WO2016187028A1 - Composés hétéroaryles, leur synthèse, et intermédiaires de ceux-ci - Google Patents

Composés hétéroaryles, leur synthèse, et intermédiaires de ceux-ci Download PDF

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Publication number
WO2016187028A1
WO2016187028A1 PCT/US2016/032422 US2016032422W WO2016187028A1 WO 2016187028 A1 WO2016187028 A1 WO 2016187028A1 US 2016032422 W US2016032422 W US 2016032422W WO 2016187028 A1 WO2016187028 A1 WO 2016187028A1
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compound
salt
formula
solvent
certain embodiments
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PCT/US2016/032422
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English (en)
Inventor
Paul Frank FERNANDEZ
Antonio Christian Ferretti
Jianxin HAN
John Traverse
Hsien-Hsin Tung
Kelvin Hin-Yeong Yong
Nanfei Zou
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Celgene Avilomics Research, Inc.
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Publication of WO2016187028A1 publication Critical patent/WO2016187028A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the present invention relates to methods for synthesizing compounds useful as inhibitors of ERK kinases, for example one or both of ERK1 and ERK2 kinases.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).
  • the processes involved in tumor growth, progression, and metastasis are mediated by signaling pathways that are activated in cancer cells.
  • the ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase.
  • ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase.
  • Activation of the ERK pathway is via a cascade of phosphorylation events that begins with activation of Ras.
  • Activation of Ras leads to the recruitment and activation of Raf, a serine- threonine kinase.
  • Raf Activated Raf then phosphorylates and activates MEKl/2, which then phosphorylates and activates one or both of ERK1 and ERK2.
  • ERKl and ERK2 When activated, one or both of ERKl and ERK2 phosphorylates several downstream targets involved in a multitude of cellular
  • the ERK/MAPK pathway is one of the most important for cell proliferation, and it is believed that the ERK/MAPK pathway is frequently activated in many tumors.
  • Ras genes which are upstream of one or both of ERKl and ERK2, are mutated in several cancers including colorectal, melanoma, breast and pancreatic tumors. The high Ras activity is accompanied by elevated ERK activity in many human tumors.
  • mutations of BRAF a serine-threonine kinase of the Raf family, are associated with increased kinase activity. Mutations in BRAF have been identified in melanomas (60%), thyroid cancers (greater than 40%) and colorectal cancers.
  • the present invention provides methods for preparing compounds useful as inhibitors of ERK kinases, for example one or both of ERKl and ERK2.
  • Such compounds include Compound I:
  • Compound I and pharmaceutically acceptable salts thereof, are useful for treating a variety of diseases, disorders or conditions, associated with abnormal cellular responses triggered by certain protein kinase-mediated events. Such diseases, disorders, or conditions include those described herein.
  • Compound I and pharmaceutically acceptable salts thereof, are also useful for the study of certain kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. Additional such compounds and methods can be found in PCT application publication number WO2014/124230, published August 14, 2014 ("the '230 publication,” the entirety of which is hereby incorporated herein by reference). The '230 publication describes certain ERK inhibitor compounds which covalently and irreversibly inhibit activity of one or both of ERK 1 and ERK2 kinases.
  • the present invention also provides synthetic intermediates useful for preparing such compounds.
  • Figure 1 depicts an XRPD pattern of Form A of compound 7.
  • Figure 2 depicts a DSC thermogram of Form A of compound 7.
  • Figure 3 depicts a an XRPD pattern of Form A of compound 8.
  • Figure 4 depicts a DSC thermogram of Form A of compound 8.
  • Figure 5 depicts a an XRPD pattern of Form A of compound 9.
  • Figure 6 depicts a DSC thermogram of Form A of compound 9.
  • Figure 7 depicts an XRPD pattern of Form B of compound 9.
  • Figure 8 depicts a DSC thermogram of Form B of compound 9.
  • Figure 9 depicts an XRPD pattern of Form A of a phosphate salt of Compound I.
  • Figure 10 depicts a DSC thermogram of Form A of a phosphate salt of Compound I.
  • Figure 11 depicts a TGA trace of Form A of a phosphate salt of Compound I.
  • Figure 12 depicts a DVS plot of Form A of a phosphate salt of Compound I.
  • Figure 13 depicts PLM images of crystals of the phosphate salt of Compound I at different stages of a crystallization process comprising ten heat-cool cycles performed on an initial portion (20% of the total final mass) of free base Compound I with an initial portion (20%) of the total phosphoric acid (1.2 mol. equiv. relative to free base Compound I).
  • Figure 14 depicts PLM images of crystals of the phosphate salt of Compound I at different stages of a crystallization process comprising ten heat-cool cycles performed on an entire batch (100% of the total final mass) of free base Compound I with an initial portion (20%) of the total phosphoric acid (1.2 mol. equiv. relative to free base Compound I).
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci ⁇ alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the (R) and (S) configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • an inhibitor is defined as a compound that binds to and /or inhibits the target protein kinase with measurable affinity.
  • an inhibitor has an IC 50 and/or binding constant of less about 50 ⁇ , less than about 1 ⁇ , less than about 500 nM, less than about 100 nM, or less than about 10 nM.
  • each of LG 1 , LG 2 , and PG 1 is as defined below and in classes and subclasses described herein.
  • each of LG 1 , LG 2 , LG 3 , LG 4 , and PG 1 is as defined below and in classes and subclasses described herein.
  • Scheme I' differs from Scheme I in that Scheme I' provides an alternative route to a compound of Formula E, i.e., via step S--1' using as starting material a compound of formula G, described in further detail below. Accordingly, embodiments described below and herein for steps S-2 through S-5 are contemplated as occurring in the context of each of Scheme I and Scheme I'.
  • step S-1 of Scheme I the amine group of commercially available compound F is protected to afford a compound of formula E.
  • the PG 1 group of a compound of formula E is a suitable amino protecting group.
  • suitable amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • Suitable amino protecting groups, taken with the -NH- moiety to which it is attached include, but are not limited to, aralkylamines, carbamates, allyl amines, amides, and the like.
  • Examples of PG 1 groups of a compound of formula E include t- butyloxycarbonyl (BOC), p-methoxybenzyloxycarbonyl (PMB), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyl oxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
  • BOC butyloxycarbonyl
  • PMB p-methoxybenzyloxycarbonyl
  • ethyloxycarbonyl ethyloxycarbonyl
  • methyloxycarbonyl methyloxycarbonyl
  • the PG 1 group of a compound of formula E is t-butyloxycarbonyl (BOC). In certain embodiments, the PG 1 group of a compound of formula E is BOC and the protecting group reagent used to generate PG 1 is di-tert-butyl dicarbonate.
  • step S-1 requires an amount of protecting group reagent of about 1.0 molar equivalents or less relative to substrate.
  • step S-1 requires an amount of protecting group reagent (e.g., di-tert-butyl dicarbonate) of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.85, 0.9, 0.95, 0.96, 0.97, 0.98, or 0.99 molar equivalents relative to substrate.
  • step S-1 requires an amount of protecting group reagent of about 1.0 to about 2.0 molar equivalents relative to substrate.
  • step S-1 requires an amount of protecting group reagent (e.g., di-tert-butyl dicarbonate) of about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 molar equivalents relative to substrate.
  • the protecting group reagent is di-tert-butyl dicarbonate and is present in an amount of about 1.0 to about 2.0 molar equivalents relative to substrate.
  • the protecting group reagent is di-tert-butyl dicarbonate and is present in an amount of about 1.1 molar equivalents relative to substrate.
  • the protecting group reagent is di-tert-butyl dicarbonate and is present in an amount of about 1.2 molar equivalents relative to substrate. In certain embodiments, the protecting group reagent is di-tert-butyl dicarbonate and is present in an amount of about 1.3 molar equivalents relative to substrate.
  • step S-1 is conducted in a solvent comprising an organic solvent. In some embodiments, step S-1 is conducted in a solvent comprising a polar aprotic solvent. In some embodiments, step S-1 is conducted in a solvent comprising an ethereal solvent. In some embodiments, step S-1 is conducted in a solvent comprising an ethereal solvent such as an optionally substituted tetrahydrofuran or a dialkylether. In certain embodiments, step S-1 is conducted in a solvent comprising a substituted tetrahydrofuran such as, e.g., 2- methyltetrahydrofuran (2-MeTHF).
  • 2-MeTHF 2- methyltetrahydrofuran
  • step S-1 is conducted in a solvent comprising tetrahydrofuran (THF). In some embodiments, step S-1 is conducted in a solvent comprising a dialkylether (e.g., diethylether). In some embodiments, step S-1 is conducted in a solvent comprising a single organic solvent. In some embodiments, step S-1 is conducted in a solvent comprising a combination of organic solvents. In certain embodiments, step S-1 is conducted in 2-MeTHF.
  • THF tetrahydrofuran
  • step S-1 is conducted in a solvent comprising a dialkylether (e.g., diethylether).
  • step S-1 is conducted in a solvent comprising a single organic solvent.
  • step S-1 is conducted in a solvent comprising a combination of organic solvents. In certain embodiments, step S-1 is conducted in 2-MeTHF.
  • step S-1 is conducted the presence of a base.
  • a base is an organic base.
  • a base is an amine base (e.g., trimethylamine).
  • a base is an inorganic base.
  • an inorganic base is an alkali hydroxide.
  • an inorganic base is LiOH.
  • an inorganic base is NaOH.
  • an inorganic base is KOH.
  • a base a carbonate.
  • a base is Na 2 CO 3 .
  • a base is K 2 CO 3 .
  • a base a bicarbonate.
  • a base is NaHCO 3 .
  • a base is KHCO 3 . In some embodiments, a base is a phosphate. In some embodiments, a base is Na 3 PO 4 . In some embodiments, a base is K 3 PO 4 . In some embodiments, a base is phosphate dibasic. In some embodiments, a base is K 2 HPO 4 .
  • step S-1 is conducted the presence of a base and di-tert-butyl dicarbonate is the protecting group reagent.
  • step S-1 is conducted in the presence of a hydroxide base (e.g., NaOH) in a suitable solvent (e.g., an ether such as 2-MeTHF) and di-tert-butyl dicarbonate is the protecting group reagent.
  • a hydroxide base e.g., NaOH
  • a suitable solvent e.g., an ether such as 2-MeTHF
  • di-tert-butyl dicarbonate is present in an amount of about 1.7 equivalents relative to substrate.
  • the solvent e
  • step S-1 is conducted in the presence of an amine base (e.g., trimethylamine) and a nucleophilic catalyst (e.g., DMAP) in a suitable solvent (e.g., an ether such as THF) and di-tert-butyl dicarbonate is the protecting group reagent.
  • a suitable solvent e.g., an ether such as THF
  • step S-1 is conducted at a temperature of about 20 °C to about 30 °C. In some such embodiments, step S-1 is conducted at a temperature of about 25 °C.
  • step S-1 is conducted in the presence of a hydroxide base (e.g., NaOH) in a suitable solvent (e.g., a mixture of an ether such as THF and water) and di-tert-butyl dicarbonate is the protecting group reagent.
  • a hydroxide base e.g., NaOH
  • a suitable solvent e.g., a mixture of an ether such as THF and water
  • di-tert-butyl dicarbonate is the protecting group reagent.
  • step S-1 is conducted at a temperature of about 20 °C to about 30 °C.
  • step S-1 is conducted at a temperature of about 25 °C.
  • step S-1 is conducted in the presence of a hydroxide base (e.g., NaOH) in an amount of about 0.1 equivalents relative to substrate, in the presence of an excess of protecting group reagent (e.g., 3 equivalents of di-tert-butyl dicarbonate relative to substrate) in a suitable solvent (e.g., a solvent comprising THF).
  • a hydroxide base e.g., NaOH
  • protecting group reagent e.g., 3 equivalents of di-tert-butyl dicarbonate relative to substrate
  • a suitable solvent e.g., a solvent comprising THF.
  • step S-1 is conducted at a temperature of about 40 °C to about 60 °C.
  • step S-1 is conducted at a temperature of about 50 °C.
  • step S-1 is conducted in the presence of a hydroxide base (e.g., NaOH) in an amount of about 0.1 equivalents relative to substrate, in the presence of an excess of protecting group reagent (e.g., 4 equivalents of di-tert-butyl dicarbonate relative to substrate) in a suitable solvent (e.g., a solvent comprising THF).
  • a hydroxide base e.g., NaOH
  • protecting group reagent e.g., 4 equivalents of di-tert-butyl dicarbonate relative to substrate
  • a suitable solvent e.g., a solvent comprising THF.
  • step S-1 is conducted at a temperature of about 45 °C to about 65 °C.
  • step S-1 is conducted at a temperature of about 55 °C.
  • step S-1 is conducted in the presence of a hydroxide base (e.g., NaOH) in an amount of about 0.1 equivalents relative to substrate, in the presence of an excess of protecting group reagent (e.g., 3 equivalents of di-tert-butyl dicarbonate relative to substrate) in a suitable solvent (e.g., a solvent comprising acetonitrile).
  • a hydroxide base e.g., NaOH
  • protecting group reagent e.g., 3 equivalents of di-tert-butyl dicarbonate relative to substrate
  • a suitable solvent e.g., a solvent comprising acetonitrile
  • step S-1 is conducted in the presence of a hydroxide base (e.g., NaOH) in an amount of about 0.1 equivalents relative to substrate, in the presence of an excess of protecting group reagent (e.g., 3 equivalents of di-tert-butyl dicarbonate relative to substrate) in a suitable solvent (e.g., a solvent comprising an ether such as 2-MeTHF).
  • a hydroxide base e.g., NaOH
  • protecting group reagent e.g., 3 equivalents of di-tert-butyl dicarbonate relative to substrate
  • a suitable solvent e.g., a solvent comprising an ether such as 2-MeTHF.
  • step S-1 is conducted at a temperature of about 60 °C to about 80 °C.
  • step S-1 is conducted at a temperature of about 70 °C.
