Synthesis of substituted tricyclic compounds

Abstract

A process for preparing a compound of Formula (I) and a bis-tartrate salt of the compound of Formula (I), diagrammed below, and intermediate Compound D.

Description

NOVEL SYNTHESIS OF SUBSTITUTED TRICYCLIC COMPOUNDS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority to Chinese Patent Application No.202510295172.4, filed March 12, 2025, the contents of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION

[0002] Described herein is a process for preparing substituted tricyclic compounds that can be used as inhibitors of poly-ADP ribose polymerase (PARP), in particular, inhibitors that exhibit selectivity for inhibiting PARP1 relative to PARP2.BACKGROUND OF THE INVENTION

[0003] Research indicates that the human genome may encode 17 different poly-ADP ribose polymerases (PARPs). See Vyas et al., Nature Communications 4:2240 at 2 and Table 1 (DOI: 10.1038 / ncomms3240). Inhibitors of PARPs may be useful in the treatment of various cancers. See W02023025307A1.

[0004] The compound 5 -(4-((3 , 6-difluoro-4-oxo-4, 5 -dihy dropy razolo[ 1 , 5 -a]quinoxalin-7-yl)me-thyl)piperazin-l-yl)-6-fluoro-N-methylpicolinamide, having the chemical structure of Formula (I) shown below, and having the chemical formula C22H20F3N7O2, is disclosed and described in WO 2023 / 169226.(I)SUMMARY OF THE INVENTION

[0005] The present disclosure provides alternative processes for synthesizing the compound of Formula (I) and corresponding synthetic intermediates. The process disclosed herein provides atleast the advantage of not employing stoichiometric alkyltin in the step of converting Compound SMI to Compound C, detailed herein, and does not proceed through a potentially mutagenic ben-zylic bromide intermediate.

[0006] In an aspect, the present disclosure provides a process for preparing Compound C, having the following structure, from Compound SMI, having the following structure, according to Step 1:Compound SMI Compound Cwherein Step 1 comprises: reacting Compound SMI with a nucleophilic reagent and a first base in a first organic solvent in the presence of a palladium catalyst; wherein: X is selected from Cl, Br, I, and OTf (trifluoromethanesulfonate); Ris OR1orNR2R3; R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, phenyl, and benzyl; and R2and R3are independently selected from H, methyl, methoxy, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, secbutyl, phenyl, benzyl, cyclopropyl, and cyclobutyl (or each independently is selected from any subgroup thereof), or R2and R3together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group, for example morpholinyl or piperidinyl. In embodiments, R2is any one of the options listed herein for it and independently R3is any one of the options listed herein for it. In other words, any pair of options for R2and R3is a combination disclosed herein. In embodiments, NR2R3comprises any two of the substituents listed. In embodiments, R2and R3are independently selected from methyl, methoxy, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl and cyclobutyl, or R2and R3together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group, for example morpholinyl or piperidinyl. In embodiments, NR2R3comprises any two of the substituents listed.

[0007] In some embodiments, R is OR1and the nucleophilic reagent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, t-butanol, phenol, benzyl alcohol. In some embodiments, R is NR2R3and the nucleophilic reagent is the corresponding HNR2R3amine. In embodiments, the nucleophilic reagent is selected from an alkylamine, a cycloalkylamine, a dialkylamine, and a dicycloalkylamine. In embodiments, the nucleophilic reagent is selected from methoxymethylamine, aniline, benzylamine, piperidine, morpholine, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, sec-butylamine, benzylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, di-sec-butylamine, dibenzylamine, dicyclopropylamine, and dicyclobutylamine. Forex-ample, if R2is H and R3is sec-butyl, then the nucleophilic reagent is sec-butyl-amine. If R2and R3are both methyl, then the nucleophilic reagent is dimethylamine.

[0008] In some embodiments of Step 1, Compound C has the formula:Compound C-lQrCompound C-2

[0009] In some embodiments of Step 1, the nucleophilic reagent is methanol, and optionally Compound C has the formula:OMeCompound C-l a

[0010] In some embodiments of Step 1, the first base is selected from tetramethylethylenediamine (TMEDA), DIPEA, NaOPh, triethylamine, DBU, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, and NaOMe. In some embodiments of Step 1, the first base is tetramethylethylenediamine (TMEDA). In embodiments of Step 1, the first organic solvent is selected from a polar protic solvent, a polar aprotic solvent, a non-polar solvent, and mixtures thereof. In embodiments of Step 1, the first organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, dimethylformamide, DMSO, DMAc,di chloroethane, chlorobenzene, 1,4-di oxane, 2-MethylTHF, THF, iPrOAc, MEK, toluene, xylene, heptane, and mixtures thereof.

[0011] In embodiments of Step 1, the first organic solvent is a mixture of dimethylformamide and methanol. For example, in some embodiments, the first organic solvent is dimethylforma-mide-methanol in a ratio of from 1 :9 to 9: 1 vol / vol, such as in a ratio of 1 :9 DMF:methanol.

[0012] In embodiments of Step 1, the palladium catalyst is a monodentate phosphine ligand / pal-ladium catalyst or a bidentate phosphine ligand / palladium catalyst. For example, in some embodiments, the palladium catalyst is selected from l,l'-bis(diphenylphosphino)ferrocene)palla-dium(II) dichloride (Pd(dppf)C12), (Rac)-BINAP + Pd(OAc)2, and dppb + Pd(OAc)2. In some embodiments, the palladium catalyst is l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)C12). In embodiments, PdCh or Pd(OAc)2 is used with a bidentate phosphine ligand, for example with l,l'-bis(diphenylphosphino)ferrocene (dppf), (Rac)-BINAP, dppb, bis(2-(2-diphenylphosphanyl)phenyl)ether (DPEphos), 1 , 1 -bi s(diphenylphosphanyl)m ethane (dppm), 2,3-bis(diphenylphosphanyl)bicyclo[2.2.1]hept-5-ene (norphos), 4,12-bis(diphe-nylphosphanyl)- [2.2]-paracy clophane (phanephos), (R)-2,2 ’ -bi s(di-p-toly Iphosphanyl)- 1,1’-binaphthyl (tol-binap), or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos). In embodiments, a palladium catalyst in combination with a monodentate phosphine ligand is used; for example, the monodentate phosphine ligand / palladium catalyst is Pd(PPhs)4 or Pd(t-BusP)2, or a palladium catalyst is used with the monodentate phosphine ligand di-(l-adamantyl)-n-bu-tylphosphine (cataCXium A) and is used with a monodentate phosphine ligand.

