Attorney Docket No.765549: 086087-032PC PROCESSES FOR PREPARING A PKC INHIBITOR CROSS-REFERENCES TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No.63/648,148 filed May 15, 2024, and U.S. Provisional Application No.63/685,130 filed August 20, 2024, each of which is incorporated herein in its entirety for all purposes. BACKGROUND International Application No. PCT/IB2015/055951 (published as WO 2016/020864) discloses a number of potent and selective PKC inhibitors including 3-amino-N-(3-(4-amino- 4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide (i.e., Formula (I)). This compound is useful in the treatment of certain cancers, including uveal melanoma. As disclosed in PCT/IB2015/055951, the compound of Formula (I) was prepared according to steps 1 to 7 as shown in FIG.1. In particular, the amide coupling reaction (i.e., step 6) was achieved by using a phosphate coupling reagent such as benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP). Accordingly, tert-butyl (l-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4- meth lpiperidin-4-yl)carbamate (i.e., Formula (XIa)) was isolated in a yield of 74%. Despite the above-described process, there remains a need for the development of more efficient and improved processes for the preparation of the compound of Formula (I). The present disclosure, for example, addresses this need and provides related advantages as well. SUMMARY The present disclosure provides processes for preparing a compound of Formula (I). In an aspect, the present disclosure provides a process for preparing a compound of Formula (I) according to steps 6a), 6b), and 7) as described herein, wherein steps 6a) and 6b) comprise a step-wise amide coupling reaction of compounds of Formulae (VIa) and (X), via an activated intermediate of Formula (VIa-AG), to form a compound of Formula (XI); and step 7) comprises a conversion of the compound of Formula (XI) to the compound of Formula (I). In one aspect, the present disclosure provides a process for preparing a compound, represented by Formula (I):
Attorney Docket No.765549: 086087-032PC
the process comprising: 6a) combining a compound of Formula (VIa):
or a salt thereof, with an activating reagent in a first solvent to provide a first mixture comprising an activated intermediate of Formula (VIa-AG):
or a salt thereof; 6b) coupling the activated intermediate of Formula (VIa-AG) or the salt thereof with a compound of Formula (X):
or a salt thereof, in a second solvent to provide a compound of Formula (XI):
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or a salt thereof; and 7) converting the compound or salt thereof of Formula (XI) to Formula (I), wherein: AG is an activated moiety; PG is an amine-protecting group; and R is hydrogen or absent when PG is a phthalimide protecting group. In one aspect, the present disclosure provides a process for preparing a compound, represented by Formula (I):
the process comprising: 6a) combining a compound of Formula (VIa):
or a salt thereof, with a non-phosphonium activating reagent in a first solvent to provide a first mixture comprising an activated intermediate of Formula (VIa-AG):
(VIa-AG),
Attorney Docket No.765549: 086087-032PC or a salt thereof; 6b) coupling the activated intermediate of Formula (VIa-AG) or the salt thereof with a compound of Formula (X):
or a salt thereof, in a second solvent to provide a compound of Formula (XI):
or a salt thereof; and 7) converting the compound or salt thereof of Formula (XI) to Formula (I), wherein: AG is an activated moiety; PG is an amine-protecting group; and R is hydrogen or absent when PG is a phthalimide protecting group. The process further comprises the preparation of the compounds of Formulae (VIa) and (X), respectively, wherein the compound of Formula (VIa) is prepared according to steps 1) to 3) as described herein; and the compound of Formula (X) is prepared according to steps 4) and 5) as described herein. The present disclosure also provides a process for preparing a compound of Formula (I) according to steps 6a), 6b), 7a), and 7b) as described herein, wherein steps 6a) and 6b) comprise a step-wise amide coupling reaction of compounds of Formulae (VIa) and (Xa), via an activated intermediate of Formula (VIa-AG1) (an N-acylimidazole activated intermediate), to form a compound of Formula (XIa); and steps 7a) and 7b) comprise a conversion of the compound of Formula (XIa) to the compound of Formula (I) via an acid hydrolysis followed by a base treatment.
Attorney Docket No.765549: 086087-032PC Accordingly, in one aspect, the present disclosure provides a process for preparing a compound of Formula (I):
the process comprising: 6a) combining a compound of Formula (VIa):
(VIa), with an activating reagent in a first solvent to provide a first mixture comprising an activated intermediate of Formula (VIa-AG1):
6b) coupling the activated intermediate of Formula (VIa-AG1) with a compound of Formula (Xa):
in a second solvent to provide a compound of Formula (XIa):
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7a) combining the compound of Formula (XIa) with a first acid to provide a salt of the compound of Formula (I); and 7b) treating the salt of compound of Formula (I) with a first base to provide the compound of Formula (I), wherein steps 6a), 6b), 7a), and 7b) are each described herein. In another aspect, the present disclosure provides a process for preparing a compound, represented by Formula (I):
the process comprising: 6a) combining a compound of Formula (VIa)
(VIa), with N,N’-carbonyldiimidazole (CDI) in NMP to form a first mixture comprising an activated intermediate of Formula (VIa-AG1):
6b) coupling the activated intermediate of Formula (VIa-AG1) with a compound of Formula (Xa):
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in NMP to provide a compound of Formula (XIa)
7a) combining the compound of Formula (XIa) with an aqueous HCl solution to provide a HCl salt of the compound of Formula (I); and 7b) treating the HCl salt of compound of Formula (I) with an aqueous NaOH solution to provide the compound of Formula (I), wherein steps 6a), 6b), 7a), and 7b) are each described herein. The present disclosure further provides a process for preparing a compound of Formula (I) according to steps 1) to 5), 6a), 6b), 7a), and 7b) as described herein. Accordingly, in one aspect, the present disclosure provides a process for preparing a compound of Formula (I):
the process comprising: 1) combining a compound of Formula (IIa):
(IIa), with a boron reagent, a first palladium catalyst, and a third base in a fifth solvent to form a compound of Formula (IIIa):
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2) reacting the compound of Formula (IIIa) with a compound of Formula (IVa): (IVa), with a second palladium catalyst and a fourth base in a sixth solvent to provide a compound of Formula (Va):
3) hydrolyzing the compound of Formula (Va) with a second base followed by acidifying with a second acid to provide a compound of Formula (VIa):
(VIa); 4) combining a compound of Formula (VIIIa): (VIIIa), a compound of Formula (VIIa):
(VIIa), and a fifth base to provide a compound of Formula (IXa):
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5) reducing the compound of Formula (IXa) under a catalytic hydrogenation to provide a compound of Formula (Xa):
6a) combining the compound of Formula (VIa) from step 3) with an activating reagent in a first solvent to provide a first mixture comprising an activated intermediate of Formula (VIa-AG1):
6b) coupling the activated intermediate of Formula (VIa-AG1) with the compound of Formula (Xa) from step 5) in a second solvent to provide a compound of Formula (XIa):
7a) combining the compound of Formula (XIa) with a first acid to provide a salt of the compound of Formula (I); and 7b) treating the salt of compound of Formula (I) with a first base to provide the compound of Formula (I), wherein steps 1) to 5), 6a), 6b), 7a), and 7b) are each described herein.
Attorney Docket No.765549: 086087-032PC In another aspect, the present disclosure provides a process for preparing a compound of Formula (I):
the process comprising: 1) combining a compound of Formula (IIa):
(IIa), with bis(pinacolato)diboron, Pd(OAc)2, Ad2BuP, and KOAc in THF to form a compound of Formula (IIIa):
2) reacting the compound of Formula (IIIa) with a compound of Formula (IVa):
with Pd(OAc)2, Ad2BuP, and K2CO3 in a mixture of THF and MeOH to provide a compound of Formula (Va):
3) hydrolyzing the compound of Formula (Va) with an aqueous NaOH solution followed by acidifying with an aqueous HCl solution to provide a compound of Formula (VIa):
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(VIa); ) combining a compound of Formula (VIIIa):
(VIIIa), a compound of Formula (VIIa):
(VIIa), and triethylamine (TEA) in THF to provide a compound of Formula (IXa):
) reducing the compound of Formula (IXa) under a catalytic hydrogenation comprising palladium on carbon (Pd/C) and H2 gas in THF to provide a compound of Formula (Xa):
a) combining the compound of Formula (VIa) from step 3) with CDI in NMP to form a first mixture comprising an activated intermediate of Formula (VIa-AG1):
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6b) coupling the activated intermediate of Formula (VIa-AG1) with the compound of Formula (Xa) from step 5) in NMP to provide a compound of Formula (XIa)
7a) combining the compound of Formula (XIa) with an aqueous HCl solution to provide a HCl salt of the compound of Formula (I); and 7b) treating the HCl salt of compound of Formula (I) with an aqueous NaOH solution to provide the compound of Formula (I), wherein steps 1) to 5), 6a), 6b), 7a), and 7b) are each described herein. In further embodiments, the process comprises a recrystallization step (e.g., step 8) to provide a crystalline form of the compound of Formula (I) as described herein. In another aspect, the present disclosure provides a compound of Formula (I) or a crystalline form thereof, prepared by processes as disclosed and described herein. In a further aspect, the present disclosure also provides compositions comprising the compound of Formula (I), wherein the composition is at least 100 g and/or the compound is present in an amount of at least 95% of the composition. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 shows the synthetic scheme for preparing 3-amino-N-(3-(4-amino-4- methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide (i.e., Formula (I)), according to steps 1 to 7 as described in WO 2016/020864. FIG.2 shows the preparation of the compound of Formula (I)) as one of embodiments according to Example 1. FIG.3 shows an XRPD diffractogram of a crystalline form of a compound of Formula (I).
Attorney Docket No.765549: 086087-032PC DETAILED DESCRIPTION I. GENERAL The present disclosure provides a process for preparing a compound of Formula (I). In an aspect, the present disclosure provides a process for preparing a compound of Formula (I) according to steps 6a), 6b), and 7) as described herein, wherein steps 6a) and 6b) comprise a step-wise amide coupling reaction of compounds of Formulae (VIa) and (X), via an activated intermediate of Formula (VIa-AG), to form a compound of Formula (XI); and step 7) comprises a conversion of the compound of Formula (XI) to the compound of Formula (I). The process further comprises the preparation of the compounds of Formulae (VIa) and (X), respectively, wherein the compound of Formula (VIa) is prepared according to steps 1) to 3) as described herein; and the compound of Formula (X) is prepared according to steps 4) and 5) as described herein. In some embodiments, when tert-butyloxycarbonyl (Boc) is used as an amino- protecting group, the compound of Formula (X) is represented by Formula (Xa); and the compound of Formula (XI) is represented by Formula (XIa). The present disclosure also provides a process for preparing a compound of Formula (I) according to steps 6a), 6b), 7a), and 7b) as described herein (e.g., Section III-6), wherein steps 6a) and 6b) comprise a step-wise amide coupling reaction of compounds of Formulae (VIa) and (Xa), via an activated intermediate of Formula (VIa-AG1) (an N-acylimidazole activated intermediate), to form a compound of Formula (XIa); and steps 7a) and 7b) comprise a conversion of the compound of Formula (XIa) to the compound of Formula (I) via an acid hydrolysis followed by a base treatment. The present disclosure further provides a process for preparing a compound of Formula (I) according to steps 1) to 5), 6a), 6b), 7a), and 7b), as described herein (e.g., Section III-7). In further embodiments, the process comprises a recrystallization step (e.g., step 8)) to provide a crystalline form of the compound of Formula (I) as described herein. The present disclosure further provides a compound of Formula (I) or a crystalline form thereof, prepared by processes as disclosed and described herein. The present disclosure also provides compositions comprising the compound of Formula (I), wherein the composition is at least 100 g and/or the compound is present in an amount of at least 95% of the composition.
Attorney Docket No.765549: 086087-032PC II. DEFINITIONS Unless otherwise indicated, the following terms are intended to have the meaning set forth below. Other terms are defined elsewhere throughout the specification. “Comprise,” “include,” and “have,” and the derivatives thereof, are used herein interchangeably as comprehensive, open-ended terms. For example, use of “comprising,” “including,” or “having” means that whatever element is comprised, had, or included, is not the only element encompassed by the subject of the clause that contains the verb. “About” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In some embodiments, the term “about” means within a standard deviation using measurements generally acceptable in the art. In some embodiments, “about” means a range extending to +/- 10% of the specified value. In some embodiments, “about” means a range of +/- 10%, +/- 9%, +/- 8%, +/- 7%, +/- 6%, +/- 5%, +/- 4%, +/- 3%, +/- 2%, or +/- 1% of the specified value. In some embodiments, “about” means a range of +/- 10% of the specified value. In some embodiments, “about” means a range of +/- 5% of the specified value. In some embodiments, “about” means the specified value. “Substantially free” refers to that other crystalline form(s), unreacted starting material(s), and/or one or more impurities are present in an amount of 10% or less in a particular desired form, preferably 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5%, or less. In some embodiments, “substantially free” means 5% or less of other crystalline form(s), unreacted starting material(s), and/or one or more impurities. In some embodiments, “substantially free” means 4% or less of other crystalline form(s), unreacted starting material(s), and/or one or more impurities. In some embodiments, “substantially free” means 4% or less of other crystalline form(s), unreacted starting material(s), and/or one or more impurities. In some embodiments, “substantially free” means 3% or less of other crystalline form(s), unreacted starting material(s), and/or one or more impurities. In some embodiments, “substantially free” means 2% or less of other crystalline form(s), unreacted starting material(s), and/or one or more impurities. In some embodiments, “substantially free” means 1% or less of other crystalline form(s), unreacted starting material(s), and/or one or more impurities. In some embodiments, “substantially free” means 0.5% or less of other crystalline form(s), unreacted starting material(s), and/or one or more impurities. In some embodiments, “substantially free” means 0.1% or less of other crystalline form(s), unreacted starting material(s), and/or one or more impurities.
Attorney Docket No.765549: 086087-032PC When ranges of values are disclosed, and the notation “from n1... to n2” or “between n1 and n2” is used, where n1 and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, because carbon atoms come in integer units. Compare, by way of example, the range “from 1.0 eq. to 1.2 eq. (equivalent),” which is intended to include 1.0 eq., 1.2 eq., and everything in between to any number of significant figures (e.g., 1.01 eq., 1.10 eq., 1.199 eq., etc.). Unless specifically indicated otherwise, the group “ ” as used herein in any one of formulae of compounds as disclosed herein, refers to methyl. For example, the compound of Formula (I) is represented by:
which has the structure as shown:
Unless specifically indicated otherwise, a purity (e.g., 95%) is measured by a HPLC method. Representative HPLC methods are described in Examples – HPLC methods. Unless specifically indicated otherwise, a purity in wt% (e.g., 95 wt%) is calculated according to the formula: Purity (wt%) = [a weight of a specific compound / a total weight of a composition comprising the specific compound] x 100 (wt%). In one embodiment, a purity in wt% (e.g., 95 wt%) of a compound of Formula (I) is calculated according to the formula: Purity (wt%) = [a weight of a compound of Formula (I) / a total weight of a composition comprising the compound of Formula (I)] x 100 (wt%). Unless specifically indicated otherwise, the term “eq.” or “equiv” is an abbreviation of the word “equivalent.”
Attorney Docket No.765549: 086087-032PC Unless specifically indicated otherwise, the amount (in an equivalent) of an activating reagent (e.g., CDI) in the activation step 6a) is calculated based on the compound of Formula (VIa) on a salt-free and anhydrous basis, provided that the activating reagent (e.g., CDI) is free of water and has a purity of 100%. One skilled in the art understands that the actual amount of the activating reagent (e.g., CDI) used in the reaction (step 6a) is adjusted accordingly, based on the water content in the compound of Formula (VIa), the compound of Formula (X) (e.g., Formula (Xa), and solvents (i.e., the first and second solvents, for example NMP). “Alkyl” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated (i.e., C1-6 means one to six carbons). Alkyl can include any number of carbon atoms, such as C1-2, C1-3, C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, C1-10, C2-3, C2- 4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. For example, C1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. “Halogen” or “halo” refers to fluorine (or fluoro), chlorine (or chloro), bromine (or bromo), and iodine (or iodo). “Haloalkyl” refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms. As for alkyl group, haloalkyl groups can have any suitable number of carbon atoms, such as C1-6. For example, haloalkyl includes trifluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, etc. “Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic, fused bicyclic, or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbon atoms, such as C3- 6, C4-6, C5-6, C3-8, C4-8, C5-8, C6-8, C3-9, C3-10, C3-11, and C3-12. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. When cycloalkyl is a saturated monocyclic C3-C8 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a saturated monocyclic C3-C6 cycloalkyl,
Attorney Docket No.765549: 086087-032PC exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless specifically indicated otherwise, C3-C6 cycloalkyl as defined in Formula (V) is a saturated monocyclic cycloalkyl. “Aryl” refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. “Heterocycloalkyl” or “heterocycle” refers to a saturated ring system having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O, and S. Unless specifically indicated otherwise, the heteroatoms are not oxidized, such as N-oxide, -S(O)- and -S(O)2-. Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. When heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently N, O, or S, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxzoalidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form a ring having 5 to 6 ring members and 1 to 2 heteroatoms each independently N, O, or S, with representative members including, but not limited to, pyrrolidine, piperidine, tetrahydrofuran,
Attorney Docket No.765549: 086087-032PC tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine. Unless specifically indicated otherwise, heterocycloalkyl as defined in Formula (V) has 4 to 6 ring members and 1 to 3 heteroatoms as ring vertices each independently N, O, or S. “Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O, or S. Unless specifically indicated otherwise, the heteroatoms are not oxidized, such as -S(O)- and -S(O)2-. Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 5 to 8, 6 to 8, 5 to 9, 5 to 10, 5 to 11, or 5 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 10 ring members and from 1 to 4 heteroatoms, from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroaryl groups, having from 5 to 8 ring members and from 1 to 3 heteroatoms each independently N, O, or S, can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Unless specifically indicated otherwise, the heteroaryl as defined in Formula (V) has from 5 to 6 ring members and from 1 to 3 heteroatoms as ring vertices each independently N, O, or S. “Sulfonate” refers to an –SO3R group where R group can be halo (e.g., –F), alkyl (e.g., methyl or ethyl), haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl, tosyl, p- fluorophenyl, or p-nitrophenyl), heteroaryl (e.g., imidazolyl). Representative sulfonate groups include fluorosulfonate, methanesulfonate (OMs), trifluoromethanesulfonate (OTf), p- toluenesulfonate (OTs), p-fluorobenzenesulfonate, p-nitrophenylsulfonate (nosylate), and imidazole-1-sulfonate (imidazylate).