  • step S-1 is conducted in the presence of aqueous hydroxide base (e.g., 10N aqueous NaOH (5 mol%)) in the presence of an excess of protecting group reagent (e.g., 2 equivalents of di-tert-butyl dicarbonate relative to substrate) in a suitable solvent (e.g., 3X volume 2-MeTHF).
  • aqueous hydroxide base e.g., 10N aqueous NaOH (5 mol%)
  • protecting group reagent e.g., 2 equivalents of di-tert-butyl dicarbonate relative to substrate
  • a suitable solvent e.g., 3X volume 2-MeTHF
  • step S-1 is conducted at a temperature of about 70 °C to about 90 °C.
  • step S-1 is conducted at a temperature of about 78 °C.
  • the reaction is run for about 30 to 40 hours. In some such embodiments, the reaction is run for about 35 hours.
  • additional protecting group reagent is optionally charged as required to improve yields.
  • the protecting group reagent e.g., di-tert-butyl dicarbonate
  • a suitable solvent e.g., an ether such as 2-MeTHF
  • step S-1 is conducted in the presence of a hydroxide base (e.g., NaOH) in an amount of about 0.05 equivalents relative to substrate, in a suitable solvent (e.g., an ether such as 2-MeTHF), wherein the solvent is present in a volume between about IX and 3X.
  • a suitable solvent e.g., an ether such as 2-MeTHF
  • the protecting group reagent is di-tert-butyl dicarbonate and is present in an amount of about 1.0 to 1.5 equivalents relative to substrate.
  • the solvent is present in a volume of about IX.
  • the solvent is present in a volume of about 2X.
  • the solvent is present in a volume of about 3X.
  • step S-1 is conducted in the presence of a hydroxide base (e.g., NaOH) in an amount of about 0.1 equivalents relative to substrate, in a suitable solvent (e.g., an ether such as 2-MeTHF), wherein the solvent is present in a volume between about IX and 3X.
  • a suitable solvent e.g., an ether such as 2-MeTHF
  • the protecting group reagent is di-tert-butyl dicarbonate and is present in an amount of about 1.0 to 1.5 equivalents relative to substrate.
  • the solvent is present in a volume of about IX.
  • the solvent is present in a volume of about 2X.
  • the solvent is present in a volume of about 3X.
  • step S-1 is conducted in the presence of a hydroxide base (e.g., NaOH) in an amount of about 0.05 equivalents relative to substrate, in about IX volume of suitable solvent (e.g., an ether such as 2-MeTHF), with about 1.25 equivalents of protecting group reagent (e.g., di-tert-butyl dicarbonate).
  • a hydroxide base e.g., NaOH
  • suitable solvent e.g., an ether such as 2-MeTHF
  • protecting group reagent e.g., di-tert-butyl dicarbonate
  • step S-1 is conducted in the presence of a hydroxide base (e.g., NaOH) in an amount of about 0.1 equivalents relative to substrate, in about IX volume of suitable solvent (e.g., an ether such as 2-MeTHF), with about 1.5 equivalents of protecting group reagent (e.g., di-tert-butyl dicarbonate).
  • a hydroxide base e.g., NaOH
  • suitable solvent e.g., an ether such as 2-MeTHF
  • protecting group reagent e.g., di-tert-butyl dicarbonate
  • step S-1 is conducted in the presence of a hydroxide base (e.g., NaOH) in an amount of about 0.1 equivalents relative to substrate, in about IX volume of suitable solvent (e.g., an ether such as 2-MeTHF), with about 1.0 equivalents of protecting group reagent (e.g., di-tert-butyl dicarbonate).
  • a hydroxide base e.g., NaOH
  • suitable solvent e.g., an ether such as 2-MeTHF
  • protecting group reagent e.g., di-tert-butyl dicarbonate
  • step S-1 is conducted in the presence of a hydroxide base (e.g., NaOH) in an amount of about 0.05 equivalents relative to substrate, in about IX volume of suitable solvent (e.g., an ether such as 2-MeTHF), with about 1.25 equivalents of protecting group reagent (e.g., di-tert-butyl dicarbonate).
  • a hydroxide base e.g., NaOH
  • suitable solvent e.g., an ether such as 2-MeTHF
  • protecting group reagent e.g., di-tert-butyl dicarbonate
  • the rate of conversion of step S-1 is determined in part by the relative amounts of base versus protecting group reagent present. For instance, in some embodiments wherein reactions are run with higher amounts of protecting group reagent (e.g., >1.3 equivalents of di-tert-butyl dicarbonate) and lower amounts of base (e.g., about 0.05 equivalents of NaOH) at least 70% conversion is achieved after about 8 hours.
  • protecting group reagent e.g., >1.3 equivalents of di-tert-butyl dicarbonate
  • base e.g., about 0.05 equivalents of NaOH
  • reactions are run with higher amounts of protecting group reagent (e.g., >1.3 equivalents of di-tert-butyl dicarbonate) and higher amounts of base (e.g., > 0.5 equivalents of NaOH), or wherein reactions are run with lower amounts of protecting group reagent (e.g., 1.3 equivalents of di-tert-butyl dicarbonate or less) and lower amounts of base (e.g., 0.5 equivalents of NaOH or less) at least 80% conversion is achieved after 24 hours.
  • protecting group reagent e.g., >1.3 equivalents of di-tert-butyl dicarbonate
  • base e.g., 0.5 equivalents of NaOH or less
  • step S-1 is conducted in the absence of a base.
  • step S-1 is conducted the absence of a base and di-tert-butyl dicarbonate is the protecting group reagent.
  • step S-1 is conducted in the presence of a nucleophilic catalyst (e.g., DMAP) in a suitable solvent (e.g., a solvent comprising acetonitrile) and di-tert-butyl dicarbonate is the protecting group reagent.
  • a nucleophilic catalyst e.g., DMAP
  • a suitable solvent e.g., a solvent comprising acetonitrile
  • step S-1 is conducted at a temperature of about 40 °C to about 70 °C.
  • step S-1 is conducted at a temperature of about 50 °C to about 60 °C.
  • step S-1 is conducted in a suitable solvent (e.g., a mixture of an ether such as THF and water) and di-tert-butyl dicarbonate is the protecting group reagent.
  • a suitable solvent e.g., a mixture of an ether such as THF and water
  • di-tert-butyl dicarbonate is the protecting group reagent.
  • step S-1 is conducted at a temperature of about 40 °C to about 60 °C.
  • step S-1 is conducted at a temperature of about 50 °C.
  • step S-1 is conducted in a suitable solvent (e.g., an ether such as 2-MeTHF), wherein the solvent is present in a volume between about IX and 3X, and di-tert- butyl dicarbonate is the protecting group reagent.
  • a suitable solvent e.g., an ether such as 2-MeTHF
  • the solvent is present in a volume of about IX. In certain embodiments, the solvent is present in a volume of about
  • the solvent is present in a volume of about 3X.
  • step S-1 is conducted in a suitable solvent (e.g., an ether such as 2-MeTHF), wherein the solvent is present in a volume of about IX and di-tert-butyl dicarbonate is present in an amount of about 1.0 equivalents relative to substrate.
  • a suitable solvent e.g., an ether such as 2-MeTHF
  • step S-1 is conducted in a suitable solvent (e.g., an ether such as 2-MeTHF), wherein the solvent is present in a volume of about IX and di-tert-butyl dicarbonate is present in an amount of about 1.1 equivalents relative to substrate.
  • a suitable solvent e.g., an ether such as 2-MeTHF
  • step S-1 is conducted in a suitable solvent (e.g., an ether such as 2-MeTHF), wherein the solvent is present in a volume of about IX and di-tert-butyl dicarbonate is present in an amount of about 1.2 equivalents relative to substrate.
  • a suitable solvent e.g., an ether such as 2-MeTHF
  • step S-1 is conducted in a suitable solvent (e.g., an ether such as 2-MeTHF), wherein the solvent is present in a volume of about IX and di-tert-butyl dicarbonate is present in an amount of about 1.3 equivalents relative to substrate.
  • a suitable solvent e.g., an ether such as 2-MeTHF
  • step S-1 is conducted in a suitable solvent (e.g., an ether such as 2-MeTHF), wherein the solvent is present in a volume of about IX and di-tert-butyl dicarbonate is present in an amount of about 1.4 equivalents relative to substrate.
  • a suitable solvent e.g., an ether such as 2-MeTHF
  • step S-1 is conducted in a suitable solvent (e.g., an ether such as 2-MeTHF), wherein the solvent is present in a volume of about IX and di-tert-butyl dicarbonate is present in an amount of about 1.5 equivalents relative to substrate.
  • a suitable solvent e.g., an ether such as 2-MeTHF
  • step S-1 is conducted at elevated temperatures. For instance, in some embodiments, step S-1 is conducted at a temperature between about 50 °C and about 100
  • the temperature is between about 55 °C and about 95 °C. In some embodiments, the temperature is between about 60 °C and about 90 °C. In certain embodiments, the reaction is conducted at about 70 °C. In certain embodiments, the reaction is conducted at about 75 °C. In certain embodiments, the reaction is conducted at about 80 °C. In certain embodiments, the reaction is conducted at about 85 °C.
  • the protecting group reagent of step S-1 e.g., di-tert-butyl dicarbonate
  • a suitable solvent e.g., 2-MeTHF
  • the dissolved protecting group reagent e.g., di-tert-butyl dicarbonate in 2-MeTHF
  • addition occurs over a period of time while the reaction mixture is held at an elevated temperature. For instance, in some embodiments, addition to the reaction mixture occurs at an elevated temperature for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours.
  • addition to the reaction mixture occurs at an elevated temperature for about 10-24 hours. In some embodiments, addition to the reaction mixture occurs at an elevated temperature for about 10-22 hours. In some embodiments, addition to the reaction mixture occurs at an elevated temperature for about 12-22 hours. In some embodiments, addition to the reaction mixture occurs at an elevated temperature for about 12-16 hours.
  • the reaction is allowed to run for an additional amount of time after the protecting group reagent has been added. For instance, in some embodiments, the reaction is allowed to run for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 more hours. In some embodiments, the reaction is allowed to run for about 6 more hours. In some embodiments, the reaction is allowed to run for about 12 more hours.
  • an additional amount of dissolved protecting group reagent is added in portions to the reaction mixture until a desired level of conversion is achieved.
  • the reaction is allowed to cool (e.g., to between about 20 °C to about 30 °C) and an amount of water and an organic solvent (e.g., 2-MeTHF) is added to it, followed by extraction of the organic layer.
  • an organic solvent e.g., 2-MeTHF
  • the organic layer is washed with water.
  • the organic layer is washed with water 1, 2, 3, 4, or 5 times.
  • removal of water occurs azeotropically by distilling (for instance using continuous vacuum distillation) a solution of the product compound and an appropriate organic solvent.
  • the process of distilling off an amount of solvent e.g., 2-MeTHF is continued until the water content of the product solution is reduced to a desired level.
  • a second, continuous vacuum distillation is performed using an organic solvent such as an alkane.
  • an organic solvent is an alkane such as a hexane or a heptane.
  • continuous vacuum distillation is performed until the solution comprises a desired solvent composition.
  • a first distillation is performed to remove solvents used during work-up, followed by a second, continuous distillation with, e.g., n-heptane, wherein the second, continuous distillation proceeds until the solvent composition or volume reaches a desired level.
  • a product solution undergoes a first distillation with, e.g., 2-MeTHF, and a second distillation with, e.g., n-heptane, wherein the second distillation proceeds until the amount of 2-MeTHF present in the distilled product solution is no more than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% (v/v).
  • a crystallization is performed. In some embodiments, the above-described distillations are performed prior to crystallization. In some embodiments, the solution containing the product compound is cooled to a desired temperature prior to crystallization. In certain embodiments the solution containing the product compound is cooled to about 40 °C, 45 °C, 50 °C, or 55 °C. In certain embodiments the solution containing the product compound is cooled to about 40 °C to about 50 °C.
  • crystallization of the solution containing the product compound is initiated by adding seed crystals.
  • seeding occurs with a particular polymorph of a compound of formula E. Exemplary such polymorphs are contemplated further below.
  • crystallization comprises a step of agitating for an amount of time. For instance, in some embodiments, agitation lasts for about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 minutes. In certain embodiments, agitation lasts for between about 45 minutes and about 65 minutes. In certain embodiments, agitation lasts for about 60 minutes.
  • crystallization comprises a step of cooling the agitated solution over a period of time.
  • the solution is cooled to between about -10 °C and about 10 °C.
  • the solution is cooled to between about -5 °C and about 10 °C.
  • the solution is cooled to between about -5 °C and about 5 °C.
  • the solution is cooled to between about 0 °C and about 10 °C.
  • cooling takes place over an amount of time, for instance, about 1, 2, 3, 4, 5, or 6 hours.
  • a solution is cooled for about 2 hours.
  • a solution is cooled for about 3 hours.
  • a solution is cooled for about 4 hours.
  • a solution is cooled for about 5 hours.
  • crystallization comprises a step of agitating the cooled solution.
  • the cooled solution is agitated for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In certain embodiments, the cooled solution is agitated for about 16 hours.
  • the cooled solution is allowed to stand for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In certain embodiments, the cooled solution is allowed to stand for about 16 hours.
  • the resulting product upon completion of crystallization, is filtered, washed with an amount of solvent (e.g., an alkane such as n-heptane), and dried.
  • solvent e.g., an alkane such as n-heptane
  • the present invention provides an alternative route to a compound of formula E wherein PG 1 of formula E is a BOC protecting group (i.e., Compound 7, depicted below).
  • PG 1 of formula E is a BOC protecting group
  • a compound of formula G is functionalized in a two-step process by first performing a methoxylation (i.e., step (a) of step S-1'), followed by amination (i.e., step (b) of step S-1') to afford a compound of formula E.
  • Each of LG 3 and LG 4 of a compound of formula G is a suitable leaving group subject to displacement.
  • each of LG 3 and LG 4 is a halogen.
  • LG 3 is halogen. In some embodiments, LG 3 is -CI. In some embodiments, LG 3 is -Br. In some embodiments, LG 3 is -I.
  • LG 4 is halogen. In some embodiments, LG 4 is -CI. In some embodiments, LG 4 is -Br. In some embodiments, LG 4 is -I.
