred substituted alkyl groups in -O-(substituted alkyl) include haloalkyl, particularly halomethyl, such as trifluoromethyl, difluoromethyl, fluoromethyl, and the like.

[0048] "Acyl" refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl are as defined herein. Acyl groups include the "acetyl" group CH3C(O)-.

[0049] "Acylamino" refers to the groups -NRC(O)alkyl, -NRC(O)substituted alkyl, -NRC(O)cycloalkyl, substituted-NRC(O)cycloalkyl, -NRC(O)alkenyl, substituted-NRC(O)alkenyl, alkoxy, substituted alkoxy-NR AC(O)alkynyl, substituted-NRC(O)alkynyl, substituted-NRC(O)aryl, substituted-NRC(O)aryl, substituted-NRC(O)heteroaryl, substituted-NRC(O)heteroaryl, -NRC(O)heterocyclyl, and substituted-NRC(O)heterocyclyl, wherein R is hydrogen or alkyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl are as defined herein.

[0050] "Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclyl-C(O)O-, and substituted heterocyclyl-C(O)O-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl are as defined herein.

[0051] "Amino" refers to the group -NH2.

[0052] "Aminocarbonyl" refers to the group -C(O)NR A R A , where R A and R B are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R A and R B and optionally joined together with the nitrogen to which it is bound to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0053] "Substituted aryl" refers to an aryl group substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SOH, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, monosaccharides (which may be covalently bonded to the aryl group through any oxygen atom on the sugar), and substituted alkylthio, wherein the substituents are defined herein.

[0054] "Carbonyl" refers to the divalent group -C(O)-, which is equivalent to -C(=O)-.

[0055] "Carboxy" or "carboxyl" refers to -COOH or a salt thereof.

[0056] "Carboxyl ester" or "carboxy "ester)" refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclyl, and -C(O)O-substituted heterocyclyl, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl are as defined herein.

[0057] "Cyano" refers to the group -C≡N.

[0058] "Cycloalkyl" refers to a saturated or unsaturated but non-aromatic cyclic alkyl group having from 3 to 10 carbon atoms, having a single cyclic ring or multiple cyclic rings including fused, bridged, and spiro ring systems. x Cycloalkyl refers to a cycloalkyl group having x number of ring carbon atoms. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more of the rings may be aryl, heteroaryl, or heterocyclic, provided that the point of attachment is through a non-aromatic, non-heterocyclic, saturated carbocyclic ring.

[0059] "Substituted cycloalkyl" refers to a cycloalkyl group having 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein the substituents are defined herein.

[0060] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine.

[0061] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0062] "Heteroaryl" refers to an aromatic group having 4 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. Such heteroaryl groups can have monocycles (e.g., pyridyl or furyl) or multiple fused rings (e.g., indolizinyl or benzothienyl), wherein the fused rings may or may not be aromatic and / or contain heteroatoms, provided that the point of attachment is an atom through an aromatic heteroaryl. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), a sulfinyl or sulfonyl moiety. Preferred heteroaryl groups include 5- or 6-membered heteroaryls, such as pyridyl, pyrrolyl, indolyl, thienyl and furyl.

[0063] The "substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the same group of substituents as defined for the substituted aryl group.

[0064] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, but non-aromatic, group having 2 to 10 ring carbon atoms and 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. x Cycloalkyl or heterocycloalkyl refers to a group having x number of ring carbon atoms excluding the ring heteroatoms. Heterocycle encompasses monocyclic or multiple fused rings including fused, bridged and spirocyclic systems. In a fused ring system, one or more of the rings may be cycloalkyl, aryl or heteroaryl, provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atom of the heterocyclic radical is optionally oxidized to provide an N-oxide, sulfinyl or sulfonyl moiety.

[0065] "Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclyl group substituted with 1 to 5, or preferably 1 to 3, substituents as defined for substituted cycloalkyl. Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, dexahydroindole, dihydropyridine, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, Phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, imidazolinone, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also known as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.

[0066] The term "salt" or "pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a subject. It will be understood that such salts with counterions will have acceptable mammalian safety for a given dosage regimen. Such salts may also be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids, and may contain organic and inorganic counterions. The neutral forms of the compounds described herein can be converted to the corresponding salt forms by contacting the compounds with a base or acid and isolating the resulting salt. Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and the like.

[0067] Other examples of salts include anions of the compounds of the present disclosure complexed with suitable cations such as N+, NH4+, NW4+ (wherein W can be a C1-C8 alkyl group), etc. For therapeutic use, the salts of the compounds of the present disclosure can be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases can also be used, for example, to prepare or purify pharmaceutically acceptable compounds.

[0068] "Substitution" or "substituted" generally refers to a group covalently bonded to an atom to replace a hydrogen atom. The atom in this general context can be a carbon atom or a heteroatom, such as a nitrogen atom.

[0069] "Tautomer" refers to alternative forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms attached to both a ring NH portion and a ring =N portion, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0070] The term "amelioration" refers to any therapeutically beneficial result in treating a disease state (eg, a cell proliferative disease state), including lessening of severity or progression, remission or cure thereof.

[0071] The term "mammal" includes humans and non-humans and includes, but is not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.

[0072] The term "therapeutically effective amount" is an amount effective to improve symptoms of a disease. In some embodiments, a therapeutically effective amount can be a "prophylactically effective amount" because a preventive approach can be considered a therapy.

[0073] "Subject" refers to a mammalian organism that is treated using a compound of the invention. A "subject" can be a human or non-human mammalian organism.

[0074] "Treating a disease or condition in a subject" or "treatment of a disease or condition in a subject" refers to ameliorating the disease as defined above.

[0075] An agent is said to be "specific" if it reacts and associates with a given target more frequently, more rapidly, with a longer duration and / or with greater affinity than it does with alternative substances, particularly substances structurally related to the target (e.g., isoforms of the target). In some embodiments, an agent is "specific" for a target if the concentration of the agent that produces the greatest effect in an in vitro or in vivo assay for the target (e.g., a binding assay or an enzyme activity assay) does not produce a measurable effect in a comparable assay performed using another substance, particularly one or more substances structurally related to the target.

[0076] The term "contacting" includes, for example, directly contacting a cell in vivo, in vitro, or ex vivo, or indirectly contacting a cell, such as by administering an agent to a subject. Further, "contacting" a cell with an agent includes administering or applying a prodrug form of the agent.

[0077] The terms "prevent," "preventing," "prevention," "prophylactic treatment," and the like refer to reducing the likelihood of a disease, disorder, or condition developing in a subject who does not have the disease, disorder, or condition but is at risk or susceptible to developing the disease, disorder, or condition. Thus, in some embodiments, an agent can be administered prophylactically to prevent the onset of a disease, disorder, or condition, or to prevent the recurrence of a disorder, disorder, or condition.

[0078] The term "mol %" refers to the percentage of the total moles of a particular component compared to the limiting reagent for any given reaction.

[0079] The term "wt %" refers to the weight percent of a particular component in a solution.

[0080] The term "ppm" means parts per million.

[0081] Other interpretative agreements

[0082] Generally, reference to or description of an element (e.g., hydrogen or H) is meant to include all isotopes of the element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Radioactive isotopes such as tritium, 14 C. 32 P and 35 Compounds of S are therefore within the scope of the present technology. Based on the disclosure herein, procedures for inserting such tags into compounds of the present technology will be apparent to those skilled in the art.

[0083] Unless a specific stereochemistry is explicitly indicated, all chiral, diastereomeric, and racemic forms of the compounds are intended. Thus, as will be apparent from the description, the compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms. Racemic mixtures and mixtures of d or l-enriched stereoisomers, as well as individual optical isomers, can be separated or synthesized substantially free of their enantiomeric or diastereomeric partners, and such stereoisomers are within the scope of the present technology.

[0084] The compounds described herein may exist as solvates, especially hydrates, and unless otherwise indicated, all such solvates and hydrates are intended. Hydrates may be formed during the manufacture of a compound or a composition comprising the compound, or may form over time due to the hygroscopicity of the compound. The compounds of the present technology may also exist as organic solvates, including DMF, ether and alcohol solvates, etc. The identification and preparation of any particular solvate are within the skill of those of ordinary skill in synthetic organic or medicinal chemistry.

[0085] It should be understood that the definitions presented herein are not intended to include impermissible substitution patterns (e.g., a methyl group substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to those skilled in the art.

[0086] Throughout this application, the text relates to various embodiments of the compounds of this invention, compositions and methods. The various embodiments described are intended to provide various illustrative examples and should not be interpreted as descriptions of alternative substances. On the contrary, it should be noted that the descriptions of the various embodiments provided herein may have overlapping scopes. The embodiments discussed herein are merely illustrative and are not intended to limit the scope of the present technology.

[0087] Unless otherwise indicated herein or obviously contradictory with context, otherwise in the context of describing element (especially in the context of appended claims), singular articles such as "a / kind (a)" and "an / kind (an)" and "said / the" and similar mentions should be interpreted as covering both singular and plural. Unless otherwise indicated herein, the enumeration of numerical ranges herein is merely intended to be used as a shorthand method for individually representing each individual numerical value (including the upper and lower limits of the range) that falls within the scope, and each individual numerical value is incorporated in this patent specification as if it were individually enumerated herein. Unless otherwise indicated herein or obviously contradictory with context, all methods described herein can be performed in any appropriate order. The use of any and all examples or exemplary language (e.g., "such as") provided herein is only intended to better illustrate the embodiment, and unless otherwise stated, will not impose restrictions on the scope of claims. The language in this patent specification should not be interpreted as indicating any unclaimed element as necessary.

[0088] Unless otherwise indicated, nomenclature of substituents not specifically defined herein is obtained by naming the terminal portion of the functionality followed by the adjacent functionality to the point of attachment. For example, the substituent "alkoxycarbonylalkyl" refers to the group (alkoxy)-C(O)-(alkyl)-.

[0089] method

[0090] In a first aspect, the present disclosure provides a method for making SRA737 (compound Formula VIII). In some embodiments, the present disclosure provides a method for making SRA737, wherein the method returns an amount of SRA737 greater than or equal to five hundred (500) grams. In some embodiments, the present disclosure provides a method for making SRA737, wherein the method returns an amount of SRA737 greater than or equal to one (1) kilogram of SRA737. In some embodiments, the present disclosure provides a method for making a novel synthetic intermediate useful in the total synthesis of SRA737.