Attorney Docket No.765549: 086087-032PC “Bidentate” refers to an alkoxy group, an aryloxy group, or a carboxylate group having at least two oxygen atoms (–O–), two of which form both bonds to the same third atom such as boron (B), provided that the two oxygen atoms are not a part of a carbonyl group (–C=O). Bidentate groups useful in the present disclosure include bidentate C2-8 alkoxy groups, bidentate C6-10 aryloxy groups, and bidentate carboxylate groups. “Tridentate” refers to an alkoxy group having at least three carbon atoms and three oxygen atoms (–O–), each of which forms a bond to the same atom such as boron (B). Tridentate groups useful in the present disclosure include tridentate C3-8 alkoxy groups. “Activating reagent” refers to a reagent capable of converting a less reactive functional group to a more reactive functional group in the molecule, which has an increased propensity to undergo a specified chemical reaction. In some embodiments, for example, the activating reagents convert the –OH group in the compound of Formula (VIa) to a reactive function group (e.g., an activated group, AG). In some embodiments, the activating reagents are peptide coupling reagents known in the art that activate the –C(O)OH group of Formula (VIa) for an amide formation (e.g., the compound of Formula (XI)). “Solvent” refers to a substance, such as a liquid, capable of dissolving a solute. Solvents can be polar or non-polar, protic or aprotic. Polar solvents typically have a dielectric constant greater than about 5 or a dipole moment above about 1.0, and non-polar solvents have a dielectric constant below about 5 or a dipole moment below about 1.0. Protic solvents are characterized by having a proton available for removal, such as by having a hydroxy or carboxy group. Aprotic solvents lack such a group. Representative polar protic solvents include alcohols (methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid, acetic acid, etc.) and water. Representative polar aprotic solvents include dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, acetone, ethyl acetate, dimethylformamide, acetonitrile, dimethyl sulfoxide, and N-methylpyrrolidone. Representative non-polar solvents include alkanes (pentanes, hexanes, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, and toluene. Other solvents are useful in the present disclosure. “Aprotic solvent” refers to solvents that lack an acidic hydrogen. Consequently, they are not hydrogen bond donors. Common characteristics of aprotic solvents are solvents that can accept hydrogen bonds, solvents do not have acidic hydrogen, and solvents dissolve salts. Examples of aprotic solvents include, but are not limited to, N-methylpyrrolidone (NMP), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (MeTHF), ethyl acetate (EtOAc), acetone,
Attorney Docket No.765549: 086087-032PC dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), propylene carbonate (PC), and hexamethylphosphoramide (HMPA). “First solvent”, “second solvent”, and so on refer to a solvent as defined above and described in embodiments of the present disclosure. The solvent naming conventions are used solely for the purpose of clarity in steps of the processes as described herein and they are not required to be in a numerical order. Some solvents may be absent in selected embodiments of the present disclosure as described herein. One skilled in the art will understand the meaning of these solvent naming conventions (e.g., “first solvent”, “second solvent”) within the context of the term’s use in the various aspects, embodiments, and claims herein. “Amino protecting group” refers a protecting group that is used to protect an amino group as defined herein. “Amino” as used herein, and unless otherwise specified, refers to - NH2. Exemplary amino protecting groups include, but are not limited to a carbobenzyloxy (Cbz) group, p-methoxybenzyl carbonyl (Moz or MeOZ) group, tert-butyloxycarbonyl (Boc) group, 9-fluorenylmethyloxycarbonyl (Fmoc) group, acetyl (Ac) group, benzoyl (Bz) group, benzyl (Bn) group, carbamate group, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMB), p-methoxyphenyl (PMP), tosyl (Ts) group, trichloroethyl chloroformate (Troc) group, and other sulfonamides (Nosyl & Nps) groups. “Acid” refers to a compound that is capable of donating a proton (H+) under the Bronsted-Lowry definition. Acids useful in the present disclosure include, but are not limited to, fluorinated carboxylic acids (trifluoroacetic acid), sulfonic acids and mineral acids, as defined herein. Mineral acids are inorganic acids such as hydrogen halides (hydrofluoric acid, hydrochloric acid, hydrobromic acid, etc.), sulfuric acid, and phosphoric acid. Sulfonic acids include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, triflouromethanesulfonic acid, among others. “Base” refers to a functional group that deprotonates water to produce a hydroxide ion. Bases useful in the present disclosure include organic bases and inorganic bases. Exemplary organic bases include amines, alkali carboxylates, alkali alkoxides, metal amides, and alkyl or alkenyl-metal compounds, as defined herein. Exemplary inorganic bases include alkali bicarbonates, alkali carbonates, alkali phosphates tribasic, alkali phosphate dibasic, alkali hydroxides, and alkali hydride, as defined herein. Amines useful in the present disclosure as bases include tertiary amines, aromatic amine bases, and amidine-based compounds, as defined herein.
Attorney Docket No.765549: 086087-032PC “First base”, “second base”, and so on refer to a base as defined above and described in embodiments of the present disclosure. The base naming conventions are used solely for the purpose of clarity in relevant steps of the processes as described herein and they are not required to be in a numerical order. Some bases may be absent in selected embodiments of the present disclosure as described herein. One skilled in the art will understand the meaning of these base naming conventions (“first base”, “second base”) within the context of the term’s use in the various aspects, embodiments, and claims herein. “Tertiary amine” refers to a compound having formula N(R)3 wherein the R groups can be alkyl, aryl, heteroalkyl, heteroaryl, among others, or two R groups together form a N- linked heterocycloalkyl. The R groups can be the same or different. Non-limiting examples of tertiary amines include triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, dimethylaniline, diethylaniline, 1,8- bis(dimethylamino)naphthalene, quinuclidine, and 1,4-diazabicylo[2.2.2]-octane (DABCO). “Aromatic amine base” refers to a N-containing 5- to 10-membered heteroaryl compound or a tertiary amine having formula N(R)3 wherein at least one R group is an aryl or heteroaryl (each of which is defined above). Aromatic amine bases useful in the present application include, but are not limited to, pyridine, lutidines (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine), collidines (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5- collidine, 2,4,6-collidine, and 3,4,5-collidine), 4-dimethylaminopyridine, imidazole, dimethylaniline, and diethylaniline. “Amidine-based compounds” herein refers to a class of chemical compounds that include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5- diazabicyclo[4.3.0]non-5-en (DBN). “Alkali carboxylate” refers to a class of chemical compounds which are composed of an alkali metal cation or a phosphonium and the carboxylate anion (RC(O)O-) where the R group can be alkyl or aryl. Carboxylates useful in the present disclosure include, but are not limited to, lithium acetate (LiOC(O)CH3), sodium acetate (NaOC(O)CH3), potassium acetate (KOC(O)CH3), cesium acetate (CsOC(O)CH3), potassium trimethylacetate (KOC(O)C(CH3)3), and tetrabutylphosphonium malonate. “Alkali bicarbonate” refers to a class of chemical compounds which are composed of an alkali metal cation and the hydrogencarbonate anion (HCO3-). Alkali carbonates useful in the present disclosure include lithium bicarbonate (LiHCO3), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), and cesium bicarbonate (CsHCO3).
Attorney Docket No.765549: 086087-032PC “Alkali carbonate” refers to a class of chemical compounds which are composed of an alkali metal cation and the carbonate anion (CO32-). Alkali carbonates useful in the present disclosure include lithium carbonate (Li2CO3), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), and cesium carbonate (Cs2CO3). “Alkali phosphate tribasic” refers to a class of chemical compounds which are composed of an alkali metal cation and the phosphate anion (PO43-). Alkali phosphates tribasic useful in the present disclosure include sodium phosphate tribasic (Na3PO4) and potassium phosphate tribasic (K3PO4). “Alkali phosphate dibasic” refers to a class of chemical compounds which are composed of an alkali metal cation and the hydrogenphosphate anion (HPO4 2-). Alkali phosphates dibasic useful in the present disclosure include sodium phosphate dibasic (Na2HPO4) and potassium phosphate dibasic (K2HPO4). “Alkali hydroxide” refers to a class of chemical compounds which are composed of an alkali metal cation and the hydroxide anion (OH-). Alkali hydroxides useful in the present disclosure include lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), and cesium hydroxide (CsOH). “Alkali alkoxide” refers to a class of chemical compounds which are composed of an alkali metal cation and the alkoxide anion (RO-), wherein R is C1-4 alkyl. Alkali alkoxides useful in the present disclosure include, but are not limited to, sodium isopropoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, and potassium isopropoxide. “Catalyst” refers to a substance that increases the rate of a chemical reaction by reducing the activation energy, but which is left unchanged by the reaction. Catalysts may be classified as either homogeneous or heterogeneous. A homogeneous catalyst is one whose molecules are dispersed in the same phase as the reactant molecules. A heterogeneous catalyst is one whose molecules are not in the same phase as the reactants, which are typically gases or liquids that are adsorbed onto the surface of the solid catalyst. Catalysts useful in the present disclosure are both homogeneous catalysts and heterogeneous catalysts. “Metal” refers to elements of the periodic table that are metallic and that can be neutral, or positively charged as a result of having more or fewer electrons in the valence shell than is present for the neutral metallic element. Metals useful in the present disclosure include the alkali metals and transition metals. Alkali metals in the present disclosure include alkali metal cations. Alkali metal cations useful in the present disclosure include Li+, Na+, K+, and Cs+. Transition metals useful in the present disclosure include Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg
Attorney Docket No.765549: 086087-032PC and Ac. Transition metals useful in the present disclosure include transition metal cations, for example, Cd2+, Co2+, Co+, Cr2+, Cr+, Cu+ (i.e., Cu(I)), Cu2+ (i.e., Cu(II)), Fe2+, Fe+, Mn2+, Mn+, Ni2+, Ni+, Pd2+ (i.e., Pd(II)), and Zn2+. “Transition-metal catalyst” refers to a compound that is composed of a transition metal as defined above that can be neutral or positively charged. In some embodiments, the transition-metal catalyst includes one or more ligands. Unless specifically indicated otherwise, “palladium on carbon (Pd/C)” refers to palladium(0) on carbon (Pd0/C)”. “Combining” refers to the process of bringing at least two distinct species such that they mix together and can react, either modifying one of the initial reactants or forming a third, distinct, species, a product. It should be appreciated, however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture. “Salt” refers to acid or base salts of the compounds of the present disclosure. The present disclosure includes applicable salt forms of the compounds or intermediates, which are not limited to pharmaceutically acceptable salts. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 23rd Edition, 2020, which is incorporated herein by reference. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. A compound in a neutral form (or a free-base form) refers to one or more nitrogen atoms in the molecule are not protonated or quaternized. For example, the compound of Formula (I) in a neutral form (or in a free-base form) is represented by:
Attorney Docket No.765549: 086087-032PC
wherein each of nitrogen atoms is not protonated or quaternized. As used in the present disclosure, naming conventions of reagents and solvents used in steps are summarized in the Table below. The naming conventions are used solely for the purpose of clarity in steps of the processes as described herein and they are not required to be in a numerical order. For Example, as steps 6a) and 6b) are presented first, a first solvent is used in step 6a) and a second solvent is used in step 6b). Accordingly, a third, fourth, fifth, sixth, seventh, and eighth solvent are used in an order in steps 7a)/7b), step 3), step 1), step 2), step 4), and step 5), respectively.
Attorney Docket No.765549: 086087-032PC
Attorney Docket No.765549: 086087-032PC
III. PROCESSES In one aspect, the present disclosure provides a process for preparing a compound, represented by Formula (I):
the process comprising: 6a) combining a compound of Formula (VIa):
(VIa), or a salt thereof, with an activating reagent in a first solvent to provide a first mixture comprising an activated intermediate of Formula (VIa-AG):
(VIa-AG), or a salt thereof; 6b) coupling the activated intermediate of Formula (VIa-AG) or the salt thereof with a compound of Formula (X):
Attorney Docket No.765549: 086087-032PC
or a salt thereof, in a second solvent to provide a compound of Formula (XI):
or a salt thereof; and 7) converting the compound or salt thereof of Formula (XI) to Formula (I), wherein: AG is an activated moiety; PG is an amine-protecting group; and R is hydrogen or absent when PG is a phthalimide protecting group. In one aspect, the present disclosure provides a process for preparing a compound, represented by Formula (I):
the process comprising: 6a) combining a compound of Formula (VIa):
Attorney Docket No.765549: 086087-032PC or a salt thereof, with a non-phosphonium activating reagent in a first solvent to provide a first mixture comprising an activated intermediate of Formula (VIa-AG):
or a salt thereof; 6b) coupling the activated intermediate of Formula (VIa-AG) or the salt thereof with a compound of Formula (X):
or a salt thereof, in a second solvent to provide a compound of Formula (XI):
or a salt thereof; and 7) converting the compound or salt thereof of Formula (XI) to Formula (I), wherein: AG is an activated moiety; PG is an amine-protecting group; and R is hydrogen or absent when PG is a phthalimide protecting group. With reference to Formula (X) or (XI) in step 6b), in some embodiments, the amine- protecting group is an acid labile protecting group. In some embodiments, the compounds of Formula (X) and Formula (XI) are represented by the formulae, respectively:
Attorney Docket No.765549: 086087-032PC
In some embodiments, the amine-protecting group is Boc, [2- (trimethylsilyl)ethoxy]methyl (SEM), 4-methoxybenzyl, 2,4-dimethoxybenzyl, or trityl (Tr). In some embodiments, the amine-protecting group is Boc. In some embodiments, the compound of Formula (X) is represented by Formula (Xa); and the compound of Formula (XI) is represented by Formula (XIa), respectively:
In another aspect, the present disclosure provides a process for preparing a compound, represented by Formula (I):
the process comprising: 6a) combining a compound of Formula (VIa):
(VIa), or a salt thereof, with an activating reagent in a first solvent to provide a first mixture comprising an activated intermediate of Formula (VIa-AG):
Attorney Docket No.765549: 086087-032PC
or a salt thereof, wherein AG is an activated moiety; 6b) coupling the activated intermediate of Formula (VIa-AG) or the salt thereof with a compound of Formula (Xa):
or a salt thereof, in a second solvent to provide a compound of Formula (XIa):
or a salt thereof; and 7) converting the compound or salt thereof of Formula (XIa) to the compound of Formula (I). III-1. Steps 6a) and 6b) Steps 6a) and 6b) are a step-wise amide coupling reaction via an activated intermediate of Formula (VIa-AG). In some embodiments, the activating reagent is a peptide coupling reagent that activates the –C(O)OH group of Formula (VIa) to form an activated intermediate of Formula (VIa-AG), which then reacts with a compound of Formula (X) or (Xa) to form a compound of Formula (XI) or (XIa). In some embodiments, the activating reagent is a non- phosphonium activating reagent. In some embodiments, the activating reagent is other than benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP).
Attorney Docket No.765549: 086087-032PC In some embodiments, the activating reagent is a reagent that is capable of forming N- acylimidazole. In some embodiments, the activating reagent CDI, N,N’-thionyldiimidazole, or N-(chlorosulfinyl)-imidazole. In some embodiments, the activating reagent is CDI. In some embodiments, the activating reagent is dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), O- (7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O- (benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), O-(7- azabenzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), O- (benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), or a combination thereof. With reference to Formula (VIa-AG), AG is an activated moiety, and its identity is dependent on the activating reagent used. For example, when the activating reagent is CDI, the compound of Formula (VIa-AG) is a compound of Formula (VIa-AG1) represented by:
As an additional example, when the activating reagent is HOAt, the compound of Formula (VIa-AG) is a compound of Formula (VIa-AG2) represented by:
In some embodiments, the activated intermediate of Formula (VIa-AG) is represented by Formula (VIa-AG1):
Attorney Docket No.765549: 086087-032PC
or a salt thereof. In some embodiments, the activated intermediate of Formula (VIa-AG) is represented by Formula (VIa-AG1). In some embodiments, the activated moiety (AG) in Formula (VIa-AG) is a reaction product of a carboxylic acid with DCC, DIC, EDCI, HATU, HBTU, TATU, TBTU, HOBt, or HOAt. When the activating reagent (e.g., DCC, DIC, EDCI, HATU, HBTU, TATU, TBTU, HOBt, or HOAt is used, steps 6a) and/or 6b) further comprise a non- nucleophilic base. In some embodiments, the non-nucleophilic base is a tertiary amine. In some embodiments, the non-nucleophilic base is TEA, Ν,Ν-diisopropylethylamine (DIPEA), or N-methylmorpholine. In some embodiments, the non- nucleophilic base is added during the activating or coupling portions of steps 6a) and/or 6b). To conduct the amide coupling reaction in a step-wise fashion, step 6a) has a conversion of compound of Formula (VIa) to the compound of Formula (VIa-AG):
, in at least about 90%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG) is at least about 90%, about 91%, about 92%, about 93%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG) is at least about 95%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG) is at least about 96%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG) is at least about 97%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG) is at least about 98%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of
Attorney Docket No.765549: 086087-032PC Formula (VIa-AG) is at least about 99%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG) is at least about 99.5%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG) is about 99.5%. In some embodiments, the compound of Formula (VIa) is quantitatively converted to the compound of Formula (VIa-AG). In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-
, is at least about 90%, about 91%, about 92%, about 93%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is at least 95%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is at least 96%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is at least 97%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is at least 98%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is at least 99%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is at least 99.5%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is about 99.5%. In some embodiments, the compound of Formula (VIa) is quantitatively converted to the compound of Formula (VIa-AG1). The activating reagent can be in an amount that is substoichiometric (less than 1.0 eq., e.g., from about 0.5 eq. to 0.99 eq.), stoichiometric (1.0 eq.), or slightly excess (e.g., from 1.01 eq. to about 1.5 eq.), relative to Formula (VIa). In some embodiments, the activating reagent is in a substoichiometric amount, relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of form about 0.9 eq. to 1.0 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in a stoichiometric amount, relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of from 1.0 eq. to about 1.5 eq., relative to Formula (VIa).