  • each of LG 3 and LG 4 is independently halogen. In some embodiments, each of LG 3 and LG 4 is -CI. [0086] In some embodiments, a compound of formula G is compound 10:
  • step (a) of step S-1 is conducted in a solvent comprising an organic solvent.
  • step (a) of step S-1 is conducted in a solvent comprising an aromatic solvent.
  • step (a) of step S-1 is conducted in a solvent comprising benzene, toluene, or xylene.
  • step (a) of step S-1 is conducted in a solvent comprising toluene.
  • step (a) of step S-1 is conducted the presence of a base.
  • a base is an inorganic base.
  • an inorganic base is an alkali methoxide.
  • an inorganic base is LiOMe.
  • an inorganic base is NaOMe.
  • an inorganic base is KOMe.
  • an inorganic base is CsOMe.
  • step (a) of step S-1 comprises a first step of heating a mixture of base (e.g., NaOMe) and solvent (e.g., toluene) at elevated temperatures.
  • a mixture of base e.g., NaOMe
  • solvent e.g., toluene
  • an elevated temperature is about 60 °C to about 120 °C.
  • an elevated temperature is about 70 °C to about 110 °C.
  • an elevated temperature is about 80 °C to about 100 °C.
  • an elevated temperature is about 85 °C to about 95 °C.
  • an elevated temperature is about 90 °C.
  • an amount of solvent e.g., toluene
  • an organic solvent rinse e.g., a toluene rinse
  • the temperature is then raised to between about 80 °C and about 120 °C, or between about 90 °C and about 110 °C, or between about 85 °C and about 110 °C, or between about 90 °C and about 110 °C, or between about 95 °C and about 110 °C, or between about 100 °C and about 110 °C. In some embodiments, the temperature is raised to about 100 °C, 101 °C, 102 °C, 103 °C, 104 °C, 105 °C, 106 °C, 107 °C, 108 °C, 109 °C, or 110 °C. In certain embodiments, the temperature is raised to about 104 °C.
  • the reaction is held at an elevated temperature for about 24 hours to about 48 hours. In some embodiments, the reaction is held at an elevated temperature for about 28 hours to about 44 hours. In some embodiments, the reaction is held at an elevated temperature for about 32 hours to about 40 hours. In some embodiments, the reaction is held at an elevated temperature for about 34 hours to about 38 hours. In some embodiments, the reaction is held at an elevated temperature for about 36 hours.
  • step (a) of step S-1 the reaction is cooled for an amount of time. In some embodiments, the reaction is cooled to between about 20 °C to about 30 °C. In some embodiments, the reaction is cooled to about 25 °C.
  • the reaction solution upon completion of step (a) of step S-1 , is washed one or more times with water. In certain embodiments, the reaction solution is washed at least twice with water. In certain embodiments, the reaction solution is washed at least three times with water.
  • the reaction solution is washed with an aqueous acid solution.
  • the reaction solution is washed with about 10% to about 15% aqueous acid.
  • the acid is citric acid.
  • the acid is acetic acid.
  • the acid is phosphoric acid.
  • the acid is tartaric acid.
  • the reaction solution is washed with an aqueous basic solution.
  • the reaction solution is washed with about 1% to about 3% aqueous base.
  • the base is sodium bicarbonate.
  • the base is potassium phosphate dibasic.
  • the base is sodium phosphate dibasic.
  • the aqueous basic solution is 2% aqueous sodium bicarbonate.
  • the crude product solution of step (a) of step S-1 (i.e., the washed reaction solution) is taken into step (b) of step S-1 without further treatment or purification.
  • the crude product solution of step (a) is added directly to an inert, fresh reaction vessel containing reagents required for step (b) of step S-1 (e.g., tert-butyl carbamate, base, catalyst, and ligand).
  • step (b) of step S-1 is conducted in the same solvent as step (a).
  • step (b) of step S-1 is conducted in a solvent comprising an aromatic solvent.
  • step (b) of step S-1 is conducted in a solvent comprising benzene, toluene, or xylene.
  • step (b) of step S-1 is conducted in a solvent comprising toluene.
  • the base of step (b) of step S-1 is an inorganic base.
  • the base is a carbonate base.
  • the base is sodium carbonate, potassium carbonate, or cesium carbonate.
  • the base is cesium carbonate.
  • the catalyst of step (b) of step S-1 is a transition metal catalyst.
  • the catalyst is a palladium catalyst.
  • the catalyst is palladium acetate.
  • the ligand is an organophosphorus ligand.
  • the ligand is a bidentate organophosphorus ligand.
  • the ligand is Xantphos (i.e., 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene).
  • Other palladium catalysts and ligands are known in the art and are contemplated herein. See, for example, 1) Surry, David S.; Buchwald, Stephen L. Chem. Sci. 2011, 2, 27-50; and 2) Maiti, Debabrata, et al., Chem. Sci. 2011, 2, 57-68) each of which are incorporated herein by reference.
  • step (b) of step S-1 comprises heating the reaction mixture to between about 80 °C and about 105 °C. In some embodiments, the reaction mixture is heated to about 80 °C, about 85 °C, about 90 °C, about 95 °C, about 100 °C, or about 105 °C. In some embodiments, the reaction mixture is heated for between about 10 hours and about 24 hours. In some embodiments, the reaction is heated for about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In certain embodiments, step (b) of step S-1 comprises heating the reaction mixture to about 95 °C for about 16 hours.
  • the reaction mixture upon reaction completion, is cooled to about 25 °C and an amount of diatomaceous earth is charged.
  • the reaction mixture is then agitated, filtered, and vacuum distilled at an elevated temperature (e.g., about 80 °C or lower) to reduce solvent volume.
  • the reaction solution is then exposed a catalyst scavenger, for instance a palladium catalyst scavenger, in order to remove residual catalyst from the reaction mixture.
  • a catalyst scavenger comprises activated carbon in the presence of trithiocyanuric acid.
  • Other such catalyst scavengers are known in the art. See, for example, Wang, Lijun et al. Org. Process Res. Dev. 2011, 15, 1371-1376, incorporated herein by reference.
  • an alkane solvent e.g., n-heptane
  • n-heptane is added to the mixture and the mixture is then agitated at about 25 °C for at least about four hours, about six hours, or about eight hours prior to being filtered.
  • the resulting filter cake is then washed at least once, twice, or three times with a solution comprising one or more organic solvents.
  • a solution comprising one or more organic solvents.
  • such a solution comprises an aromatic solvent (e.g., toluene).
  • such a solution comprises an alkane solvent (e.g., n-heptane).
  • such a solution comprises an aromatic solvent (e.g., toluene) and an alkane solvent (e.g., n-heptane).
  • such a solution comprises an excess of an alkane solvent relative to aromatic solvent (e.g., about 5/1 v/v n-heptane/toluene).
  • the filter cake is washed at least twice with such a solution prior to charging the filtrate with fresh activated carbon.
  • the filtrate containing fresh activated carbon is agitated for at least about 1, about 2, about 3, or about 4 hours at about 25 °C, again filtered, and again washed at least once with a solution as described above (e.g., a solution comprising about 5/1 v/v n-heptane/toluene).
  • the resulting filtrate is vacuumed distilled at a temperature of about 65 °C or lower in order to reduce solvent volume.
  • a second solvent is added to the filtrate to effect a solvent exchange.
  • such a solvent exchange employs an alkane solvent (e.g., n- heptane) as a second solvent.
  • the solution is cooled to about 10 °C, seeded intermittently with a crystalline form of a compound of formula E (e.g., compound 7, depicted below), and agitated at about 10 °C or higher for an amount of time to allow crystallization to occur.
  • the resulting solids are then filtered and washed at least once with an alkane solvent (e.g., n- heptane).
  • an alkane solvent e.g., n- heptane
  • the washed solids are then dried under reduced pressure at a temperature of between about 20 °C and about 60 °C.
  • the washed solids are dried at a temperature of between about 25 °C and about 55 °C.
  • the washed solids are dried at a temperature of between about 30 °C and about 50 °C.
  • the washed solids are dried at a temperature of between about 35 °C and about 45 °C.
  • the washed solids are dried at a temperature of about 40 °C.
  • a compound of formula E is compound 7:
  • compound 7 can exist in a variety of physical forms.
  • compound 7 can be in solution, suspension, or in solid form.
  • compound 7 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides a form of compound 7 substantially free of impurities.
  • substantially free of impurities means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include different forms of compound 7, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 7.
  • a form of compound 7 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of compound 7 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • a form of compound 7 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • compound 7 can exist in a variety of solid forms.
  • Exemplary such forms include polymorphs such as the polymorph described herein.
  • polymorph refers to the different crystal structures into which a compound, or a salt or solvate thereof, can crystallize.
  • compound 7 is a crystalline solid. In certain embodiments, compound 7 is a crystalline solid substantially free of amorphous compound 7. As used herein, the term "substantially free of amorphous compound 7" means that the compound contains no significant amount of amorphous compound 7. In certain embodiments, at least about 95% by weight of crystalline compound 7 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 7 is present.
  • compound 7 can exist in at least one distinct polymorphic form.
  • the present invention provides a polymorphic form of compound 7 referred to herein as Form A of compound 7.
  • Form A of compound 7 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 1 below.
  • the position 2 ⁇ is within ⁇ 0.2.
  • Form A of compound 7 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 16.7, 19.6, and 19.9. In some embodiments, Form A of compound 7 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 16.7, 19.6, and 19.9. In some embodiments, Form A of compound 7 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 16.7, 19.6, and 19.9. In some embodiments, Form A of compound 7 is characterized in that it has one or more peaks in its X- ray powder diffraction pattern selected from those at about 16.7 and 19.6.
  • Form A of compound 7 is characterized in that it has at least three peaks in its X- ray powder diffraction pattern selected from those at about 13.4, 14.4, 16.7, 19.6, and 19.9. [00112] As used herein, the term "about”, when used in reference to a degree 2-theta value refers to the stated value ⁇ 0.2 degree 2-theta.
  • Form A of compound 7 is characterized by having an X-ray powder diffraction pattern substantially similar to the XRPD provided in Figure 1.
  • Form A of compound 7 is characterized by having a DSC thermogram substantially similar to that of Figure 2.
  • a compound of formula D is coupled to a compound of formula E via nucleophilic displacement of LG 1 by the amine group of formula E to provide a compound of formula C.
  • Suitable conditions for the nucleophilic displacement are well known in the art, including but not limited to those described in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5th Edition, John Wiley & Sons, 2001; and Comprehensive Organic Transformaions, R. C. Larock, 2nd Edition, John Wiley & Sons, 1999.
  • Each of LG 1 and LG 2 is independently a suitable leaving group that is subject to nucleophilic displacement.
  • a suitable "leaving group” that is "subject to nucleophilic displacement” is a chemical group that is readily displaced by a desired incoming nucleophilic chemical entity.
  • Suitable leaving groups are well known in the art, e.g., see generally, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5 th Edition, John Wiley & Sons, 2001.
  • Such leaving groups include, but are not limited to, halogen, alkoxy, ester, carbonate, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, phosphonate, sulfoxide, sulphone, and diazonium moieties.
  • the moieties may be optionally substituted with Ci_ 4 aliphatic, fluoro-substituted Ci_ 4 aliphatic, halogen, or nitro.
  • Suitable leaving groups include chloro, iodo, bromo, fluoro, sulfoxide, sulphone, methanesulfonyloxy (mesyloxy), tosyloxy, triflyloxy, benzenesulfonyloxy, nitro-phenylsulfonyloxy (nosyloxy), and bromo-phenylsulfonyloxy (brosyloxy).
  • a leaving group is chloro
  • LG 1 is halogen. In some embodiments, LG 1 is -CI. In some embodiments, LG 1 is -Br. In some embodiments, LG 1 is -I. [00120] In some embodiments, LG 2 is halogen. In some embodiments, LG 2 is -CI. In some embodiments, LG 2 is -Br. In some embodiments, LG 2 is -I.
  • each of LG 1 and LG 2 is independently halogen. In some embodiments, each of LG 1 and LG 2 is -CI.
  • a provided compound of formula D is compound 2:
  • step S-2 is conducted in the presence of a base.
  • a suitable base for a provided step can be either organic or inorganic.
  • step S-2 is conducted in an inorganic base.
  • a base is an alkoxide.
  • a base is LiOR, NaOR, or KOR, wherein R is optionally substituted Ci -6 aliphatic or aryl.
  • a base is an alkoxide such as LiOR, NaOR, or KOR, wherein
  • R is optionally substituted Ci -6 aliphatic.
  • a base is an alkoxide such as
  • the base is LiOtBU, NaOtBU , or KOtBU.
  • the base is KOtBU.
  • a base is an amide base.
  • a base is lithium hexamethyldisilazide, sodium hexamethyldisilazide, or potassium hexam ethyl di sil azi de .
  • step S-2 is conducted in a solvent comprising a polar aprotic solvent. In some embodiments, step S-2 is conducted in a solvent comprising an ether. In some embodiments, an ether is TUF. Numerous other aprotic solvents are known in the art and are contemplated herein.
  • step S-2 is conducted at reduced temperatures. For instance, in some embodiments, step S-2 is conducted at temperatures below about 0 °C. In some embodiments, step S-2 is conducted at temperatures below about -5 °C. In some embodiments, step S-2 is conducted at temperatures below about -10 °C. In some embodiments, step S-2 is conducted at temperatures below about -15 °C. In some embodiments, step S-2 is conducted at temperatures below about -20 °C. In some embodiments, step S-2 is conducted at temperatures below about -25 °C. In some embodiments, step S-2 is conducted at temperatures between about -5 °C and about -25 °C.
  • step S-2 is conducted at temperatures between about -5 °C and about -20 °C. In some embodiments, step S-2 is conducted at temperatures between about -10 °C and about -25 °C. In some embodiments, step S-2 is conducted at temperatures between about -5 °C and about -15 °C. In some embodiments, step S-2 is conducted at temperatures between about -10 °C and about -20 °C. In some embodiments, step S-2 is conducted at a temperature of about -15 °C.