[0013] In embodiments of Step 1, X is Br.

[0014] In embodiments of Step 1, the reaction proceeds under an atmosphere of carbon monoxide (CO). For example, the reaction proceeds under an atmosphere of CO wherein the CO pressure is from 0.2 to 2 MPa, 0.3 to 0.6 MPa, 0.34 to 1.5 MPa, 0.3 to 0.4 MPa, 0.4 to 0.5 MPa, or 0.5 to 0.6 MPa.

[0015] In embodiments of Step 1, the reaction proceeds at a temperature of from about 75°C to about 85°C, or at a temperature of from about 70°C to about 80°C, from about 75°C to about 85°C, from about 80°C to about 90°C, or at a temperature of about 80°C, e g., at 80°C.

[0016] In an aspect, the present disclosure provides a process for preparing Compound D, having the following structure, from Compound C, having the following structure, according to Step 2:R Compound C Compound D wherein Step 2 comprises reacting Compound C with a first reducing agent in a second organic solvent; wherein R is OR1or NR2R3; R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, phenyl, and benzyl; and R2and R3are independently selected from H, methyl, methoxy, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, and cyclobutyl (or each independently is selected from any subgroup thereof), or R2and R3together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group, for example morpholinyl or piperidinyl. In embodiments, R2is any one of the options listed herein for it and independently R3is any one of the options listed herein for it. In other words, any pair of options for R2and R3is a combination disclosed herein. In embodiments, NR2R3comprises any two of the substituents listed.

[0017] In embodiments of Step 2, R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, phenyl, and benzyl, e.g., R1is methyl. In embodiments of Step 2, the first reducing agent is selected from DIBAL-morpholine, DIBAL, Cp2ZrHCl, lithium aluminum hydride, DIB AL -H, NaBHsCN, sodium bi s(2-m ethoxy ethoxy)aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, lithium tritertbutoxyaluminum hydride (LTBA), poly(methylhydrosiloxane) + TiCp2F2, TiCL / NaBEL, and EtaSiH + (2,6-difluoro-phenyl)bis(2,3,5,6-tetrafluorophenyl)borane catalyst. In embodiments of Step 2, the first reducing agent is selected from DIBAL-morpholine, sodium bi s(2-m ethoxy ethoxy)aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, and lithium tri tertbutoxy alumnium hydride (LTBA); for example, the first reducing agent is DIBAL-morpholine. In embodiments ofStep 2, in Compound C, R is NR2R3and the first reducing agent is (Cp2ZrHCl). In embodiments of Step 2, R2is Me, R3is OMe and the reducing agent is a hydride source, for example lithium aluminum hydride, DIBAL-H, LTBA and NaBHsCN.

[0018] In embodiments of Step 2, the second organic solvent is selected from a non-polar solvent, a polar aprotic solvent, and mixtures thereof. In embodiments of Step 2, the second organic solvent is selected from toluene, heptane, hexanes, cyclohexane, THF, 2-MeTHF, 1,4-dioxane, dichloromethane, CPME, and mixtures thereof In embodiments of Step 2, the second organic solvent is a mixture of THF and toluene; in some embodiments, the ratio of THF to toluene is from 1:1 to 2:1 vol / vol, or from 1:1 to 1.5:1 vol / vol, or from about 1.2:1 vol / vol to about 1.4:1 vol / vol, e.g., from 1.2:1 vol / vol to 1.4:1 vol / vol.

[0019] In embodiments of Step 2, the reaction proceeds at a temperature of from -15°C to 5°C, or from -10°C to 10°C, or at a temperature of -15°C, -10°C, -5°C, 0°C, 5°C, or 10°C.

[0020] In an aspect, the present disclosure provides a process for preparing a compound of Formula (I), comprising the step of combining Compound D with Compound SM21 according to Step 3 :HN' / Compound D (I)wherein Step 3 comprises reacting Compound D with Compound SM21 under suitable conditions for reductive amination.

[0021] In embodiments of Step 3, Compound D is reacted with Compound SM21 in the presence of a reducing agent and an additive in a solvent, e.g. in the presence of the reducing agent STAB (sodium triacetoxyborohydride) and the additive acetic acid (AcOH). In embodiments of Step 3, Compound D is reacted with Compound SM21 in the presence of a reductive aminase enzymeand NADPH, or Compound D is reacted with Compound SM21 under catalytic reductive amination conditions e g. in the presence of palladium catalyst, platinum catalyst or nickel catalyst under a hydrogen atmosphere. In embodiments of Step 3, the reducing agent is selected from sodium triacetoxyborohydride (STAB) and sodium cyanoborohyride. The reducing agent may also be sodium borohydride, optionally sodium borohydride in combination with acetic acid. In addition, in embodiments, the additive is selected from acetic acid, DIPEA, and Ti(O-iPr)4. In some embodiments, the additive is acetic acid. In embodiments, the solvent is a polar aprotic solvent. For example, the solvent may be selected from NMP, DMAc, DMF, pyridine, and mixtures thereof. In some embodiments, the solvent is NMP.

[0022] In embodiments of Step 3, the reaction proceeds at about 25°C to about 45°C, for example, from about 30°C to about 40°C, e.g. at about 35°C or at 35°C.