[0091] I. Crystallization

[0092] In some embodiments, the present disclosure provides a method of crystallizing a compound or salt.

[0093] In some embodiments, crystallization methods are used to purify the compound from the mixture after the coupling step.

[0094] In some embodiments, crystallization methods are used to purify the compound from the mixture after the deprotection step.

[0095] In some embodiments, crystallization methods are used to purify salts from mixtures.

[0096] In some embodiments, crystallization methods are used to isolate the compound from the mixture after the coupling step.

[0097] In some embodiments, crystallization methods are used to isolate the compound from the mixture after the deprotection step.

[0098] In some embodiments, crystallization methods are used to separate the salt from the mixture.

[0099] In some embodiments, the crystallization method comprises adding water, an acid, or an alcohol to the mixture.

[0100] In some embodiments, the crystallization method comprises maintaining the temperature of the mixture at about -78°C, about -15°C, about 0°C, about 10°C, about 20°C, about 30°C, about 40°C, or about 50°C.

[0101] II. Coupling reaction

[0102] In some embodiments, the present disclosure provides a method of coupling two heterocyclic compounds, each of the two heterocyclic compounds containing one or more nitrogen atoms.

[0103] In some embodiments, the present disclosure provides methods of coupling two heterocyclic compounds together. In some embodiments, the methods couple two heterocyclic compounds, each of the two heterocyclic compounds containing one or more nitrogen atoms.

[0104] In some embodiments, the coupling is performed in the presence of relatively low concentrations of metal catalyst (eg, about 0.01 to about 0.3 mol %) and ligand additive (eg, about 0.01 to about 0.4 mol %).

[0105] In some embodiments, the present disclosure provides a method comprising:

[0106] a) Formula A: Compound with formula B: The compounds are coupled under cross-coupling reaction conditions to form Formula C: compounds; and

[0107] b) crystallizing and isolating the compound of formula C from the reaction mixture of step a);

[0108] where R 1 and R 2 Independently selected from: C 1-12 Alkyl, substituted C 1-12 Alkyl, C 1-12 Alkenyl, substituted C 1-12 Alkenyl, C 1-12 Alkynyl, substituted C 1-12 Alkynyl, C 1-12 Alkoxy, substituted C 1-12 Alkoxy, amino, substituted amino, C 3-8 Cycloalkyl and substituted C 3-8 Cycloalkyl;

[0109] And where R 3 Selected from: cyano, halogen, nitro, carboxylate and amido.

[0110] In some embodiments, the cross-coupling reaction conditions further comprise:

[0111] a) providing a first mixture comprising a compound of formula A, a compound of formula B, a catalyst, a ligand, and DMF;

[0112] b) providing a second mixture comprising an inorganic base and DMF, wherein the second mixture has been heated to between about 125° C. and 135° C.;

[0113] c) contacting the first mixture with the second mixture to provide a third mixture, wherein the temperature of the third mixture is maintained between about 125-135°C for a period of time sufficient to produce the compound of Formula C.

[0114] In some embodiments, crystallization methods are used to purify the compound from the mixture after the cross-coupling step.

[0115] In some embodiments, crystallization methods are used to isolate the compound from the mixture after the cross-coupling step.

[0116] In some embodiments, the methods provide cross-coupling reaction conditions comprising a palladium compound, an organophosphorus compound, an inorganic base, and a polar aprotic organic solvent.

[0117] In some embodiments, the method provides cross-coupling reaction conditions wherein the amount of palladium does not exceed about 0.3 mol %.

[0118] In some embodiments, the method provides cross-coupling reaction conditions wherein the amount of palladium does not exceed about 0.25 mol %.

[0119] In some embodiments, the method provides cross-coupling reaction conditions wherein the amount of palladium does not exceed about 0.2 mol %.

[0120] In some embodiments, the method provides cross-coupling reaction conditions wherein the amount of palladium does not exceed about 0.15 mol %.

[0121] In some embodiments, the method provides cross-coupling reaction conditions wherein the amount of palladium does not exceed about 0.1 mol %.

[0122] In some embodiments, the method provides cross-coupling reaction conditions involving an organophosphorus compound, wherein the organophosphorus compound is selected from the group consisting of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos), XPhos [2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl], 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos), CyJohnPhos [(2-biphenyl)dicyclohexylphosphine], DavePhos [2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl], JohnPhos [(2-biphenyl)di-tert-butylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-(di-tert-butylphosphine)] PhDave-Phos[2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)-2-amine], SPhos[2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl], RuPhos[2-dicyclohexylphosphino-2′,6′-diisopropylbiphenyl], sSPhos[2′-dicyclohexylphosphino-2, 6-dimethoxy-1,1′-biphenyl-3-sulfonate sodium salt], tBuMePhos [2-di-tert-butylphosphino-2′-methylbiphenyl], 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tert-butyl XPhos), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, 2-di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl (tBuDavePhos), 2-(dicyclohexylphosphino)biphenyl (cyclohexyl JohnPhos), 2-dicyclohexylphosphino-2′,6′-diisopropylbiphenyl, 2-diphenylphosphino-2′-(N,N-dimethylamino)biphenyl (PhDavePhos). Phos), sodium 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl-3'-sulfonate, 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos), diadamantyl BrettPhos-2-(diadamantylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl [AdBrettPhos], (2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl) [RockPhos], 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl, [t-Bu Brett Phos] or Josiphos [(R) or (S)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine].

[0123] In some embodiments, the method provides cross-coupling reaction conditions involving an organophosphorus compound, wherein the organophosphorus compound is selected from the group consisting of: 2-(di-tert-butylphosphino)-2′,4′,6-triisopropyl-3,6-dimethoxy-1,1′-biphenyl, [t-Bu Brett Phos], [(1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane)-2-(2′-amino-1,1′-biphenyl)], and [(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)][cataCXium-A].

[0124] In some embodiments, the methods provide cross-coupling reaction conditions involving an organophosphorus compound, wherein the organophosphorus compound is cataCXium-A[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)].

[0125] In some embodiments, the methods provide cross-coupling reaction conditions involving an organophosphorus compound, wherein the organophosphorus compound is Josiphos [(R) or (S)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butylphosphine].

[0126] In some embodiments, the methods provide cross-coupling reaction conditions involving a palladium compound, wherein the palladium compound is [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. In some embodiments, the methods provide cross-coupling reaction conditions involving a palladium compound, wherein the palladium compound is [2-(2'-methylamino-1,1'-biphenyl)]palladium(II) methanesulfonate (i.e., a methyl group on the nitrogen atom).

[0127] In some embodiments, the methods provide cross-coupling reaction conditions involving a palladium compound, wherein the palladium compound is Pd(dba)2[bis(dibenzylideneacetone)palladium(0)].

[0128] In some embodiments, the methods provide cross-coupling reaction conditions involving a palladium compound, wherein the palladium compound is Pd(OAc)2 [palladium(II) acetate].

[0129] In some embodiments, the present disclosure provides methods of making a compound of Formula VII:

[0130]

[0131] Methods include:

[0132] Make V: Compounds of formula VI: The compounds are coupled under cross-coupling reaction conditions to form a compound of formula VII;

[0133] crystallizing and isolating the compound of formula VII from the reaction mixture;

[0134] wherein Pg is an organic group serving as an amino protecting group and LvG is an organic group serving as a leaving group.

[0135] In some embodiments, the method for making the compound of Formula VII further comprises:

[0136] a) providing a first mixture comprising a compound of formula V, a compound of formula VI, a catalyst, a ligand, and DMF;

[0137] b) providing a second mixture comprising an inorganic base and DMF, wherein the second mixture has been heated to between about 125° C. and 135° C.;

[0138] c) contacting the first mixture with the second mixture to provide a third mixture, wherein the temperature of the third mixture is maintained between about 125-135°C for a period of time sufficient to produce the compound of Formula VII.

[0139] In some embodiments, a method for making a compound of formula VII is provided, wherein N-Pg forms a sulfonamide group. In some embodiments, N-Pg forms a carbamate group. In some embodiments, N-Pg forms an amide group. In some embodiments, N-Pg forms a urea group.

[0140] In some embodiments, a method for making a compound of formula VII is provided, wherein Pg is selected from the group consisting of Boc, Fmoc, acetamide, trifluoroacetamide, tosylate, mesylate, and allyl.

[0141] In some embodiments, isolating the compound is accomplished by crystallization of the compound.

[0142] In some embodiments, the method of making the compound of Formula VII comprises heating the mixture during deprotection.

[0143] In some embodiments, the method of making the compound of Formula VII comprises maintaining the temperature of the mixture at about 0°C, about 5°C, about 10°C, about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, or about 80°C during the deprotection step.

[0144] In some embodiments, the method of making the compound of Formula VII includes heating and does not include additional reagents for deprotection.

[0145] In some embodiments, the method of making the compound of Formula VII comprises heating the mixture during the coupling.

[0146] In some embodiments, the method of making the compound of Formula VII comprises cooling the mixture during crystallization.

[0147] In some embodiments, a method for making a compound of formula VII is provided, wherein the method further comprises maintaining the temperature of the mixture at about -78°C, about -15°C, about 0°C, about 10°C, about 20°C, about 30°C, about 40°C, or about 50°C during crystallization.

[0148] III. Manufacturing of SRA737

[0149] In another aspect, the present disclosure provides a method of making a compound of SRA737 according to Formula VIII:

[0150]

[0151] Methods include:

[0152] a) Formula XI: Compounds of formula II: Compounds are coupled to provide Formula XII: Compounds;

[0153] b) making formula XII: Compounds of formula VI: The compounds are coupled under cross-coupling reaction conditions to provide Formula X: Compounds;

[0154] c) crystallizing and isolating the compound of formula X from the reaction mixture;

[0155] d) subjecting the compound of formula X to deprotection conditions to provide a compound of formula VIII.

[0156] In some embodiments, the method of making the compound of Formula VIII further comprises:

[0157] d) providing a first mixture comprising a compound of formula XII, a compound of formula VI, a catalyst, a ligand, and DMF;

[0158] e) providing a second mixture comprising an inorganic base and DMF, wherein the second mixture has been heated to between about 125° C. and 135° C.;

[0159] f) contacting the first mixture with the second mixture to provide a third mixture, wherein the temperature of the third mixture is maintained between about 125-135°C for a period of time sufficient to produce the compound of formula X.

[0160] In some embodiments, the method of making a compound of Formula VIII comprises heating one or more of the mixtures for a period of time sufficient to produce the desired compound.