  • the base of step S-2 (e.g., KOt-Bu) is added to the reaction mixture over a period of time.
  • addition occurs while the reaction mixture is held at a reduced temperature.
  • addition to the reaction mixture occurs at a reduced temperature for about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120 minutes.
  • addition to the reaction mixture occurs at a reduced temperature for about 60 to about 120 minutes.
  • addition to the reaction mixture occurs at a reduced temperature for about 90 minutes.
  • an additional amount of base is added in portions to the reaction mixture until a desired level of conversion is achieved.
  • the reaction is allowed to warm (e.g., to about 0 °C) and is quenched (e.g., with water).
  • an organic solvent e.g., heptane
  • the organic layer is then washed with water 1, 2, 3, 4, or 5 times.
  • the organic layer is treated (e.g., stirred) with a filter media (e.g., activated carbon) for an amount of time.
  • a filter media e.g., activated carbon
  • treatment with a filter media occurs for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours.
  • treatment occurs for between about 12 and about 20 hours.
  • treatment occurs for about 16 hours.
  • the organic layer is filtered (e.g., through a pad of diatomaceous earth).
  • the filter media is washed with several portions of an organic solvent (e.g., THF), the filtrates are combined, and an amount of solvent is removed (e.g., via distillation).
  • an organic solvent e.g., THF
  • continuous vacuum distillation is performed using an organic solvent such as an alkane (e.g., a pentane, a hexane, or a heptane).
  • an alkane e.g., a pentane, a hexane, or a heptane.
  • continuous vacuum distillation is performed until the solution comprises a desired solvent volume or composition.
  • a first distillation is performed to remove solvents used during work-up and/or treatment with a filter media (e.g., activated carbon), followed by a second, continuous distillation (with, e.g., n-heptane), wherein the second, continuous distillation proceeds until a particular solvent composition or volume is achieved.
  • a filter media e.g., activated carbon
  • a second, continuous distillation with, e.g., n-heptane
  • the above-described distillations are performed prior to crystallization.
  • the product solution comprising a desired composition of solvent is set to a particular temperature (e.g., between about 50 °C to about 60 °C) and seeded with seed crystals.
  • seeding occurs with a particular polymorph of a compound of formula C. Exemplary such polymorphs are contemplated further below.
  • crystallization further comprises one or more steps of agitating for an amount of time.
  • agitation lasts for about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 minutes.
  • agitation lasts for between about 45 minutes to about 65 minutes. In certain embodiments, agitation lasts for about 60 minutes.
  • crystallization comprises a step of cooling the agitated solution over a period of time.
  • the solution is cooled to between about 0 °C and about 20 °C.
  • the solution is cooled to between about 5 °C and about 15 °C.
  • the solution is cooled to about 10 °C.
  • cooling takes place over an amount of time, for instance, over about 1, 2, 3, 4, 5, or 6 hours.
  • a solution is cooled for about 2 hours.
  • a solution is cooled for about 3 hours.
  • a solution is cooled for about 4 hours.
  • crystallization comprises a step of agitating the cooled solution.
  • the cooled solution is agitated for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours.
  • the cooled solution is agitated for between about 2 hours and about 6 hours.
  • the cooled solution is agitated for about 4 hours.
  • the resulting product i.e., a compound of formula C
  • solvent e.g., an alkane such as n-heptane
  • a provided compound of formula C is compound 8:
  • compound 8 can exist in a variety of physical forms.
  • compound 8 can be in solution, suspension, or in solid form.
  • compound 8 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides a form of compound 8 substantially free of impurities.
  • substantially free of impurities means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include different forms of compound 8, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 8.
  • a form of compound 8 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of compound 8 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • a form of compound 8 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • compound 8 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as the polymorph described herein.
  • compound 8 is a crystalline solid. In certain embodiments, compound 8 is a crystalline solid substantially free of amorphous compound 8. As used herein, the term "substantially free of amorphous compound 8" means that the compound contains no significant amount of amorphous compound 8. In certain embodiments, at least about 95% by weight of crystalline compound 8 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 8 is present.
  • compound 8 can exist in at least one distinct polymorphic form.
  • the present invention provides a polymorphic form of compound 8 referred to herein as Form A of compound 8.
  • Form A of compound 8 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 2 below.
  • the position 2 ⁇ is within ⁇ 0.2.
  • Form A of compound 8 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 9.3, 19.6, and 20.0. In some embodiments, Form A of compound 8 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 9.3, 19.6, and 20.0. In some embodiments, Form A of compound 8 is characterized in that it has all three peaks in its X- ray powder diffraction pattern selected from those at about 9.3, 19.6, and 20.0. In some embodiments, Form A of compound 8 is characterized in that it has one or more peaks in its X- ray powder diffraction pattern selected from those at about 9.3 and 20.0. In some embodiments, Form A of compound 8 is characterized in that it has at least three peaks in its X-ray powder diffraction pattern selected from those at about 9.3, 19.6, 20.0, 23.3, and 24.5.
  • Form A of compound 8 is characterized by having an X-ray powder diffraction pattern substantially similar to the XRPD provided in Figure 3.
  • Form A of compound 8 is characterized by having a DSC thermogram substantially similar to that of Figure 4.
  • a compound of formula C is coupled to compound B via nucleophilic displacement of LG 2 by the amine group of compound B.
  • compound B is provided in the form of a salt. Accordingly, compound B as depicted in Scheme I will be understood to contemplate the use of either the free base form of compound B or the salt form of compound B. In certain embodiments, compound B is provided as the HC1 salt:
  • step S-3 occurs via metal-catalyzed cross-coupling, such as a Pd-catalyzed cross-coupling. In some embodiments, the coupling is not metal- catalyzed.
  • step S-3 is conducted in the presence of a base.
  • a base is an organic base, such as a tertiary amine.
  • a tertiary amine is triethylamine (TEA).
  • a tertiary amine is diisopropylethylamine (DIPEA).
  • an organic base is a heteroaromatic compound comprising an aromatic and basic nitrogen atom.
  • a base is pyridine.
  • a base is 2,6-lutidine.
  • a base is DMAP.
  • step S-3 is conducted in a polar aprotic solvent.
  • a solvent comprises an amine.
  • step S-3 is conducted in an amine solvent such as, e.g., dimethylformamide (DMF), dimethylacetamide (DMAc) or N- methyl-2-pyrrolidinone (NMP).
  • an amine solvent is N-methyl-2- pyrrolidinone (NMP).
  • step S-3 is initiated at a temperature between about 10 °C and about 40 °C. In some embodiments, step S-3 is initiated at a temperature between about 20 °C and about 30 °C. In certain embodiments, step S-3 comprises one or more steps of heating. For instance, in some embodiments, step S-3 comprises one or more steps of heating to between about 60 °C and about 80 °C. In certain embodiments, step S-3 comprises a first step of heating to between about 65 °C and about 70 °C for about 10, 15, 20, 25, or 30 hours, followed by a second step of heating to between about 67 °C and about 73 °C for about 1, 2, 3, 4, 5, 6, 7, or 8 hours. In some embodiments, a step of heating is continued until no more than about 1%, 2%, 3%, 4%, or 5% of starting material (i.e., a compound of formula C) remains.
  • starting material i.e., a compound of formula C
  • the reaction is allowed to cool (e.g., to between about 25 °C and about 35 °C) prior to quenching.
  • the reaction is diluted with an organic solvent (e.g., isopropyl acetate) and quenched with aqueous acid (e.g., aqueous citric acid).
  • aqueous acid e.g., aqueous citric acid
  • the organic layer is washed repeatedly with aqueous acid (e.g., aqueous citric acid).
  • the organic layer is washed with aqueous acid 1, 2, 3, 4, or 5 times.
  • the organic layer is washed repeatedly with aqueous base (e.g., a sodium bicarbonate solution). In some embodiments, the organic layer is washed with aqueous base 1, 2, 3, 4, or 5 times. In some embodiments, the organic layer is washed with water. In some embodiments, the organic layer is washed with water 1, 2, 3, 4, or 5 times. [00161] In some embodiments, the organic layer is treated (e.g., stirred) with a filter media (e.g., activated carbon) for an amount of time. In some embodiments, an amount of solvent is removed from the organic layer (e.g., via distillation) prior to treatment with a filter media (e.g., activated carbon).
  • a filter media e.g., activated carbon
  • an amount solvent e.g., isopropyl acetate
  • treatment with a filter media occurs for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In certain embodiments, treatment occurs for between about 2 and about 6 hours. In certain embodiments, treatment occurs for about 4 hours.
  • the organic layer is filtered (e.g., through a pad of diatomaceous earth). In some such embodiments, the filter media is washed with several portions of an organic solvent (e.g., isopropyl acetate), the filtrates are combined, and an amount of solvent is removed (e.g., via distillation).
  • an organic solvent e.g., isopropyl acetate
  • continuous vacuum distillation is performed using an organic solvent (e.g., an alkane).
  • an organic solvent e.g., an alkane
  • continuous vacuum distillation is performed until a desired solvent composition or volume is achieved.
  • a first distillation is performed to remove solvents (e.g., isopropyl acetate) used during work-up and/or treatment with a filter media, followed by a second, continuous distillation with an organic solvent such as an alkane (e.g., n-heptane), wherein the second, continuous distillation proceeds until a desired solvent composition or volume is achieved.
  • solvents e.g., isopropyl acetate
  • an organic solvent such as an alkane (e.g., n-heptane)
  • the above-described distillations are performed prior to crystallization.
  • the solution is set to a particular temperature (e.g., between about 45 °C and about 55 °C) and seeded with seed crystals of a compound of formula A.
  • seeding occurs with a particular polymorph of a compound of formula A. Exemplary such polymorphs are contemplated further below.
  • crystallization comprises one or more steps of agitating for an amount of time. For instance, in some embodiments, agitation lasts for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours. In some embodiments, crystallization further comprises a step of cooling (e.g., to about 25 °C). [00165] In some embodiments, crystallization comprises a step of aging at a particular temperature for a particular amount of time. For instance, in certain embodiments, crystallization comprises aging at about 25 °C for about 1, 2, 3, 4, 5, or 6 hours.
  • the resulting product i.e., a compound of formula A
  • an amount of solvent e.g., a 1 :4 isopropyl acetate: heptane solution
  • a provided com ound of formula A is compound 9:
  • compound 9 can exist in a variety of physical forms.
  • compound 9 can be in solution, suspension, or in solid form.
  • compound 9 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides a form of compound 9 substantially free of impurities.
  • the term "substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include different forms of compound 9, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 9.
  • a form of compound 9 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of compound 9 contains no more than about 3.0 area percent UPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent UPLC total organic impurities relative to the total area of the UPLC chromatogram.
  • a form of compound 9 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • compound 9 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 9 is a crystalline solid. In other embodiments, compound 9 is a crystalline solid substantially free of amorphous compound 9. As used herein, the term "substantially free of amorphous compound 9" means that the compound contains no significant amount of amorphous compound 9. In certain embodiments, at least about 95% by weight of crystalline compound 9 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 9 is present.
  • compound 9 can exist in at least two distinct polymorphic forms.
  • the present invention provides a polymorphic form of compound 9 referred to herein as Form A of compound 9.
  • the present invention provides a polymorphic form of compound 9 referred to herein as Form B of compound 9.
  • Form A of compound 9 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 3 below.
  • the position 2 ⁇ is within ⁇ 0.2.
  • Form A of compound 9 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.8, 8.4 and 11.5. In some embodiments, Form A of compound 9 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.8, 8.4 and 11.5. In some embodiments, Form A of compound 9 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 5.8, 8.4 and 11.5. In some embodiments, Form A of compound 9 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.8 and 8.4. In some embodiments, Form A of compound 9 is characterized in that it has at least three peaks in its X-ray powder diffraction pattern selected from those at about 5.8, 8.4, 10.6, 11.5, and 18.8.
  • Form A of compound 9 is characterized by having an X-ray powder diffraction pattern substantially similar to the XRPD provided in Figure 5.
  • Form A of compound 9 is characterized by having a DSC thermogram substantially similar to that of Figure 6.
  • Form B of compound 9 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 4 below.
  • the position 2 ⁇ is within ⁇ 0.2.
  • Form B of compound 9 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 7.0, 14.1, and 21.2. In some embodiments, Form B of compound 9 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 7.0, 14.1, and 21.2. In some embodiments, Form B of compound 9 is characterized in that it has all three peaks in its X- ray powder diffraction pattern selected from those at about 7.0, 14.1, and 21.2.
  • Form B of compound 9 is characterized in that it has one or more peaks in its X- ray powder diffraction pattern selected from those at about 7.0 and 21.2. In some embodiments, Form B of compound 9 is characterized in that it has at least three peaks in its X-ray powder diffraction pattern selected from those at about 7.0, 9.9, 14.1, 16.6, and 21.2.
  • Form B of compound 9 is characterized by having an X-ray powder diffraction pattern substantially similar to the XRPD provided in Figure 7.
  • Form B of compound 9 is characterized by having a DSC thermogram substantially similar to that of Figure 8.
  • a compound of formula A is deprotected to provide free amine Compound I.
  • the PG 1 group of formula A is removed by acid.
  • the acid is a Lewis acid.
  • the acid is a Bronsted acid.
  • the PG 1 group of formula A is removed with sulfuric acid.
  • the PG 1 group of formula A is removed with a solution of sulfuric acid in a medium such as an alcohol (e.g., methanol).
  • the PG 1 group of formula A is removed with a sulfonic acid, for instance, ⁇ -toluenesulfonic acid (PTSA) or methanesulfonic acid.
  • PTSA ⁇ -toluenesulfonic acid
  • the PG 1 group of formula A is removed with phosphoric acid.
  • acids are useful for removing amino protecting groups that are acid-labile.
  • the solution of acid of step S-4 (e.g., sulfuric acid in methanol) is added to the reaction mixture over a period of time. In some embodiments, addition occurs while the reaction mixture is held at a temperature of no more than about 30 °C.