[0023] In embodiments of Step 3, the reaction is quenched with a suitable solvent. In some embodiments, the quenching solvent is or comprises, for example, methanol or water or a mixture thereof.

[0024] In an aspect, the present disclosure provides a process for preparing a bis(tartrate) salt of the compound of Formula (I), having the following structure, from the compound of Formula (I), having the following structure, according to Step 4:bis(tartrate) salt of (I) wherein Step 4 comprises: (i) combining the compound of Formula (I) and L-(+)-tartaric acid in a solvent; (ii) seeding the mixture of (i) with the bis(tartrate) salt of the compound of Formula (I); and (iii) adding a solvent to the mixture of (ii). In embodiments of Step 4, the solvent in (i) is selected from acetic acid, water, and mixtures thereof. In embodiments of Step 4, the solvent in (iii) is ethyl acetate or IPA or acetone.

[0025] In an aspect, the present disclosure provides a process for preparing Compound D, having the following structure, from Compound SMI, having the following structure, according to Steps 1 and 2:Compound SMI Compound C-l Compound D wherein Step 1 comprises: reacting Compound SMI with a nucleophilic reagent and a first base in a first organic solvent in the presence of a palladium catalyst; wherein X is selected from Cl, Br, I, and OTf; and R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-bu-tyl, phenyl, and benzyl; and Step 2 comprises: reacting Compound C-l with a first reducing agent in a second organic solvent.

[0026] In embodiments of the process for preparing Compound D, Step 1 takes place under one or more of the following conditions:(i) the nucleophilic reagent is selected from methanol, ethanol, n-propanol, isopropanol, n- butanol, 2-butanol, t-butanol, phenol, and benzyl alcohol;(ii) the first base is selected from tetramethylethylenediamine (TMEDA), DIPEA, NaOPh, triethylamine, DBU, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, and NaOMe, optionally wherein the first base is tetramethylethylenediamine (TMEDA);(iii) the first organic solvent is selected from a polar protic solvent, a polar aprotic solvent, a non-polar solvent, and mixtures thereof, orthe first organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-buta- nol, 2-butanol, dimethylformamide, DMSO, DMAc, di chloroethane, chlorobenzene, 1,4-di- oxane, 2-MethylTHF, THF, iPrOAc, MEK, toluene, xylene, heptane, and mixtures thereof, or the first organic solvent is a mixture of dimethylformamide and methanol that optionally is 1:9 dimethylformamide-methanol;(iv) the palladium catalyst is a bidentate phosphine ligand / palladium catalyst, optionally wherein the palladium catalyst is selected from 1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)C12), (Rac)-BINAP + Pd(OAc)2, and dppb + Pd(OAc)2, or the palladium catalyst is l,l'-bis(diphenylphosphino)fer- rocene)palladium(II) dichloride (Pd(dppf)Ch);(v) the palladium catalyst is PdCL or Pd(OAc)2 and is used with a bidentate phosphine ligand, for example with l,l'-bis(diphenylphosphino)ferrocene (dppf), (Rac)-BINAP, dppb, bis(2-(2-diphenylphosphanyl)phenyl)ether (DPEphos), 1,1 -bi s(diphenylphosphanyl)m ethane (dppm), 2,3-bis(diphenylphosphanyl)bicyclo[2.2.1]hept-5-ene (norphos), 4,12-bis(diphe- nylphosphanyl)-[2.2]-paracyclophane (phanephos), (R)-2,2’-bis(di-p-tolylphosphanyl)-l,l’- binaphthyl (tol-binap), or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos); (vi) a palladium catalyst in combination with a monodentate phosphine ligand is used; for example, the monodentate phosphine ligand / palladium catalyst is Pd(PPh3)4 or Pd(t-BusP)2, or a palladium catalyst is used with the monodentate phosphine ligand di-(l-adamantyl)-n-bu- tylphosphine (cataCXium A) and is used with a monodentate phosphine ligand;(vii) X is Br;(viii) the reaction proceeds under an atmosphere of CO, optionally wherein the CO pressure is 0.34 MPa to 1.5 MPa; and(ix) the reaction proceeds at a temperature of from about 75°C to about 85°C.

[0027] In embodiments of the process for preparing Compound D, the nucleophilic reagent is methanol. In embodiments of the process for preparing Compound D, the nucleophilic reagent is methanol and Compound C-l has the formula:OMeCompound C-l a

[0028] In embodiments of the process for preparing Compound D, Step 2 takes place under one or more of the following conditions:(i) the first reducing agent is selected from DIBAL-morpholine, DIBAL, Cp2ZrHCl, lithium aluminum hydride, DIBAL-H, NaBHsCN, sodium bis(2-methoxyethoxy)aluminum dihydride(Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert- butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, lithium tritertbutoxyalumnium hydride (LTBA), poly(methylhydrosiloxane) + TiCp2F2, TiCh / NaBFL, and EtsSiH + (2,6-difluoro- phenyl)bis(2,3,5,6-tetrafluorophenyl)borane catalyst, orthe first reducing agent is selected from DIBAL-morpholine, sodium bis(2-methoxyeth- oxy)aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, and lithium tritertbutoxyalumnium hydride (LTBA), orthe first reducing agent is DIBAL-morpholine; and(ii) the second organic solvent is selected from a non-polar solvent, a polar aprotic solvent, and mixtures thereof, or the second organic solvent is selected from toluene, heptane, hexanes, cyclohexane, THF, 2-MeTHF, 1,4-dioxane, dichloromethane, CPME, and mixtures thereof, orthe second organic solvent is a mixture of THF and toluene.