[0161] In some embodiments, the method of making the compound of Formula VIII comprises heating the mixture during deprotection.

[0162] In some embodiments, the method of making the compound of Formula VIII comprises maintaining the temperature of the mixture at about 0°C, about 5°C, about 10°C, about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, or about 80°C during the deprotection step.

[0163] In some embodiments, the method of making the compound of Formula VIII includes heating and does not include additional reagents for deprotection.

[0164] In some embodiments, the method of making the compound of Formula VIII comprises heating the mixture during coupling.

[0165] In some embodiments, the method of making the compound of Formula VIII comprises cooling the mixture during crystallization.

[0166] In some embodiments, a method for making a compound of formula VIII is provided, wherein the method further comprises maintaining the temperature of the mixture at about -78°C, about -15°C, about 0°C, about 10°C, about 20°C, about 30°C, about 40°C, or about 50°C during crystallization.

[0167] In another aspect, the present disclosure provides a method of making a salt of a compound of Formula IX:

[0168]

[0169] Methods include:

[0170] a) providing a compound comprising formula VIII: a first mixture of acetic acid, water, and alcohol;

[0171] b) combining the first mixture with citric acid to provide a second mixture;

[0172] c) crystallizing and isolating Formula IX from the second mixture: Compound salts.

[0173] In some embodiments, the first mixture is prepared by combining the compound of Formula VIII, acetic acid, water, and an alcohol at about 30-45 °C.

[0174] In some embodiments, the second mixture is prepared by combining the first mixture with citric acid at about 20-25°C.

[0175] In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, tert-butanol, and isopropanol.

[0176] IV. Crystallization Solvate

[0177] In another aspect, the present disclosure provides a method of preparing a solvate of any one of the compounds disclosed herein, the method comprising crystallizing the solvate from a mixture comprising the compound, water, and dimethylformamide (DMF).

[0178] In some embodiments, the present disclosure provides a method of preparing a solvate of any one of the compounds disclosed herein, wherein the method further comprises maintaining the temperature of the mixture at about -78°C, about -15°C, about 0°C, about 10°C, about 20°C, about 30°C, about 40°C, or about 50°C during crystallization.

[0179] In some embodiments, the present disclosure provides a method for preparing a solvate of a compound of formula VII:

[0180]

[0181] The method comprises crystallizing the solvate from a mixture comprising the compound of formula VII, water and dimethylformamide (DMF).

[0182] In some embodiments, the present disclosure provides a method for preparing a solvate of a compound of Formula VII, comprising crystallizing the solvate from a mixture comprising a compound of Formula VII, water, and dimethylformamide (DMF), wherein Pg is selected from the group consisting of Boc, Fmoc, acetamide, trifluoroacetamide, tosylate, mesylate, and allyl.

[0183] Compound

[0184] The present disclosure provides compounds that are novel synthetic intermediates in the total synthesis of SRA737.

[0185] In yet another aspect, the present disclosure provides novel solvates and crystalline solids of the heterocyclic compounds described herein.

[0186] In some embodiments, the present disclosure provides novel solvates of protected forms of SRA737 comprising a nitrogen atom protecting group (Pg).

[0187] In some embodiments, the compound is in the form of a solvate of a compound of Formula I:

[0188]

[0189] where R 1 Selected from the group consisting of: C 1-12 Alkyl, substituted C 1-12 Alkyl, C 1-12 Alkenyl, substituted C 1-12 Alkenyl, C 1-12 Alkynyl, substituted C 1-12 Alkynyl, C 1-12 Alkoxy, substituted C 1-12 Alkoxy, C 3-8 Cycloalkyl, substituted C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, substituted C 3-8 Heterocycloalkyl, C 1-12 amino, C 1-12 Substituted amino, phenyl, substituted phenyl, C 3-8 Heteroaryl and substituted C 3-8 heteroaryl;

[0190] and wherein the solvate is a dimethylformamide (DMF) solvate.

[0191] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is C1-12 alkoxy or substituted C1-12 alkoxy.

[0192] In some embodiments, the compound is in the form of a solvate of a compound of Formula I, wherein R1 is substituted C12 alkoxy.

[0193] In some embodiments, the compound is in the form of a solvate of a compound of Formula I, wherein R1 is C1-12 alkyl or substituted C1-12 alkyl.

[0194] In some embodiments, the compound is in the form of a solvate of a compound of Formula I, wherein R1 is C1 alkyl.

[0195] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is substituted C1 alkyl.

[0196] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is substituted C10 alkyl.

[0197] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is substituted C12 alkyl.

[0198] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is C10 alkyl.

[0199] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is substituted C2 alkyl.

[0200] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is C2 alkyl.

[0201] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is C3-8 cycloalkyl or substituted C3-8 cycloalkyl.

[0202] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is C3 cycloalkyl.

[0203] In some embodiments, the compound is in the form of a solvate of a compound of Formula I, wherein R1 is C5 cycloalkyl.

[0204] In some embodiments, the compound is in the form of a solvate of a compound of Formula I, wherein R1 is C6 cycloalkyl.

[0205] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is C3-8 heterocycloalkyl or C3-8 heteroaryl.

[0206] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is C3 heterocycloalkyl.

[0207] In some embodiments, the compound is in the form of a solvate of a compound of Formula I, wherein R1 is C4 heterocycloalkyl.

[0208] In some embodiments, the compound is in the form of a solvate of a compound of Formula I, wherein R1 is C5 heterocycloalkyl, wherein the C5 heterocycloalkyl contains 1 nitrogen atom.

[0209] In some embodiments, the compound is in the form of a solvate of a compound of Formula I, wherein R1 is C6 heterocycloalkyl, wherein the C6 heterocycloalkyl contains 1 nitrogen atom.

[0210] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is C1-12 alkenyl or substituted C1-12 alkenyl.

[0211] In some embodiments, the compound is in the form of a solvate of a compound of Formula I, wherein R1 is C2 alkenyl.

[0212] In some embodiments, the compound is in the form of a solvate of a compound of Formula I, wherein R1 is C3 alkenyl.

[0213] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is substituted C2 alkenyl.

[0214] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is -OC(CH3)3.

[0215] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is -C(CH3)3.

[0216] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is -CH(CH3)2.

[0217] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is -O(CH)CH2.

[0218] In some embodiments, the compound is a solvate form of a compound of Formula I, wherein R1 is -OCH2(CH)CH2.

[0219] In some embodiments, the compound is a solvate of any one of the compounds disclosed herein and is substantially purified.

[0220] In some embodiments, the compound is a solvate of any one of the compounds disclosed herein and is substantially free of small molecule impurities.

[0221] In some embodiments, the compound is a solvate of any one of the compounds disclosed herein and is substantially purified, free of small organic compounds (<500 Da) carried forward as impurities, i.e., organic compounds that are by-products from reactions used to prepare intermediates, SRA737, protected forms of SRA737, compounds of Formula I, or any other compound disclosed herein.

[0222] In some embodiments, the compound is in the form of a solvate of any one of the compounds disclosed herein and is substantially free of impurities, ie, small molecules that are undesirable isomers of the disclosed compounds.

[0223] In some embodiments, the compound is purified by crystallization. In further embodiments, the compound is further purified by recrystallization from a polar aprotic solvent.

[0224] In some embodiments, the recrystallization method comprises:

[0225] a) mixing a purified crystalline form of a compound disclosed herein with a polar aprotic solvent;

[0226] b) heating the mixture to a temperature of about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, about 100°C, or about 110°C;

[0227] c) cooling the mixture to a temperature of about 40°C, about 30°C, about 20°C, about 10°C, about 0°C, about -10°C, about -20°C, about -30°C, or about -78°C;

[0228] d) isolating the recrystallized crystalline form of the compound.

[0229] In some embodiments, polar aprotic solvents include acetonitrile, dimethylformamide, ethanol, methanol, isopropanol, tetrahydrofuran, pyridine, and diethyl ether.

[0230] In some embodiments, the compound is a solvate of any compound disclosed herein, and it is substantially purified or substantially free of impurities. In some embodiments, the compound is a solvate of any compound disclosed herein, and it is substantially purified or substantially free of impurities and is crystalline. In some embodiments, the compound is a solvate of any compound disclosed herein, and it is substantially purified or substantially free of palladium impurities. In some embodiments, the compound is a solvate of any compound disclosed herein, and it is substantially purified or substantially free of organic impurities. In some embodiments, the compound is a solvate of any compound disclosed herein, and it is substantially purified or substantially free of organic impurities and palladium impurities. In one embodiment, the compound is crystalline and is a polymorph. In some embodiments, the compound is polymorphic and has more than one form.

[0231] I. Synthetic Intermediates

[0232] In some embodiments, the compound is a solid form of a compound of Formula VII:

[0233]

[0234] wherein Pg is an organic group serving as an amino protecting group.

[0235] In some embodiments, the compound of formula VII is a crystalline compound. In some embodiments, the compound of formula VII is a semi-crystalline compound. In some embodiments, the compound of formula VII is an amorphous compound. In some embodiments, the compound of formula VII is a solid form of a compound having one or more polymorphic forms.

[0236] In some embodiments, the compound of formula VII has a Pg group selected from the group consisting of: acyl, formyl, acylamino, aminocarbonyl, aminothiocarbonyl, aminosulfonyl, amidino, carboxyl ester, benzyl, benzylidene, hydroxyl, substituted sulfonyl, substituted sulfinyl, and sulfonyloxy. In some embodiments, the compound of formula VII has a Pg group selected from the group consisting of: Boc, Ms, Ts, benzyl (-CH2Ph), allyl and vinyl.

[0237] In some embodiments, the compound of Formula VII has a Pg group that is Boc.

[0238] In some embodiments, the compound of formula VII has an allyl group Pg group.

[0239] In some embodiments, the compound of Formula VII has a Pg group that is Ts.

[0240] In some embodiments, the compound of Formula VII has a Pg group that is Fmoc.

[0241] In some embodiments, the compound of Formula VII has a Pg group that is trimethylsilyl (TMS).

[0242] In some embodiments, the compound of Formula VII has a Pg group that is a vinyl group.

[0243] In some embodiments, the compound of formula VII is a crystalline compound. In some embodiments, the compound of formula VII is a semi-crystalline compound. In some embodiments, the compound of formula VII is an amorphous compound. In some embodiments, the compound of formula VII is a solid form of a compound having one or more polymorphic forms.