  • a reaction mixture is heated to about 35 °C to about 45 °C and agitated for about 1, 2, 3, 4, 5, 6, 7 or 8 hours. In some embodiments, a step of heating is continued until less than about 0.5%, 1%, 2%, 3%, 4%, or 5% of starting material (i.e., a compound of formula A) remains.
  • the step of deprotecting is followed by an additional step of treating the deprotected material with an amount of base. In certain embodiments, the deprotected material is treated with an amine base (e.g., triethylamine or diisopropylethylamine).
  • an amine base (e.g., triethylamine) is first dissolved in a solvent such as an alcohol (e.g., methanol).
  • a solvent such as an alcohol (e.g., methanol).
  • the solution of amine base of step S-4 (e.g., triethylamine in methanol) is added to the reaction mixture over a period of time.
  • addition occurs while the reaction mixture is held at a temperature of no more than about 20 °C to about 30 °C.
  • the reaction is stirred until Compound I precipitates out of solution.
  • the reaction is stirred for about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes.
  • the reaction is stirred for about 45 minutes to about 75 minutes.
  • the reaction is stirred for about 60 minutes.
  • the reaction is agitated for about 1, 2, 3, 4, 5, 6, 7, or 8 hours. In certain embodiments, the reaction is agitated for about 3 hours to about 5 hours. In some embodiments, the reaction is agitated for about 4 hours.
  • the precipitate is filtered, washed with an organic solvent (e.g., an alcoholic solvent such as methanol), and dried to afford Compound I:
  • an organic solvent e.g., an alcoholic solvent such as methanol
  • Compound I may be treated with a suitable acid to form a salt thereof.
  • a suitable acid for instance, at step S-5 of Scheme I, Compound I is treated with a suitable acid to afford the corresponding salt of Compound I.
  • suitable acids and salts are as described above and herein.
  • Compound I may be treated with a suitable Bransted acid (herein denoted as ⁇ "), as depicted in step S-5, to form a pharmaceutically acceptable salt thereof (represented by Compound ⁇ ).
  • a suitable Bransted acid herein denoted as ⁇
  • Exemplary acids include, but are not limited to, organic and inorganic acids such as acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, salicylic, benzoic, or similarly known acceptable acids.
  • compound I is treated with phosphoric acid to form a compound of formula ⁇ wherein X represents a phosphate conjugate base.
  • salt formation comprises dissolving Compound I in an amount of suitable solvent (e.g., THF and water), performing a polish filtration, charging the reaction with an amount of an acid (e.g., H 3 PO 4 ), seeding with a selected form of Compound I (e.g., polymorph Form A of a phosphate salt form of Compound I), performing a solvent exchange (e.g., from THF and water to EtOH or EtOAc), filtering the reaction, and drying the reaction to afford an particular form of a salt of Compound I (e.g., polymorph Form A of a phosphate salt form of Compound I).
  • suitable solvent e.g., THF and water
  • an acid e.g., H 3 PO 4
  • seeding with a selected form of Compound I e.g., polymorph Form A of a phosphate salt form of Compound I
  • performing a solvent exchange e.g., from THF and water to EtOH or EtOAc
  • filtering the reaction e.
  • salt formation comprises dissolving Compound I in an amount of suitable solvent (e.g., THF and water), performing a polish filtration, performing a solvent exchange (e.g., from THF and water to EtOH), crystallizing Compound I, charging the reaction with an amount of an acid (e.g., H 3 PO 4 in EtOH), seeding with a selected form of Compound I (e.g., polymorph Form A of a phosphate salt form of Compound I), filtering the reaction, and drying the reaction to afford an particular form of a salt of Compound I (e.g., polymorph Form A of a phosphate salt form of Compound I).
  • suitable solvent e.g., THF and water
  • solvent exchange e.g., from THF and water to EtOH
  • crystallizing Compound I e.g., charging the reaction with an amount of an acid (e.g., H 3 PO 4 in EtOH), seeding with a selected form of Compound I (e.g., polymorph Form A of
  • salt formation comprises dissolving Compound I in an amount of suitable solvent (e.g., THF and water), performing a polish filtration, performing a solvent exchange (e.g., from THF and water to EtOAc, wherein residual THF is no more than 2.0 wt%), seeding with a selected form of Compound I (e.g., polymorph Form A of a phosphate salt form of Compound I), charging the reaction with an amount of an acid (e.g., H 3 PO 4 in EtOH, wherein the final ratio of EtOAc:EtOH is 13:5), filtering the reaction, and drying the reaction to afford an particular form of a salt of Compound I (e.g., polymorph Form A of a phosphate salt form of Compound I).
  • suitable solvent e.g., THF and water
  • solvent exchange e.g., from THF and water to EtOAc, wherein residual THF is no more than 2.0 wt
  • seeding with a selected form of Compound I e.g.
  • salt formation comprises a first step of treating Compound I, for instance by dissolving Compound I in a suitable solvent and atmospherically distilling the solution until a particular solvent volume or composition is achieved.
  • a solvent is an ether (e.g., THF).
  • a solvent is a mixture of an aqueous and organic solvent.
  • a solvent is a mixture of an ether and water (e.g., 95:5 THF : water v/v).
  • a solvent comprises a polar aprotic solvent such as an alkyl acetate.
  • a solvent comprises ethyl acetate.
  • a solvent is ethyl acetate.
  • a solvent comprises isopropyl acetate.
  • a solvent is isopropyl acetate.
  • a solvent comprises an alcohol.
  • a solvent comprises ethanol.
  • a solvent comprises an alkyl acetate and an alcohol, for instance ethyl acetate and ethanol.
  • a solvent comprises ethanol
  • at least one other solvent e.g., ethyl acetate
  • continuous vacuum distillation is performed until a desired solvent volume or composition is achieved.
  • salt formation does not comprise a first step of pretreating Compound I.
  • a solvent comprises a polar aprotic solvent such as an alkyl acetate.
  • the solvent is ethyl acetate.
  • the solvent is isopropyl acetate.
  • a solvent comprises an alcohol.
  • a solvent comprises ethanol.
  • a solvent comprises an alkyl acetate and an alcohol, for instance ethyl acetate and ethanol.
  • at least one other solvent e.g., ethyl acetate
  • a solution of free base Compound I is seeded with an amount of crystalline Compound I prior to salt formation.
  • seeding occurs with a particular polymorph of a salt form of Compound I.
  • seeding occurs with a particular polymorph of a phosphate salt form of Compound I.
  • seeding occurs with polymorph Form A of a phosphate salt form of Compound I.
  • Polymorph Form A of a phosphate salt of Compound I is as described below and as described in United States Provisional Application No. 62/037,066, filed August 13, 2014, incorporated herein in its entirety.
  • a suitable acid for forming a salt of Compound I is dissolved in a suitable solvent prior to addition to Compound I.
  • a suitable solvent for instance, in some embodiments, an acid is dissolved in an alcoholic solvent prior to addition to Compound I.
  • the acid is phosphoric acid (H 3 PO 4 ) and the alcoholic solvent is ethanol.
  • the acid of step S-5 (e.g., H 3 PO 4 ) is added to the reaction mixture over a period of time.
  • addition to the reaction mixture occurs while the reaction mixture is held at a particular temperature.
  • addition to the reaction mixture occurs at a temperature of about 20 °C to about 40 °C for about 60, 70, 80, 90, 100, 110, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, or 180 minutes.
  • addition to the reaction mixture occurs for between about 90 and about 150 minutes.
  • addition to the reaction mixture occurs for about 120 minutes.
  • the reaction is agitated for at least about 6, 7, 8, 9, 10, 11, 12,
  • the reaction is agitated for about 10 to about 14 hours. In some embodiments, the reaction is agitated for about 12 hours.
  • the precipitate is filtered, washed with an organic solvent (e.g., a polar aprotic solvent such as ethyl acetate), and dried to afford a salt of Compound I.
  • an organic solvent e.g., a polar aprotic solvent such as ethyl acetate
  • a phosphate salt of compound I can exist in a variety of physical forms.
  • a phosphate salt of compound I can be in solution, suspension, or in solid form.
  • a phosphate salt of compound I is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • methods of the present invention provide a phosphate salt of Compound I in a particular polymorphic form.
  • methods of the present invention use a particular form of a phosphate salt of Compound I for seeding, for instance as described above in the context of the step of salt formation.
  • Form A of a phosphate salt of Compound I is used for seeding.
  • methods of the present invention provide Form A of a phosphate salt of Compound I, described herein.
  • Form A of a phosphate salt of Compound I has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 5 below.
  • the position 2 ⁇ is within ⁇ 0.2.
  • Form A of a phosphate salt of Compound I is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8, 10.1, and 20.8. In some embodiments, Form A of a phosphate salt of Compound I is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8, 10.1, and 20.8. In some embodiments, Form A of a phosphate salt of Compound I is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 6.8, 10.1, and 20.8.
  • the X-ray powder diffraction pattern of Form A of a phosphate salt of Compound I is substantially similar to the XRPD provided in Figure 9.
  • the DSC thermogram of Form A of a phosphate salt of Compound I is as depicted in Figure 10.
  • the TGA trace of Form A of a phosphate salt of Compound I is as depicted in Figure 11.
  • the DVS plot of Form A of a phosphate salt of Compound I is as depicted in Figure 12.
  • the present invention provides methods of salt formation / crystallization that generate crystals having certain physical properties, which properties facilitate product processing.
  • the present invention provides crystallization methods that generate crystals having certain flow properties.
  • the present invention provides crystallization methods that generate crystals having reduced stickiness for ease of product processing.
  • crystals are generated in the form of thin plates.
  • the crystals are Form A of the phosphate salt of Compound I.
  • a provided method comprises charging a portion of the total final mass of free base Compound I to a reactor, along with an amount of solvent comprising one or more polar organic solvents (e.g., ethyl acetate and ethanol).
  • the portion of free base charged is about 5% to about 40% of the total final mass of free base Compound I.
  • the portion of free base charged is about 10% to about 30% of the total final mass of free base Compound I.
  • the portion of free base charged is about 15% to about 25% of the total final mass of free base Compound I.
  • the portion of free base charged is about 20% of the total final mass of free base Compound I.
  • the solvent comprising one or more polar organic solvents is a mixture of ethyl acetate and ethanol, wherein the ethyl acetate is present in an amount greater than the ethanol.
  • the ratio of ethyl acetate to ethanol is about 13:5 vol. ethyl acetate: ethanol.
  • the mixture of free base Compound I and organic solvent is agitated for an amount of time at a suitable temperature.
  • agitation is initiated and the temperature is raised to between about 20 °C and about 40 °C.
  • agitation is initiated and the temperature is raised to between about 25 °C and about 35 °C.
  • agitation is initiated and the temperature is raised to about 30 °C.
  • a solution of phosphoric acid in organic solvent is prepared for addition to the reaction undergoing agitation.
  • a solution of phosphoric acid comprises one or more polar organic solvents.
  • the one or more polar organic solvents comprises ethyl acetate.
  • the one or more polar organic solvents comprises ethanol,
  • the one or more polar organic solvents is a mixture of ethyl acetate and ethanol, wherein the ethyl acetate is present in an amount greater than the ethanol.
  • the ratio of ethyl acetate to ethanol is about 13:5 vol. ethyl acetate : ethanol.
  • phosphoric acid is present in an amount of about 1.0, 1.1, 1.2, 1.3, or 1.4 molar equivalents relative to substrate (i.e., free base Compound I). In some embodiments, phosphoric acid is present in an amount of about 1.2 molar equivalents relative to substrate (i.e., free base Compound I).
  • a first portion of the solution of phosphoric acid is charged to the reactor over an amount of time. For example, in some embodiments, about 10% to about 30%) of the solution of phosphoric acid is charged to the reactor over about 10 minutes to about 30 minutes. In some embodiments, about 20%> of the solution of phosphoric acid is charged to the reactor over about 10 minutes to about 30 minutes. In some embodiments, about 20%> of the solution of phosphoric acid is charged to the reactor over about 20 minutes.
  • an amount of crystal seeds of a phosphate salt of Compound I (e.g., Form A of the phosphate salt of Compound I) is charged to the reaction and the batch is aged for an amount of time. In some embodiments, about 1% (by wt) crystal seeds are charged. In some embodiments, about 2% (by wt) crystal seeds are charged. In some embodiments, about 3% (by wt) crystal seeds are charged. In some embodiments, about 4, 5, 6, 7, 8, 9, or 10% (by wt) crystal seeds are charged. In some embodiments, the batch is then aged for about 5 minutes to about 60 minutes. In some embodiments, the batch is aged for about 15 minutes to about 45 minutes. In some embodiments, the batch is aged for about 20 minutes to about 40 minutes. In some embodiments, the batch is aged for about 30 minutes.
  • a phosphate salt of Compound I e.g., Form A of the phosphate salt of Compound I
  • the batch is then aged for about 5 minutes to about 60 minutes. In some embodiments, the
  • heat-cool cycle refers to the process of alternately heating and cooling a reaction mixture to desired temperatures at desired rates.
  • the heat-cool cycles are carried out at a temperature of between about 10 °C to about 50 °C. In some embodiments, the heat-cool cycles are carried out at a temperature of between about 20 °C to about 40 °C. In some embodiments, at least one heat-cool cycle is carried out at a different temperature range than another heat-cool cycle. In some embodiments, at least one heat-cool cycle is carried out at a temperature of between about 30 °C to about 40 °C. In some embodiments, at least one heat-cool cycle is carried out at a temperature of between about 20 °C to about 30 °C.
  • heating occurs at a rate of about 0.1 °C/min, 0.2 °C/min, 0.3
  • heating occurs at a rate of about 0.4 °C/min, 0.5 °C/min, or 0.6
  • heating occurs at a rate of about 0.5 °C/min.
  • cooling occurs at a rate of about 0.1 °C/min, 0.2 °C/min, 0.3
  • cooling occurs at a rate of about 0.1 °C/min.
  • the remaining starting material free base Compound I is added to the reaction following completion of one or more heat-cool cycles, along with the remaining solution of phosphoric acid.
  • the solution of phosphoric acid is charged over at least about 1.5 hours.
  • the solution of phosphoric acid is charged over about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours.
  • the charge occurs at an elevated temperature.