Attorney Docket No.765549: 086087-032PC The activating reagent can be in any amount sufficient to effectively convert the compound of Formula (VIa) to the compound of Formular (VIa-AG) (e.g., Formula (VIa- AG1)). In some embodiments, the activating reagent is in an amount of at least about 1.0 eq. relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of from about 1.0 eq.to about 1.5 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of from about 1.0 eq. to about 1.25 eq., from about 1.01 eq. to about 1.25 eq., from about 1.02 eq. to about 1.25 eq., from about 1.03 eq. to about 1.25 eq., from about 1.04 eq. to about 1.25 eq., or from about 1.05 eq. to about 1.25 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of from 1.0 eq. to about 1.25 eq., from 1.01 eq. to about 1.25 eq., from 1.02 eq. to 1.25 eq., from 1.03 eq. to about 1.25 eq., from 1.04 eq. to about 1.25 eq., or from 1.05 eq. to about 1.25 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of from 1.0 eq. to 1.25 eq., from 1.01 eq. to 1.25 eq., from 1.02 eq. to 1.25 eq., from 1.03 eq. to 1.25 eq., from 1.04 eq. to 1.25 eq., or from 1.05 eq. to 1.25 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of from 1.0 eq. to 1.1 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of from 1.01 eq. to 1.05 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of from 1.02 eq. to 1.05 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of from 1.02 eq. to 1.04 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of from 1.02 eq. to 1.03 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of 1.01 eq., 1.02 eq., 1.03 eq., 1.04 eq., or 1.05 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of 1.01 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of 1.02 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of 1.04 eq., relative to Formula (VIa). In some embodiments, the activating reagent is in an amount of 1.05 eq., relative to Formula (VIa). When CDI is used, CDI can be in an amount that is substoichiometric (less than 1.0 eq., e.g., from about 0.5 eq. to 0.99 eq.), stoichiometric (1.0 eq.), or slightly excess (e.g., from 1.01 eq. to about 1.5 eq.), relative to Formula (VIa). In some embodiments, CDI is in a substoichiometric amount, relative to Formula (VIa). In some embodiments, CDI is in an amount of form about 0.9 eq. to 1.0 eq., relative to Formula (VIa). In some embodiments,
Attorney Docket No.765549: 086087-032PC CDI is in a stoichiometric amount, relative to Formula (VIa). In some embodiments, CDI is in an amount of from 1.0 eq. to about 1.5 eq., relative to Formula (VIa). When CDI is used, in some embodiments, CDI is in an amount of at least about 1.0 eq. relative to Formula (VIa). In some embodiments, CDI is in an amount of from about 1.0 eq.to about 1.5 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of from about 1.0 eq. to about 1.25 eq., from about 1.01 eq. to about 1.25 eq., from about 1.02 eq. to about 1.25 eq., from about 1.03 eq. to about 1.25 eq., from about 1.04 eq. to about 1.25 eq., or from about 1.05 eq. to about 1.25 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of from 1.0 eq. to about 1.25 eq., from 1.01 eq. to about 1.25 eq., from 1.02 eq. to 1.25 eq., from 1.03 eq. to about 1.25 eq., from 1.04 eq. to about 1.25 eq., or from 1.05 eq. to about 1.25 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of from 1.0 eq. to 1.25 eq., from 1.01 eq. to 1.25 eq., from 1.02 eq. to 1.25 eq., from 1.03 eq. to 1.25 eq., from 1.04 eq. to 1.25 eq., or from 1.05 eq. to 1.25 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of from 1.0 eq. to 1.1 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of from 1.0 eq. to 1.0 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of from 1.01 eq. to 1.0 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of from 1.01 eq. to 1.05 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of from 1.02 eq. to 1.05 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of from 1.02 eq. to 1.04 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of from 1.02 eq. to 1.03 eq., relative to Formula (VIa). When CDI is used, in some embodiments, CDI is in an amount of 1.01 eq., 1.02 eq., 1.03 eq., 1.04 eq., 1.05 eq., 1.06 eq., 1.07 eq., 1.08 eq., 1.09 eq., or 1.10 eq., relative to Formula (VIa). When CDI is used, in some embodiments, CDI is in an amount of 1.01 eq., 1.02 eq., 1.03 eq., 1.04 eq., or 1.05 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of 1.01 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of 1.02 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of 1.04 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of 1.05 eq., relative to Formula (VIa). In some embodiments, the first mixture (from step 6a)) comprising the activated intermediate of Formula (VIa-AG) is added to the compound of Formula (X) or (Xa) in step 6b). In some embodiments, the first mixture comprising the activated intermediate of Formula (VIa-AG) is added to the compound of Formula (X) or (Xa) in the second solvent.
Attorney Docket No.765549: 086087-032PC When CDI is used in step 6a), in some embodiments, the first mixture comprising the activated intermediate of Formula (VIa-AG1) is added to the compound of Formula (X) or (Xa) in step 6b). In some embodiments, the first mixture comprising the activated intermediate of Formula (VIa-AG1) is added to the compound of Formula (X) or (Xa) in the second solvent. In some embodiments, the first mixture comprising the activated intermediate of Formula (VIa-AG1) is added to the compound of Formula (Xa) in the second solvent. The compound of Formula (X) can be in an amount that is substoichiometric (less than 1.0 eq., e.g., from about 0.5 eq. to 0.99 eq.), stoichiometric (1.0 eq.), or slightly excess (e.g., from 1.01 eq. to about 1.5 eq.), relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in a substoichiometric amount, relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of form about 0.9 eq. to 1.0 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in a stoichiometric amount, relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of from 1.0 eq. to about 1.5 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of at least about 1.0 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of at least 1.0 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of from 1.0 eq. to about 1.5 eq., from 1.0 eq. to about 1.4 eq., from 1.0 eq. to about 1.3 eq., or from 1.0 eq. to about 1.2 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of from 1.0 eq. to 1.2 eq., from 1.0 eq. to 1.1 eq., from 1.0 eq. to 1.05 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of from 1.0 eq. to 1.2 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of from 1.0 eq. to 1.1 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of from 1.0 eq. to 1.05 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of 1.0 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of 1.01 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of 1.02 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of 1.03 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (X) is in an amount of 1.04 eq., relative to Formula
Attorney Docket No.765549: 086087-032PC (VIa). In some embodiments, the compound of Formula (X) is in an amount of 1.05 eq., relative to Formula (VIa). When Boc is the amine-protecting group, the compound of Formula (Xa) can be in an amount that is substoichiometric (less than 1.0 eq., e.g., from about 0.5 eq. to 0.99 eq.), stoichiometric (1.0 eq.), or slightly excess (e.g., from 1.01 eq. to about 1.5 eq.), relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in a substoichiometric amount, relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of form about 0.9 eq. to 1.0 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in a stoichiometric amount, relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of from 1.0 eq. to about 1.5 eq., relative to Formula (VIa). When Boc is the amine-protecting group, in some embodiments, the compound of Formula (Xa) is in an amount of at least about 1.0 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of at least 1.0 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of from 1.0 eq. to about 1.5 eq., from 1.0 eq. to about 1.4 eq., from 1.0 eq. to about 1.3 eq., or from 1.0 eq. to about 1.2 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of from 1.0 eq. to 1.2 eq., from 1.0 eq. to 1.1 eq., from 1.0 eq. to 1.05 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of from 1.0 eq. to 1.2 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of from 1.0 eq. to 1.1 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of from 1.0 eq. to 1.05 eq., relative to Formula (VIa). When Boc is the amine-protecting group, in some embodiments, the compound of Formula (Xa) is in an amount of 1.0 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of 1.01 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of 1.02 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of 1.03 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of 1.04 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of 1.05 eq., relative to Formula (VIa). The first and/or second solvents can be any aprotic solvents that are suitable for the amide coupling reaction via steps 6a) and 6b). In some embodiments, the first and second solvents are independently NMP, THF, MeTHF, EtOAc, DMAc, DMF, MeCN, DMSO,
Attorney Docket No.765549: 086087-032PC DCM, toluene, dioxane, or a mixture thereof. In some embodiments, the first and second solvents are the same. In some embodiments, the first and second solvents are different. In some embodiments, the second solvent comprises the first solvent. In some embodiments, the first and second solvents are each NMP. In general, step 6a) can be conducted at any suitable temperature (e.g., room temperature). In some embodiments, step 6a) is conducted at a temperature of no more than 40°C. In some embodiments, step 6a) is conducted at a temperature of from about 0°C to about 35°C, from about 0°C to about 30°C, from about 5°C to about 30°C, from about 10°C to about 30°C, from about 10°C to about 25°C, or from about 15°C to about 25°C. In some embodiments, step 6a) is conducted at a temperature of from about 15°C to about 25°C. In some embodiments, step 6a) is conducted at a room temperature. In some embodiments, step 6a) is conducted at a temperature of about 20°C. In general, step 6b) can be conducted at any suitable temperature that is sufficient for reacting the activated intermediate of Formula (VIa-AG) with the compound of Formula (X). In some embodiments, step 6b) is conducted at a temperature of from about 20°C to about 40°C, from about 40°C to about 80°C, or from about 80°C to about 120°C. When the compound of Formula (VIa-AG) is Formula (VIa-AG1), in some embodiments, step 6b) is conducted at a temperature of from about 80°C to about 120°C. In some embodiments, step 6b) is conducted at a temperature of from about 90°C to about 110°C. In some embodiments, step 6b) is conducted at a temperature of about 100°C. In some embodiments, the compound of Formula (X) in the second solvent is preheated to a temperature of step 6b), prior to reacting with the activated intermediate of Formula (VIa-AG). In some embodiments, the compound of Formula (Xa) in the second solvent is preheated to about 100°C, prior to reacting with the activated intermediate of Formula (VIa-AG1). The activated intermediate of Formula (VIa-AG) can be used directly in step 6b) without isolation, or isolated and then used in step 6b). In some embodiments, the activated intermediate of Formula (VIa-AG) is used directly in step 6b) without isolation. In some embodiments, the activated intermediate of Formula (VIa-AG1) is used directly in step 6b) without isolation. The compound of Formula (XI) or (XIa) can be prepared in a high yield according to steps 6a) and 6b). In some embodiments, the compound of Formula (XI) or (XIa) is obtained in a yield of at least about 80% via steps 6a) and 6b). In some embodiments, the compound of Formula (XI) or (XIa) is obtained in a yield of at least about 85% via steps 6a) and 6b). In
Attorney Docket No.765549: 086087-032PC some embodiments, the compound of Formula (XIa) is obtained in a yield of at least about 80% via steps 6a) and 6b). In some embodiments, the compound of Formula (XIa) is obtained in a yield of at least about 85% via steps 6a) and 6b). The compound of Formula (XI) or (XIa) can be prepared in a high yield with a high purity according to steps 6a) and 6b). In some embodiments, the compound of Formula (XI) or (XIa) has a purity of at least about 90%, about 95%, about 98%, or about 99%. In some embodiments, the compound of Formula (XI) or (XIa) has a purity of at least about 95%. In some embodiments, the compound of Formula (XI) or (XIa) has a purity of at least about 98%. In some embodiments, the compound of Formula (XI) or (XIa) has a purity of at least about 99%. In some embodiments, the compound of Formula (XI) or (XIa) has a purity of at least about 99.5%. In some embodiments, the compound of Formula (XI) or (XIa) has a purity of about 99.5%. In some embodiments, the compound of Formula (XIa) has a purity of at least about 99%. In some embodiments, the compound of Formula (XIa) has a purity of at least about 99.5%. In some embodiments, the compound of Formula (XIa) has a purity of about 99.5%. Steps 6a) and 6b) can be performed on a large scale, for example up to a 100 kg scale. In some embodiments, steps 6a) and 6b) are performed at a scale of at least 100 g, 500 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25, kg, 30 kg, or 40 kg. In some embodiments, steps 6a) and 6b) are performed at a scale of at least 10 kg. In some embodiments, steps 6a) and 6b) are performed at a scale of at least 25 kg. In some embodiments, steps 6a) and 6b) are performed at a scale of from about 30 kg to about 35 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of at least 100 g, 500 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25, kg, 30 kg, or 40 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of at least 10 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of at least 25 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of from about 30 kg to about 35 kg. Steps 6a) and 6b) can be performed on a manufacturing scale of at least 100 kg scale. In some embodiments, steps 6a) and 6b) are performed at a scale of at least 100 kg, 150 kg, 200 kg, 250 kg, 300 kg, 350 kg, 400 kg, 450kg, or 500 kg. In some embodiments, steps 6a) and 6b) are performed at a scale of at least 100 kg. In some embodiments, steps 6a) and 6b) are performed at a scale of at least 200 kg. In some embodiments, steps 6a) and 6b) are performed at a scale of at least 500 kg. In some embodiments, steps 6a) and 6b) are
Attorney Docket No.765549: 086087-032PC performed at a scale of from about 100 kg to about 500 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of at least 100 kg, 150 kg, 200 kg, 250 kg, 300 kg, 350 kg, 400 kg, 450kg, or 500 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of at least 100 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of at least 200 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of at least 500 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of from about 100 kg to about 500 kg. In some embodiments, the compound of Formula (XI) or (XIa) from step 6b) is free of genotoxic impurities derived from the activating reagent. In some embodiments, the compound of Formula (XIa) from step 6b) is free of genotoxic impurities, when the activating reagent in step 6a) is a non-phosphonium activating reagent. In some embodiments, the compound of Formula (XIa) from step 6b) is free of genotoxic impurities, when the activating reagent in step 6a) is other than BOP. In some embodiments, the compound of Formula (XIa) from step 6b) is free of genotoxic impurities, when the activating reagent in step 6a) is CDI. III-2. Step 7 When PG is an acid labile protecting group, in some embodiments, the converting of the compound of Formula (XI) to Formula (I) according to step 7) further comprises: 7a) combining the compound of Formula (XI) with a first acid to provide a salt of the compound of Formula (I); and 7b) treating the salt of compound of Formula (I) with a first base to provide the compound of Formula (I). In some embodiments, the converting of the compound of Formula (XI) to Formula (I) according to step 7) further comprises: 7a) combining the compound of Formula (XIa) with a first acid to provide a salt of the compound of Formula (I); and 7b) treating the salt of compound of Formula (I) with a first base to provide the compound of Formula (I). The first acid can be any suitable acid that is capable of removing the acid-labile amino-protecting group. In some embodiments, the first acid is HCl, HBr, H2SO4, TFA, H3PO4, p-TsOH, or a mixture thereof. In some embodiments, the first acid is HCl, HBr,
Attorney Docket No.765549: 086087-032PC H2SO4, TFA, H3PO4, p-TsOH, MsOH, or a mixture thereof. In some embodiments, the first acid is HCl. In some embodiments, the first acid is an aqueous HCl solution. The first base can be any base suitable for preparing a neutral form (or a free-base form) of the compound of Formula (I). In some embodiments, the first base is an alkali bicarbonate, an alkali carbonate, an alkali phosphate tribasic, an alkali phosphate dibasic, an alkali hydroxide, or a combination thereof. In some embodiments, the first base is an alkali hydroxide. In some embodiments, the first base is LiOH, NaOH, KOH, or CsOH. In some embodiments, the first base is NaOH. In some embodiments, the first base is an aqueous NaOH solution. In step 7b), a pH is generally controlled under about 13. In some embodiments, step 7b) is conducted at a pH value of no more than about 13, about 12.5, about 12, or about 11.5. In some embodiments, step 7b) is conducted at a pH value of no more than about 12. In some embodiments, step 7b) is conducted at a pH value of no more than about 11.5. In some embodiments, step 7b) is conducted at a pH value of from about 10.5 to about 11.5. In general, step 7a) is conducted in a solvent that is suitable for removing the acid- labile amino-protecting group (e.g., Boc group); and/or step 7b) is conducted in an aqueous solvent suitable for forming a neutral form (or a free-base form) of the compound of Formula (I). In some embodiments, steps 7a) and 7b) are each conducted in a third solvent comprising a C1-4 alcohol and water. In some embodiments, steps 7a) and 7b) are each conducted in a third solvent comprising methanol and water. In general, steps 7a) and 7b) can be conducted at a temperature of below about 60°C. In some embodiments, steps 7a) and 7b) are each conducted at a temperature of from about 10°C to about 50°C. In some embodiments, step 7a) is conducted at a temperature of about 45°C. In some embodiments, step 7b) is conducted at a temperature of about 40°C. The compound of Formula (I) can be prepared in a high yield with a high purity according to steps 7a) and 7b). In some embodiments, the compound of Formula (I) has a yield of at least about 85% or about 90%. In some embodiments, the compound of Formula (I) has a yield of at least about 85% or at least about 90%. In some embodiments, the compound of Formula (I) has a yield of from about 90% to about 93%. In some embodiments, the compound of Formula (I) has a yield of from about 90% to about 94%. In some embodiments, the compound of Formula (I) has a yield of from about 90% to about 95%. In some embodiments, the compound of Formula (I) has a yield of from about 90% to about 96%. In some embodiments, the compound of Formula (I) has a yield of from about 90% to about 97%.