[0244] In some embodiments, the compound is a solid form of Formula II, Formula VII, or Formula VIII. In some embodiments, the compound is a crystalline or semi-crystalline solid form of Formula II.

[0245] In some embodiments, the compound is of Formula II: A crystalline solid form of the compound.

[0246] In some embodiments, the compound is a crystalline solid form of a compound of Formula II having an X-ray powder diffraction pattern comprising peaks at about 12.9°, about 18.1°, about 20.6°, about 21.6°, about 22.3°, about 26.5°, and 27.8°, based on 2-theta.

[0247] In some embodiments, the compound is a crystalline solid form of a compound of Formula II having substantially Figure 2 The X-ray powder diffraction pattern is shown.

[0248] In some embodiments, the compound is a crystalline solid form of a compound of Formula II having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 215.1°C.

[0249] In some embodiments, the compound is a crystalline solid form of a compound of Formula II having substantially Figure 3 Differential Scanning Calorimetry (DSC) thermogram shown.

[0250] In some embodiments, the compound is a crystalline solid form of a compound of Formula II having substantially Figure 4 Thermogravimetric analysis (TGA) is shown.

[0251] In some embodiments, the compound is a crystalline solid form of a compound of Formula II that is substantially purified or substantially free of impurities. In some embodiments, the crystalline solid form of a compound of Formula II is substantially free of organic compound impurities.

[0252] In some embodiments, the compound is of Formula X: A crystalline solid form of the compound.

[0253] In some embodiments, the compound is a crystalline solid form of a compound of Formula X having an X-ray powder diffraction pattern comprising peaks at about 5.6°, about 11.1°, about 14.8°, about 16.7°, about 19.0°, about 19.4°, about 24.4°, and about 28.0°, in °2Θ.

[0254] In some embodiments, the compound is a crystalline solid form of a compound of Formula X: having substantially Figure 5 The X-ray powder diffraction pattern is shown.

[0255] II. General Methods for Preparing and Using Solvates and Synthetic Intermediates

[0256] Solvates and / or solid form compounds described herein can be prepared from readily available starting materials using the following general methods and procedures.

[0257] In short, morpholine derivative (formula I or have for example the nitrogen protecting group different from Boc or another kind of this derivative compound of the handle-shaped group (handle group) different from hydroxyl) is converted into the mesylated compound that can be crystallized.Then this mesylated morpholine intermediate product can be made to stand the nucleophilic displacement of amino-pyridine heterocyclic compound (optionally substituted), and this nucleophilic displacement is optionally carried out under the existence of weak inorganic or organic base.Then optionally on silica gel-filled chromatographic column or by filtering and washing or by crystallization purification obtained intermediate product.Then purified intermediate product and optional substituted aminopyrazine compound can be coupled.The intermediate product obtained is precipitated out, then it is next subjected to the deprotection for nitrogen-atoms, thereby obtaining required final product.

[0258] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA), CombiChem (San Diego, CA). Others can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0259] It will also be understood that, if typical process conditions for preparing these compounds are given (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.), minor modifications of these process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the specific reactants or solvents used, but as long as the reagents remain constant, those skilled in the art can determine such conditions through routine optimization procedures.

[0260] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undesirable reactions. It will be understood herein that amino, keto, sulfhydryl, hydroxyl and any other necessary protecting groups and methods for their deprotection are known in the art, such as those described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, 3rd edition, Wiley, New York, 1999, which is incorporated herein in its entirety, along with the references cited therein.

[0261] If the compounds described herein contain one or more chiral centers, such compounds can be prepared or separated as pure stereoisomers, i.e., prepared or separated as individual enantiomers or d(l) stereoisomers, or prepared or separated as mixtures enriched in stereoisomers. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present technology. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0262] Composition

[0263] On the other hand, a composition comprising at least one compound as described herein is provided. In some embodiments, a composition comprising at least one compound as described herein and an excipient and / or antioxidant and no more than about 1ppm of palladium impurities is provided. In some embodiments, a composition comprising at least one compound as described herein and an excipient and / or antioxidant and no more than about 10ppb, no more than about 5ppb, no more than about 2ppb, or no more than about 1ppb of palladium impurities is provided. In some embodiments, a composition is provided that is at least about 99%, at least about 99.5%, at least about 99.7%, at least about 99.9%, or at least about 99.99% pure compound by weight. In some embodiments, the composition provided comprises a compound as described herein and an excipient and / or antioxidant. Those skilled in the art will understand that these purity percentages are based on the relative amounts of the desired compounds in the dry weight composition.

[0264] I. Salt Forms of SRA737

[0265] In another aspect, the present disclosure provides a method for manufacturing a salt form of SRA737 (e.g., as described herein). In some cases, the salt is SRA737 citrate. In some cases, SRA737 citrate comprises SRA737 and citric acid in a 1:1 ratio.

[0266] In some embodiments, the salt form of SRA737 is of Formula IX: It should be understood that the structure of Formula IX is one representation of the salt form of SRA737 and that alternative representations are possible. All such representations of salts are intended to be included.

[0267] In some embodiments, the method of making a salt of the compound of Formula IX involves a crystallization process.

[0268] In some embodiments, the compound is a crystalline solid form of a salt of the compound of Formula IX.

[0269] In some embodiments, the compound is a crystalline solid form of a salt of the compound of Formula IX having an X-ray powder diffraction pattern comprising peaks at about 5.9°, about 11.3°, about 11.8°, about 14.5°, about 14.8°, about 17.8°, about 18.4°, about 18.7°, about 19.0°, about 19.3°, about 20.2°, about 20.6°, about 20.9°, about 21.2°, about 21.7°, about 23.0°, about 23.7°, about 24.0°, about 24.4°, and about 24.7°, based on 2-theta.

[0270] In some embodiments, the compound is a crystalline solid form of a salt of a compound of Formula IX: having substantially Figure 7 The X-ray powder diffraction pattern is shown.

[0271] II. Pharmaceutical Compositions

[0272] In a further aspect, a pharmaceutical composition is provided comprising SRA737 and very low concentrations of one or more palladium compounds as impurities as described herein and a pharmaceutically acceptable carrier or excipient.

[0273] In some embodiments, the pharmaceutical composition comprises no more than 1 mol%, 0.9 mol%, 0.8 mol%, 0.7 mol%, 0.6 mol%, 0.5 mol%, 0.4 mol%, 0.3 mol%, 0.2 mol%, 0.1 mol%, 0.05 mol%, 0.04 mol%, 0.03 mol%, 0.02 mol%, 0.01 mol%, 0.005 mol%, 0.004 mol%, 0.003 mol%, 0.002 mol%, 0.001 mol%, or 0.0001 mol% of one or more palladium compounds as an impurity.

[0274] In some embodiments, the pharmaceutical composition contains no more than 5 ppm, 4 ppm, 3 ppm, 2 ppm, 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6, ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm, 0.05 ppm, 0.04 ppm, 0.03 ppm, 0.02 ppm, or 0.01 ppm of one or more palladium compounds as an impurity.

[0275] In some embodiments, the pharmaceutical composition comprises no more than 5 ng / ml, 4 ng / ml, 3 ng / ml, 2 ng / ml, 1 ng / ml, 0.9 ng / ml, 0.8 ng / ml, 0.7 ng / ml, 0.6 ng / ml, 0.5 ng / ml, 0.4 ng / ml, 0.3 ng / ml, 0.2 ng / ml, 0.1 ng / ml, 0.09 ng / ml, 0.08 ng / ml, 0.07 ng / ml, 0.06 ng / ml, 0.05 ng / ml, 0.04 ng / ml, 0.03 ng / ml, 0.02 ng / ml, 0.01 ng / ml, 0.005 ng / ml, 0.004 ng / ml, 0.003 ng / ml, 0.002 ng / ml, or 0.001 ng / ml of one or more palladium compounds as an impurity.

[0276] In some embodiments, the pharmaceutical composition comprises SRA737 to one or more palladium compounds as an impurity in a weight ratio of no less than 100:1, 200:1, 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1, 1000:1, 2000:1, 3000:1, 4000:1, 5000:1, 6000:1, 7000:1, 8000:1, 9000:1, 10,000:1, 50,000:1, or 100,000:1.

[0277] In some embodiments, the pharmaceutical composition comprises a salt form of SRA737 (measured as the free base of SRA737) and one or more palladium compounds as an impurity in a weight ratio of 100:1, 200:1, 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1, 1000:1, 2000:1, 3000:1, 4000:1, 5000:1, 6000:1, 7000:1, 8000:1, 9000:1, 10,000:1, 50,000:1, or 100,000:1.

[0278] In some embodiments, the pharmaceutical composition comprises SRA737 and very low concentrations of one or more organic compounds that are impurities as described herein.

[0279] In some embodiments, the pharmaceutical composition comprises no more than 1 mol%, 0.9 mol%, 0.8 mol%, 0.7 mol%, 0.6 mol%, 0.5 mol%, 0.4 mol%, 0.3 mol%, 0.2 mol%, 0.1 mol%, 0.05 mol%, 0.04 mol%, 0.03 mol%, 0.02 mol%, 0.01 mol%, 0.005 mol%, 0.004 mol%, 0.003 mol%, 0.002 mol%, 0.001 mol%, or 0.0001 mol% of one or more organic compounds as impurities.

[0280] In some embodiments, the pharmaceutical composition contains no more than 5 ppm, 4 ppm, 3 ppm, 2 ppm, 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm, 0.05 ppm, 0.04 ppm, 0.03 ppm, 0.02 ppm, or 0.01 ppm of one or more organic compounds as impurities.

[0281] In some embodiments, the pharmaceutical composition comprises no more than 5 ng / ml, 4 ng / ml, 3 ng / ml, 2 ng / ml, 1 ng / ml, 0.9 ng / ml, 0.8 ng / ml, 0.7 ng / ml, 0.6 ng / ml, 0.5 ng / ml, 0.4 ng / ml, 0.3 ng / ml, 0.2 ng / ml, 0.1 ng / ml, 0.09 ng / ml, 0.08 ng / ml, 0.07 ng / ml, 0.06 ng / ml, 0.05 ng / ml, 0.04 ng / ml, 0.03 ng / ml, 0.02 ng / ml, 0.01 ng / ml, 0.005 ng / ml, 0.004 ng / ml, 0.003 ng / ml, 0.002 ng / ml, or 0.001 ng / ml of one or more organic compounds as an impurity.