[0029] In an aspect, the present disclosure provides a process for preparing a bis(tartrate) salt of the compound of Formula (I), having the following structure, from Compound SMI, having the following structure, according to Steps 1-4:Compound SMI Compound C-l Compound DHN^(I)bis(tartrate) salt of (I)wherein:(i) Step 1 comprises reacting Compound SMI with a nucleophilic reagent and a first base in a first organic solvent in the presence of a palladium catalyst, wherein X is selected from Cl, Br, I, and OTf (trifluoromethanesulfonate); and R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, phenyl, and benzyl;(ii) Step 2 comprises: reacting Compound C-l with a first reducing agent in a second organic solvent;(iii) Step 3 comprises reacting Compound D with Compound SM21 under suitable conditions for reductive amination, and(iv) Step 4 comprises: (a) combining the compound of Formula (I) and L-(+)-tartaric acid in a fourth solvent; (b) seeding the mixture of (i) with the bis(tartrate) salt of the compound of Formula (I); and (c) adding to the mixture of (b) a fifth solvent.

[0030] In embodiments of the process for preparing a bis(tartrate) salt of the compound of Formula (I) from Compound SMI, Step 1 takes place under one or more of the following conditions:(i) the nucleophilic reagent is selected from methanol, ethanol, n-propanol, isopropanol, n- butanol, 2-butanol, t-butanol, phenol, and benzyl alcohol;(ii) the first base is selected from tetramethylethylenediamine (TMEDA), DIPEA, NaOPh, tri ethyl amine, DBU, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, and NaOMe, optionally wherein the first base is tetramethylethylenediamine (TMEDA);(iii) the first organic solvent is selected from a polar protic solvent, a polar aprotic solvent, a non-polar solvent, and mixtures thereof, orthe first organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-buta- nol, 2-butanol, dimethylformamide, DMSO, DMAc, di chloroethane, chlorobenzene, 1,4-di- oxane, 2-MethylTHF, THF, iPrOAc, MEK, toluene, xylene, heptane, and mixtures thereof, or the first organic solvent is a mixture of dimethylformamide and methanol that optionally is 1:9 dimethylformamide-methanol;(iv) the palladium catalyst is a bidentate phosphine ligand / palladium catalyst, optionally wherein the palladium catalyst is selected from l,l'-bis(diphenylphosphino)ferrocene)palla- dium(II) dichloride (Pd(dppf)C12), (Rac)-BINAP + Pd(OAc)2, and dppb + Pd(OAc)2, or the palladium catalyst is l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Cl2);(v) the palladium catalyst is PdCh or Pd(OAc)2 and is used with a bidentate phosphine ligand, for example with l,l'-bis(diphenylphosphino)ferrocene (dppf), (Rac)-BINAP, dppb, bis(2-(2-diphenylphosphanyl)phenyl)ether (DPEphos), l,l-bis(diphenylphosphanyl)methane (dppm), 2,3-bis(diphenylphosphanyl)bicyclo[2.2.1]hept-5-ene (norphos), 4,12-bis(diphe- nylphosphanyl)-[2.2]-paracyclophane (phanephos), (R)-2,2’-bis(di-p-tolylphosphanyl)-l,r- binaphthyl (tol-binap), or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos); (vi) a palladium catalyst in combination with a monodentate phosphine ligand is used; for example, the monodentate phosphine ligand / palladium catalyst is Pd(PPh3)4 or Pd(t-BusP)2, or a palladium catalyst is used with the monodentate phosphine ligand di-(l-adamantyl)-n-bu- tylphosphine (cataCXium A) and is used with a monodentate phosphine ligand;(vii) X is Br;(viii) the reaction proceeds under an atmosphere of CO, optionally wherein the CO pressure is 0.34 MPa to 1.5 MPa; and(ix) the reaction proceeds at a temperature of from about 75°C to about 85°C.

[0031] In embodiments of the process for preparing a bis(tartrate) salt of the compound of Formula (I) from Compound SMI, the nucleophilic reagent is methanol. In embodiments of the process for preparing a bi s(tartrate) salt of the compound of Formula (I) from Compound SMI , the nucleophilic reagent is methanol and Compound C-l has the formula:OMeCompound C- 1 a

[0032] In embodiments of the process for preparing a bis(tartrate) salt of the compound of Formula (I) from Compound SMI, Step 2 takes place under one or more of the following conditions:(i) the first reducing agent is selected from DIBAL-morpholine, DIBAL, Cp2ZrHCl, lithium aluminum hydride, DIBAL -H, NaBFLCN, sodium bis(2-methoxyethoxy)aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert- butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, lithium tritertbutoxyaluminum hydride (LTBA), poly(methylhydrosiloxane) + TiCp2F2, TiCL / NaBFL, and EtsSiH + (2,6-difluoro- phenyl)bis(2,3,5,6-tetrafluorophenyl)borane catalyst,or the first reducing agent is selected from DIBAL-morpholine, sodium bi s(2 -methoxy ethoxy )aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, and lithium tritertbutoxyalumnium hydride (LTBA),or the first reducing agent is DIBAL-morpholine; and(ii) in Compound C, R is NR2R3and the first reducing agent is (Cp2ZrHCl). In embodiments of Step 2, R2is Me, R3is OMe and the reducing agent is a hydride source, for example lithium aluminum hydride, DIBAL-H, LTBA and NaBHsCN;(iii) the second organic solvent is selected from a non-polar solvent, a polar aprotic solvent, and mixtures thereof, or the second organic solvent is selected from toluene, heptane, hexanes, cyclohexane, THF, 2-MeTHF, 1,4-dioxane, dichloromethane, CPME, and mixtures thereof,or the second organic solvent is a mixture of THF and toluene.

[0033] In embodiments of the process for preparing a bis(tartrate) salt of the compound of Formula (I) from Compound SMI, in Step 3, Compound D is reacted with a reducing agent, an additive, and Compound SM21 in a solvent. In embodiments, Compound D is reacted with a reducing agent, an additive, and Compound SM21 in a solvent under one or more of the following conditions:(i) the second reducing agent is selected from sodium triacetoxyborohydride (STAB) and sodium cyanoborohyride;(ii) the additive is selected from acetic acid, DIPEA, and Ti(O-iPr)4, optionally wherein the additive is acetic acid;(iii) the third solvent is a polar aprotic solvent, or the third solvent is selected from NMP, DMAc, DMF, pyridine, and mixtures thereof, or the third solvent is NMP; and(iv) the reaction proceeds at about 35°C.