  • the charge occurs at about 30 °C.
  • the reaction is held at an elevated temperature and agitated for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours.
  • the reaction is held at an elevated temperature and agitated for about 12, 24, 36, or 48 hours. In certain embodiments, the reaction is held at an elevated temperature and agitated for about 12 hours. In some embodiments, the elevated temperature is between about 20 °C and about 40°C. In some embodiments, the elevated temperature is about 30 °C. For instance, in some embodiments, the reaction is held at about 30 °C and agitated for about 12 hours.
  • the reaction after agitation for a suitable amount of time the reaction is cooled, filtered, washed, dried under reduced pressure, and de-lumped. In some embodiments, the reaction is cooled after agitation to between about 15 °C and about 35 °C. In some embodiments, the reaction is cooled after agitation to between about 15 °C and about 30 °C. In some embodiments, the reaction is cooled after agitation to between about 20 °C and about 25 °C. In some embodiments, the reaction is cooled after agitation to about 23 °C. In some embodiments, after cooling the reaction after agitation, the reaction is filtered and washed one or more times with a suitable solvent (e.g., an organic solvent).
  • a suitable solvent e.g., an organic solvent
  • the reaction is filtered and washed one or more times with a polar aprotic solvent such as ethyl acetate. In some embodiments, the reaction is filtered and washed twice with a polar aprotic solvent such as ethyl acetate. In some embodiments, the product is then dried under reduced pressure with a nitrogen bleed. In some embodiments, drying occurs at a temperature of between about 30 °C and about 60 °C. In some embodiments, drying occurs at a temperature of between about 35 °C and about 55 °C. In some embodiments, drying occurs at a temperature of between about 40 °C and about 50 °C. In some embodiments, the dried product is then de- lumped using any method known in the pharmaceutical and/or process chemistry arts.
  • methods described herein provide a crystalline form of a phosphate salt of Compound I, e.g., Form A of the phosphate salt of Compound I, which crystalline form exhibit certain desirable properties, e.g., a desirable size or shape.
  • the present invention provides a method for preparing Compound I:
  • PG 1 is a suitable amine protecting group
  • LG 1 and LG 2 are independently a suitable leaving group, under suitable conditions to provide a compound of formula C:
  • the present invention provides a method for preparing a pharmaceutically acceptable salt of Compound I:
  • HX is any suitable acid comprising at least one hydrogen atom.
  • the present invention provides a method for preparing a pharmaceutically acceptable salt of Compound I:
  • HX is any suitable acid comprising at least one hydrogen atom
  • the present invention provides a method for preparing a phosphate salt of Compound I, comprising steps of:
  • compound B is prepared according to Scheme II set forth below:
  • compound B is produced according to Scheme II in the form of the HC1 salt.
  • PG group of a compound of formula B-3 is a suitable amino protecting group.
  • Suitable amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • Suitable amino protecting groups, taken with the - H- moiety to which it is attached, include, but are not limited to, aralkylamines, carbamates, allyl amines, amides, and the like.
  • Examples of PG 3 groups of a compound of formula B-3 include t-butyloxycarbonyl (BOC),p-methoxybenzyloxycarbonyl (PMB), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyl oxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, formyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
  • BOC t-butyloxycarbonyl
  • PMB p-methoxybenzyloxycarbonyl
  • ethyloxycarbonyl ethyloxycarbonyl
  • methyloxycarbonyl methyloxy
  • the PG 3 group of a compound of formula B-3 is formyl. In certain embodiments, the PG 3 group of a compound of formula B-3 is formyl and the reagent used to generate PG 3 is formic acid. In certain embodiments, the PG 3 group of a compound of formula B-3 is formyl and the reagent used to generate PG 3 is an alkyl formate (e.g., ethyl formate). Other such formylating reagents are known in the chemical and synthetic arts and are contemplated herein.
  • the PG 3 group of a compound of formula B-3 is BOC.
  • the reagent used to generate PG 3 is di-tert-butyl dicarbonate.
  • step S-1 is conducted in a solvent comprising an organic solvent.
  • step S-1 is conducted neat.
  • the protecting group reagent e.g., formic acid or an equivalent thereof acts as the solvent.
  • step S-1 is conducted at elevated temperatures. For instance, in some embodiments, step S-1 is conducted at a temperature between about 25 °C and about 75 °C. In some embodiments, the temperature is between about 30 °C and about 70 °C. In some embodiments, the temperature is between about 40 °C and about 90 °C. In some embodiments, the temperature is between about 65 °C and about 60 °C. In some embodiments, the temperature is between about 45 °C and about 65 °C. In some embodiments, the temperature is about 50 °C.
  • the reaction is heated for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours. In some embodiments, the reaction is heated for between about 4 and about 6 hours. In certain embodiments, the reaction is heated for about 5 hours. [00243] In some embodiments, after heating for an amount of time, the reaction is cooled to between about 15 °C and about 20 °C and charged to an amount of water. In certain embodiments, addition to water takes place in portions over an amount of time. For instance, in some embodiments, addition to water occurs over about 30, 45, 60, 75, or 90 minutes. In certain embodiments, addition to water occurs over about 60 minutes. In some embodiments, the resulting slurry is agitated for an additional amount of time after addition of water.
  • the resulting slurry is agitated for about 1, 2, or 3 hours. In certain embodiments, the resulting slurry is agitated for about 2 hours. In certain embodiments, the temperature of the slurry is maintained at about 15 °C during agitation.
  • a compound of formula B-3 is compound 11:
  • step S-2 of Scheme II the nitro group of B-3 is reduced to afford a compound of formula B-2.
  • a solvent comprises an ether.
  • a solvent comprises tetrahydrofuran (TUF).
  • a solvent comprises water.
  • a solvent comprises water and an ether (e.g., water and TUF).
  • step S-2 occurs under a hydrogen atmosphere. In certain embodiments, step S-2 is initiated under a hydrogen atmosphere of between about 5 psi and about 20 psi. In certain embodiments, step S-2 is initiated at about 5, 10, 15, or 20 psi. [00248] In some embodiments, step S-2 is exothermic and is initiated at a temperature of no more than about 60 °C. In some embodiments, step S-2 is initiated at a temperature of no more than about 50 °C. In some embodiments, step S-2 is initiated at a temperature of no more than about 40 °C.
  • the pressure of the hydrogen atmosphere is increased.
  • the pressure of the hydrogen atmosphere is increased to about 25, 30, 35, 40, 45, or 50 psi for a particular amount of time and at a particular temperature, until conversion of B-3 to B-2 is complete.
  • the pressure of the hydrogen atmosphere is increased to between about 30 and about 40 psi for about 3 hours at about 50 °C.
  • the hydrogen atmosphere is exchanged for an inert atmosphere (e.g., nitrogen) and the reaction is cooled to between about 20 °C to about 30 °C.
  • the reaction is filtered (e.g., through Celite) and the cake is washed with additional solvent (e.g., 13:2 THF:water).
  • a compound of formula B-2 is compound 12:
  • the resulting solution of B-2 is taken on without isolation or purification.
  • the resulting solution of B-2 e.g., in TUF and water
  • the base is a carbonate base such as lithium carbonate, sodium carbonate, or potassium carbonate.
  • the solution of base is aqueous potassium carbonate.
  • bases for instance hydroxide bases, alkoxide bases, amine bases, amide bases, etc. are known in the art and contemplated herein for use in step S-3.
  • B-2 is isolated prior to exposure to base.
  • the solution of base and B-2 is cooled prior to addition of acryloyl chloride.
  • the solution of base e.g., aqueous potassium carbonate
  • B-2 is cooled to between about 0 °C and about 10 °C prior to addition of acryloyl chloride.
  • addition of acryloyl chloride occurs over an amount of time at reduced temperatures. For instance, in some embodiments, addition of acryloyl chloride occurs over about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes at a temperature no higher than about 10 °C. In certain embodiments, addition of acryloyl chloride occurs over about 30 minutes at a temperature no higher than about 10 °C.
  • the reaction is held at reduced temperature (e.g., between about 5 °C and about 10 °C) for a period of time (e.g., about 30 minutes), warmed (e.g., to about 25 °C), and diluted with an amount of solvent.
  • the solvent is an ethereal solvent (e.g., THF).
  • the reaction is allowed to settle and the aqueous layer is removed.
  • the volume of solvent is reduced (e.g., by vacuum distillation) prior to further work up.
  • an amount of water is added to the solution of acrylate B-l and stirred at a slightly elevated temperature (e.g., about 35 °C) until B-l crystallizes out of solution.
  • a slightly elevated temperature e.g., about 35 °C
  • the resulting slurry of crystallized B-l is then cooled (e.g., to about 25 °C), agitated for an amount time (e.g., about 3 hours), filtered, washed with solvent (e.g., 1 :2 THF:water) and dried (e.g., under reduced pressure) to afford B-l.
  • a compound of formula B-l is compound 13:
  • step S-4 of Scheme II the protected amine group of B-l is deprotected to afford compound B, or an acceptable salt thereof.
  • deprotection of B-l requires treatment of B-l with an acid.
  • B-l is slurried in a suitable solvent and an acid is slowly added over an amount of time at a reduced temperature.
  • a suitable solvent comprises an alcohol (e.g., methanol).
  • a suitable solvent comprises an ether (e.g., methyl tert-butyl ether).
  • a suitable solvent comprises an alcohol and an ether (e.g., methanol and methyl tert-butyl alcohol).
  • the acid is an inorganic acid (e.g., HC1).
  • the inorganic acid is an aqueous inorganic acid (e.g., 36% HC1).
  • addition occurs over about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes.
  • addition occurs between about 20 minutes and about 40 minutes.
  • addition occurs over about 30 minutes.
  • addition occurs at reduced temperatures. For instance, in some embodiments, addition occurs at temperatures below about 25 °C. In some embodiments, addition occurs at temperatures between about 15 °C and about 25 °C.
  • the reaction is heated and agitated for an amount of time.
  • the reaction is heated and agitated for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours. In certain embodiments, the reaction is heated to between about 20 °C and about 25 °C and agitated for between about 4 hours and about 6 hours. In certain embodiments, the reaction is agitated for about 5 hours.
  • additional solvent is added to the agitated reaction.
  • the additional solvent is an ether (e.g., methyl tert-butyl ether).
  • the reaction is agitated for an additional amount of time (e.g., about 1 hour), the filtered, washed with solvent (e.g., 1 :2 methanol :methyltert-butyl ether), and dried (e.g., under reduced pressure) to afford compound B in salt form.
  • solvent e.g., 1 :2 methanol :methyltert-butyl ether
  • compound B is provided as the HC1 salt.
  • a salt form of compound B is exposed to an amount of base in order to afford compound B as the free base.
  • compound B is added to an aqueous base and stirred to afford the free base of compound B.
  • the base is a hydrogen carbonate base such as LiHCO 3 , NaHCO 3 , or KHCO3.
  • the solution of base is aqueous NaHCO 3 .
  • the present invention provides a method for preparing compound B:
  • PG 3 is a suitable amine protecting group
  • compound B is produced according to Scheme III in the form of the HC1 salt.
  • step S-1 of Scheme III the amine of compound B-12 is reacted with 3- chloropropionyl chloride to afford amide B-5.
  • amide B-5 acts as a protecting group and precursor to the acrylamide of compound B.
  • step S- 1 occurs in a suitable solvent in the presence of a base.
  • the base is a carbonate base such as Li 2 CO 3 , Na 2 CO 3 , or K 2 CO 3 .
  • the base is
  • step S-2 of Scheme III the nitro group of B-5 is reduced to the corresponding amine of B-6.
  • reduction occurs as described above at step S-2 of Scheme II.
  • other reduction conditions are employed.
  • Various other such reducing agents are known in the chemical and synthetic arts and are contemplated herein.
  • step S-3 of Scheme III elimination of HC1 affords the acrylate of compound B.
  • elimination occurs in the presence of a suitable base.
  • step S-3 is potentially performed during any point in the synthesis. Accordingly, in some embodiments, step S-3 is not performed directly after step S-2. That is, in some embodiments, B-6 acts as the coupling partner at step S-3 of Scheme I, and step S-3 of Scheme III is performed at a different point during the synthesis of Compound I, for instance, any time during the synthesis up to the last step.
  • the present invention provides a method for preparing compound B:
  • compound B is produced according to Scheme IV in the form of the HC1 salt.
  • step S-1 of Scheme IV the amine of compound B-12 is reacted with acryloyl chloride to afford acrylamide B-7.
  • step S-1 occurs in a suitable solvent in the presence of a base.
  • a suitable solvent is a polar aprotic solvent such as an alkyl acetate (e.g., ethyl acetate).
  • the base is a carbonate base such as L12CO3, Na 2 C03, or K2CO3.
  • the base is K2CO3.
  • B-7 is exposed to methanol in the presence of a suitable base to provide B-8.
  • the base is a hydroxide base.
  • the base is LiOH, NaOH, or KOH.
  • the base is NaOH.
  • step S-3 of Scheme IV the nitro group of B-8 is reduced to the corresponding amine of B-9.
  • reduction occurs as described above at step S-2 of Scheme II.
  • other reduction conditions are employed.
  • Various other such reducing agents are known in the chemical and synthetic arts and are contemplated herein.
  • step S-4 of Scheme IV elimination of MeOH affords acrylamide compound B.
  • elimination occurs in the presence of a base.
  • the base is an alkoxide base such as a lithium, sodium, or potassium alkoxide.
  • the alkoxide base is t-BuOLL t-BuONa, or t-BuOK.
  • the present invention provides a method for preparing compound B:
  • compound B is produced according to Scheme V in the form of the HC1 salt.
  • step S-1 of Scheme V the amine of compound B-10 is reacted with acryloyl chloride to non-selectively afford, inter alia, compound B. Purification to remove, inter alia, the monoacrylate and/or bisacrylate byproducts depicted below:
  • the present invention provides a method for preparing compound B:
  • each of R 1 and R 2 are independently hydrogen or a suitable amino protecting group described above and herein.
  • suitable amino protecting groups include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • LG 3 is a suitable leaving group as defined above and herein for LG 1 and LG 2 .