[0282] In some embodiments, the pharmaceutical composition comprises SRA737 to one or more organic compounds as an impurity in a weight ratio of no less than 100:1, 200:1, 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1, 1000:1, 2000:1, 3000:1, 4000:1, 5000:1, 6000:1, 7000:1, 8000:1, 9000:1, 10,000:1, 50,000:1 or 100,000:1.

[0283] In some embodiments, the pharmaceutical composition comprises a salt form of SRA737 (measured as the free base of SRA737) to one or more organic compounds as an impurity in a weight ratio of 100:1, 200:1, 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1, 1000:1, 2000:1, 3000:1, 4000:1, 5000:1, 6000:1, 7000:1, 8000:1, 9000:1, 10,000:1, 50,000:1 or 100,000:1.

[0284] In some embodiments, pharmaceutical compositions comprise SRA737 and very low concentrations of one or more palladium compounds and one or more organic compounds, together as impurities as described herein.

[0285] In some embodiments, the pharmaceutical composition comprises no more than 1 mol%, 0.9 mol%, 0.8 mol%, 0.7 mol%, 0.6 mol%, 0.5 mol%, 0.4 mol%, 0.3 mol%, 0.2 mol%, 0.1 mol%, 0.05 mol%, 0.04 mol%, 0.03 mol%, 0.02 mol%, 0.01 mol%, 0.005 mol%, 0.004 mol%, 0.003 mol%, 0.002 mol%, 0.001 mol%, or 0.0001 mol% of one or more palladium compounds and one or more organic compounds together as impurities.

[0286] In some embodiments, the pharmaceutical composition comprises no more than 5 ppm, 4 ppm, 3 ppm, 2 ppm, 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm, 0.05 ppm, 0.04 ppm, 0.03 ppm, 0.02 ppm, or 0.01 ppm of one or more palladium compounds and one or more organic compounds together as impurities.

[0287] In some embodiments, the pharmaceutical composition comprises no more than 5 ng / ml, 4 ng / ml, 3 ng / ml, 2 ng / ml, 1 ng / ml, 0.9 ng / ml, 0.8 ng / ml, 0.7 ng / ml, 0.6 ng / ml, 0.5 ng / ml, 0.4 ng / ml, 0.3 ng / ml, 0.2 ng / ml, 0.1 ng / ml, 0.09 ng / ml, 0.08 ng / ml, 0.07 ng / ml, 0.06 ng / ml, 0.05 ng / ml, 0.04 ng / ml, 0.03 ng / ml, 0.02 ng / ml, 0.01 ng / ml, 0.005 ng / ml, 0.004 ng / ml, 0.003 ng / ml, 0.002 ng / ml, or 0.001 ng / ml of one or more palladium compounds and one or more organic compounds together as impurities.

[0288] In some embodiments, the pharmaceutical composition comprises SRA737 in a weight ratio of 100:1, 200:1, 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1, 1000:1, 2000:1, 3000:1, 4000:1, 5000:1, 6000:1, 7000:1, 8000:1, 9000:1, 10,000:1, 50,000:1, or 100,000:1 together with one or more palladium compounds and one or more organic compounds as impurities.

[0289] In some embodiments, the pharmaceutical composition comprises a salt form of SRA737 (measured as the free base of SRA737) in a weight ratio of 100:1, 200:1, 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1, 1000:1, 2000:1, 3000:1, 4000:1, 5000:1, 6000:1, 7000:1, 8000:1, 9000:1, 10,000:1, 50,000:1 or 100,000:1 together with one or more palladium compounds and one or more organic compounds as impurities.

[0290] In some embodiments, the pharmaceutical composition comprises 1, 2, 3, 4, or 5 or more compounds described herein, wherein SRA737 is the API and the other organic compounds are trace impurities. In some embodiments, the composition comprises multiple compounds.

[0291] In some embodiments, the pharmaceutical composition comprises at least one compound of Formula I or a tautomer, stereoisomer, salt, solvate, or hydrate thereof.

[0292] In some embodiments, the pharmaceutical composition comprises at least one compound of Formula II or a tautomer, stereoisomer, salt, solvate, or hydrate thereof.

[0293] In some embodiments, the pharmaceutical composition is formulated for an enteral route of administration.In various embodiments, the pharmaceutical composition is formulated for an intravenous route of administration.

[0294] The pharmaceutical composition for enteral administration can be in tablet, capsule, powder or liquid form. Tablets can include solid carriers, such as gelatin or adjuvants. Liquid pharmaceutical compositions generally include liquid carriers, such as water, petroleum, animal or vegetable oils, mineral oils or synthetic oils. Physiological saline solutions, dextrose or other sugar solutions or glycols, such as ethylene glycol, propylene glycol or polyethylene glycol can be included. The pharmaceutical composition can include cyclodextrins. The pharmaceutical composition can contain poloxamer and / or D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS).

[0295] In some embodiments where the pharmaceutical composition is formulated for enteral administration in a solid dosage form, the composition will contain about 0.01-99.99 wt% of the present technology compound based on the total formulation by weight percentage (wt%), the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt%.

[0296] In some embodiments, the pharmaceutical composition is formulated for inhalation in the form of a solution or mixture of excipients (e.g., preservatives, viscosity modifiers, emulsifiers, buffers) suspended in a non-pressurized or pressurized dispenser that delivers a spray containing a metered dose of at least one compound as described herein. In certain inhalation embodiments, the pharmaceutical composition is formulated for nasal or oral administration.

[0297] In some embodiments, the pharmaceutical composition is formulated for topical administration.In certain topical embodiments, the pharmaceutical composition is formulated for a dermally administered route, an epidermal route, an infusion, or a smear / rub.

[0298] In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In certain parenteral embodiments, the pharmaceutical composition is formulated for intravenous, subcutaneous, or intradermal administration. In some embodiments, the pharmaceutical composition is formulated for intrathecal or intracerebroventricular administration.

[0299] In a typical parenteral embodiment, the composition will be in the form of a pyrogen-free, parenterally acceptable aqueous solution having a suitable pH, isotonicity, and stability. Those skilled in the art are fully capable of preparing suitable solutions using, for example, isotonic vehicles such as sodium chloride injection, Ringer's injection, lactated Ringer's injection. Preservatives, stabilizers, buffers, antioxidants, and / or other additives may be incorporated as needed. Example

[0300] The following synthetic and biological examples are provided to illustrate the present technology and should not be construed in any way as limiting the scope of the present technology.Unless otherwise specified, all temperatures are in degrees Celsius.

[0301] The examples provided are for illustrative purposes only and are not intended to limit the scope of the invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (eg, amounts, temperatures, etc.), but some experimental errors and deviations should be allowed for.

[0302] The present technology will be further understood by reference to the following examples, which are intended to serve purely as examples of the present technology. The scope of the present technology is not limited by the exemplary embodiments, which are intended to serve only as illustrations of individual embodiments of the present technology. Any functionally equivalent methods are within the scope of the present technology. Various modifications to the present technology other than those described herein will be apparent to those skilled in the art based on the foregoing description and accompanying drawings. Such modifications fall within the scope of the appended claims.

[0303] In the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

[0304] aq. =water-based

[0305] LC-MS = Liquid Chromatography-Mass Spectrometry

[0306] MS = Mass Spectrometry

[0307] THF = Tetrahydrofuran

[0308] NaHCO3 = sodium bicarbonate

[0309] DIEA = diisopropylethylamine

[0310] MS = Mass Spectrometry

[0311] NaH = sodium hydride

[0312] o / n = over-liquid

[0313] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-

[0314] Triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0315] rt = room temperature

[0316] LAH = lithium aluminum hydride

[0317] DCM = dichloromethane

[0318] DMF = dimethylformamide

[0319] DMSO = dimethyl sulfoxide

[0320] equiv. = equivalent

[0321] EtOAc = ethyl acetate

[0322] EtOH = ethanol

[0323] g = grams

[0324] h = hours

[0325] HCl = hydrochloric acid

[0326] HPLC = High Performance Liquid Chromatography

[0327] HOAc = acetic acid

[0328] M = moles

[0329] MeOH = methanol

[0330] mg = milligrams

[0331] mL = milliliters

[0332] mmol = millimole

[0333] mp = melting point

[0334] m / z = mass-to-charge ratio

[0335] NaCl = sodium chloride

[0336] Na2CO3 = sodium carbonate

[0337] NMR = Nuclear Magnetic Resonance

[0338] NaOH = sodium hydroxide

[0339] Na2SO4 = sodium sulfate

[0340] ppm = parts per million

[0341] TFA = trifluoroacetic acid

[0342] TLC = Thin layer chromatography

[0343] TsOH = p-toluenesulfonic acid

[0344] UV = Ultraviolet

[0345] wt% = weight percentage

[0346] μM = micrometer

[0347] Example 1 - Total Synthesis of SRA737

[0348] General experimental details

[0349] The final compound was confirmed by HPLC / MS analysis and determined to be > 90% pure by weight. 1 H and 13C NMR spectra were recorded in CDCl (residual internal standard CHCl = δ 7.26), DMSO-d (residual internal standard CD SOCD H = δ 2.50), methanol-d (residual internal standard CD HOD = δ 3.20), or acetone-d (residual internal standard CD COCD H = δ 2.05). Chemical shifts (δ) are reported in parts per million (ppm), and coupling constants (J) are in Hertz (Hz). Spin multiplicities are reported as s = singlet, bs = broad singlet, bm = broad multiplet, d = doublet, t = triplet, q = quartet, p = quintet, dd = doublet of doublets, ddd = doublet of doublets of doublets, dt = doublet of triplet, td = triplet of doublets, tt = triplet of triplet, and m = multiplet.

[0350] HPLC-MS analysis was performed using gradient elution.Medium pressure liquid chromatography (MPLC) was performed using silica gel columns in normal and reverse phase.