Attorney Docket No.765549: 086087-032PC The purity of the compound of Formula (I) can be determined by a HPLC method (e.g., according to Table 2). In some embodiments, the compound of Formula (I) has a purity of at least about 90%, about 95%, about 98%, or about 99%. In some embodiments, the compound of Formula (I) has a purity of at least about 95%. In some embodiments, the compound of Formula (I) has a purity of at least about 98%. In some embodiments, the compound of Formula (I) has a purity of at least about 99%. In some embodiments, the compound of Formula (I) has a purity of at least about 99.5%. In some embodiments, the compound of Formula (I) has a purity of about 99.9%. The purity of the compound of Formula (I) can also be presented in wt% (as calculated according to the definition given herein). In some embodiments, the compound of Formula (I) has a purity of at least about 90 wt%, about 95 wt%, about 98 wt%, or about 99 wt%. In some embodiments, the compound of Formula (I) has a purity of at least about 95 wt%. In some embodiments, the compound of Formula (I) has a purity of at least about 98 wt%. In some embodiments, the compound of Formula (I) has a purity of at least about 99 wt%. In some embodiments, the compound of Formula (I) has a purity of at least about 99.5 wt%. In some embodiments, the compound of Formula (I) has a purity of about 99.9 wt%. III-3. Step 8 The compound of Formula (I) from step 7b) can be further purified by recrystallization. In some embodiments, after step 7b), the process further comprises: 8a) dissolving the compound of Formula (I) in a recrystallization solvent to form a mixture; 8b) filtering the mixture to produce a solution comprising the compound of Formula (I); 8c) adding an anti-solvent to the solution to form a slurry comprising a solid; and 8d) isolating the solid to provide a recrystallized form of the compound of Formula (I). In some embodiments, the recrystallization solvent comprises a C1-4 alcohol and/or water. In some embodiments, the recrystallization solvent comprises EtOH, water, or a mixture thereof. In some embodiments, the recrystallization solvent comprises water and EtOH. In some embodiments, the recrystallization solvent is a mixture of water and EtOH. In some embodiments of step 8a), the recrystallization solvent is a mixture of water and EtOH; and a ratio of water and EtOH (water : EtOH) is at least about 1:1 (w/w). In some embodiments, a ratio of water and EtOH (water : EtOH) is from about 1.5:1 to about 1:1 (w/w). In some embodiments, a ratio of water and EtOH (water : EtOH) is from about 1.3:1
Attorney Docket No.765549: 086087-032PC to about 1:1 (w/w). In some embodiments, a ratio of water and EtOH (water : EtOH) is about 1.2:1 (w/w). In some embodiments, the mixture in step 8a) is a solution. In some embodiments, step 8a) is conducted at a temperature of from about 35°C to about 60°C. In some embodiments, step 8a) is conducted at a temperature of about 55°C. In some embodiments, the solution from step 8b) is adjusted to a temperature of from about 30°C to about 50°C. In some embodiments, the solution from step 8a) is adjusted to about 45°C and then cooled to about 35°C. In some embodiments, a seed of Formula (I) is added to the solution from step 8b), prior to the addition of an anti-solvent. In some embodiments, the anti-solvent is water. In some embodiments, step 8c) is conducted at a temperature of from about 20°C to about 40°C. In some embodiments, step 8c) is conducted at a temperature of about 35°C. In some embodiments, the slurry from step 8c) is further cooled. In some embodiments, the slurry from step 8c) is further cooled to about 5°C. In some embodiments, the slurry from step 8c) is further milled to provide a solid having a particle size distribution of from about 20 µm to about 100 µm, measured by D50 (a median particle diameter). In some embodiments, the slurry from step 8c) is further milled to provide a solid having a particle size distribution of from about 30 µm to about 65 µm, measured by D50. In some embodiments, in step 8d), the solid is isolated by filtration followed by drying. In some embodiments, the drying is conducted under vacuum at about 55°C. The compound of Formula (I) can have a further improved purity after recrystallization. In some embodiments, the compound of Formula (I) has a purity of at least 99.5%. In some embodiments, the compound of Formula (I) has a purity of 99.9%. In some embodiments, the compound of Formula (I) has a purity of 100.0%. In some embodiments, the compound of Formula (I) has a purity of at least 99.5 wt%. In some embodiments, the compound of Formula (I) has a purity of 99.8 wt%. In some embodiments, the compound of Formula (I) has a purity of 99.9 wt%. In some embodiments, the compound of Formula (I) has a purity of 100.0 wt%. III-4. Steps 1-3 For Preparing a Compound of Formula (VIa) The compound of Formula (VIa) is prepared according to steps 1) to 3), as described herein. In some embodiments, the process further comprises: 3) hydrolyzing a compound of Formula (V)
Attorney Docket No.765549: 086087-032PC
with a second base followed by acidifying with a second acid to provide a compound of Formula (VIa):
wherein: R1 is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, C6-12 aryl, C6-12 aryl-C1-4 alkyl, heterocycloalkyl, heterocycloalkyl-C1-4 alkyl, heteroaryl, or heteroaryl-C1-4 alkyl; and the heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently N, O, or S; and the heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently N, O, or S. In some embodiments, R1 is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-12 aryl, or heteroaryl. In some embodiments, R1 is C6-12 aryl or C6-12 aryl-C1-4 alkyl. In some embodiments, R1 is phenyl or benzyl. In some embodiments, R1 is C1-6 alkyl or C1-6 haloalkyl. In some embodiments, R1 is C1-6 alkyl. In some embodiments, R1 is C1-4 alkyl. In some embodiments, R1 is methyl or ethyl. In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, the compound of Formula (V) is represented by Formula (Va)
Attorney Docket No.765549: 086087-032PC In some embodiments, the compound of Formula (VIa) is prepared by: 3) hydrolyzing a compound of Formula (Va)
with a second base followed by acidifying with a second acid to provide the compound of Formula (VIa). In some embodiments, the second base is an alkali hydroxide, an alkali alkoxide, an alkali carbonate, an alkali phosphate tribasic, an amidine-based compound, a tertiary amine, an aromatic amine base, or a combination thereof. In some embodiments, the second base is an alkali hydroxide. In some embodiments, the second base is LiOH, NaOH, KOH, or CsOH. In some embodiments, the second base is NaOH. In some embodiments, the second base is an aqueous NaOH solution. In some embodiments, the second acid is HCl, HBr, H2SO4, trifluoroacetic acid (TFA), phosphoric acid (H3PO4), p-toluenesulfonic acid (p-TsOH), or a mixture thereof. In some embodiments, the second acid is HCl, HBr, H2SO4, TFA, H3PO4, p-TsOH, methanesulfonic acid (MsOH), or a mixture thereof. In some embodiments, the second acid is HCl. In some embodiments, the second acid is an aqueous HCl solution. In general, the hydrolysis and acidification can be conducted in a solvent comprising water. In some embodiments, step 3) is conducted in a fourth solvent comprising water. In general, step 3) is conducted at any suitable temperature (e.g., from 0°C to 60°C). In some embodiments, the hydrolysis is conducted at about 45°C; and/or the acidification is conducted at an initial temperature of about 20°C and at a temperature of about 10°C. In some embodiments, prior to step 3), the process further comprises: 1) combining a compound of Formula (II):
with a boron reagent, a first transition metal catalyst, and a third base in a fifth solvent to form a compound of Formula (III):
Attorney Docket No.765549: 086087-032PC
2) reacting the compound of Formula (III) with a compound of Formula (IV):
with a second transition metal catalyst and a fourth base in a sixth solvent to provide a compound of Formula (V):
wherein: X1 and X2 are each independently halogen or a sulfonate; B represents a boron-containing group; R1 is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, C6-12 aryl, C6-12 aryl-C1-4 alkyl, heterocycloalkyl, heterocycloalkyl-C1-4 alkyl, heteroaryl, or heteroaryl-C1-4 alkyl; the heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently N, O, or S; and the heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently N, O, or S. The boron reagent can be any boron reagent that is capable of reacting with halo or sulfonate in the compound of Formula (II) to form a boron-containing compound of Formula (III). In some embodiments, the boron reagent is tetrahydroxydiboron, bis(catecholato)diboron, bis(hexylene glycolato)diboron, bis(neopentyl glycolato)diboron, or bis(pinacolato)diboron. In some embodiments, the “B” group in Formula (III) is represented by the formula: i) –BY2, wherein Y is –OH, C1-6 alkyl, C1-6 alkoxy, C6-10 aryloxy, or a carboxylate group;
Attorney Docket No.765549: 086087-032PC ii) –BY, wherein Y is a bidentate C2-8 alkoxy group, a bidentate C6-10 aryloxy group, or a bidentate carboxylate group; iii) a 9-borabycyclo[3,3,l]nonane (9-BBN) group; iv) –BY3M, wherein Y is F or C1-6 alkoxy and M is an alkaline metal ion, an ammonium ion, or a phosphonium ion; or v) –BYM, wherein Y is a tridentate C3-10 alkoxy group and M is an alkaline metal ion, an ammonium ion, or a phosphonium ion. In some embodiments, the “B” group in Formula (III) is –B(OH)2, –B(OEt)2,
wherein M is Li+, Na+, or K+; and the wavy line indicates the attachment to the remainder of Formula (III). In some embodiments, the boron reagent is bis(pinacolato)diboron, represented by the formula:
. In some embodiments, the compound of Formula (III) is represented by Formula (IIIa):
(IIIa). With reference to Formula (II) or (IV), in some embodiments, X1 and X2 are each halo. In some embodiments, X1 and X2 are each bromo. In some embodiments, the compound of Formula (II) is represented by Formula (IIa):
Attorney Docket No.765549: 086087-032PC
(IIa). In some embodiments, the compound of Formula (IV) is represented by Formula (IVa):
In some embodiments, prior to step 3), the process further comprises: 1) combining a compound of Formula (IIa):
(IIa), with a boron reagent, a first transition metal catalyst, and a third base in a fifth solvent to form a compound of Formula (IIIa):
2) reacting the compound of Formula (IIIa) with a compound of Formula (IVa):
with a second transition metal catalyst and a fourth base in a sixth solvent to provide a compound of Formula (Va):
Attorney Docket No.765549: 086087-032PC The first and/or second transition metal catalysts can be a metal catalyst that is commonly used in a Suzuki coupling reaction or a similar coupling reaction. In some embodiments, the first transition metal catalyst is a first palladium catalyst; and the second transition metal catalyst is a second palladium catalyst. In some embodiments, the first and second palladium catalysts are independently selected from the group consisting of Pd(acac)2, [Pd(allyl)Cl]2, Pd(CH3CN)2Cl2, Pd(dba)2, Pd2(dba)3, Pd2(dba)3-CHCl3, Pd(PPh3)4, Pd(OAc)2, Pd(PCy3)2Cl2, Pd(PPh3)2Cl2, Pd[P(o- tol)3]2Cl2, Pd(amphos)Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2-CH2Cl2, Pd(dtbpf)Cl2, Pd(CH3CN)4(BF4)2, PdCl2, XPhos-Pd-G3, Pd-PEPPSl™-lPr, Pd-PEPPSl™-SlPr, or Pd- PEPPSI™-lPent. In some embodiments, the first and second palladium catalysts are each Pd(OAc)2. In some embodiments, the third and fourth bases are independently sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate tribasic, potassium phosphate tribasic, sodium acetate, potassium acetate, cesium acetate, or a combination thereof. In some embodiments, the third and fourth bases are independently sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, or a combination thereof. In some embodiments, the third base is potassium acetate; and the fourth base is potassium carbonate. In some embodiments, steps 1) and 2) further comprises a phosphine reagent. In some embodiments, the phosphine reagent is Ad2BuP, tBu3P-HBF4, (4-(N,N- dimethylamino)phenyl)di-tert-butyl phosphine (Aphos), dicyclohexyl[2′,4′,6′-tris(propan-2- yl)[1,1′-biphenyl]-2-yl]phosphane (XPhos), dicyclohexyl(2′,6′-dimethoxy[1,1′-biphenyl]-2- yl)phosphane (SPhos), 2′-(dicyclohexylphosphanyl)-N2,N2,N6,N6-tetramethyl[1,1′-biphenyl]- 2,6-diamine (CPhose), or 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos). In some embodiments, the phosphine reagent is Ad2BuP. In general, the fifth and/or sixth solvents comprise an aprotic solvent as defined and described herein. In some embodiments, the fifth and/or sixth solvents comprise THF. In some embodiments, the fifth solvent is THF; and the sixth solvent is a mixture of THF and MeOH. In general, steps 1) and 2) are conducted at any suitable temperature (e.g., from 20°C to 70°C). In some embodiments, the boronating reaction of step 1) is conducted at about 65°C. In some embodiments, the coupling reaction of step 2) is conducted at about 50°C. III-5. Steps 4-5 For Preparing a Compound of Formula (X)
Attorney Docket No.765549: 086087-032PC The compound of Formula (X) is prepared according to steps 4) and 5), as described herein. In some embodiments, the process further comprises: 5) converting a compound of Formula (IX):
under a reducing condition to provide a compound of Formula (X):
wherein: PG is an amine-protecting group; and R is hydrogen or absent when PG is a phthalimide protecting group. In some embodiments, prior to step 5, the process further comprises: 4) combining a compound of Formula (VIII):
a compound of Formula (VII):
a fifth base to provide the compound of Formula (IX), wherein PG is an amine-protecting group; R is hydrogen or absent when PG is a phthalimide protecting group; and
Attorney Docket No.765549: 086087-032PC X3 is halogen or a sulfonate. In some embodiments, the amine-protecting group is an acid labile protecting group. In some embodiments, the compounds of Formulae (IX), (X), and (VIII) are represented by the formulae, respectively:
In some embodiments, the amine-protecting group is Boc, SEM, 4-methoxybenzyl, 2,4-dimethoxybenzyl, or Tr. In some embodiments, the amine-protecting group is Boc. In some embodiments, the compounds of Formulae (IX), (X), and (VIII) are represented by Formulae (IXa), (Xa), and (VIIIa), respectively:
In some embodiments, in Formula (VII), X3 is halogen. In some embodiments, X3 is F. In some embodiments, the compound of Formula (VII) is represented by Formula (VIIa):
In some embodiments, the process further comprises: 5) converting a compound of Formula (IXa):
under a reducing condition to provide a compound of Formula (Xa):
Attorney Docket No.765549: 086087-032PC
In some embodiments of step 5), the reducing condition comprises a catalytic hydrogenation. In some embodiments, the catalytic hydrogenation comprises palladium on carbon (Pd/C) and H2 gas. In some embodiments, the catalytic hydrogenation comprises palladium(0) on carbon (Pd0/C) and H2 gas. In some embodiments, prior to step 5), the process further comprises: 4) combining a compound of Formula (VIIIa): (VIIIa), a compound of Formula (VIIa):
(VIIa), and a fifth base to provide a compound of Formula (IXa):
In some embodiments, the fifth base in step 4) is an alkali hydroxide, an alkali alkoxide, an alkali carbonate, an alkali phosphate tribasic, an amidine-based compound, a tertiary amine, an aromatic amine base, or a combination thereof. In some embodiments, the fifth base is a tertiary amine. In some embodiments, the tertiary amine is TEA, DIPEA, pyridine, trimethylamine, N-methylmorpholine, or a mixture thereof. In some embodiments, the tertiary amine is TEA. In some embodiments, the fifth base is TEA. In general, step 4) is conducted in an aprotic solvent as defined and described herein. In some embodiments, step 4) is conducted in an aprotic solvent (as a seventh solvent)
Attorney Docket No.765549: 086087-032PC comprising THF. In some embodiments, step 4) is conducted in a seventh solvent comprising THF. In general, step 5) is conducted in a solvent that is suitable for hydrogenation. In some embodiments, step 5) is conducted in an aprotic solvent (as an eighth solvent) comprising THF. In some embodiments, step 8) is conducted in an eight solvent comprising THF. In general, step 4) is conducted at any suitable temperature (e.g., from 20°C to 60°C). In some embodiments, step 4) is conducted at about 50°C. In general, step 5) is conducted at any suitable temperature (e.g., from 20°C to 60°C). In some embodiments, step 5) is conducted at about 30°C. III-6. Steps 6) to 8) for Preparing a Compound of Formula (I) In one aspect, the present disclosure provides a process for preparing a compound of Formula (I):
the process comprising: 6a) combining a compound of Formula (VIa):
(VIa), with an activating reagent in a first solvent to provide a first mixture comprising an activated intermediate of Formula (VIa-AG1):
Attorney Docket No.765549: 086087-032PC 6b) coupling the activated intermediate of Formula (VIa-AG1) with a compound of Formula (Xa):
in a second solvent to provide a compound of Formula (XIa):
7a) combining the compound of Formula (XIa) with a first acid to provide a salt of the compound of Formula (I); and 7b) treating the salt of compound of Formula (I) with a first base to provide the compound of Formula (I). Steps 6a), 6b), 7a), and 7b) are any one of applicable embodiments as described in Sections III-1 and III-2. With reference to step 6a), in some embodiments, the activating reagent is N,N’- carbonyldiimidazole (CDI), N,N’-thionyldiimidazole, or N-(chlorosulfinyl)-imidazole. In some embodiments, the activating reagent is CDI. In some embodiments, the first solvent is NMP. With reference to steps 6a) and 6b), in some embodiments, the first and second solvents each comprise NMP. In some embodiments, the first and second solvents are each NMP. With reference to step 7a), in some embodiments, the first acid is HCl. In some embodiments, the first acid is an aqueous HCl solution. With reference to step 7b), in some embodiments, the first base is NaOH. In some embodiments, the first base is an aqueous NaOH solution. In another aspect, the present disclosure provides a process for preparing a compound, represented by Formula (I):
Attorney Docket No.765549: 086087-032PC
the process comprising: 6a) combining a compound of Formula (VIa)
with CDI in NMP to form a first mixture comprising an activated intermediate of Formula (VIa-AG1):
6b) coupling the activated intermediate of Formula (VIa-AG1) with a compound of Formula (Xa):
Attorney Docket No.765549: 086087-032PC 7a) combining the compound of Formula (XIa) with an aqueous HCl solution to provide a HCl salt of the compound of Formula (I); and 7b) treating the HCl salt of compound of Formula (I) with an aqueous NaOH solution to provide the compound of Formula (I). With reference to step 6a), in some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is at least 99%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is about 99%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is at least 99.0%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is about 99.0%. With reference to step 6a), in some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is at least 99.5%. In some embodiments, a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is about 99.5%. In some embodiments, the compound of Formula (VIa) is quantitatively converted to the compound of Formula (VIa-AG1). With reference to step 6a), in some embodiments, CDI is in an amount of from 1.01 eq. to 1.05 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of from 1.02 eq. to 1.03 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of 1.02 eq., relative to Formula (VIa). In some embodiments, CDI is in an amount of 1.03 eq., relative to Formula (VIa). With reference to step 6b), in some embodiments, the first mixture comprising the activated intermediate of Formula (VIa-AG1) is added to the compound of Formula (Xa) in the second solvent. In some embodiments, the first mixture comprising the activated intermediate of Formula (VIa-AG1) is added to the compound of Formula (Xa) in NMP. With reference to step 6b), in some embodiments, the compound of Formula (Xa) is in an amount of from 1.0 eq. to 1.05 eq., relative to Formula (VIa). In some embodiments, the compound of Formula (Xa) is in an amount of 1.02 eq., relative to Formula (VIa). In some embodiments, step 6a) is conducted at a temperature of from about 15°C to about 25°C. In some embodiments, step 6a) is conducted at a temperature of about 20°C. In some embodiments, step 6b) is conducted at a temperature of from about 90°C to about 110°C. In some embodiments, step 6a) is conducted at a temperature of about 100°C. In some embodiments, the compound of Formula (Xa) in the second solvent comprising NMP is preheated to about 100°C, prior to reacting with the activated
Attorney Docket No.765549: 086087-032PC intermediate of Formula (VIa-AG1). In some embodiments, the compound of Formula (Xa) in NMP is preheated to about 100°C, prior to reacting with the activated intermediate of Formula (VIa-AG1). In some embodiments, the activated intermediate of Formula (VIa-AG1) is used directly in step 6b) without isolation. In some embodiments, the compound of Formula (XIa) is obtained in a yield of at least about 85% via steps 6a) and 6b). In some embodiments, the compound of Formula (XIa) has a purity of at least about 95%. In some embodiments, the compound of Formula (XIa) has a purity of at least about 98%. In some embodiments, the compound of Formula (XIa) has a purity of at least about 99%. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of at least 10 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of at least 25 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of from about 30 kg to about 35 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a manufacturing scale of at least 100 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of at least 200 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of at least 500 kg. In some embodiments, steps 6a) and 6b), via Formulae (VIa-AG1) and (Xa), are performed at a scale of from about 100 kg to about 500 kg. In some embodiments, step 7b) is conducted at a pH value of no more than about 11.5. In some embodiments, step 7b) is conducted at a pH value of from about 10.5 to about 11.5. In some embodiments, steps 7a) and 7b) are each conducted in a third solvent comprising MeOH and water. In some embodiments, step 7a) is conducted at a temperature of about 45°C. In some embodiments, step 7b) is conducted at a temperature of about 40°C. In some embodiments, the compound of Formula (I), via steps 7a) and 7b), has a yield of from about 90% to about 93%. In some embodiments, the compound of Formula (I) has a purity of at least about 99%. In some embodiments, the compound of Formula (I) has a purity of at least about 99.5%. In some embodiments, the compound of Formula (I) has a purity of about 99.9%. In
Attorney Docket No.765549: 086087-032PC some embodiments, the compound of Formula (I) has a purity of at least about 98 wt%. In some embodiments, the compound of Formula (I) has a purity of at least about 99 wt%. In some embodiments, the compound of Formula (I) has a purity of at least about 99.5 wt%. In some embodiments, the compound of Formula (I) has a purity of about 99.9 wt%. In some embodiments, the compound of Formula (I) from step 7b) is further purified by recrystallization. In some embodiments, after step 7b), the process further comprises: 8a) dissolving the compound of Formula (I) in a recrystallization solvent comprising water and EtOH to form a mixture; 8b) filtering the mixture to produce a solution comprising the compound of Formula (I); 8c) adding water to the solution to form a slurry comprising a solid; and 8d) isolating the solid to provide a recrystallized form of the compound of Formula (I). In some embodiments of step 8a), a ratio of water and EtOH (water : EtOH) is from about 1.3:1 to about 1:1 (w/w). In some embodiments of step 8a), a ratio of water and EtOH (water : EtOH) is about 1.2:1 (w/w). In some embodiments, the mixture in step 8a) is a solution. In some embodiments, step 8a) is conducted at a temperature of about 55°C. In some embodiments, the solution from step 8a) is adjusted to about 45°C and then cooled to about 35°C. In some embodiments, a seed of Formula (I) is added to the solution from step 8b), prior to the addition of water. In some embodiments, step 8c) is conducted at a temperature of about 35°C. In some embodiments, the slurry from step 8c) is further cooled to about 5°C. In some embodiments, the slurry from step 8c) is further milled to provide a solid having a particle size distribution of about 30 µm to 65 µm, measured by D50. In some embodiments, in step 8d), the solid is isolated by filtration followed by drying. In some embodiments, the compound of Formula (I) has a purity of at least 99.5%. In some embodiments, the compound of Formula (I) has a purity of about 99.9%. In some embodiments, the compound of Formula (I) has a purity of about 100.0%. In some embodiments, the compound of Formula (I) has a purity of at least 99.5 wt%. In some embodiments, the compound of Formula (I) has a purity of about 99.9 wt%. In some embodiments, the compound of Formula (I) has a purity of about 100.0 wt%.