[0034] In embodiments of the process for preparing a bis(tartrate) salt of the compound of Formula (I) from Compound SMI, Step 4 takes place under one or more of the following conditions:(i) the fourth solvent is selected from acetic acid, water, and mixtures thereof, and(ii) the fifth solvent is ethyl acetate or acetone.

[0035] In an aspect, the present disclosure provides a compound having the following structure:Compound Dor a salt thereof

[0036] In an aspect, the present disclosure provides a process for preparing Compound 6-B, having the following structure, from Compound 6-A, having the following structure, according to Step 1:Step 1Compound 6-Awherein Step 1 comprises reacting Compound 6-A with an electrophilic reagent in a first organic solvent, forming a first intermediate; and reacting the first intermediate with methylamine and hydrochloric acid.

[0037] In some embodiments of the process for preparing Compound 6-B, the electrophilic rea-gent is N, N'-carbonyldiimidazole, 2-(lH-benzotriazol-l-yl)-l, 1,3,3-tetramethyluronium hexafluorophosphate, oxalyl chloride, trichlorotriazine and N-methylmorpholine, hexafluorophosphate azabenzotriazole tetramethyl uronium, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropyl-carbodiimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, propylphosphonic anhydride, or diphenylphosphinic chloride. In some embodiments, the electrophilic reagent is N, N'-carbon-yldiimidazole. In some embodiments, the first organic solvent is dichloromethane, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethylformamide, acetonitrile, or dioxane. In some embodiments, the first organic solvent is dichloromethane. In some embodiments, the reaction proceeds at about 15±5 °C.

[0038] In an aspect, the present disclosure provides a process for preparing Compound 6-C, having the following structure, from Compound 6-B, having the following structure, according to Step 2:o HN-CH3Step 2 Compound 6-Cwherein Step 2 comprises reacting Compound 6-B with an oxidizing agent and an activator in a second organic solvent.

[0039] In some embodiments of the process for preparing Compound 6-C, the oxidizing agent and activator are hydrogen peroxide-urea and trifluoroacetic anhydride, hydrogen peroxide and acetic acid, or meta-chloroperoxybenzoic acid and acetic acid. In some embodiments, the oxidiz-ing agent and activator are hydrogen peroxide-urea and trifluoroacetic anhydride. In some embodiments, the second organic solvent is dichloromethane, acetonitrile, acetic acid, or ethyl acetate. In some embodiments, the second organic solvent is dichloromethane. In some embodiments, the reaction proceeds at about 15±5 °C.

[0040] In an aspect, the present disclosure provides a process for preparing Compound 6-C-l, having the following structure, from Compound 6-C, having the following structure, according to Step 3 :Step 3Compound 6-C Compound 6-C-lwherein Step 3 comprises reacting Compound 6-C with 1-boc-piperazine in the presence of a palladium catalyst and a base in a third organic solvent.

[0041] In some embodiments of the process for preparing Compound 6-C-l, the palladium catalyst is Ruphos PdG3, palladium (II) acetate or Tris(dibenzylideneacetone)dipalladium(0) with 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, l,l-bis(diphenylphosphino)ferrocene, orXPhos. In some embodiments, the palladium catalyst is Ruphos PdG3. In some embodiments, the base is potassium phosphate, cesium carbonate, or sodium tert-butoxide. In some embodiments, the base is potassium phosphate. In some embodiments, the third organic solvent is dioxanedimethylformamide, toluene, tetrahydrofuran, acetonitrile, N-methyl-2-pyrrolidone, 2-methyl tetrahydrofuran, isopropyl alcohol, cyclopentyl methyl ether, isopropyl acetate, dimethyl sulfoxide, dichloroethane, dimethylacetamide, or dimethyl ether. In some embodiments, the third organic solvent is dioxane. In some embodiments, the reaction proceeds at about 85±5 °C.

[0042] In an aspect, the present disclosure provides a process for preparing Compound 6-D-2, having the following structure, from Compound 6-C-l, having the following structure, according to Step 4:Step 4 Compound 6-C-l Compound 6-D-2wherein Step 4 comprises reacting Compound 6-C-l with an organic base and an acid anhydride or oxalyl chloride in a fourth organic solvent.

[0043] In some embodiments of the process for preparing Compound 6-D-2, the organic base is trimethyl amine. In some embodiments, the acid anhydride is trifluoroacetic anhydride, p-tol-uenesulfonic anhydride, or methanesulfonic anhydride. In some embodiments, the fourth organic solvent is tetrahydrofuran. In some embodiments, the reaction proceeds at about 15±5 °C.

[0044] In an aspect, the present disclosure provides a process for preparing Compound 6-5, having the following structure, from Compound 6-D-2, having the following structure, according to Step 5:OCompound 6-D-2 Compound 6-59 wherein Step 5 comprises reacting Compound 6-D-2 with an organic fluoride source in a fifth organic solvent.

[0045] In some embodiments of the process for preparing Compound 6-5, the organic fluoride source is tetrabutylammonium fluoride. In some embodiments, the fifth organic solvent is acetonitrile. In some embodiments, the reaction proceeds at about 60±5 °C.

[0046] In an aspect, the present disclosure provides a process for preparing Compound SM21, having the following structure, from Compound 6-5, having the following structure, according to Step 6:Compound 6-5 Compound SM219 wherein Step 6 comprises reacting Compound 6-5 with an acid in a sixth organic solvent.