[0351] Step 1: Synthesis of tert-butyl (R)-2-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate

[0352]

[0353] Tert-butyl (R)-2-(hydroxymethyl)morpholine-4-carboxylate (1000 g, 4.6 mol, 1.0 eq.) was suspended in MTBE (8600 g, 8.6 w / w) and EtN (559 g, 5.52 mol, 1.2 eq.) was added with stirring under an N atmosphere. The mixture was cooled to -5°C and methanesulfonyl chloride (580 g, 5.06 mol, 1.1 eq.) was added dropwise over 15 minutes. The mixture was stirred at 0°C for 30 minutes and then warmed to room temperature over 2 hours. 10% aqueous HCl (1000 g) was added and allowed to stir at 15°C for 10 minutes. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution and then with brine. The organic layer was then distilled at atmospheric pressure to reduce the water content, and more MTBE was added, followed by heptane. The cloudy mixture was seeded with crystals of the mesylate product and more heptane was added over 6 hours. The resulting slurry was filtered and washed with heptane and dried in a vacuum oven to provide the compound of Formula II, (R)-tert-butyl 2-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate, as a white crystalline solid (1250 g, 99.6% purity by weight). 1H NMR (400MHz, CDCl3) δ (ppm) 4.23 (d, 2H), 3.92 (m, 3H), 3.69 (m, 1H), 3.54 (dt, 1H), 3.07 (s, 3H), 2.95 (br s, 1H), 2.77 (brs, 1H), 1.47 (s, 9H). 13 CNMR (100 MHz, CDCl3) δ 154.6, 80.5, 73.0, 69.4, 66.5, 37.7, 28.4.; HRMS calculated value C 11 H 22 NO6S[M+H + ]:296.1168; Found: 296.1161DSC 63.92℃(peak); Position [°2θ](relative intensity%) 12.868820(8.85), 18.084000(100), 20.606050(45.58), 21.569860(21.94), 22.349710(9.99), 26.472810(13.55), 27.782060(10.77).

[0354] Step 2: Synthesis of tert-butyl 2-(((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)methyl)morpholine-4-carboxylate

[0355]

[0356] Tert-butyl (R)-2-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate (12.8 Kg), 2-chloro-5-(trifluoromethyl)pyridin-4-amine (8.5 Kg, 1.0 eq.), potassium phosphate (36.8 Kg), and tetrabutylammonium bromide (700 g) were suspended in toluene (96 L) and water (400 g) was added. The mixture was heated to 103-108° C. with stirring over 2 hours. After 31 hours, the reaction was determined to be complete by HPLC analysis. The mixture was cooled to 0-5° C. and water (77 L) was added over 30 minutes. The aqueous layer was discarded, and the organic layer was washed with dilute HCl, 10% bicarbonate solution, and water. The batch was concentrated to approximately 3 volumes and seeded at 35-40° C. for 1 hour. The resulting suspension was cooled to 20-25° C. and stirred for 12 hours. The product was collected by filtration and washed with a 3:1 mixture of heptane and toluene, followed by heptane. The filter cake was dried to afford the compound of Formula XII, (S)-tert-butyl 2-(((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)methyl)morpholine-4-carboxylate, as a yellow crystalline solid. 1H NMR(400MHz, CDCl3)δ(ppm)8.23(s,1H),6.60(s,1H),5.32(br s,1H),3.93(br d,2H),3.67(m,1H),3.57(dt,1H),3.33(m,1H),3.20(m,1H),2.97(br m,4H),2.76(br m,4H),3.21(d,1H),1.47(s,9H), 13 C NMR(100MHz, CDCl3)δ156.15,154.74,152.27,147.39(q,J=6Hz).124.44(q, J=271Hz)109.89(q,J=30Hz),105.61,80.70,73.03,66.74,44.99,28.54:DSC 108.82℃(peak);[°2θ](relative intensity%)8.0498(21),10.6105(13.86),12.9914(25.34),13.0971(24.75),14.7335(11.00),16.0964(71.38),16.4040(11.84),17.0986(12.15),17.2 313(18.69),18.5062(12.10),19.0810(17.33),19.3499(100),20.51.35(27.49),20.9726(20.31),21.1684(18.05),22.9569(12.14),23.6437(29.38),25.7977(12.15).

[0357] Step 3 - Synthesis of tert-butyl (S)-2-(((2-((5-cyanopyrazin-2-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)methyl)morpholine-4-carboxylate

[0358]

[0359] Reactor A was charged with (S)-tert-butyl 2-(((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)methyl)morpholine-4-carboxylate (5.55 Kg), 5-aminopyrazine-2-carbonitrile (1.78 Kg), palladium acetate (9.44 g, 0.28 mol%), (R)-1-[(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (23.44 g, 0.30 mol%), and then sparged with argon for three cycles. Degassed DMF (12.9 Kg) was added, followed by degassed water (2.22 g), and the solution was stirred under a steady stream of argon for 1 hour. Potassium phosphate (3.72 Kg) was added to reactor B containing degassed DMF (20 L) under a constant stream of argon. The slurry was stirred and heated to 125-135°C. The contents of Reactor A were added to Reactor B over 45 minutes, maintaining the temperature in Reactor B between 125°C and 135°C. The reaction mixture was maintained at this temperature for 1 hour, at which point HPLC analysis confirmed the reaction was complete. The mixture was cooled to room temperature and water (8.5 L) was added with stirring, maintaining the temperature below 40°C (the mixture could be seeded at this point). Water (51.2 L) was then added and the slurry stirred for an additional 30 minutes. The product, Formula IX salt (S)-tert-butyl 2-(((2-((5-cyanopyrazin-2-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)methyl)morpholine-4-carboxylate, was collected by filtration and washed with 1:1 DMF / water, followed by water and then heptane, and then dried in a vacuum oven to yield the product as a crystalline DMF solvate (7.36 Kg). The DMF solvate product was recrystallized from 3.1 volumes of acetonitrile to yield the unsolvated product as a crystalline solid (79% recovery). 1 H NMR(400MHz,DMSO)δ(ppm)10.76(br s,1H),9.05(d,1H),8.78(d,1H),8.21(s,1H),7.28(s,1H),6.51(br s,1H),3.89(br s,1H).3.78(br dd,2H),3.64(br m,1H),3.44-3.27(br,m,4H),2.90(br s,1H),2.66(br s,1H),2.51(m,1H),1.38(s,9H). 13C NMR (100MHz, DMSO) δ155.74, 153.88, 151.89, 151.50, 147.19, 145.97 (q, J = 7Hz), 136.83.124 .79(q,J=269Hz),118.78,117.06,104.44(q,J=30Hz),93.39,79.16,72.58,65.81,27.93; DSC 198.37℃ (peak); [°2θ] (relative intensity %) 5.6080(100), 11.1507(28.25), 14.8083(1.74), 16.7334(9.81), 19.0723(1.77), 19.4601(3.46), 24.4798(0.81), 28.0267(1.14).

[0360] Step 4: Synthesis of 5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile

[0361]

[0362] (S)-tert-Butyl 2-(((2-((5-cyanopyrazin-2-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)methyl)morpholine-4-carboxylate (6.835 Kg) was added to a reactor followed by acetonitrile (39.98 Kg) and the slurry was cooled to 0-10°C. Iodotrimethylsilane (3.68 Kg) was added over 30 minutes and the clear mixture was stirred for an additional 45 minutes. The reaction mixture was quenched into 10% potassium carbonate solution (4.1 Kg potassium carbonate) and ethyl acetate (36.2 Kg) was added. The resulting slurry was filtered and washed with ethyl acetate (16.5 Kg), water (49.8 Kg) and ethyl acetate (18.4 Kg). The product, Formula VIII, was dried in a vacuum oven to afford (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile as a crystalline solid (3.88 Kg) in an isolated yield of 71.7%. 1H NMR(400MHz,DMSO-d6)δ(ppm)10.76(br s,1H),10.33(br s,4H),9.06(d,1H),8.81(d,1H),8.23(s,3H),7.28(s,1H),6.56(br t,1H),4.00(dd,1H),3.95-3.85(m,1H),3.68(br t,1H),3.40-3.29(m,2H),3.21(d,1H),3.14(d,1H),2.98(dt,1H),2.80(br t,1H),2.58(d,2H),2.51(2,2H). 13 C NMR(100MHz,DMSO-d6)δ156.03,152.07,151.58,147.27,145.91(q,J=6Hz),136.93,124.89(q ,J=270Hz),118.55,117.22,104.31(q,J=29Hz),93.40,73.66,67.29,48.94,45.46,44.96; DSC 91.25,227.89℃(peak);[°2θ](relative intensity%)7.8452(35.54),10.55754(98.75),12.1764(42.38),16.09.4(12.66),16.8197(100),17.0873(33.00),17.7144(9.67),18.0371(4 4.39),20.5020(11.45),21.0506(14.23),21.9434(49.47),24.3626(18.77),25.2738(34.48),26.1521(13.61),27.0430(15.52),32.3872(21.35),36.0001(13.30).

[0363] Step 5-(R)-2-(((2-((5-cyanopyrazin-2-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)

[0364] Synthesis of (amino)methyl)morpholin-4-ium-3-carboxy-2-(carboxymethyl)-2-hydroxypropionate

[0365]

[0366] The reactor was charged with the free base (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (7.73 kg), ethanol (36.6 Kg) and water (38.8 Kg). The slurry was briefly heated to 40°C and cooled to room temperature. Acetic acid (2.44 Kg) was added and the mixture was warmed to 30-35°C with stirring until a homogeneous mixture was obtained. The warm solution was filtered into another reactor and citric acid (786 g in 1 L of water) was added and then seeded. Citric acid in water (3.9 Kg, 5 L) was added and the slurry was allowed to stir overnight at ambient temperature. The product was isolated by filtration and washed with a 1:1 solution of ethanol and water (2 times) and then with anhydrous ethanol. The material was dried in a vacuum oven to give the salt of the compound of formula IX as a crystalline solid (10.5 Kg). Use 1 The citrate salt of the compound was confirmed to be a 1:1 salt by H NMR or ion chromatography. 1 H NMR (400MHz, DMSO) δ (ppm) 10.76 (br s, 1H), 10.26 (br s,4H),9.07(s,1H),8.80(s,1H),8.23(s,1H),7.28(s,1H),6.55(t,J=8Hz,1H) ,3.98(dd,J=12,4Hz,1H),3.91(dtd,J=8.1,5.8,2.1Hz,1H),3.68(dt,J=12,4Hz 1H),3.35(dt,J=8,4Hz,2H),3.21(d,J=12Hz 1H),3.14(d,J=12Hz 1H),2.98(dt,J=12,4Hz 1H),2.80(br t,1H),2.56(ap q,J=16,4H)Hz. 13 C NMR (100MHz, DMSO) δ176.93,171.43,155.79,151.87,151.53,147.32,146.08(q,J=6Hz),136.80,124.76(q,J=2 70Hz),118.86,117.12,104.53(q,J=29Hz),93.41,71.42,71.14,63.79,45.56,44.40,44.30,42.66; FTIR(KBr)ν max3439,3422,2996,2875,2521,2229,1732,1618,1578,1520,1460,1441,1386; [M+H]=380.0; ES Pos.; DSC 206.26℃(peak); [°2θ](relative intensity %)5.9735(100),14.5577(14.06),17.8673(17.00),18.8133(30.79),23.8752(17.46),27.7527(11.68).