Attorney Docket No.765549: 086087-032PC III-7. Steps 1) to 8) for Preparing a Compound of Formula (I) In one aspect, the present disclosure provides a process for preparing a compound of Formula (I):
the process comprising: 1) combining a compound of Formula (IIa):
(IIa), with a boron reagent, a first palladium catalyst, and a third base in a fifth solvent to form a compound of Formula (IIIa):
2) reacting the compound of Formula (IIIa) with a compound of Formula (IVa):
with a second palladium catalyst and a fourth base in a sixth solvent to provide a compound of Formula (Va):
Attorney Docket No.765549: 086087-032PC 3) hydrolyzing the compound of Formula (Va) with a second base followed by acidifying with a second acid to provide a compound of Formula (VIa):
4) combining a compound of Formula (VIIIa): (VIIIa), a compound of Formula (VIIa):
(VIIa), and a fifth base to provide a compound of Formula (IXa):
5) reducing the compound of Formula (IXa) under a catalytic hydrogenation to provide a compound of Formula (Xa):
6a) combining the compound of Formula (VIa) from step 3) with an activating reagent in a first solvent to provide a first mixture comprising an activated intermediate of Formula (VIa-AG1):
Attorney Docket No.765549: 086087-032PC
6b) coupling the activated intermediate of Formula (VIa-AG1) with the compound of Formula (Xa) from step 5) in a second solvent to provide a compound of Formula (XIa):
7a) combining the compound of Formula (XIa) with a first acid to provide a salt of the compound of Formula (I); and 7b) treating the salt of compound of Formula (I) with a first base to provide the compound of Formula (I). In some embodiments, steps 1) to 7b) are any one of applicable embodiments as described in Sections III-1, III-2, III-4, and III-5. In some embodiments, Steps 6a), 6b), 7a), and 7b) are any one of embodiments as described in Section III-6. With reference to step 1), in some embodiments, the boron reagent is bis(pinacolato)diboron, represented by the formula:
. With reference steps 1) and 2), in some embodiments, the first and second palladium catalysts are each Pd(OAc)2. With reference steps 1) and 2), in some embodiments, the third base is potassium acetate; and the fourth base is potassium carbonate. With reference steps 1) and 2), in some embodiments, steps 1) and 2) further comprise a phosphine reagent that is Ad2BuP. With reference steps 1) and 2), in some embodiments, the fifth solvent is THF; and the sixth solvent is a mixture of THF and MeOH.
Attorney Docket No.765549: 086087-032PC With reference to step 3), in some embodiments, the second base is NaOH. In some embodiments, the second base is an aqueous NaOH solution. With reference to step 3), in some embodiments, the second acid is HCl. In some embodiments, the second acid is an aqueous HCl solution. With reference to step 3), in some embodiments, the hydrolysis and acidification are conducted in a fourth solvent comprising water. With reference to step 4), in some embodiments, the fifth base is a tertiary amine. In some embodiments, the fifth base is TEA. With reference to step 4), in some embodiments, step 4) is conducted in an aprotic solvent as a seventh solvent. In some embodiments, step 4) is conducted in a seventh solvent comprising THF. With reference to step 5), in some embodiments, the catalytic hydrogenation comprises palladium on carbon (Pd/C) and H2 gas. In some embodiments, the catalytic hydrogenation comprises palladium(0) on carbon (Pd0/C) and H2 gas. With reference to step 5), in some embodiments, step 5) is conducted in an aprotic solvent as an eighth solvent. In some embodiments, step 8) is conducted in an eight solvent comprising THF. In another aspect, the present disclosure provides a process for preparing a compound of Formula (I):
the process comprising: 1) combining a compound of Formula (IIa):
(IIa), with bis(pinacolato)diboron, Pd(OAc)2, Ad2BuP, and KOAc in THF to form a compound of Formula (IIIa):
Attorney Docket No.765549: 086087-032PC
2) reacting the compound of Formula (IIIa) with a compound of Formula (IVa): (IVa), with Pd(OAc)2, Ad2BuP, and K2CO3 in a mixture of THF and MeOH to provide a compound of Formula (Va):
3) hydrolyzing the compound of Formula (Va) with an aqueous NaOH solution followed by acidifying with an aqueous HCl solution to provide a compound of Formula (VIa):
(VIa); 4) combining a compound of Formula (VIIIa): (VIIIa), a compound of Formula (VIIa):
(VIIa), and TEA in THF to provide a compound of Formula (IXa):
Attorney Docket No.765549: 086087-032PC
) reducing the compound of Formula (IXa) under a catalytic hydrogenation comprising palladium on carbon (Pd/C) and H2 gas in THF to provide a compound of Formula (Xa):
a) combining the compound of Formula (VIa) from step 3) with CDI in NMP to form a first mixture comprising an activated intermediate of Formula (VIa-AG1):
b) coupling the activated intermediate of Formula (VIa-AG1) with the compound of Formula (Xa) from step 5) in NMP to provide a compound of Formula (XIa)
a) combining the compound of Formula (XIa) with an aqueous HCl solution to provide a HCl salt of the compound of Formula (I); and b) treating the HCl salt of compound of Formula (I) with an aqueous NaOH solution to provide the compound of Formula (I).
Attorney Docket No.765549: 086087-032PC In some embodiments, steps 1) to 5) are any one of applicable embodiments as described in Sections III-4 and III-5. In some embodiments, steps 6a), 6b), 7a), and 7b) are any one of embodiments as described in Section III-6. In some embodiments, after step 7b), the process further comprises a recrystallization step according to steps 8a) to 8d) as described in Sections III-3 and III-6. In some embodiments, the recrystallization step is any one of embodiments as described in Section III-6. In some embodiments, the process is according to steps 1) to 8) in FIG.2. IV. COMPOUND OF FORMULA (I) In one aspect, the present disclosure provides a compound of Formula (I):
prepared by a process according to steps 6a), 6b), 7a), and 7b), as described herein. In another aspect, the present disclosure provides a compound of Formula (I), prepared by a process according to steps 6a), 6b), 7a), 7b), and a recrystallization step, each of which is described herein. In some embodiments, the recrystallization step is according to steps 8a) to 8d), as described herein. In another aspect, the present disclosure provides a compound of Formula (I), prepared by a process according to steps 1) to 8), as described herein. In some embodiments, the compound of Formula (I) is prepared according to any one of embodiments as described in Sections III-1 to III-7. In some embodiments, the compound of Formula (I) is prepared according to any one of embodiments as described in Section III-6. In some embodiments, the compound of Formula (I) is prepared according to any one of embodiments as described in Section III-7. In some embodiments, the compound of Formula (I) is prepared according to steps 1) to 8) in FIG.2. In one aspect, the present disclosure provides a crystalline form of a compound of Formula (I), which is substantially free of impurities and other crystalline forms, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.3, 15.0,
Attorney Docket No.765549: 086087-032PC and 16.6 degrees 2θ (± 0.2 degrees 2θ). In one aspect, the present disclosure provides a crystalline form of a compound of Formula (I), which is substantially free of unreacted starting materials, impurities and other crystalline forms, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.3, 15.0, and 16.6 degrees 2θ (± 0.2 degrees 2θ). In another aspect, the present disclosure provides a crystalline form of a compound of Formula (I), prepared according to steps 6a), 6b), 7a), 7b), and recrystallization step 8), each of which is described herein. In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.3, 15.0, and 16.6 degrees 2θ (± 0.2 degrees 2θ). In another aspect, the present disclosure provides a crystalline form of a compound of Formula (I), prepared according to steps 6a), 6b), 7a), 7b), and recrystallization step 8), each of which is described herein, wherein the crystalline form is substantially free of impurities and other crystalline forms; and characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.3, 15.0, and 16.6 degrees 2θ (± 0.2 degrees 2θ). In another aspect, the present disclosure provides a crystalline form of a compound of Formula (I), prepared according to steps 6a), 6b), 7a), 7b), and recrystallization step 8), each of which is described herein, wherein the crystalline form is substantially free of unreacted starting materials, impurities and other crystalline forms; and characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.3, 15.0, and 16.6 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the compound of Formula (I), prepared according to the processes as described herein, is in an anhydrous crystalline form. In an embodiment, the present disclosure provides an anhydrous crystalline form of the compound of Formula (I) having an XRPD pattern substantially as shown in FIG.3. In some embodiments, the crystalline form of a compound of Formula (I) is prepared according to any one of embodiments as described in Section III-3. In some embodiments, the crystalline form of a compound of Formula (I) is prepared according to any one of embodiments as described in Section III-6. In some embodiments, the crystalline form of a compound of Formula (I) is prepared according to any one of embodiments as described in Section III-7. In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.3, 15.0, and 16.6 degrees 2θ (± 0.2 degrees 2θ).
Attorney Docket No.765549: 086087-032PC In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.3, 15.0, 16.6, 25.0, and 23.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.3, 15.0, 16.6, 25.0, 23.1, 11.8, and 22.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.3, 15.0, 16.6, 25.0, 23.1, 11.8, 22.4, and 23.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.3. In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 246.0°C. In some embodiments, the crystalline Form is further characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 245.2°C and an endothermic peak at about 246.0°C. In some embodiments, the crystalline form is further characterized by a weight percent loss of about 0.19 wt% upon heating to about 245°C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, the compound of Formula (I), prepared according to the processes as described herein, is in a crystalline form characterized by an XRPD diffractogram depicted in FIG.3. In any one of embodiments of the compound of Formula (I) or a crystalline form thereof disclosed herein, the compound of Formula (I) has a purity of at least 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%. With reference to the compound of Formula (I) or a crystalline form thereof disclosed herein, in some embodiments, the compound of Formula (I) has a purity of at least 99%. In some embodiments, the compound of Formula (I) has a purity of from 99.1% to 100.0%. In some embodiments, the compound of Formula (I) has a purity of 99 wt%. In some embodiments, the compound of Formula (I) has a purity of from 99.1 wt% to 100.0 wt%. With reference to the compound of Formula (I) or a crystalline form thereof disclosed herein, in some embodiments, the compound of Formula (I) has a purity of at least 99.5%. In some embodiments, the compound of Formula (I) has a purity of from 99.5% to 100.0%. In some embodiments, the compound of Formula (I) has a purity of 99.9%. In some
Attorney Docket No.765549: 086087-032PC embodiments, the compound of Formula (I) has a purity of 100.0%. In some embodiments, the compound of Formula (I) has a purity of at least 99.5 wt%. In some embodiments, the compound of Formula (I) has a purity of from 99.5 wt% to 100.0 wt%. In some embodiments, the compound of Formula (I) has a purity of 99.8 wt%. In some embodiments, the compound of Formula (I) has a purity of 99.9 wt%. In some embodiments, the compound of Formula (I) has a purity of 100.0 wt%. With reference to the compound of Formula (I) or a crystalline form thereof disclosed herein, in some embodiments, the compound of Formula (I) further comprises one or more impurities comprising:
wherein the one or more impurities are present in a total amount of no more than about 5%. In some embodiments, the one or more impurities are present in a total amount of no more than 5%, 4%, 3%, 2%, or 1.5%. In some embodiments, the one or more impurities are present in a total amount of no more than 1.5%. In some embodiments, the one or more impurities are present in a total amount of no more than 1%. In some embodiments, the one or more impurities are present in a total amount of no more than 0.5%. In some embodiments, the one or more impurities are present in a total amount of no more than 0.2%. In some embodiments, the one or more impurities are present in a total amount of no more than 0.1%. In some embodiments, the one or more impurities are present in a total amount of no more than 5 wt%, 4 wt%, 3 wt%, 2 wt%, or 1.5 wt%. In some embodiments, the one or more impurities are present in a total amount of no more than 1.5 wt%. In some embodiments, the one or more impurities are present in a total amount of no more than 1 wt%. In some embodiments, the one or more impurities are present in a total amount of no more than 0.5 wt%. In some embodiments, the one or more impurities are present in a total amount of no more than 0.2 wt%. In some embodiments, the one or more impurities are present in a total amount of no more than 0.1 wt%.