  • LG 3 is selected from chloro, iodo, bromo, fluoro, sulfoxide, sulphone, methanesulfonyloxy, tosyloxy, triflyloxy, benzenesulfonyloxy, nitro-phenylsulfonyloxy, and bromo-phenylsulfonyloxy.
  • compound B is produced according to Scheme VI in the form of the HC1 salt.
  • compound B' is produced according to Scheme VI' in the form of the HC1 salt.
  • step S-1 of Scheme VI compound B-ll is coupled to acrylamide to afford acrylamide B.
  • coupling occurs in the presence of one of more suitable catalysts, for instance one or more metal catalysts.
  • a catalyst is Pd.
  • a catalyst is Cu.
  • Various other such metal reagents are known in the chemical and synthetic arts and are contemplated herein.
  • the present invention provides a method for preparing compound B:
  • LG 3 is a suitable leaving group
  • the present invention provides a composition comprising Compound I:
  • Compound I As described generally above, Compound I, and pharmaceutically acceptable salts thereof described herein, are inhibitors of one or both of ERK1 and ERK2.
  • ERK is one of the key components in the RAS-RAF-MEK-ERK MAPK pathway and that ERK1 and ERK2 are downstream nodes within the MAPK pathway.
  • an ERK inhibitor can treat disease or disorders in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role, including one or both of ERK 1 and ERK2 as well as other nodes in the MAPK pathway upstream from ERK (such as Ras, Raf and Mek).
  • ERK is a downstream target
  • ERK inhibitors are believed to be able to overcome, in some instances, drug resistance induced by inhibitors of targets upstream of ERK within the MAPK pathway.
  • RAF or MEK utilized in the treatment of K-RAS and B-RAF mutant tumors have resulted in such drug resistance.
  • drug resistance has been associated with other tumors driven by hyperactivation of the MAPK pathway (such as NF1 mutant tumors).
  • Kinase selectivity was achieved through silencing the selective Cys in a combination of the interactions between the covalent inhibitors of the invention and unique amino acids in the ATP binding pocket. Targeting the selective Cys provides for prolonged pharmacodynamics in silencing ERK activity, as well as potential lower doses in cancer treatment, compared to reversible inhibitors.
  • the activity of Compound I, and pharmaceutically acceptable salts thereof, as inhibitors of one or both of an ERK1 and ERK2 kinase, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of downstream phosphorylation, changes in gene expression, subsequent functional markers and consequences, and/or kinase activity of one or both of activated ERK1 and ERK2 kinase, or a mutant thereof. Alternate in vitro assays quantitate the ability of the test compound to bind to one or both of ERK1 and ERK2.
  • Test compound binding may be measured by radiolabeling the test compound prior to binding, isolating one or both of the compound / ERK1 complex and the compound / ERK2 complex, and determining the amount of radiolabel bound.
  • test compound binding may be determined by running a competition experiment where test compounds are incubated with one or both of ERK1 and ERK2 kinase bound to known radioligands.
  • Test compound binding may be determined by competition with an ERK covalent probe that is amenable to further functionalization with a detection probe, such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification.
  • a detection probe such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification.
  • a detection probe such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification
  • the term "measurably inhibit”, as used herein means a measurable change in one or both of ERKl and ERK2 protein kinase activity between a sample comprising a provided composition, and one or both of an ERKl and ERK2 protein kinase and an equivalent sample comprising one or both of ERKl and ERK2 protein kinase in the absence of a provided composition.
  • Such measurements of protein kinase activity are known to one of ordinary skill in the art and include those methods set forth herein below and/or in the Examples of the '230 publication.
  • Compound I, and pharmaceutically acceptable salts thereof, as inhibitors of one or both of ERKl and ERK2 protein kinases, and ERK1 and ERK2 are downstream targets within the MAPK pathway.
  • such compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role.
  • Such disease, condition, or disorder may be referred to herein as associated with the MAPK pathway or alternatively as associated with one or both of ERKl and ERK2.
  • Such diseases, conditions, or disorders may also be referred to herein as an "ERKl- or ERK2-mediated disease, condition, or disorder.”
  • the present invention provides methods of making compounds useful for treating or lessening the severity of a disease, condition, or disorder where activation of the MAPK pathway (at any level in Ras-Raf-Mek-ERK), including one or both of ERKl and ERK2 protein kinases, is implicated in said disease, condition, or disorder.
  • the present invention provides methods of making compounds useful for inhibiting one or both of ERKl and ERK2 protein kinase activity in a patient.
  • the present invention provides methods of making compounds useful for treating a disease, condition, or disorder mediated by one or both of ERKl and ERK2 kinase, or a mutant thereof.
  • the present invention provides methods of making compounds useful for overcoming drug resistance to Raf or MEK inhibitors.
  • the mechanism of drug resistance is through mutation of a target protein or reactivation of the MAPK pathway.
  • the term “resistance” may refer to changes in a wild-type nucleic acid sequence coding a target protein, and/or to the amino acid sequence of the target protein and/or to the amino acid sequence of another protein, which changes, decreases or abolishes the inhibitory effect of the inhibitor on the target protein.
  • the term “resistance” may also refer to overexpression or silencing of a protein differing from a target protein that can reactivate the MAPK pathway or other survival pathways.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment is administered after one or more symptoms have developed.
  • treatment is administered in the absence of symptoms.
  • treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment is also continued after symptoms have resolved, for example to prevent, delay or lessen the severity of their recurrence.
  • the present invention provides methods of making compounds useful for treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ERK1 and ERK2.
  • General diseases, conditions, or disorders treated by compounds prepared using methods of the present invention include cancer, an autoimmune disorder, a neurodegenerative or neurological disorder, liver disease, a cardiac disorder, schizophrenia, or a bone-related disorder.
  • the present invention provides methods of making compounds useful for treating or lessening the severity of a disease, condition, or disorder selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone-related diseases, wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention.
  • the present invention provides methods of making compounds useful for treating a cancer.
  • the cancer is recurring.
  • the cancer is refractory.
  • the cancer is metastatic.
  • the cancer is locally advanced.
  • the cancer is a RAF inhibitor-resistant cancer.
  • the RAF inhibitor-resistant cancer is a BRAF inhibitor-resistant cancer.
  • the cancer is a MEK inhibitor-resistant cancer.
  • the cancer is a MAPK pathway-mediated cancer.
  • the cancer is a BRAF-mutated cancer.
  • the BRAF-mutated cancer is a BRAF V600 -mutated cancer, such as BRAF
  • BRAF V600K , BRAF V600R , and BRAF V600D are BRAF V600K , BRAF V600R , and BRAF V600D .
  • the cancer is a RAS-mutated cancer.
  • the RAS-mutated involves codons 12, 13, or 61.
  • the RAS-mutated cancer is a KRAS-mutated cancer, including, but not limited to, KRAS G12C D V , KRAS G13C D , or KRAS Q61L H R .
  • the RAS-mutated cancer is an RAS-mutated cancer, including, but not limited to, RAS Q61R , RAS Q61K , RAS Q61L , or RAS Q61H .
  • the RAS-mutated cancer is an HRAS-mutated cancer, including, but not limited to, HRAS G12V , HRAS Q61R , and HRAS G12S .
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is selected from multiple myeloma, breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach (gastric), skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung, bone, colon, thyroid, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma (including uveal melanoma) sarcoma, bladder carcinoma, liver carcinoma (e.g., hepatocellular carcinoma (HCC)) and biliary passage carcinoma), kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccal cavity
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is selected from carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
  • a sarcoma is a soft tissue sarcoma.
  • a lymphoma is non-hodgkins lymphoma.
  • a lymphoma is large cell immunoblastic lymphoma.
  • the cancer is selected from adenocarcinoma; adenoma; adrenocortical cancer; bladder cancer; bone cancer; brain cancer; breast cancer; cancer of the buccal cavity; cervical cancer; colon cancer; colorectal cancer; endometrial or uterine carcinoma; epidermoid carcinoma; esophogeal cancer; eye cancer; follicular carcinoma; gallbladder cancer; prostate, AML, multiple myeloma (MM), gastrointestinal cancer, such as, for example, gastrointestinal stromal tumor; cancer of the genitourinary tract; glioblastoma; hairy cell carcinoma; various types of head and neck cancer; hepatic carcinoma; hepatocellular cancer; Hodgkin's disease; keratoacanthoma; kidney cancer; large cell carcinoma; cancer of the large intestine; laryngeal cancer; liver cancer; lung cancer, such as, for example, adenocarcinoma of the lung, anaplastic carcinoma of the lung,
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is selected from melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer (e.g., non-small cell lung cancer), breast cancer, endometrial cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma (HCC), multiple myeloma (MM), and leukemia.
  • a leukemia is an acute leukemia.
  • a leukemia is acute myeloid leukemia.
  • a leukemia is acute lymphoblastic leukemia.
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is selected from melanoma, colorectal cancer, lung cancer, or pancreatic.
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is melanoma.
  • the melanoma is uveal melanoma.
  • the melanoma is a melanoma of the skin.
  • the melanoma is locally advanced.
  • the melanoma is metastatic.
  • the melanoma is recurring.
  • the melanoma is BRAF v600 -mutated melanoma.
  • the melanoma is a RAS-mutated melanoma.
  • the melanoma is NRAS- mutated melanoma. In certain embodiments, the melanoma is wild type for KRAS, NRAS or BRAF. In certain embodiments, the melanoma is a BRAF inhibitor-resistant melanoma. In certain embodiments, the cancer is a VemR (i.e., Vemurfenib-resistant) BRAF-mutated melanoma. In some embodiments, the melanoma is relapsed. In some embodiments, the melanoma is refractory.
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is colorectal cancer.
  • the colorectal cancer is locally advanced.
  • the colorectal cancer is metastatic.
  • the colorectal cancer is a BRAF-mutated colorectal cancer.
  • the colorectal cancer is a BRAF v600 -mutated colorectal cancer.
  • the colorectal cancer is a RAS-mutated colorectal cancer.
  • the colorectal cancer is a KRAS-mutated colorectal cancer.
  • the colorectal cancer is a NRAS-mutated colorectal cancer.
  • the colorectal cancer is relapsed.
  • the colorectal cancer is refractory.
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is pancreatic cancer.
  • the pancreatic cancer is locally advanced.
  • the pancreatic cancer is metastatic.
  • the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC).
  • the pancreatic cancer is a RAS-mutated pancreatic cancer.
  • the pancreatic cancer is a KRAS-mutated pancreatic cancer.
  • the pancreatic cancer is KRAS-mutated pancreatic cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R .
  • the pancreatic cancer is relapsed.
  • the pancreatic cancer is refractory.
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is a papillary thyroid cancer.
  • the papillary thyroid cancer is locally advanced.
  • the papillary thyroid cancer is metastatic.
  • the papillary thyroid cancer is recurring.
  • the papillary thyroid cancer is BRAF-mutated papillary thyroid cancer.
  • the papillary thyroid cancer is BRAF v600 -mutated papillary thyroid cancer.
  • the papillary thyroid cancer is relapsed.
  • the papillary thyroid cancer is refractory.
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is lung cancer.
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • the lung cancer is locally advanced.
  • the lung cancer is metastatic.
  • the lung cancer is a RAS-mutated lung cancer.
  • the lung cancer is KRAS-mutated lung cancer.
  • the lung cancer is a KRAS- mutated lung cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R .
  • the lung cancer is relapsed.
  • the lung cancer is refractory.
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is a leukemia.
  • a leukemia is a chronic leukemia.
  • a leukemia is chronic myeloid leukemia.
  • a leukemia is an acute leukemia.
  • a leukemia is acute myeloid leukemia (AML).
  • a leukemia is acute monocytic leukemia (AMoL, or AML-M5).
  • a leukemia is acute lymphoblastic leukemia (ALL).
  • a leukemia is acute T cell leukemia.
  • a leukemia is myelomonoblastic leukemia. In certain embodiments, a leukemia is human B cell precursor leukemia. In certain embodiments, a leukemia has a Flt3 mutation or rearrangement. In some embodiments, the leukemia is relapsed. In some embodiments, the leukemia is refractory.
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is a CNS cancer, for instance CNS tumors.
  • a CNS tumor is a glioblastoma or glioblastoma multiforme (GBM).
  • GBM glioblastoma multiforme
  • the present invention relates to a method of treating stomach (gastric) and esophageal tumors and cancers.
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is multiple myeloma (MM).
  • the multiple myeloma is locally advanced.
  • the multiple myeloma is metastatic.
  • the multiple myeloma is a RAS-mutated multiple myeloma.
  • the multiple myeloma is KRAS-mutated multiple myeloma.
  • the multiple myeloma is a KRAS-mutated multiple myeloma, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R .
  • the multiple myeloma is relapsed. In some embodiments, the multiple myeloma is refractory.
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • the HCC is locally advanced.
  • the HCC is metastatic.
  • the HCC is a RAS-mutated HCC.
  • the HCC is KRAS-mutated HCC.
  • the HCC is a KRAS-mutated HCC, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R .
  • the hepatocellular carcinoma is relapsed.
  • the hepatocellular carcinoma is refractory.
  • the present invention provides methods of making compounds useful for treating a cancer, wherein the cancer is selected from breast, colorectal, endometrial, hematological, leukemia (e.g., AML), liver, lung, melanoma, ovarian, pancreatic, prostate, or thyroid.
  • the cancer is selected from breast, colorectal, endometrial, hematological, leukemia (e.g., AML), liver, lung, melanoma, ovarian, pancreatic, prostate, or thyroid.
  • the solution of di-tert- butyl dicarbonate in 2-methyltetrahydrofuran was charged to the solution of compound 4 over about 12 to 16 hours while maintaining a reaction temperature for 75 °C to 80 °C.
  • the batch was further reacted at this temperature for about 6 hours, followed by a second charge of di-tert-butyl dicarbonate (16 g, 0.1 equiv) dissolved in 2-methyltetrahydrofuran (10 ml, 0.1 volume).
  • the batch was further agitated at 75 °C to 80 °C for 6 hours.