[0367] Example 2 - Deprotection of Compound X with Trifluoroacetic Acid on Small and Large Scale

[0368]

[0369] This example shows the difference in the reaction profiles for the deprotection of the compound of formula X to obtain SRA737 free base (Formula VIII) on a 1 gram and a 10 gram scale.

[0370] Initially, 1 gram of formula X compound was dissolved in DCM, followed by addition of trifluoroacetic acid (TFA) and triisopropylsilane. The reaction curve was analyzed by LC, and the analysis showed that the reaction was complete after 30 minutes. The reaction mixture was then concentrated in vacuo and the resulting crude material was subjected to DCM and toluene stripping. The crude material was then dissolved in a mixture of DCM and methanol and passed through a 10g Biotage NH separation column. The fractions containing the product were concentrated in vacuo to obtain a yellow solid. LC-MS further analyzed the desired formula VIII product as confirmed by H NMR analysis, showing a purity of 94.5%. The crude material was then further purified with 10% methanol in ether to obtain the desired formula VIII product with a purity of >97% and a yield of 80%.

[0371] Next, the deprotection reaction was repeated on a 10 gram scale. Similar to the 1 gram scale test, the reaction was complete after 30 minutes. A portion of the reaction mixture was taken out and kept at room temperature overnight to check the stability of the product in the reaction medium, while the remaining mixture was vacuum concentrated and azeotroped with toluene to produce an orange oil. However, LC-MS analysis of this material showed significant degradation, with a purity of 77%, with two major impurities being 13% and 5% respectively. Inspection of the reaction mixture kept at room temperature overnight showed degradation to 87%, with the same impurities being 9% and 2% respectively.

[0372] The impurities formed in this 10 gram scale reaction were identified as the tert-butylamide compound of Formula XIII and the corresponding tert-butyl methylimidate compound of Formula XIV. Further examination of the 1 gram reaction also indicated that the compound of Formula XIII was an impurity, but at a much lower level (<1%), which was easily removed by treatment with 10% methanol in diethyl ether.

[0373]

[0374] Thus, this example demonstrates that TFA / DCM deprotection conditions are not suitable for large-scale production of the free base of SRA737 from compounds of formula X.

[0375] This application involves the following technical solutions:

[0376] 1. A compound of formula I:

[0377]

[0378] where R 1 Selected from: C 1-12 Alkyl, substituted C 1-12 Alkyl, C 1-12 Alkenyl, substituted C 1-12 Alkenyl, C 1-12 Alkynyl, substituted C 1-12 Alkynyl, C 1-12 Alkoxy, substituted C 1-12 Alkoxy, C 3-8 Cycloalkyl, substituted C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, substituted C 3-8 Heterocycloalkyl, C 1-12 amino, C 1-12 Substituted amino, phenyl, substituted phenyl, C 3-8 Heteroaryl and substituted C 3-8 heteroaryl;

[0379] And wherein the compound is a dimethylformamide (DMF) solvate.

[0380] 2. The compound as described in 1, wherein R 1 C 1-12 Alkoxy or substituted C 1-12 Alkoxy.

[0381] 3. The compound as described in 1, wherein R 1 C 1-12 Alkyl or substituted C 1-12 alkyl.

[0382] 4. The compound as described in 1, wherein R 1 C3-8 Heterocycloalkyl or C 3-8 Heteroaryl.

[0383] 5. The compound as described in 1, wherein R 1 It is -OC(CH3)3.

[0384] 6. The compound of any one of 1-5, which is substantially purified and crystalline.

[0385] 7. A pharmaceutical composition comprising the compound according to any one of 1-6 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer and / or N-oxide thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0386] 8. The pharmaceutical composition according to 7, wherein the composition contains not more than 1 mol% of one or more palladium compounds as impurities.

[0387] 9. The pharmaceutical composition of 7, wherein the composition contains not more than 0.5 mol% of one or more palladium compounds as impurities.

[0388] 10. The pharmaceutical composition according to 7, wherein the composition contains not more than 0.1 mol% of one or more palladium compounds as impurities.

[0389] 11. The pharmaceutical composition of 7, wherein the composition contains not more than 0.05 mol% of one or more palladium compounds as impurities.

[0390] 12. The pharmaceutical composition of 7, wherein the composition contains no more than 0.01 mol% of one or more palladium compounds as impurities.

[0391] 13. The pharmaceutical composition of 7, wherein the composition contains no more than 0.005 mol% of one or more palladium compounds as impurities.

[0392] 14. The pharmaceutical composition of 7, wherein the composition contains no more than 0.001 mol% of one or more palladium compounds as impurities.

[0393] 15. The pharmaceutical composition of 7, wherein the composition contains no more than 1 mol% of one or more organic compounds as impurities.

[0394] 16. The pharmaceutical composition of 7, wherein the composition contains no more than 0.5 mol% of one or more organic compounds as impurities.

[0395] 17. The pharmaceutical composition of 7, wherein the composition contains no more than 0.1 mol% of one or more organic compounds as impurities.

[0396] 18. The pharmaceutical composition of 7, wherein the composition contains no more than 0.05 mol% of one or more organic compounds as impurities.

[0397] 19. The pharmaceutical composition of 7, wherein the composition contains no more than 0.01 mol% of one or more organic compounds as impurities.

[0398] 20. The pharmaceutical composition of 7, wherein the composition contains no more than 0.005 mol% of one or more organic compounds as impurities.

[0399] 21. The pharmaceutical composition of 7, wherein the composition contains no more than 0.001 mol% of one or more organic compounds as impurities.

[0400] 22. The pharmaceutical composition of 7, wherein the composition comprises not more than 1 mol% of one or more organic compounds and one or more palladium compounds together as impurities.

[0401] 23. The pharmaceutical composition of 7, wherein the composition comprises not more than 0.5 mol% of one or more organic compounds and one or more palladium compounds together as impurities.

[0402] 24. The pharmaceutical composition of 7, wherein the composition comprises no more than 0.1 mol% of one or more organic compounds and one or more palladium compounds together as impurities.

[0403] 25. The pharmaceutical composition of 7, wherein the composition comprises no more than 0.05 mol% of one or more organic compounds and one or more palladium compounds together as impurities.

[0404] 26. The pharmaceutical composition of 7, wherein the composition comprises not more than 0.01 mol% of one or more organic compounds and one or more palladium compounds together as impurities.

[0405] 27. The pharmaceutical composition of 7, wherein the composition comprises no more than 0.005 mol% of one or more organic compounds and one or more palladium compounds together as impurities.

[0406] 28. The pharmaceutical composition of 7, wherein the composition comprises no more than 0.001 mol% of one or more organic compounds and one or more palladium compounds together as impurities.

[0407] 29. The pharmaceutical composition of any one of 7-28, wherein the composition is formulated for parenteral administration.

[0408] 30. The pharmaceutical composition of any one of 7-28, wherein the composition is formulated for intravenous administration.

[0409] 31. The pharmaceutical composition of any one of 7-28, wherein the composition is formulated for subcutaneous administration.

[0410] 32. The pharmaceutical composition of any one of 7-28, wherein the composition is formulated for enteral administration.

[0411] 33. The pharmaceutical composition of 32, wherein the composition is formulated for oral administration.

[0412] 34. A process for preparing a solvate according to any one of 1 to 6, comprising crystallizing the solvate from a mixture comprising a compound of formula I, water and dimethylformamide (DMF).

[0413] 35. A formula II: A crystalline solid form of the compound.

[0414] 36. The solid form of 35, having an X-ray powder diffraction pattern comprising peaks at about 12.9°, about 18.1°, about 20.6°, about 21.6°, about 22.3°, about 26.5°, and 27.8°, in terms of 2-theta.

[0415] 37. A solid form as described in 35, which has substantially Figure 2 The X-ray powder diffraction pattern is shown.

[0416] 38. The solid form of any of 35-37, having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 215.1°C.

[0417] 39. A solid form as described in any one of 35-38, having substantially Figure 3 Differential Scanning Calorimetry (DSC) thermogram shown.

[0418] 40. A solid form as described in any one of 35-39, having substantially Figure 4 Thermogravimetric analysis (TGA) is shown.

[0419] 41. The solid form of any one of 35-40, which is substantially purified.

[0420] 42. A formula VIII: A crystalline solid form of the compound.

[0421] 43. The solid form of 42, having an X-ray powder diffraction pattern comprising peaks at about 7.8°, about 10.5°, about 12.1°, about 16.0°, about 16.8°, about 17.0°, about 17.7°, about 18.0°, about 20.5°, about 21.0°, about 21.9°, about 24.3°, about 25.2°, about 26.1°, about 27.0°, about 32.3°, and about 36.0°, based on 2-theta.

[0422] 44. A solid form as described in 42, which has substantially Figure 6 The X-ray powder diffraction pattern is shown.

[0423] 45. The solid form of any one of 42-44, which is substantially purified.

[0424] 46. A crystalline solid form of a salt of a compound of formula IX:

[0425]

[0426] 47. The solid form of 46, having an X-ray powder diffraction pattern comprising peaks at about 5.9°, about 11.3°, about 11.8°, about 14.5°, about 14.8°, about 17.8°, about 18.4°, about 18.7°, about 19.0°, about 19.3°, about 20.2°, about 20.6°, about 20.9°, about 21.2°, about 21.7°, about 23.0°, about 23.7°, about 24.0°, about 24.4°, and about 24.7°, based on 2-theta.

[0427] 48. A solid form as described in 46, which has substantially Figure 7 The X-ray powder diffraction pattern is shown.

[0428] 49. The solid form of any one of 46-48, which is substantially purified.

[0429] 50. A formula X: A crystalline solid form of the compound.

[0430] 51. The solid form of 50, having an X-ray powder diffraction pattern comprising peaks at about 5.6°, about 11.1°, about 14.8°, about 16.7°, about 19.0°, about 19.4°, about 24.4°, and about 28.0°, in terms of 2-theta.

[0431] 52. A solid form as described in 50, which has substantially Figure 5 The X-ray powder diffraction pattern is shown.

[0432] 53. The solid form of any one of 50-52, which is substantially purified.