[0047] In some embodiments of the process for preparing Compound SM21, the acid is hydrochloric acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, or p-toluenesulfonic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the sixth organic solvent is dioxane, dichloromethane, or a mixture of dioxane and dichloromethane. In some embodiments, the reaction proceeds at about 40±5 °C.

[0048] In an aspect, the present disclosure provides a process for preparing Compound SM21, having the following structure, from Compound 6-A, having the following structure, according to Steps 1-6:Step 1 Step 2Compound 6-A Compound 6-BStep 3 Step 4 Compound 6-C-lCompound 6-D-2Compound 6-5 Compound SM21wherein:(i) Step 1 comprises:reacting Compound 6-A with an electrophilic reagent in a first organic solvent, forming a first intermediate; andreacting the first intermediate with methylamine and hydrochloric acid;(ii) Step 2 comprises reacting Compound 6-B with an oxidizing agent and an activator in a second organic solvent;(iii) Step 3 comprises reacting Compound 6-C with 1-boc-piperazine in the presence of a palladium catalyst and a base in a third organic solvent, and (iv) Step 4 comprises reacting Compound 6-C-l with an organic base and an acid anhydride or oxalyl chloride in a fourth organic solvent;(v) Step 5 comprises reacting Compound 6-D-2 with an organic fluoride source in a fifth organic solvent; and(vi) Step 6 comprises reacting Compound 6-5 with an acid in a sixth organic solvent.

[0049] In some embodiments of the process for preparing Compound SM21, in Step 1, the electrophilic reagent isN, N'-carbonyldiimidazole, 2-(lH-benzotriazol-l-yl)-l, 1,3,3-tetramethyluronium hexafluorophosphate, oxalyl chloride, trichlorotriazine and N-methylmor-pholine, hexafluorophosphate azabenzotriazole tetramethyl uronium, N,N'-dicyclohexylcar-bodiimide, N,N'-diisopropylcarbodiimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, propylphosphonic anhydride, or diphenylphosphinic chloride. In some embodiments, the electrophilic reagent is N, N'-carbonyldiimidazole. In some embodiments, the first organic solvent is dichloromethane, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethylformamide, acetonitrile, or dioxane. In some embodiments, the first organic solvent is dichloromethane. In some embodiments, the reaction proceeds at about 15±5 °C.

[0050] In some embodiments of the process for preparing Compound SM21, in Step 2, the oxidizing agent and activator are hydrogen peroxide-urea and trifluoroacetic anhydride, hydrogen peroxide and acetic acid, or meta-chloroperoxybenzoic acid and acetic acid. In some embodiments, the oxidizing agent and activator are hydrogen peroxide-urea and trifluoroacetic anhydride. In some embodiments, the second organic solvent is dichloromethane, acetonitrile, acetic acid, or ethyl acetate. In some embodiments, the second organic solvent is dichloromethane. In some embodiments, the reaction proceeds at about 15±5 °C.

[0051] In some embodiments of the process for preparing Compound SM21, in Step 3, the palladium catalyst is Ruphos PdG3, palladium (II) acetate or Tris(dibenzylideneacetone)dipalla-dium(0) with 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, l,l-bis(diphenylphosphino)ferrocene, or XPhos. In some embodiments, the palladium catalyst is Ruphos PdG3. In some embodiments, the base is potassium phosphate, cesium carbonate, or sodium tert-butoxide. In some embodiments, the base is potassium phosphate. In some embodiments, the third organic solvent is dioxanedimethylformamide, toluene, tetrahydrofuran, acetonitrile, N-methyl-2-pyrrolidone, 2-methyl tetrahydrofuran, isopropyl alcohol, cyclopentyl methyl ether, isopropyl acetate, dimethyl sulfoxide, di chloroethane, dimethylacetamide, or dimethyl ether. In some embodiments, the third organic solvent is dioxane. In some embodiments, the reaction proceeds at about 85±5 °C.

[0052] In some embodiments of the process for preparing Compound SM21, in Step 4, the organic base is trimethyl amine. In some embodiments, the acid anhydride is trifluoroacetic anhydride, p-toluenesulfonic anhydride, or methanesulfonic anhydride. In some embodiments, the fourth organic solvent is tetrahydrofuran. In some embodiments, the reaction proceeds at about 15±5 °C.

[0053] In some embodiments of the process for preparing Compound SM21, in Step 5, the organic fluoride source is tetrabutylammonium fluoride. In some embodiments, the fifth organic solvent is acetonitrile. In some embodiments, the reaction proceeds at about 60±5 °C.

[0054] In some embodiments of the process for preparing Compound SM21, in Step 6, the acid is hydrochloric acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, or p-toluenesul-fonic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the sixth organic solvent is dioxane, dichloromethane, or a mixture of dioxane and dichloromethane. In some embodiments, the reaction proceeds at about 40±5 °C.DETAILED DESCRIPTION

[0055] WO 2023 / 169226 provides a current process for synthesizing 5-(4-((3,6-difluoro-4-oxo- 4, 5 -dihy dropyrazolo[ 1 , 5 -a]quinoxalin-7 -yl)methyl)piperazin- 1 -yl)-6-fluoro-N-methylpi co-linamide (see Scheme 8 at page 75 and pages 121-123). This process has the disadvantage of using stoichiometric amounts of BuaSnCFbOH, which is toxic. Also, stoichiometric amounts of stannane waste are difficult and expensive to remove at scale The present disclosure provides alternative processes for synthesizing the compound of Formula (I) and corresponding synthetic intermediates. The process disclosed herein provides at least the advantage of not employing stoichiometric amounts of the alkyltin reagent in the step of converting Compound SMI to Compound C, detailed herein, and does not proceed through a potentially mutagenic benzylic bromide intermediate.Definitions

[0056] In order for the present invention to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. The publications and other reference materials referenced herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference.

[0057] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can beused in the practice or testing of the present invention, exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein Is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0058] As used throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.

[0059] As used throughout the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.