Attorney Docket No.765549: 086087-032PC V. COMPOSITIONS In one aspect, the present disclosure provides a composition comprising a compound of Formula (I):
wherein the composition is at least 100 g. In one aspect, the present disclosure provides a composition comprising a compound of Formula (I):
wherein the composition is at least 100 g and is prepared by a single run of the process via steps 1 to 8, as disclosed herein. In some embodiments, the composition is in an amount of at least 500 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25 kg, 30 kg, or 40 kg. In some embodiments, the composition is in an amount of at least 500 g. In some embodiments, the composition is in an amount of at least 1 kg. In some embodiments, the composition is in an amount of at least 5 kg. In some embodiments, the composition is in an amount of at least 10 kg. In some embodiments, the composition is in an amount of at least 20 kg. In some embodiments, the composition is in an amount of at least 30 kg. In some embodiments, the composition is in an amount of at least 50 kg, 75 kg, 100 kg, 150 kg, 200 kg, 250 kg, 300 kg, 350 kg, 400 kg, 450 kg, or 500 kg. In some embodiments, the composition is in an amount of at least 100 kg. In some embodiments, the composition is in an amount of at least 150 kg. In some embodiments, the composition is in an amount of at least 200 kg. In some embodiments, the composition is in an amount of at least 300 kg. In some embodiments, the composition is in an amount of at least 400 kg. In some embodiments, the composition is in an amount of at least 500 kg. In another aspect, the present disclosure provides a composition comprising a compound of Formula (I):
Attorney Docket No.765549: 086087-032PC
wherein the compound is present in an amount of at least 95% of the composition. In some embodiments, the compound is present in an amount of from about 95% to 100% of the composition. In some embodiments, the compound is present in an amount of at least 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the composition. In some embodiments, the compound is present in an amount of at least 96% of the composition. In some embodiments, the compound is present in an amount of at least 97% of the composition. In some embodiments, the compound is present in an amount of at least 98% of the composition. In some embodiments, the compound is present in an amount of at least 99% of the composition. In some embodiments, the compound is present in an amount of from 99.1% to 100% of the composition. In some embodiments, the compound is present in an amount of at least 99.1% of the composition. In some embodiments, the compound is present in an amount of at least 99.2% of the composition. In some embodiments, the compound is present in an amount of at least 99.3% of the composition. In some embodiments, the compound is present in an amount of at least 99.4% of the composition. In some embodiments, the compound is present in an amount of at least 99.5% of the composition. In some embodiments, the compound is present in an amount of at least 99.6% of the composition. In some embodiments, the compound is present in an amount of at least 99.7% of the composition. In some embodiments, the compound is present in an amount of at least 99.8% of the composition. In some embodiments, the compound is present in an amount of at least 99.9% of the composition. In some embodiments, the compound is present in an amount of 99.9% of the composition. In some embodiments, the compound is present in an amount of 100.0% of the composition. In some embodiments, the compound is present in an amount of at least 95 wt% of the composition. In some embodiments, the compound is present in an amount of from 95 wt% to 100 wt% of the composition. In some embodiments, the compound is present in an
Attorney Docket No.765549: 086087-032PC amount of at least 96 wt%, 97 wt%, 98 wt%, 99 wt%, 99.1 wt%, 99.2 wt%, 99.3 wt%, 99.4 wt%, 99.5 wt%, 99.6 wt%, 99.7 wt%, 99.8 wt%, or 99.9 wt% of the composition. In some embodiments, the compound is present in an amount of at least 96 wt% of the composition. In some embodiments, the compound is present in an amount of at least 97 wt% of the composition. In some embodiments, the compound is present in an amount of at least 98 wt% of the composition. In some embodiments, the compound is present in an amount of at least 99 wt% of the composition. In some embodiments, the compound is present in an amount of from 99.1 wt% to 100 wt% of the composition. In some embodiments, the compound is present in an amount of at least 99.1 wt% of the composition. In some embodiments, the compound is present in an amount of at least 99.2 wt% of the composition. In some embodiments, the compound is present in an amount of at least 99.3 wt% of the composition. In some embodiments, the compound is present in an amount of at least 99.4 wt% of the composition. In some embodiments, the compound is present in an amount of at least 99.5 wt% of the composition. In some embodiments, the compound is present in an amount of at least 99.6 wt% of the composition. In some embodiments, the compound is present in an amount of at least 99.7 wt% of the composition. In some embodiments, the compound is present in an amount of at least 99.8 wt% of the composition. In some embodiments, the compound is present in an amount of at least 99.9 wt% of the composition. In some embodiments, the compound is present in an amount of 99.9 wt% of the composition. In some embodiments, the compound is present in an amount of 100.0 wt% of the composition. In another aspect, the present disclosure provides a composition comprising a compound of Formula (I)
wherein the composition is in an amount of at least 100 g and the compound is present in an amount of at least 95% of the composition. In another aspect, the present disclosure provides a composition comprising a compound of Formula (I)
Attorney Docket No.765549: 086087-032PC
wherein the composition is in an amount of at least 100 g and is prepared by a single run of the process via steps 1 to 8, as disclosed herein; and the compound is present in an amount of at least 95% of the composition. In some embodiments, the composition is in an amount of at least 500 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25 kg, 30 kg, or 40 kg; and the compound is present in an amount of from 95% to 100% of the composition. In some embodiments, the composition is in an amount of at least 500 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25 kg, 30 kg, or 40 kg; and the compound is present in an amount of at least 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the composition. In some embodiments, the composition is in an amount of at least 500 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25 kg, 30 kg, or 40 kg; and the compound is present in an amount of from 99.1% to 100% of the composition. In some embodiments, the composition is in an amount of at least 50 kg, 75 kg, 100 kg, 150 kg, 200 kg, 250 kg, 300 kg, 350 kg, 400 kg, 450 kg, or 500 kg; and the compound is present in an amount of from 95% to 100% of the composition. In some embodiments, the composition is in an amount of at least 50 kg, 75 kg, 100 kg, 150 kg, 200 kg, 250 kg, 300 kg, 350 kg, 400 kg, 450 kg, or 500 kg; and the compound is present in an amount of at least 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the composition. In some embodiments, the composition is in an amount of at least 50 kg, 75 kg, 100 kg, 150 kg, 200 kg, 250 kg, 300 kg, 350 kg, 400 kg, 450 kg, or 500 kg; and the compound is present in an amount of from 99.1% to 100% of the composition. In some embodiments, the composition is in an amount of at least 500 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25 kg, 30 kg, or 40 kg; and the compound is present in an amount of from 95 wt% to 100 wt% of the composition. In some embodiments, the composition is in an amount of at least 500 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25 kg, 30 kg, or 40 kg; and the compound is present in an amount of at least 96 wt%, 97 wt%, 98 wt%, 99 wt%, 99.1 wt%, 99.2 wt%, 99.3 wt%, 99.4 wt%, 99.5 wt%, 99.6 wt%, 99.7 wt%, 99.8 wt%, or 99.9 wt% of the composition. In some embodiments, the composition is in an amount of at least 500 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25 kg, 30 kg,
Attorney Docket No.765549: 086087-032PC or 40 kg; and the compound is present in an amount of from 99.1 wt% to 100 wt% of the composition. In some embodiments, the composition is in an amount of at least 50 kg, 75 kg, 100 kg, 150 kg, 200 kg, 250 kg, 300 kg, 350 kg, 400 kg, 450 kg, or 500 kg; and the compound is present in an amount of from 95 wt% to 100 wt% of the composition. In some embodiments, the composition is in an amount of at least 50 kg, 75 kg, 100 kg, 150 kg, 200 kg, 250 kg, 300 kg, 350 kg, 400 kg, 450 kg, or 500 kg; and the compound is present in an amount of at least 96 wt%, 97 wt%, 98 wt%, 99 wt%, 99.1 wt%, 99.2 wt%, 99.3 wt%, 99.4 wt%, 99.5 wt%, 99.6 wt%, 99.7 wt%, 99.8 wt%, or 99.9 wt% of the composition. In some embodiments, the composition is in an amount of at least 50 kg, 75 kg, 100 kg, 150 kg, 200 kg, 250 kg, 300 kg, 350 kg, 400 kg, 450 kg, or 500 kg; and the compound is present in an amount of from 99.1 wt% to 100 wt% of the composition. In some embodiments, the composition is in an amount of at least 10 kg; and the compound is present in an amount of 99.9% of the composition. In some embodiments, the composition is in an amount of at least 10 kg and is prepared by a single run of the process via steps 1 to 8, as disclosed herein; and the compound is present in an amount of 99.9% of the composition. In some embodiments, the composition is in an amount of at least 10 kg; and the compound is present in an amount of 100.0% of the composition. In some embodiments, the composition is in an amount of at least 20 kg; and the compound is present in an amount of 99.9% of the composition. In some embodiments, the composition is in an amount of at least 20 kg; and the compound is present in an amount of 100.0% of the composition. In some embodiments, the composition is in an amount of at least 30 kg; and the compound is present in an amount of 99.9% of the composition. In some embodiments, the composition is in an amount of at least 30 kg; and the compound is present in an amount of 100.0% of the composition. In some embodiments, the composition is in an amount of at least 100 kg; and the compound is present in an amount of 99.9% of the composition. In some embodiments, the composition is in an amount of at least 100 kg; and the compound is present in an amount of 100.0% of the composition. In some embodiments, the composition is in an amount of at least 150 kg; and the compound is present in an amount of 99.9% of the composition. In some embodiments, the composition is in an amount of at least 150 kg; and the compound is present in an amount of 100.0% of the composition. In some embodiments, the composition is in an amount of at least 200 kg; and the compound is present in an amount of 99.9% of the
Attorney Docket No.765549: 086087-032PC composition. In some embodiments, the composition is in an amount of at least 200 kg; and the compound is present in an amount of 100.0% of the composition. In some embodiments, the composition is in an amount of at least 10 kg; and the compound is present in an amount of 99.9 wt% of the composition. In some embodiments, the composition is in an amount of at least 10 kg; and the compound is present in an amount of 100.0 wt% of the composition. In some embodiments, the composition is in an amount of at least 20 kg; and the compound is present in an amount of 99.9 wt% of the composition. In some embodiments, the composition is in an amount of at least 20 kg; and the compound is present in an amount of 100.0 wt% of the composition. In some embodiments, the composition is in an amount of at least 30 kg; and the compound is present in an amount of 99.9 wt% of the composition. In some embodiments, the composition is in an amount of at least 30 kg; and the compound is present in an amount of 100.0 wt% of the composition. In some embodiments, the composition is in an amount of at least 100 kg; and the compound is present in an amount of 99.9 wt% of the composition. In some embodiments, the composition is in an amount of at least 100 kg; and the compound is present in an amount of 100.0 wt% of the composition. In some embodiments, the composition is in an amount of at least 150 kg; and the compound is present in an amount of 99.9 wt% of the composition. In some embodiments, the composition is in an amount of at least 150 kg; and the compound is present in an amount of 100.0 wt% of the composition. In some embodiments, the composition is in an amount of at least 200 kg; and the compound is present in an amount of 99.9 wt% of the composition. In some embodiments, the composition is in an amount of at least 200 kg; and the compound is present in an amount of 100.0 wt% of the composition. In any one of embodiments described above, the composition further comprises one or more impurities comprising:
wherein the one or more impurities are present in a total amount of no more than about 5% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than about 5%, about 4%, about 3%, about 2%, or about 1.5% of the composition. In
Attorney Docket No.765549: 086087-032PC some embodiments, the one or more impurities are present in a total amount of no more than about 1.5% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than about 1.0 % of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than about 0.9 %, about 0.8 %, about 0.7 %, about 0.6 %, about 0.5 %, about 0.4 %, about 0.3 %, about 0.2 %, or about 0.1% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than about 0.5 % of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than about 0.2 % of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than about 0.1 % of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than 5%, 4%, 3%, 2%, or 1.5% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than 1.5% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than 1.0 % of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than 0.9 %, 0.8 %, 0.7 %, 0.6 %, 0.5 %, 0.4 %, 0.3 %, 0.2 %, or 0.1% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than 0.5 % of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than 0.2 % of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than 0.1 % of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, or about 1.5 wt% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than about 1.5 wt% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than about 1.0 wt% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than about 0.9 wt%, about 0.8 wt%, about 0.7 wt%, about 0.6 wt%,, about 0.5 wt%, about 0.4 wt%, about 0.3 wt%, about 0.2 wt%, or about 0.1 wt% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than about 0.5 wt% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than about 0.2 wt% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than 5 wt%, 4 wt%, 3 wt%, 2 wt%, or 1.5 wt% of the composition. In some
Attorney Docket No.765549: 086087-032PC embodiments, the one or more impurities are present in a total amount of no more than 1.5 wt% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than 1.0 wt% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than 0.9 wt%, 0.8 wt%,, 0.7 wt%, 0.6 wt%,, 0.5 wt%,, 0.4 wt%, 0.3 wt%, 0.2 wt%, or 0.1 wt% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than 0.5 wt% of the composition. In some embodiments, the one or more impurities are present in a total amount of no more than 0.2 wt% of the composition. VI. COMPOUND OF FORMULA (VIa-AG) In one aspect, the present disclosure provides a compound of Formula (VIa-AG):
or a salt thereof, wherein AG is imidazole or a reaction product of a carboxylic acid with DCC, DIC, EDCI, HATU, HBTU, TATU, TBTU, HOBt, or HOAt. In another aspect, the present disclosure provides a compound represented by Formula (VIa-AG1):
or a salt thereof. In some embodiments, the compound of Formula (VIa-AG1) is in a neutral form (or a free-base form), represented by:
Attorney Docket No.765549: 086087-032PC VII. NON-LIMITING EXEMPLARY EMBODIMENTS In further numbered embodiments below, the present disclosure includes: Embodiment 1. A process for preparing a compound, represented by Formula (I):
comprising: 6a) combining a compound of Formula (VIa):
or a salt thereof, with an activating reagent in a first solvent to provide a first mixture comprising an activated intermediate of Formula (VIa-AG):
(VIa-AG), or a salt thereof; 6b) coupling the activated intermediate of Formula (VIa-AG) or the salt thereof with a compound of Formula (X):
or a salt thereof, in a second solvent to provide a compound of Formula (XI):
Attorney Docket No.765549: 086087-032PC
or a salt thereof; and 7) converting the compound or salt thereof of Formula (XI) to Formula (I), wherein: AG is an activated moiety; PG is an amine-protecting group; and R is hydrogen or absent when PG is a phthalimide protecting group. Embodiment 2. The process of embodiment 1, wherein the activating reagent is a non- phosphonium activating reagent. Embodiment 3. A process for preparing a compound, represented by Formula (I):
the process comprising: 6a) combining a compound of Formula (VIa):
(VIa), or a salt thereof, with a non-phosphonium activating reagent in a first solvent to provide a first mixture comprising an activated intermediate of Formula (VIa-AG):
Attorney Docket No.765549: 086087-032PC
or a salt thereof; 6b) coupling the activated intermediate of Formula (VIa-AG) or the salt thereof with a compound of Formula (X):
or a salt thereof, in a second solvent to provide a compound of Formula (XI):
or a salt thereof; and 7) converting the compound or salt thereof of Formula (XI) to Formula (I), wherein: AG is an activated moiety; PG is an amine-protecting group; and R is hydrogen or absent when PG is a phthalimide protecting group. Embodiment 4. The process of embodiment 1, 2, or 3, wherein a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG) is at least about 90%, about 91%, about 92%, about 93%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%. Embodiment 5. The process of embodiment 4, wherein the conversion is at least about 99.5%. Embodiment 6. The process of embodiment 4, wherein the conversion is about 99.5%.
Attorney Docket No.765549: 086087-032PC Embodiment 7. The process of embodiment 4, wherein the compound of Formula (VIa) is quantitatively converted to the compound of Formula (VIa-AG). Embodiment 8. The process of any one of embodiments 1 to 7, wherein the first mixture comprising the activated intermediate of Formula (VIa-AG) is added to the compound of Formula (X) in the second solvent. Embodiment 9. The process of any one of embodiments 1 to 8, wherein the amine- protecting group is an acid labile protecting group. Embodiment 10. The process of any one of embodiments 1 to 9, wherein the compound of Formula (X) and Formula (XI) are represented by the formulae, respectively:
Embodiment 11. The process of embodiment 9 or 10, wherein the amine-protecting group is Boc, SEM, 4-methoxybenzyl, 2,4-dimethoxybenzyl, or Tr. Embodiment 12. The process of embodiment 11, wherein the amine-protecting group is Boc. Embodiment 13. The process of any one of embodiments 1 to 12, wherein the compound of Formula (X) is represented by Formula (Xa):
Embodiment 14. The process of any one of embodiments 1 to 13, wherein the compound of Formula (XI) is represented by Formula (XIa):
Attorney Docket No.765549: 086087-032PC Embodiment 15. The process of any one of embodiments 1 to 14, wherein the activating reagent is CDI, N,N’-thionyldiimidazole, or N-(chlorosulfinyl)-imidazole. Embodiment 16. The process of any one of embodiments 1 to 15, wherein the activating reagent is CDI. Embodiment 17. The process of embodiment 16, wherein CDI is in an amount of from 1.0 eq. to about 1.25 eq., from 1.01 eq. to about 1.25 eq., from 1.02 eq. to about 1.25 eq., from 1.03 eq. to about 1.25 eq., from 1.04 eq. to about 1.25 eq., or from 1.05 eq. to about 1.25 eq., relative to Formula (VIa). Embodiment 18. The process of embodiment 16 or 17, wherein CDI is in an amount of from 1.01 eq. to 1.1 eq., relative to Formula (VIa). Embodiment 19. The process of any one of embodiments 16 to 18, wherein CDI is in an amount of 1.01 eq., 1.02 eq., 1.03 eq., 1.03 eq., or 1.05 eq., relative to Formula (VIa). Embodiment 20. The process of any one of embodiments 16 to 19, wherein CDI is in an amount of from 1.02 eq. to 1.03 eq., relative to Formula (VIa). Embodiment 21. The process of any one of embodiments 16 to 20, wherein CDI is in an amount of 1.02 eq., relative to Formula (VIa). Embodiment 22. The process of any one of embodiments 16 to 20, wherein CDI is in an amount of 1.03 eq., relative to Formula (VIa). Embodiment 23. The process of any one of embodiments 1 to 22, wherein the activated intermediate of Formula (VIa-AG) is represented by Formula (VIa-AG1):
or a salt thereof. Embodiment 24. The process of embodiment 23, wherein a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG1) is about 99.5%. Embodiment 25. The process of embodiment 23, wherein the compound of Formula (VIa) is quantitatively converted to the compound of Formula (VIa-AG1). Embodiment 26. The process of any one of embodiments 1 to 14 wherein the activating reagent is DCC, DIC, EDCI, HATU, HBTU, TATU, TBTU, HOBt, HOAt, or a combination thereof.
Attorney Docket No.765549: 086087-032PC Embodiment 27. The process of any one of embodiments 1 to 14 and 26, wherein the activated moiety (AG) is a reaction product of a carboxylic acid with DCC, DIC, EDCI, HATU, HBTU, TATU, TBTU, HOBt, or HOAt. Embodiment 28. The process of any one of embodiments 1 to 27, wherein the compound of Formula (X) is in an amount of from 1.0 eq. to 1.2 eq., from 1.0 eq. to about 1.1 eq., from 1.0 eq. to 1.05 eq., relative to Formula (VIa). Embodiment 29. The process of any one of embodiments 1 to 27, wherein the compound of Formula (X) is in an amount of from 1.0 eq. to 1.05 eq., relative to Formula (VIa). Embodiment 30. The process of any one of embodiments 1 to 29, wherein the compound of Formula (X) is in an amount of 1.02 eq., relative to Formula (VIa). Embodiment 31. The process of any one of embodiments 1 to 30, wherein the first solvent is NMP, THF, MeTHF, EtOAc, DMAc, DMF, MeCN, DMSO, DCM, toluene, dioxane, or a mixture thereof. Embodiment 32. The process of any one of embodiments 1 to 31, wherein the second solvent is NMP, THF, MeTHF, EtOAc, DMAc, DMF, MeCN, DMSO, DCM, toluene, dioxane, or a mixture thereof. Embodiment 33. The process of any one of embodiments 1 to 32, wherein the first and second solvents are the same. Embodiment 34. The process of embodiment 33, wherein the first and second solvents are each NMP. Embodiment 35. The process of any one of embodiments 1 to 34, wherein step 6a) is conducted at a temperature of from about 0°C to about 35°C, from about 0°C to about 30°C, from about 5°C to about 30°C, from about 10°C to about 30°C, from about 10°C to about 25°C, or from about 15°C to about 25°C. Embodiment 36. The process of embodiment 35, wherein step 6a) is conducted at a temperature of from about 15°C to about 25°C. Embodiment 37. The process of embodiment 36, wherein step 6a) is conducted at a temperature of about 20°C. Embodiment 38. The process of any one of embodiments 1 to 37, wherein step 6b) is conducted at a temperature of from about 20°C to about 40°C, from about 40°C to about 80°C, or from about 80°C to about 120°C.