[0433] 54. A pharmaceutical composition comprising the compound or solid according to any one of 35 to 53, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer and / or N-oxide thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0434] 55. The pharmaceutical composition of 54, wherein the composition comprises no more than 1 mol% of one or more palladium compounds as impurities.

[0435] 56. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.5 mol% of one or more palladium compounds as impurities.

[0436] 57. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.1 mol % of one or more palladium compounds as impurities.

[0437] 58. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.05 mol% of one or more palladium compounds as impurities.

[0438] 59. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.01 mol% of one or more palladium compounds as impurities.

[0439] 60. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.005 mol% of one or more palladium compounds as impurities.

[0440] 61. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.001 mol% of one or more palladium compounds as impurities.

[0441] 62. The pharmaceutical composition of 54, wherein the composition comprises no more than 1 mol% of one or more organic compounds as impurities.

[0442] 63. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.5 mol% of one or more organic compounds as impurities.

[0443] 64. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.1 mol% of one or more organic compounds as impurities.

[0444] 65. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.05 mol% of one or more organic compounds as impurities.

[0445] 66. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.01 mol% of one or more organic compounds as impurities.

[0446] 67. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.005 mol% of one or more organic compounds as impurities.

[0447] 68. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.001 mol% of one or more organic compounds as impurities.

[0448] 69. The pharmaceutical composition of 54, wherein the composition comprises no more than 1 mol % of one or more organic compounds and one or more palladium compounds together as impurities.

[0449] 70. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.5 mol % of one or more organic compounds and one or more palladium compounds together as impurities.

[0450] 71. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.1 mol % of one or more organic compounds and one or more palladium compounds together as impurities.

[0451] 72. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.05 mol % of one or more organic compounds and one or more palladium compounds together as impurities.

[0452] 73. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.01 mol % of one or more organic compounds and one or more palladium compounds together as impurities.

[0453] 74. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.005 mol % of one or more organic compounds and one or more palladium compounds together as impurities.

[0454] 75. The pharmaceutical composition of 54, wherein the composition comprises no more than 0.001 mol % of one or more organic compounds and one or more palladium compounds together as impurities.

[0455] 76. The pharmaceutical composition of any one of 54-75, wherein the composition is formulated for parenteral administration.

[0456] 77. The pharmaceutical composition of any one of 54-75, wherein the composition is formulated for intravenous administration.

[0457] 78. The pharmaceutical composition of any one of 54-75, wherein the composition is formulated for subcutaneous administration.

[0458] 79. The pharmaceutical composition of any one of 54-75, wherein the composition is formulated for enteral administration.

[0459] 80. The pharmaceutical composition of 79, wherein the composition is formulated for oral administration.

[0460] 81. A method for producing a compound of formula VII:

[0461]

[0462] The method comprises

[0463] a) Formula V: Compounds of formula VI: The compounds are coupled under cross-coupling reaction conditions to provide a compound of formula VII;

[0464] b) crystallizing and isolating the compound of formula VII from the mixture;

[0465] wherein Pg is an organic group serving as an amino protecting group and LvG is an organic group serving as a leaving group.

[0466] 82. The method of 81, further comprising:

[0467] a) providing a first mixture comprising a compound of formula V, a compound of formula VI, a catalyst, a ligand, and DMF;

[0468] b) providing a second mixture comprising an inorganic base and DMF, wherein the second mixture has been heated to between about 125° C. and 135° C.;

[0469] c) combining the first mixture with the second mixture to provide a third mixture, wherein the temperature of the third mixture is maintained between about 125-135°C.

[0470] 83. The method of 82, wherein Pg is C 1-12 Alkoxycarbonyl or substituted C 1-12 Alkoxycarbonyl protecting group.

[0471] 84. The method of 82, wherein Pg is C 1-12 Alkylcarbonyl or substituted C 1-12 Alkylcarbonyl protecting group.

[0472] 85. The method of claim 82, wherein Pg is (tert-butyloxycarbonyl or Boc group).

[0473] 86. The method of 82, wherein a palladium compound is used for the cross-coupling reaction conditions.

[0474] 87. The method of 82, wherein a copper compound is used in the cross-coupling reaction conditions.

[0475] 88. The method of 86, wherein the cross-coupling reaction conditions comprise a palladium compound, an organophosphorus compound, an inorganic base, and an organic solvent.

[0476] 89. The method of 88, wherein the palladium compound is a Pd(II) compound.

[0477] 90. The method of 89, wherein the palladium compound is Pd(OAc)2 and the organophosphorus compound is (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine.

[0478] 91. The method of 90, wherein the inorganic base is K 3 PO 4 .

[0479] 92. The method of 91, wherein the organic solvent is a polar aprotic organic solvent.

[0480] 93. The method of 92, wherein the polar aprotic organic solvent is dimethylformamide (DMF).

[0481] 94. The method of any one of 88-93, wherein the amount of palladium does not exceed 0.3 mol%.

[0482] 95. The method of any one of 88-93, wherein the amount of palladium does not exceed 0.25 mol%.

[0483] 96. The method of any one of 81-95, wherein water is added to the reaction mixture to crystallize the compound of Formula VII.

[0484] 97. methods as described in any one of 81-96, wherein said formula V compound is

[0485] 98. as described in any one of the methods 81-97, wherein LvG is chlorine.

[0486] 99. A method for producing a compound of formula VIII:

[0487]

[0488] The method comprises:

[0489] a) Formula III: Compounds of formula II: Compounds are coupled to provide Formula XII: Compounds;

[0490] b) making formula XII: Compounds of formula VI: The compounds are coupled under cross-coupling reaction conditions to provide Formula X: Compounds;

[0491] c) crystallizing and isolating the compound of formula X from the mixture;

[0492] d) subjecting the compound of formula X to deprotection conditions to provide the compound of formula VIII.

[0493] 100. The method according to claim 99, further comprising:

[0494] a) providing a first mixture comprising a compound of formula XII, a compound of formula VI, a catalyst, a ligand, and DMF;

[0495] b) providing a second mixture comprising an inorganic base and DMF, wherein the second mixture has been heated to between about 125° C. and 135° C.;

[0496] c) combining the first mixture with the second mixture to provide a third mixture, wherein the temperature of the third mixture is maintained between about 125-135°C.

[0497] 101. The method of claim 99, wherein the deprotection conditions comprise contacting the compound of formula X with trimethylsilyl iodide (TMSI) in acetonitrile.

[0498] 102. A method for preparing a salt of a compound of formula IX:

[0499]

[0500] The method comprises:

[0501] a) providing a compound comprising formula VIII: a first mixture of a compound, acetic acid, water, and an alcohol;

[0502] b) combining the first mixture with citric acid to provide a second mixture;

[0503] c) crystallizing and isolating Formula IX from said second mixture: Compound salts.

[0504] 103. The method of 102, wherein the first mixture is prepared by combining the compound of formula VIII, acetic acid, water, and alcohol at about 30-45°C.

[0505] 104. The method of 103, wherein the second mixture is prepared by combining the first mixture with citric acid at about 20-25°C.

[0506] 105. The method of any one of 102-104, wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, tert-butanol, and isopropanol.

[0507] 106. The method of 105, wherein the alcohol is ethanol.

[0508] Although some embodiments have been illustrated and described, those of ordinary skill in the art, after reading the foregoing description, may implement changes, substitutions of equivalents, and other types of modifications to the compounds of the present technology as described herein, or their salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers, or racemic mixtures. Each aspect and embodiment described above may also include or incorporate such variations or embodiments as disclosed for any or all other embodiments and embodiments.

[0509] The present technology is also not limited to the specific embodiments described herein, which are intended to be a single illustration of the various embodiments of the present technology. Many modifications and variations of the present technology can be made without departing from its spirit and scope, which will be apparent to those skilled in the art. In addition to the functional equivalent methods listed here, functional equivalent methods within the scope of the present technology will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. It should be understood that the present technology is not limited to specific methods, reagents, compounds, compositions, labeled compounds or biological systems, which can of course vary. It will also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to be restrictive. Therefore, it is intended that this patent specification be considered merely exemplary, and the breadth, scope and spirit of the present technology are indicated only by the appended claims, the definitions therein and any equivalents thereof.

[0510] In addition, where features or embodiments of the present disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the present technology. This includes the general description of the present technology with proviso or negative limitation to remove any subject matter from the genus, regardless of whether the deleted material is specifically enumerated herein.

[0511] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated as being incorporated by reference in its entirety. Definitions contained in text incorporated by reference are excluded to the extent they conflict with definitions in this disclosure.

[0512] Other embodiments are set forth within the following claims, along with the full scope of equivalents to which such claims are entitled.

[0513] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and details may be made therein without departing from the spirit and scope of the invention.

[0514] All references, issued patents, and patent applications cited within the body of this specification are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A compound of formula I: where R 1 Selected from: C 1-12 Alkyl, substituted C 1-12 Alkyl, C 1-12 Alkenyl, substituted C 1-12 Alkenyl, C 1-12 Alkynyl, substituted C 1-12 Alkynyl, C 1-12 Alkoxy, substituted C 1-12 Alkoxy, C 3-8 Cycloalkyl, substituted C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, substituted C 3-8 Heterocycloalkyl, C 1-12 amino, C 1-12 Substituted amino, phenyl, substituted phenyl, C 3-8 Heteroaryl and substituted C 3-8 heteroaryl; And wherein the compound is a dimethylformamide (DMF) solvate.

2. The compound of claim 1, wherein R 1 C 1-12 Alkoxy or substituted C 1-12 Alkoxy.

3. The compound of claim 1, wherein R 1 C 1-12 Alkyl or substituted C 1-12 alkyl.

4. The compound of claim 1, wherein R 1 C 3-8 Heterocycloalkyl or C 3-8 Heteroaryl.

5. The compound of claim 1, wherein R 1 It is -OC(CH3)3.

6. The compound of any one of claims 1-5, which is substantially purified and crystalline.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer and / or N-oxide thereof, and at least one pharmaceutically acceptable carrier or excipient.

8. The pharmaceutical composition of claim 7, wherein the composition comprises no more than 1 mol% of one or more palladium compounds as impurities.

9. The pharmaceutical composition of claim 7, wherein the composition comprises no more than 0.5 mol% of one or more palladium compounds as impurities.

10. The pharmaceutical composition of claim 7, wherein the composition comprises no more than 0.1 mol% of one or more palladium compounds as impurities.

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