  • An in process control was taken, and if required additional di-tert-butyl dicarbonate was charged in 16 g (0.1 mol) portions until at least 95% conversion was reached.
  • the batch was reduced to 5 volumes by vacuum distillation (batch temperature 40 °C to 50 0 C) followed by a continuous vacuum distillation with fresh 2-methyltetrahydrofuran at 40 °C to 50 °C until a water content of no more than 0.2% was reached.
  • the batch temperature was adjusted to 55 °C to 65 °C and vacuum distilled at this temperature range while maintaining 5 volumes by the addition of n-heptane until a level of no more than 6% 2-methyltetrahyrofuran with respect to n-heptane was reached.
  • the batch was further reduced to 4.5 volumes, cooled to 40 to 45 °C, seeded with seed crystals of the product compound 7 (i.e., tert-butyl(2-methoxy-5- methylpyridin-4-yl)carbamate), agitated for 1 hour, cooled to -5 °C to 5 °C over 3 hours, and held at this temperature range to 16 hours.
  • the batch was filtered, washed with n-heptane (100 ml, 1 volume, cooled to -5 °C to 5 °C), and dried under reduced pressure at 30 °C to 40 °C to yield 120 g of compound 7 (70% yield).
  • the batch was cooled to 20 °C to 30 °C and diluted with 2-methyltetrahydrofuran (200 ml, 2 volumes) and n-heptane (200 ml, 2 volumes).
  • the batch was washed with 1% wt aqueous citric acid solution (300 ml, 3 volumes), water (300 ml, 3 volumes), 1% wt aqueous sodium bicarbonate (300 ml, 3 volumes), and water (300 ml, 3 volumes).
  • the batch was distilled at 50 °C to 65 °C under reduced pressure to 550 ml (5.5 volumes), then continuously distilled at 50 °C to 65 °C while maintaining a volume of 550 ml (5.5 volumes) by the addition of n-heptane until 2-methyltetrahydrofuran was less than 5% by mole with respect to n-heptane (about 1200 ml, 12 volumes n-heptane).
  • Step 1 Sodium methoxide (142 g, 2629 mmol) and toluene (795 ml) were charged to a reactor, heated to about 90 °C, and distilled under reduced pressure to remove about 2 volumes (210 ml) of toluene. The batch was then cooled, and compound 10 (i.e., 2,4-dichloro-5- methylpyridine) (106 g, 654 mmol) was charged, followed by a toluene rinse (53 ml). The batch was then heated to about 104 °C and reacted for about 36 hours.
  • compound 10 i.e., 2,4-dichloro-5- methylpyridine
  • Step 2 Tert-butylcarbamate (89 g, 760 mmol), cesium carbonate (318 g, 976 mmol), palladium acetate (2.94 g, 13.1 mmol), and Xantphos (4,5-bis(diphenylphosphino)-9,9- dimethylxanthene, 9.09 g, 15.7 mmol) were charged to a fresh reactor and inerted.
  • the batch from step 1, above, in toluene was transferred and heated to about 95 °C for about 16 hours. After reaction completion the batch was cooled to about 25 °C, diatomaceous earth (10.6 g) was charged, and the resulting mixture was agitated for about 30 minutes, followed by filtration. The batch was reduced in volume to about 424 ml via vacuum distillation at about 80 °C.
  • the batch was then transferred to a fresh reactor containing activated carbon (42.4 g) and trithiocyanuric acid (42.4 g) followed by addition of n-heptane (2120 ml).
  • the batch was agitated at about 25 °C for at least 8 hours, then filtered.
  • the filter cake was washed twice with 1/5 v/v toluene/n-heptane (106 ml each), and the combined filtrates were charged to fresh activated carbon (42.4 g).
  • the batch was agitated for at least 4 hours at about 25 °C and filtered.
  • the filter cake was then washed once with 1/5 v/v toluene/n-heptane (106 ml).
  • the batch was reduced in volume to about 530 ml via vacuum distillation (about 65 °C) and the solvent was exchanged to n-heptane while maintaining this volume and temperature.
  • the batch was then cooled to about 10 °C with intermittent seeding with compound 7, agitated at about 10 °C, filtered, washed once with n-heptane (106 ml), and dried under reduced pressure at about 40 °C to afford about 115.4 g of product (74% molar yield).
  • Potassium tert-butyoxide (1.6 to 1.7 M in THF, 2.90 L, 0.95 equiv) was charted over about 1.5 hours, maintaining a batch temperature between -20 °C to -10 °C (targeting -15 °C).
  • the batch was sampled for reaction completion by HPLC, additional potassium tert-butoxide was charged portion-wise while maintaining a temperature between -20 °C to -10 °C until no more than 1% compound 7 remained.
  • Water (3.6 L, 3X vol ) was charged to quench while maintaining a batch temperature of no more than 0 °C.
  • the batch temperature was adjusted to 20 °C to 25 °C, agitated, settled and split.
  • Heptane (3.6 L, 3X vol) and water (3.6 L, 3X vol) were charged, the batch was agitated, settled and split. The batch was washed two more times with water (3.6 L, 3X vol each). The batch was transferred to a separate reactor with activated carbon (600 g, 0.5X wt) for agitation. The batch was agitated between 20 °C to 30 °C for 16 hours and filtered over a pad of diatomaceous earth (180 g, 0.15X wt). The cake was washed twice with THF (1.2 L, IX vol each).
  • the combined filtrates were distilled under reduced pressure to 5X volumes followed by a continuous vacuum distillation with heptane until a composition of no more than 1 % mol tetrahydrofuran and no more than 8 % mol toluene was achieved.
  • the batch was adjusted to 50 °C to 60 °C, compound 8 seeds were charged (12 g) , the batch was agitated at 50 °C to 60 °C for 1 hour, then cooled to 10 °C over 3 hours. The batch was further agitated at 10 °C for 4 hours, filtered, and washed with heptane (1.2 L, IX vol).
  • the batch was heated to 65 °C to 70 °C over about 1 hour, reacted at 65 °C to 70 °C for about 20 hrs, then heated to 67 °C to 73 °C for another 4 hours until compound 8 was no more than 2% by HPLC.
  • the batch was cooled to 25 °C to 35 °C and isopropyl acetate (11.25 L, 15X vol) was charged.
  • a separately prepared citric acid 5% (wt/vol) aqueous solution (2.25 L, 3X vol) was charged to the batch while maintaining a temperature of 25 °C to 35 °C.
  • the batch was agitated, settled and the aqueous layer (bottom) was removed.
  • the citric acid wash was repeated three more times.
  • a sodium bicarbonate 5% (wt/vol) aqueous solution (2.25 L, 3X vol) was charged to the batch while maintaining a temperature of 25 °C to 35 °C.
  • the batch was agitated, settled and the aqueous layer (bottom) was removed.
  • the batch was finally washed with water (2.25 L, 3X vol) while maintaining a temperature of 25 °C to 35 °C.
  • the batch was vacuum distilled to about 7X volumes while maintaining a temperature of 45 °C to 55 °C then adjusted to 12X volumes by the addition of fresh isopropylacetate.
  • the batch was transferred to a fresh vessel with activate carbon (150 g, 0.2 X wt) and agitated at 20 °C to 30 °C for about 4 hrs.
  • the batch was filtered through diatomaceous earth, the filter cake was washed with isopropyl acetate (1.5 L, 2X vol).
  • a solution of sulfuric acid in methanol was prepared by slowly diluting sulfuric acid (98%, 147 g, 1.2 equiv) in methanol (1.4 L, 2X vol).
  • sulfuric acid 98%, 147 g, 1.2 equiv
  • methanol 5.6 L, 8X vol
  • the sulfuric acid- methanol solution was charged to the batch while maintaining a temperature of no more than 30 °C.
  • the batch was heated to 35 °C to 45 °C and agitated for 4 hours at which time an in process control sample by HPLC detected no more than 0.2% compound 9.
  • the batch was cooled to 20 °C to 30 °C.
  • Form A of Compound I was prepared using any one of the following procedures.
  • Procedure A Compound I was dissolved in 15X tetrahydrofuran. One molar equivalent of 2 molar phosphoric acid in acetonitrile was charged. The batch was slurried at 20 °C for 1 to 2 hours. The solvent was removed under reduced pressure. The resulting solids were slurried in acetone for about 16 hours at 20 °C, filtered and dried.
  • Procedure B Compound I was dissolved in THF. Equal molar equivalent of 1.08 M phosphoric acid in acetonitrile was charged. The sample was shaken at ambient temperature at 200 RPM for 1 hour. The solvent was removed under nitrogen purge. The resulting solids were slurried in acetone with a stirring bar at ambient temperature overnight, then filtered and dried in vacuum oven at 30 °C overnight.
  • Procedure C Compound I was dissolved in THF (20X vol) at 20° C. Seeds of Form A of the phosphate salt of Compound I (5% wt) were charged. A I M solution of phosphoric acid (1 mol eq.) in ethanol was charged. The batch was left under vigorous agitation for two hours. Solvent exchange to isopropyl acetate was carried out with a constant volume distillation under reduced pressure, with temperature not exceeding 40° C. The batch was cooled to 20° C. The solvent was removed under nitrogen purge. The batch was filtered, washed two times with isopropyl acetate and dried in a vacuum oven at -40 ° C overnight, under vacuum with nitrogen bleed.
  • Procedure D Compound I was dissolved in 9X vol THF/ H 2 0 (95:5 vol). A solution of H 3 PO 4 (1.2 mol eq.) in ethanol was charged to a second flask, seeds of Form A of the phosphate salt of Compound I (5%) were charged and vigorous agitation was started. The solution of Compound I was charged to the H 3 PO 4 solution (reverse addition) over one hour. The slurry was aged for one hour. Solvent exchange to ethanol was started (constant volume vacuum distillation with continuous addition of ethanol, final THF NMT 0.5%). The batch was cooled to 20° C, filtered and dried in a vacuum oven at -40 0 C overnight, under vacuum with nitrogen bleed.
  • Procedure E Compound I was dissolved in 10X vol THF/H 2 0 (95:5 vol). Isopropyl alcohol (5X vol) was charged. Constant volume distillation, with continuous addition of isopropyl alcohol was started at atmospheric pressure. Solvent exchange was carried out until THF content was below 5%. Compound I recrystallized during the solvent exchange. The batch was cooled to 30 °C. A I M solution of H 3 PO 4 in IPA was charged over 2 hours. Seeds of Form A of the phosphate salt of Compound I (1%) were then charged. The batch was stirred vigorously overnight. The batch was filtered and dried in a vacuum oven at -40 °C overnight, under vacuum with nitrogen bleed.
  • Procedure F Compound I was dissolved in 9X vol THF/H 2 0 (95:5 vol). After polish filtration, distillation to reduce volume from 9X to 5X was performed, followed by addition of 8X ethyl acetate to bring the total volume to 13X. Solvent exchange to ethyl acetate, with constant volume distillation was carried out (final THF NMT 2%). The temperature was then reduced to 30 °C. Seeds of a phosphate salt of Compound I (1% wt) were charged. A solution of H 3 PO 4 (1.2 eq.) in ethanol (5X) was then dosed in over 2 hours. The temperature was reduced to 20 °C, the batch was aged for 12 hours under vigorous stirring, then filtered, washed two times with ethyl acetate and dried in a vacuum oven at -40 °C overnight, under vacuum with nitrogen bleed.
  • Procedure G Compound I was charged to a reactor, then ethanol (4X vol) and ethyl acetate (6X), were charged. The batch was agitated at 30° C. A solution of H 3 PO 4 (1.2 mol eq.) in ethanol (2X vol) was charged over 2 hours. Seeds of Form A of the phosphate salt of Compound I (1%) were charged. The batch was filtered, washed two times with ethyl acetate, dried overnight at -40° C, under vacuum with nitrogen bleed. [00372] Characterization of the resulting material demonstrated a crystalline, anhydrous Form A of the phosphate salt of Compound I. Up to 0.9% water uptake was observed for this Form at 95% relative humidity.
  • the position 2 ⁇ is within ⁇ 0.2.
  • Figure 9 depicts an XRPD pattern of Form A of the phosphate salt of Compound I.
  • Figure 10 depicts a DSC thermogram of Form A of the phosphate salt of Compound I
  • Figure 11 depicts a TGA trace of Form A of the phosphate salt of Compound I.
  • Figure 12 depicts a DVS plot of Form A of the phosphate salt of Compound I.
  • the present invention provides a crystallization procedure that generates crystals having certain physical properties that facilitate product processing.
  • a crystallization procedure that generates crystals having certain physical properties that facilitate product processing.
  • One such exemplary method is described below.
  • a 20% (0.2X weight) portion of the total final mass of Compound I (i.e., 20% of the total amount of free base Compound I by weight) was charged to a reactor.
  • a mixture of ethyl acetate/ethanol 13:5 vol (13X vol) was charged. Agitation was started and the temperature was raised to 30 °C and held at that temperature for 30 minutes.
  • a solution of phosphoric acid (1.2 molar equiv.) was prepared in 5X ethyl acetate/ethanol (13:5 vol). A portion (20% of the 1.2 molar equiv) of the phosphoric acid solution was charged to the reactor over about 20 minutes. Seeds (2% by wt) of the phosphate salt of Compound I (Form A) were charged and the batch was aged for 30 minutes.
  • the batch was exchanged to a nitrogen atmosphere, cooled to 20 °C to 30 °C, filtered through Celite 503 (2.5 g, 0.1X weight), followed by two cake washes (25 ml, 1 volume, of 13:2 THF:water each).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des méthodes de synthèse de composés utiles en tant qu'inhibiteurs de ERK1 et ERK2 kinases, leurs dérivés, et des intermédiaires de ceux-ci.
PCT/US2016/032422 2015-05-15 2016-05-13 Composés hétéroaryles, leur synthèse, et intermédiaires de ceux-ci WO2016187028A1 (fr)

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CN114560815A (zh) * 2022-03-04 2022-05-31 北京工业大学 (2-((5-氯-取代苯基氨基嘧啶-2-基)氨基)苯基)氨基甲酸叔丁酯类衍生物

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