Attorney Docket No.765549: 086087-032PC Embodiment 39. The process of any one of embodiments 1 to 37, wherein the compound of Formula (X) in the second solvent is preheated to a temperature of step 6b), prior to reacting with the activated intermediate of Formula (VIa-AG). Embodiment 40. The process of any one of embodiments 1 to 39, wherein step 6b) is conducted at a temperature of from about 80°C to about 120°C. Embodiment 41. The process of embodiment 40, wherein step 6b) is conducted at a temperature of from about 90°C to about 110°C. Embodiment 42. The process of embodiment 41, wherein step 6b) is conducted at a temperature of about 100°C. Embodiment 43. The process of embodiment 42, wherein the compound of Formula (X) in the second solvent is preheated to about 100°C, prior to reacting with the activated intermediate of Formula (VIa-AG). Embodiment 44. The process of any one of embodiments 1 to 43, wherein the activated intermediate of Formula (VIa-AG) is used directly in step 6b) without isolation. Embodiment 45. The process of any one of embodiments 1 to 44, wherein the compound of Formula (XI) is obtained in a yield of at least about 80% via steps 6a) and 6b). Embodiment 46. The process of any one of embodiments 1 to 44, wherein the compound of Formula (XI) is obtained in a yield of at least about 85% via steps 6a) and 6b). Embodiment 47. The process of any one of embodiments 1 to 46, wherein the compound of Formula (XI) has a purity of at least about 90%, about 95%, about 98%, or about 99%. Embodiment 48. The process of any one of embodiments 1 to 47, wherein the compound of Formula (XI) has a purity of at least about 95%. Embodiment 49. The process of any one of embodiments 1 to 47, wherein the compound of Formula (XI) has a purity of at least about 98%. Embodiment 50. The process of any one of embodiments 1 to 47, wherein the compound of Formula (XI) has a purity of at least about 99%. Embodiment 51. The process of any one of embodiments 1 to 50, wherein steps 6a) and 6b) are performed at a scale of at least 100 g, 500 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25, kg, 30 kg, or 40 kg. Embodiment 52. The process of any one of embodiments 1 to 51, wherein steps 6a) and 6b) are performed at a scale of at least 10 kg. Embodiment 53. The process of any one of embodiments 1 to 52, wherein steps 6a) and 6b) are performed at a scale of at least 25 kg.
Attorney Docket No.765549: 086087-032PC Embodiment 54. The process of any one of embodiments 1 to 53, wherein steps 6a) and 6b) are performed at a scale of from about 30 kg to about 35 kg. Embodiment 55. The process of any one of embodiments 1 to 54, wherein the compound of Formula (XI) from step 6b) is free of genotoxic impurities derived from the activating reagent. Embodiment 56. The process of any one of embodiments 1 to 55, wherein step 7) comprises: 7a) combining the compound of Formula (XI) with a first acid to provide a salt of the compound of Formula (I); and 7b) treating the salt of compound of Formula (I) with a first base to provide the compound of Formula (I). Embodiment 57. The process of embodiment 56, wherein the first acid is HCl, HBr, H2SO4, TFA, H3PO4, p-TsOH, or a mixture thereof. Embodiment 58. The process of embodiment 56, wherein the first acid is HCl. Embodiment 59. The process of embodiment 56, wherein the first acid is an aqueous HCl solution. Embodiment 60. The process of any one of embodiments 56 to 59, wherein the first base is NaOH. Embodiment 61. The process of any one of embodiments 56 to 59, wherein the first base is an aqueous NaOH solution. Embodiment 62. The process of any one of embodiments 56 to 60, wherein step 7b) is conducted at a pH value of no more than about 13, about 12.5, about 12, or about 11.5. Embodiment 63. The process of any one of embodiments 56 to 62, wherein step 7b) is conducted at a pH value of no more than about 11.5. Embodiment 64. The process of any one of embodiments 56 to 63, wherein step 7b) is conducted at a pH value of from about 10.5 to about 11.5. Embodiment 65. The process of any one of embodiments 56 to 64, wherein steps 7a) and 7b) are each conducted in a third solvent comprising methanol and water. Embodiment 66. The process of any one of embodiments 56 to 65, wherein, after step 7b), the process further comprises: 8a) dissolving the compound of Formula (I) in a recrystallization solvent to form a mixture; 8b) filtering the mixture to produce a solution comprising the compound of Formula (I); 8c) adding an anti-solvent to the solution to form a slurry comprising a solid; and
Attorney Docket No.765549: 086087-032PC 8d) isolating the solid to provide a recrystallized form of the compound of Formula (I). Embodiment 67. The process of embodiment 66, wherein the recrystallization solvent comprises EtOH, water, or a mixture thereof. Embodiment 68. The process of embodiment 66 or 67, wherein the anti-solvent is water. Embodiment 69. The process of any one of embodiments 65 to 68, wherein the recrystallization solvent is a mixture of water and EtOH; and a ratio of water and EtOH is at least about 1:1 (w/w). Embodiment 70. The process of embodiment 66 to 68, wherein the recrystallization solvent is a mixture of water and EtOH; and a ratio of water and EtOH is from about 1.5:1 to about 1:1 (w/w). Embodiment 71. The process of any one of embodiments 66 to 68, and 70, wherein the recrystallization solvent is a mixture of water and EtOH; and a ratio of water and EtOH is about 1.2:1 (w/w). Embodiment 72. The process of any one of embodiments 1 to 71, wherein the compound of Formula (VIa) is prepared by: 3) hydrolyzing a compound of Formula (V):
with a second base followed by acidifying with a second acid to provide the compound of Formula (VIa), wherein: R1 is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, C6-12 aryl, C6-12 aryl-C1-4 alkyl, heterocycloalkyl, heterocycloalkyl-C1-4 alkyl, heteroaryl, or heteroaryl-C1-4 alkyl; and the heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently N, O, or S; and the heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently N, O, or S. Embodiment 73. The process of embodiment 72, wherein R1 is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-12 aryl, or heteroaryl.
Attorney Docket No.765549: 086087-032PC Embodiment 74. The process of embodiment 72 or 73, wherein R1 is C1-6 alkyl or C1-6 haloalkyl. Embodiment 75. The process of any one of embodiments 72 to 74, wherein the second base is an alkali hydroxide, an alkali alkoxide, an alkali carbonate, an alkali phosphate tribasic, an amidine-based compound, a tertiary amine, an aromatic amine base, or a combination thereof. Embodiment 76. The process of any one of embodiments 72 to 74, wherein the second base is an alkali hydroxide selected from LiOH, NaOH, KOH, and CsOH. Embodiment 77. The process of any one of embodiments 72 to 76, wherein the second base is NaOH. Embodiment 78. The process of any one of embodiments 72 to 76, wherein the second base is an aqueous NaOH solution. Embodiment 79. The process of any one of embodiments 72 to 78, wherein the second acid is HCl, HBr, H2SO4, TFA, H3PO4, p-TsOH, or a mixture thereof. Embodiment 80. The process of embodiment 79, wherein the second acid is HCl. Embodiment 81. The process of embodiment 79, wherein the second acid is an aqueous HCl solution. Embodiment 82. The process of any one of embodiments 72 to 81, wherein the hydrolysis and acidification are conducted in a fourth solvent comprising water. Embodiment 83. The process of any one of embodiments 72 to 82, wherein the compound of Formula (V) is represented by Formula (Va):
Embodiment 84. The process of any one of embodiments 72 to 83, wherein the compound of Formula (V) is prepared by: 1) combining a compound of Formula (II):
Attorney Docket No.765549: 086087-032PC with a boron reagent, a first transition metal catalyst, and a third base in a fifth solvent to form a compound of Formula (III):
2) reacting the compound of Formula (III) with a compound of Formula (IV):
with a second transition metal catalyst and a fourth base in a sixth solvent to provide the compound of Formula (V), wherein: X1 and X2 are each independently halogen or a sulfonate; B represents a boron-containing group; R1 is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, C6-12 aryl, C6-12 aryl-C1-4 alkyl, heterocycloalkyl, heterocycloalkyl-C1-4 alkyl, heteroaryl, or heteroaryl-C1-4 alkyl; the heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently N, O, or S; and the heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently N, O, or S. Embodiment 85. The process of embodiment 84, wherein the boron reagent is tetrahydroxydiboron, bis(catecholato)diboron, bis(hexylene glycolato)diboron, bis(neopentyl glycolato)diboron, or bis(pinacolato)diboron. Embodiment 86. The process of embodiment 84, wherein B is represented by the formula: i) –BY2, wherein Y is –OH, C1-6 alkyl, C1-6 alkoxy, C6-10 aryloxy, or a carboxylate group; ii) –BY, wherein Y is a bidentate C2-8 alkoxy group, a bidentate C6-10 aryloxy group, or a bidentate carboxylate group; iii) a 9-borabycyclo[3,3,l]nonane (9-BBN) group; iv) –BY3M, wherein Y is F or C1-6 alkoxy and M is an alkaline metal ion, an ammonium ion, or a phosphonium ion; or
Attorney Docket No.765549: 086087-032PC v) –BYM, wherein Y is a tridentate C3-10 alkoxy group and M is an alkaline metal ion, an ammonium ion, or a phosphonium ion. Embodiment 87. The process of embodiment 84, wherein B is -B(OH)2, -B(OEt)2, - B(OiPr) wherein
Embodiment 88. The process of embodiment 84, wherein the boron reagent is bis(pinacolato)diboron, represented by the formula:
. Embodiment 89. The process of embodiment 84, wherein the compound of Formula (III) is represented by Formula (IIIa):
Embodiment 90. The process of any one of embodiments 84 to 89, wherein X1 and X2 are each halo. Embodiment 91. The process of embodiment 84, wherein the compound of Formula (II) is represented by Formula (IIa):
(IIa). Embodiment 92. The process of embodiment 84, wherein the compound of Formula (IV) is represented by Formula (IVa):
Attorney Docket No.765549: 086087-032PC
Embodiment 93. The process of any one of embodiments 84 to 92, wherein the first transition metal catalyst is a first palladium catalyst; and the second transition metal catalyst is a second palladium catalyst. Embodiment 94. The process of embodiment 93, wherein the first and second palladium catalysts are independently selected from the group consisting of Pd(acac)2, [Pd(allyl)Cl]2, Pd(CH3CN)2Cl2, Pd(dba)2, Pd2(dba)3, Pd2(dba)3-CHCl3, Pd(PPh3)4, Pd(OAc)2, Pd(PCy3)2Cl2, Pd(PPh3)2Cl2, Pd[P(o-tol)3]2Cl2, Pd(amphos)Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2-CH2Cl2, Pd(dtbpf)Cl2, Pd(CH3CN)4(BF4)2, PdCl2, XPhos-Pd-G3, Pd-PEPPSl™-lPr, Pd-PEPPSl™- SlPr, or Pd-PEPPSI™-lPent. Embodiment 95. The process of embodiment 93 or 94, wherein the first and second palladium catalysts are each Pd(OAc)2. Embodiment 96. The process of any one of embodiments 84 to 95, wherein the third and fourth bases are independently sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate tribasic, potassium phosphate tribasic, sodium acetate, potassium acetate, cesium acetate, or a combination thereof. Embodiment 97. The process of embodiment 96, wherein the third base is potassium acetate; and the fourth base is potassium carbonate. Embodiment 98. The process of any one of embodiments 84 to 97, wherein steps 1) and 2) further comprises a phosphine reagent. Embodiment 99. The process of embodiment 98, wherein the phosphine reagent is Ad2BuP, tBu3P-HBF4, (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine (Aphos), dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane (XPhos), dicyclohexyl(2’,6’-dimethoxy[1,1’-biphenyl]-2-yl)phosphane (SPhos), 2’- (dicyclohexylphosphanyl)-N2,N2,N6,N6-tetramethyl[1,1’-biphenyl]-2,6-diamine (CPhose), or 2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl (RuPhos). Embodiment 100. The process of embodiment 98, wherein the phosphine reagent is Ad2BuP. Embodiment 101. The process of any one of embodiments 84 to 100, wherein the fifth solvent is THF; and the sixth solvent is a mixture of THF and MeOH. Embodiment 102. The process of any one of embodiments 1 to 101, wherein the compound of Formula (X) is prepared by:
Attorney Docket No.765549: 086087-032PC 5) converting a compound of Formula (IX):
under a reducing condition to provide a compound of Formula (X), wherein: PG is an amine-protecting group; and R is hydrogen or absent when PG is a phthalimide protecting group. Embodiment 103. The process of embodiment 102, wherein the compound of Formula (IX) is represented by Formula (IXa):
Embodiment 104. The process of embodiment 102 or 103, wherein the reducing condition comprises a catalytic hydrogenation. Embodiment 105. The process of embodiment 104, wherein the catalytic hydrogenation comprises palladium on carbon (Pd/C) and H2 gas. Embodiment 106. The process of any one of embodiments 102 to 105, wherein the compound of Formula (IX) is prepared by: 4) combining a compound of Formula (VIII):
a compound of Formula (VII):
a fifth base to provide the compound of Formula (IX),
Attorney Docket No.765549: 086087-032PC wherein PG is an amine-protecting group; R is hydrogen or absent when PG is a phthalimide protecting group; and X3 is halogen or a sulfonate. Embodiment 107. The process of embodiment 106, wherein the compound of Formula (VIII) is represented by Formula (VIIIa): (VIIIa). Embodiment 108. The process of embodiment 106, wherein X3 is halogen. Embodiment 109. The process of embodiment 106, wherein the compound of Formula (VII) is represented by Formula (VIIa):
(VIIa). Embodiment 110. The process of any one of embodiments 106 to 109, wherein the fifth base is an alkali hydroxide, an alkali alkoxide, an alkali carbonate, an alkali phosphate tribasic, an amidine-based compound, a tertiary amine, an aromatic amine base, or a combination thereof. Embodiment 111. The process of embodiment 110, wherein the fifth base is a tertiary amine. Embodiment 112. The process of embodiment 111, wherein the tertiary amine is TEA, DIPEA, pyridine, trimethylamine, N-methylmorpholine, or a mixture thereof. Embodiment 113. The process of embodiment 111, wherein the tertiary amine is TEA. Embodiment 114. A process for preparing a compound, represented by Formula (I):
comprising: 6a) combining a compound of Formula (VIa)
Attorney Docket No.765549: 086087-032PC
with CDI in NMP to form a first mixture comprising an activated intermediate of Formula (VIa-AG1):
6b) coupling the activated intermediate of Formula (VIa-AG1) with a compound of Formula (Xa):
in NMP to provide a compound of Formula (XIa):
7a) combining the compound of Formula (XIa) with an aqueous HCl solution to provide a HCl salt of the compound of Formula (I); and 7b) treating the HCl salt of compound of Formula (I) with an aqueous NaOH solution to provide the compound of Formula (I). Embodiment 115. A process for preparing a compound, represented by Formula (I):
Attorney Docket No.765549: 086087-032PC
comprising: 1) combining a compound of Formula (IIa):
(IIa), with bis(pinacolato)diboron, Pd(OAc)2, Ad2BuP, and KOAc in THF to form a compound of Formula (IIIa):
2) reacting the compound of Formula (IIIa) with a compound of Formula (IVa):
with Pd(OAc)2, Ad2BuP, and K2CO3 in a mixture of THF and MeOH to provide a compound of Formula (Va):
3) hydrolyzing the compound of Formula (Va) with an aqueous NaOH solution followed by acidifying with an aqueous HCl solution to provide a compound of Formula (VIa):
Attorney Docket No.765549: 086087-032PC
) combining a compound of Formula (VIIIa): (VIIIa), a compound of Formula (VIIa):
(VIIa), and TEA to provide a compound of Formula (IXa):
) reducing the compound of Formula (IXa) under a catalytic hydrogenation comprising palladium on carbon (Pd/C) and H2 gas to provide a compound of Formula (Xa):
a) combining the compound of Formula (VIa) from step 3 with CDI in NMP to form a first mixture comprising an activated intermediate of Formula (VIa-AG1):
Attorney Docket No.765549: 086087-032PC 6b) coupling the activated intermediate of Formula (VIa-AG1) with the compound of Formula (Xa) from step 5) in NMP to provide a compound of Formula (XIa):
7a) combining the compound of Formula (XIa) with an aqueous HCl solution to provide a HCl salt of the compound of Formula (I); and 7b) treating the HCl salt of compound of Formula (I) with an aqueous NaOH solution to provide the compound of Formula (I). Embodiment 116. A compound, represented by Formula (VIa-AG1):
or a salt thereof. Embodiment 117. A composition, comprising a compound of Formula (I):
wherein the composition is in an amount of at least 100 g. Embodiment 118. The composition of embodiment 117, wherein the composition is in an amount of at least 500 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25, kg, 30 kg, or 40 kg. Embodiment 119. A composition, comprising a compound of Formula (I):
Attorney Docket No.765549: 086087-032PC
wherein the compound is present in an amount of at least 95% of the composition. Embodiment 120. The composition of embodiment 118, wherein the compound is present in an amount of at least 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% of the composition. Embodiment 121. A composition comprising a compound of Formula (I)
wherein the composition is in an amount of at least 100 g and the compound is present in an amount of at least 95% of the composition. Embodiment 122. The composition of embodiment 121, wherein the composition is in an amount of at least 500 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25, kg, 30 kg, or 40 kg. Embodiment 123. The composition of embodiment 121 or 122, wherein the compound of Formula (I) is present in an amount of at least 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% of the composition. Embodiment 124. The composition of any one of embodiments 117 to 123, wherein the composition further comprises one or more compounds represented by Formula (VIa) and Formula (XIa), respectively:
or salts thereof, wherein a total amount of the compound of Formula (VIa), the compound of Formula (XIa), and salts thereof is no more than about 5% of the composition.