[0060] The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the use of the term “about” is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise.

[0061] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0062] As used in the description and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such compositions.

[0063] Throughout the description and claims of this specification the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.

[0064] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0065] Improve, increase, or reduce'. As used herein, the terms “improve,” “increase,” or “reduce,” or grammatical equivalents, indicate values that are relative to a baseline measurement, such as a measurement in the same individual prior to initiation of the treatment described herein, or a measurement in a control subject (or multiple control subject) in the absence of the treatment described herein. A “control subject” is a subject afflicted with the same form of disease as the subject being treated, who is about the same age as the subject being treated.

[0066] Patient: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). In some embodiments, a patient is a human. A human includes pre- and post-natal forms.

[0067] Dry solvent: as used herein, dry solvents are solvents that contain water at a level at or below 300 ppm, such as less than or equal to 300 ppm water, less than or equal to 250 ppm water, less than or equal to 200 ppm water, less than or equal to 150 ppm water, and less than or equal to 100 ppm water. In embodiments herein, dry solvents have water at a level of less than 200 ppm.

[0068] Pharmaceutically acceptable: The term “pharmaceutically acceptable,” as used herein, refers to substances that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Accordingly, pharmaceutically acceptable relates to substances that are not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the relevant active compound without causing clinically unacceptable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

[0069] Pharmaceutically acceptable form: Unless otherwise indicated herein, any description of a formula or compound also includes any pharmaceutically acceptable forms of the compound. As used herein, a “pharmaceutically acceptable form” of a disclosed formula or compound includes, but is not limited to, pharmaceutically acceptable salts, hydrates, solvates, isomers, polymorphs, prodrugs, and isotopically labeled derivatives of disclosed formulas and compounds. Inembodiments, a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, isomers, prodrugs and isotopically labeled derivatives of disclosed compounds. In embodiments, a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, stereoisomers, prodrugs and isotopically labeled derivatives of disclosed compounds. In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt of a disclosed formula or compound as described herein.

[0070] Pharmaceutically acceptable salt: Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci 4-alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate, and aryl sulfonate. Further pharmaceutically acceptable salts include salts formed from the quaternization of an amine using an appropriate electrophile, e.g., an alkyl halide, to form a quaternized alkylated amino salt.

[0071] Substantially. As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the chemical or biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0072] The variable groups defined herein, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted unless otherwise indicated. In embodiments, a variable group is unsubstituted. In embodiments, a variable group is substituted (e.g., comprising 1, 2, 3, 4, or 5 substituents (e g., as described herein) and as valency and stability permits). Still further embodiments are described herein.

[0073] Aliphatic: As used herein, the term aliphatic refers to hydrocarbons and includes both saturated and unsaturated hydrocarbons. An aliphatic may be linear, branched, or cyclic. For example, C1-C20 aliphatics can include C1-C20 alkyls (e.g., linear or branched C1-C20 saturated alkyls), C2-C20 alkenyls e.g., linear or branched C4-C20 dienyls, linear, or branched C6-C20 trienyls, and the like), and C2-C20 alkynyls (e.g., linear or branched C2-C20 alkynyls). C1-C20 aliphatics can include C3-C20 cyclic aliphatics (e.g., C3-C20 cycloalkyls, C4-C20 cycloalkenyls, or C8-C20 cycloalkynyls). In certain embodiments, the aliphatic may comprise one or more cyclic aliphatic and / or one or more heteroatoms such as oxygen, nitrogen, or sulfur and may optionally be substituted with one or more substituents such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester or amide. An aliphatic group is unsubstituted or substituted with one or more substituent groups as described herein. For example, an aliphatic may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR’, -CO2H, -CO2R’, -CN, -OH, -OR’, -OCOR’, -OCO2R’, -NH2, -NHR’, -N(R’)2, -SR’ or-SO2R’, wherein each instance of R’ independently is C1-C20 aliphatic (e.g., C1-C20 alkyl, C1-C15 alkyl, C1-C10 alkyl, or C1-C3 alkyl). In some embodiments, R’ independently is an unsubstituted alkyl (e.g., unsubstituted C1-C20 alkyl, C1-C15 alkyl, Ci-C 10 alkyl, or C1-C3 alkyl). In some embodiments, R’ independently is unsubstituted C1-C3 alkyl. In some embodiments, the aliphatic is unsubstituted. In some embodiments, the aliphatic does not include any heteroatoms.

[0074] Alkyl: As used herein, the term “alkyl” means acyclic linear and branched hydrocarbon groups, e.g., “C1-C20 alkyl” refers to alkyl groups having 1-20 carbons and “C1-C4 alkyl” refers to alkyl groups having 1-4 carbons. Alkyl groups include C1-C20 alkyl, C1-C15 alkyl, C1-C10 alkyl, C1-C4 alkyl, and C1-C3 alkyl). In embodiments, an alkyl group is C1-C4 alkyl. An alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl tert-pen-tylhexyl, isohexyl, etc. The term “lower alky”" means an alkyl group straight chain or branched alkyl having 1 to 6 carbon atoms. Other alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. An alkyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR’, -CO2H, -CO2R’, -CN, -OH, -OR’, -OCOR’, -OCO2R’, -NH2, -NHR’, -N(R’)2, -SR’ or-SO2R’, wherein each instance of R’ independently is C1-C20 aliphatic (e.g., C1-C20 alkyl, C1-C15 alkyl, C1-C10 alkyl, C1-C4 alkyl, or C1-C3 alkyl). In some embodiments, R’ independently is an unsubstituted alkyl (e.g., unsubstituted C1-C20 alkyl, C1-C15 alkyl, C1-C10 alkyl, or C1-C3 alkyl). In some embodiments, R’ independently is unsubstituted C1-C3 alkyl. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, zso-propyl, n-butyl, ec-butyl, isobutyl, tert-butyl, and the like. In some embodiments, the alkyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). In some embodiments, an alkyl group is substituted with a-OH group and may also be referred to herein as a “hydroxyalkyl” group, where the prefix denotes the -OH group and “alkyl” is as described herein. In some embodiments, an alkyl group is substituted with a-OR’ group. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1 -chloroethyl, 2-hydroxy-ethyl, 1,2-difluoroethyl, 3-carboxypropyl, and the like. In substituent groups with multiple alkyl groups such as (Ci-Ce alkyl)2 amino, the alkyl groups may be the same or different.