Attorney Docket No.765549: 086087-032PC Embodiment 125. The composition of embodiment 124, wherein a total amount of the compound of Formula (VIa), the compound of Formula (XIa), and salts thereof is no more than about 5%, about 4%, about 3%, about 2%, or about 1.5% of the composition. Embodiment 126. The composition of embodiment 124, wherein a total amount of the compound of Formula (VIa), the compound of Formula (XIa), and salts thereof is no more than about 1.5% of the composition. Embodiment 127. The composition of any one of embodiments 119 to 126, wherein the content is determined by a HPLC method. Embodiment 128. A crystalline form of a compound of Formula (I):
which is substantially free of impurities and other crystalline forms, characterized by an X- ray powder diffraction (XRPD) pattern comprising peaks at 8.3, 15.0, and 16.6 degrees 2θ (± 0.2 degrees 2θ). Embodiment 129. The crystalline form of embodiment 128, wherein the compound of Formula (I) has a purity of at least 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%. Embodiment 130. The crystalline form of embodiment 128 or 129, wherein the compound of Formula (I) has a purity of at least 99%. Embodiment 131. The crystalline form of any one of embodiments 128 to 130, wherein the purity is determined by a HPLC method. Embodiment 132. A crystalline form of a compound of Formula (I):
which is substantially free of unreacted starting materials, impurities, and other crystalline forms, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.3, 15.0, and 16.6 degrees 2θ (± 0.2 degrees 2θ).
Attorney Docket No.765549: 086087-032PC Embodiment 133. The crystalline form of embodiment 132, wherein the compound of Formula (I) has a purity of at least 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%. Embodiment 134. The crystalline form of embodiment 132 or 133, wherein the compound of Formula (I) has a purity of at least 99%. Embodiment 135. The crystalline form of any one of embodiments 132 to 134, wherein the purity is determined by a HPLC method. Embodiment 136. An anhydrous crystalline form prepared by the process of any one of embodiments 1 to 115, wherein said compound Formula I is further converted to an anhydrous crystalline form of a compound of Formula (I) thereof:
wherein the anhydrous crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.3, 15.0, and 16.6 degrees 2θ (± 0.2 degrees 2θ). Embodiment 137. The process of any one of embodiments 1 to 115, wherein a conversion of the compound of Formula (VIa) to the compound of Formula (VIa-AG) ranges from about 90% to about 99.5%. Embodiment 138. The process of any one of embodiments 1 to 115, and 137, wherein steps 6a) and 6b) are each performed at a scale to provide about 200 g of the compound or salt of Formula (XIa). Embodiment 139. The process of any one of embodiments 1 to 65, 114, 115, 137, and 138, wherein the process further comprises converting the compound of Formula (I) to a recrystallized form of the compound of Formula (I). Embodiment 140. A composition comprising PKC inhibitor means and one or more compounds selected from a compound of Formula (VIa) and a compound of Formula (XIa):
Attorney Docket No.765549: 086087-032PC or a salt thereof, wherein a total amount of the compound of Formula (VIa), the compound of Formula (XIa), and salts thereof is no more than about 5% of the composition. Embodiment 141. The process of any one of embodiments 1 to 115, and 137, wherein steps 6a) and 6b) are each performed at a scale to provide about 200 kg of the compound or salt of Formula (XIa). VIII. EXAMPLES HPLC Methods: A representative HPLC Method for Steps 6a) and 6b) is shown in Table 1: Table 1.
Attorney Docket No.765549: 086087-032PC
A representative HPLC Method in Steps 7) and 8) for analyzing the compound of Formula (I) is shown in Table 2: Table 2.
Attorney Docket No.765549: 086087-032PC
Example 1: Preparation of the Compound of Formula (I) The compound of Formula (I) was prepared according to steps 1) to 8), as one of embodiments as shown in FIG.2. Step 1)
Methyl 3-amino-6-bromopyrazine-2-carboxylate (IIa) (50.00 g, 1.00 equiv (equivalent)) was dissolved in THF (888 g) in reactor (R1) at 25°C. Potassium acetate (32.5 g, 1.54 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (65.5 g, 1.20 equiv), Pd(OAc)2 (0.43 g, 0.005 equiv) and Ad2BuP (0.67 g, 0.010 equiv) were added, followed by THF (220 g). The reaction was then degassed and blanketed with nitrogen three times, before being heated to 67°C for 10 h. The reaction was cooled to 40°C, then THF (445 g) was added, followed by microcrystalline cellulose (10 g). After stirring for 1.5 h at 45°C, the slurry was filtered into a second reactor (R2). The microcrystalline cellulose cake was washed with THF (180 g), and the wash solution was added to R2. The resulting solution was then concentrated to approximately ~225 mL under vacuum, while maintaining the solution temperature below 40°C. The solution temperature was adjusted to 30°C and n- heptane (340 g) was added to R2 over a 3 h period. The resulting slurry was stirred at 30°C for 1 h, cooled to 20 °C over 3 h, and then stirred for 12 h at 20°C. The slurry was filtered
Attorney Docket No.765549: 086087-032PC and the cake washed with n-heptane (135 g). The resulting solid was dried under vacuum at 35°C for 12 h to yield methyl 3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazine-2-carboxylate (IIIa) (64.7 g, 99.0% HPLC purity, 84.4 wt% assay, 90.8% yield) as a dark brown solid. This step was also performed on a large scale with about 49 kg of methyl 3-amino-6- bromopyrazine-2-carboxylate (IIa) which resulted in 54.79 kg , 93.0% yield, and 99.7% HPLC purity. Step 2)
THF (3200 g), MeOH (315 g) and 2-bromo-3-(trifluoromethyl)pyridine (IVa) (425 g, 1.06 equiv) were charged to a reactor (R1) at 25°C. K2CO3 (500 g, 2.02 equiv), Ad2BuP (7.12 g, 0.015 equiv) and Pd(OAc)2 (2.25 g, 0.0075 equiv) were then added to R1. The mixture was stirred for 1 h at 25°C, after which methyl 3-amino-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazine-2-carboxylate (IIIa) (500 g, 1.0 equiv, corrected for potency) was added, and the R1 contents were degassed and blanketed with nitrogen three times. After heating for 6 h at 50°C, the temperature was decreased to 25°C and concentrated to 5V (~2500 mL) under vacuum while maintaining the temperature below 35°C. The reactor contents were cooled to 20°C, methanol (800 g) was added, followed by the dropwise addition of AcOH (550 g) over 3 h. Water (9000 g) was then added to R1 over 4 h, after which the temperature was adjusted to 10°C over 2 h. After stirring for 10 h at 10°C, the reactor contents were filtered, the cake was washed with a mixture of THF/MeOH/H2O (1450 g 0.45:0.2:2.3 THF/MeOH/H2O weight ratio), followed by water (1500 g). The wet cake was then dried under vacuum at 50°C for 20 h to yield methyl 3-amino-6-(3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylate (Va) (512.90 g, 97.9% HPLC purity, 95.7 wt% assay, 91.9% yield) as a dark brown solid. This step was also performed on a large scale with about 54 kg of methyl 3-amino-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxylate (IIIa), which resulted in 54.14 kg , 86.5% yield over two steps, and 97.7% HPLC purity. Step 3)
Attorney Docket No.765549: 086087-032PC
Water (2730 g) and aqueous NaOH (390 g, 30 wt% NaOH, 2.24 equiv) was charged to a reactor (R1), and the internal temperature was adjusted to 25°C. Methyl 3-amino-6-(3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylate (Va) (390 g, 1.00 equiv, potency corrected) and water (780 g) was added to R1, and the reactor contents were stirred at 45°C for 6 h. The reaction was then cooled to 25°C, and the mixture filtered to remove insoluble material. The filter was washed with water (780 g) and the resulting wash was added to the previous filtrate. The resulting aqueous solution was washed with toluene (1365 g) at 25°C, and then L-cysteine (78 g) and THF (1404 g) were added to the aqueous layer, and the solution stirred at 45°C for 2 h. The solution was then cooled to 20°C, and aqueous hydrochloric acid (18 wt%) was added dropwise to adjust the pH below 1.5. The slurry was then cooled to 10°C over 3 h and held at this temperature for 4 h. The slurry was filtered, and the resulting solid was washed with water (2340 g), and then dried under vacuum at 60°C for 16 h to yield 3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic acid (VIa) (354.56 g, 99.9% HPLC purity, 99.2 wt% assay, 94.6% yield) as a yellow solid. This step was also performed on a large scale with about 54 kg of methyl 3-amino-6- (3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylate (Va), which resulted in 47.95 kg , 94.6% yield, and 99.9% HPLC purity. Step 4)
THF (1950 g), tert-butyl (4-methylpiperidin-4-yl)carbamate (VIIIa) (770 g, 1.02 equiv) and TEA (535 g, 1.50 equiv) were added to a reactor, and stirred at 20°C for 1 h. 3- Fluoro-2-nitropyridine (VIIa) (500 g, 1.00 equiv) and THF (250 g) were added, and the reactor contents were heated to 50°C for 18 h. The reaction was cooled to 20°C and IPA
Attorney Docket No.765549: 086087-032PC (400 g) was added, followed by tert-butyl (4-methyl-1-(2-nitropyridin-3-yl)piperidin-4- yl)carbamate (IXa, 2.5 g) seed crystals, and the resulting slurry was stirred at 20°C for 1 h. Water (5000 g) was added dropwise over 7 h, and then the reaction was cooled to 0°C over 3 h, and held at this temperature for 12 h. The solid was filtered, washed with a mixture of THF/IPA/water (1900 g, 1.1:0.2:2.5 wt ratio), and then washed with water (1250 g). The solid was then dried at 50°C for 20 h under vacuum to yield tert-butyl (4-methyl-1-(2- nitropyridin-3-yl)piperidin-4-yl)carbamate (IXa) (1130 g, 99.9% HPLC purity, 100.0 wt% assay, 95.4% yield.) as an orange solid. This step was also performed on a large scale with about 39 kg of tert-butyl (4- methylpiperidin-4-yl)carbamate (VIIIa) and about 25 kg of 3-fluoro-2-nitropyridine (VIIa), which resulted in 55.99 kg, 93.0% yield, and 99.9% HPLC purity. Step 5)
THF (636 g), tert-butyl (4-methyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate (IXa) (120 g, 1.0 equiv), and Pd/C (3.96 g of 10 wt%) were charged to a reactor. The reactor contents were subjected to three cycles of vacuum followed by nitrogen purge, and then three cycles of vacuum followed by hydrogen purge. The reaction was heated to 30°C, and the hydrogen pressure set to 50 psi, after which the reaction was maintained at these conditions for 12 h. The reactor contents were then filtered through Celite (48 g) into a second reactor. The celite cake was washed with THF (432 g) and added to R2. The reaction mixture was then concentrated to 500 mL (~4 vol) under vacuum while maintaining the internal temperature below 40°C. The R2 temperature was adjusted to 50°C and n-heptane (204 g) was add dropwise at 50°C over 1 h. tert-Butyl (1-(2-aminopyridin-3-yl)-4-methylpiperidin-4- yl)carbamate (Xa, 0.60 g) seed crystals were added and the resulting slurry was stirred at 50°C for 1 h. n-Heptane (1240 g) was then added dropwise over 4 h, and then the slurry was cooled to 0°C over 4 h, and then stirred at 0°C for 6 h. The slurry was filtered, and the cake was washed with a mixture of THF and n-heptane (252 g, THF/n-heptane wt ratio = 0.4:1.7), and then washed with n-heptane (252 g). The solid was then dried under vacuum at 45°C for
Attorney Docket No.765549: 086087-032PC 20 h to yield tert-butyl (1-(2-aminopyridin-3-yl)-4-methylpiperidin-4-yl)carbamate (Xa) (103.16 g, 99.9% HPLC purity, 99.6 wt% assay, 94.0% yield) as an off-white solid. This step was also performed on a large scale with about 43 kg of tert-butyl (4- methyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate (IXa), which resulted in 37.2 kg, 94.9 % yield, and 99.9% HPLC purity.
Into a reactor (R1) was added NMP (480 g) and 3-amino-6-(3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic acid (VIa) (120 g, 1.00 equiv), and the internal temperature was set to 20°C. CDI (76.8 g, 1.09 equiv) was added to R1 portion- wise, followed by NMP (60 g), and the reaction was stirred at 20°C for 2 h. In a second reactor (R2), tert-butyl (1-(2-aminopyridin-3-yl)-4-methylpiperidin-4-yl)carbamate (Xa) (132 g, 1.02 equiv) was dissolved in NMP (300 g) and the solution heated to 100°C. The solution in R1 was then added dropwise to R2 over 2 h, R1 was rinsed with NMP (60 g) and this rinse solution was transferred to R2. The solution in R2 was held at 100°C for 5 h, and then cooled to 40°C. tert-Butyl (1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate (XIa, 0.6 g) seed crystals were added to R2, the resulting slurry was stirred for 2 h at 40°C, cooled to 20°C over 13 h and then stirred at 20°C for 3 h. A NMP/water solution (840 g, 2:5 wt ratio NMP/water) was then added over 13 h at 20°C, and then the slurry was stirred at the temperature for 12 h. The slurry was filtered, and the solid was washed with an NMP/water solution (480 g, 2:1 wt ratio NMP/water), followed by water (480 g). The solid was then dried under vacuum at 70°C for 20 h to yield tert-butyl (1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate (XIa) (243.15 g, 99.4% HPLC purity, 85.3 wt% assay, 85.8% yield) as a yellow solid. This step was also performed on a large scale with about 27 kg of 3-amino-6-(3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic acid (VIa) and 29 kg of tert-butyl (1-(2- aminopyridin-3-yl)-4-methylpiperidin-4-yl)carbamate (Xa), which resulted in 46.38 kg, 86.6% yield, and 99.5% HPLC purity.
Attorney Docket No.765549: 086087-032PC Step 7)
Water (231 g) and aqueous HCl (119.2 g, 35 wt% HCl, 9.9 equiv) were charged to a reactor, and the contents mixed for 30 min at 25 °C. tert-Butyl (1-(2-(3-amino-6-(3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4- yl)carbamate (XIa) (70 g, 85.6 wt%, 1.00 equiv), and methanol (112 g) were added to the reactor, and the contents were heated to 45°C for 3 h. The reaction was cooled to 20°C, methanol (168 g) was added, and then then the reaction was heated to 40°C. Aqueous sodium hydroxide (168 g, 30 wt%) was added, then 3-amino-N-(3-(4-amino-4- methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide (I, 0.35 g) seed crystals were added and the resulting slurry was stirred at 40°C for 2 h. The pH was then adjusted within the range of pH 10.5 to 11.5 using 5% aqueous NaOH, after which the slurry was stirred for 2.5 h at 40°C. Water (560 g) was then added dropwise over 4 h at 40°C, the slurry was cooled to 15°C over 4 h and then held at 15°C for 6 h. The slurry was filtered, the solid was washed with water (364 g), and then the solid was dried under vacuum at 50°C for 20 h to yield 3-amino-N-(3-(4-amino-4-methylpiperidin-1- yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide (I) (46.89 g, 100.0% purity, 99.4 wt% assay, 94.3% yield) as a yellow solid. This step was also performed on a large scale with about 45 kg of tert-butyl (1-(2-(3- amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4- methylpiperidin-4-yl)carbamate (XIa), which resulted in 35.56 kg, 93.1% yield, and 99.9% HPLC purity. Step 8)
Attorney Docket No.765549: 086087-032PC EtOH (714 g), 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide (I) (210 g, 1.00 equiv) and water (861 g) were added to a Reactor (R1). The slurry was heated to 55°C for 1 h to obtain a clear solution, which was filtered to Reactor 2 (R2). A mixture of ethanol and water (107 g, 0.23:0.28 wt ratio of EtOH/water) was used to rinse R1 and then filtered into R2. The temperature of the solution in R2 was adjusted to 45°C, then cooled to 35°C over 1 h and then 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide (I, 1.1 g) seed crystals were added to R2. The resulting slurry in R2 was stirred at 35°C for 5 h, before adding water (1680 g) over 8 h at 35°C. The contents of R2 were cooled to 5°C over 5 h, and then stirred at 5°C for 3 h. The slurry was then wet-milled until the particle size distribution target was met (d50 range = 30-65 µm). The slurry was filtered, the resulting solid was washed with water (420 g) and the solid was then dried under vacuum at 55°C for 20 h to yield 3-amino-N-(3-(4-amino-4- methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide (I) (190.7 g, 99.9% purity, 99.8 wt% assay, 90.6% yield) as a pale yellow solid. MS (ESI, m/z): 473.2024 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 10.60 (s, 1H), 8.96 (dd, J = 4.7, 1.0 Hz, 1H), 8.75 (s, 1H), 8.40 (dd, J = 8.1, 1.3 Hz, 1H), 8.10 (dd, J = 4.8, 1.6 Hz, 1H), 8.05 (br. s, 2H), 7.72 (dd, J = 7.9, 4.8 Hz, 1H), 7.55 (dd, J = 7.9, 1.6 Hz, 1H), 7.14 (dd, J = 7.8, 4.8 Hz, 1H), 2.90 - 2.84 (m, 2H), 2.67 - 2.63 (m, 2H), 1.24 - 1.12 (m, 6H), 0.60 (s, 3H). This step was also performed on a large scale with about 35 kg of 3-amino-N-(3-(4- amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide (I), which resulted in 33.89 kg, 96.0% yield, and 99.9% HPLC purity. Table 3 below shows a linking table. Table 3
Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in
Attorney Docket No.765549: 086087-032PC its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.