[0075] Alkylene: The term “alkylene,” as used herein, represents a saturated divalent straight or branched chain hydrocarbon group and is exemplified by methylene, ethylene, isopropylene and the like. Likewise, the term “alkenylene” as used herein represents an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon double bonds that may occur in any stable point along the chain, and the term “alkynylene” herein represents an unsaturated divalent straight or branched chain hydrocarbon group havingone or more unsaturated carbon-carbon triple bonds that may occur in any stable point along the chain. In certain embodiments, an alkylene, alkenylene, or alkynylene group may comprise one or more cyclic aliphatic and / or one or more heteroatoms such as oxygen, nitrogen, or sulfur and may optionally be substituted with one or more substituents such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester or amide. For example, an alkylene, alkenylene, or alkynylene may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR’, -CO2H, -CO2R’, -CN, -OH, -OR’, -OCOR’, -OCO2R’, -NH2, -NHR’, -N(R’)2, -SR’ or -SO2R’, wherein each instance of R’ independently is Ci-C2o aliphatic (e.g., Ci-C2o alkyl, C1-C15 alkyl, C1-C10 alkyl, or C1-C3 alkyl). In some embodiments, R’ independently is an unsubstituted alkyl e.g., unsubstituted Ci-C2o alkyl, C1-C15 alkyl, C1-C10 alkyl, or C1-C3 alkyl). In some embodiments, R’ independently is unsubstituted C1-C3 alkyl. In certain embodiments, an alkylene, alkenylene, or alkynylene is unsubstituted. In certain embodiments, an alkylene, alkenylene, or alkynylene does not include any heteroatoms.

[0076] Alkenyl'. As used herein, “alkenyl” means any linear or branched hydrocarbon chains having one or more unsaturated carbon-carbon double bonds that may occur in any stable point along the chain, e.g., “C2-C2o alkenyl” refers to an alkenyl group having 2-20 carbons. For example, an alkenyl group includes prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like. In some embodiments, the alkenyl comprises 1, 2, or 3 carbon-carbon double bond. In some embodiments, the alkenyl comprises a single carbon-carbon double bond. In some embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. An alkenyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkenyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR’, -CO2H, -CO2R’, -CN, -OH, -OR’, -OCOR’, -OCO2R’, -NH2, -NHR’, -N(R’)2, -SR’ or-SO2R’, wherein each instance of R’ independently is Ci-C2o aliphatic (e.g., Ci-C2o alkyl, C1-C15 alkyl, C1-C10 alkyl, or C1-C3 alkyl). In some embodiments, R’ independently is an unsubstituted alkyl (e.g., unsubstituted Ci-C2o alkyl, C1-C15 alkyl, C1-C10 alkyl, or C1-C3 alkyl). In some embodiments, R’ independently is unsubstituted C1-C3 alkyl. In some embodiments, the alkenyl is unsubstituted. In some embodiments, the alkenyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). In some embodiments, an alkenyl group is substituted with a-OH group and may also be referred to herein as a “hydroxyalkenyl” group, where the prefix denotes the -OHgroup and “alkenyl” is as described herein. Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2-methylethenyl), isopropenyl (also 2-methylethen-2-yl), bu-ten-4-yl, and the like. Nonlimiting examples of substituted alkenyl groups include 2-chloroe-thenyl (also 2-chlorovinyl), 4-hydroxybuten-l-yl, 7-hydroxy-7-methyloct-4-en-2-yl, 7-hydroxy-7-methyloct-3,5-dien-2-yl, and the like.

[0077] AlkynyV As used herein, “alkynyl” means any hydrocarbon chain of either linear or branched configuration, having one or more carbon-carbon triple bonds occurring in any stable point along the chain, e.g., “C2-C20 alkynyl” refers to an alkynyl group having 2-20 carbons. Examples of an alkynyl group include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, etc. In some embodiments, an alkynyl comprises one carbon-carbon triple bond. An alkynyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkynyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR’, -CO2H, -CO2R’, -CN, -OH, -OR’, -OCOR’, -OCO2R’, -NH2, -NHR’, -N(R’)2, -SR’ or-SO2R’, wherein each instance of R’ independently is C1-C20 aliphatic (e.g., Ci-C2o alkyl, C1-C15 alkyl, C1-C10 alkyl, or C1-C3 alkyl). In some embodiments, R’ independently is an unsubstituted alkyl (e.g., unsubstituted C1-C20 alkyl, C1-C15 alkyl, C1-C10 alkyl, or C1-C3 alkyl). In some embodiments, R’ independently is unsubstituted C1-C3 alkyl. In some embodiments, the alkynyl is unsubstituted. In some embodiments, the alkynyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-l-yl, and 2-methyl-hex-4-yn-l-yl. Nonlimiting examples of substituted alkynyl groups include, 5-hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl, 5-hydroxy-5-ethylhept-3-ynyl, and the like.

[0078] Alkoxy: The term “alkoxy” refers to the group -O-alkyl, wherein the alkyl group is as defined above, including from 1 to 10 carbon atoms of a straight, branched, saturated cyclic configuration and combinations thereof, attached to the parent molecular structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, cyclopropyloxy, cyclohexyloxy and the like. “Lower alkoxy” refers to alkoxy groups containing one to six carbons. In some embodiments, C1.4 alkoxy is an alkoxy group which encompasses both straight and branched chain alkyls of from 1 to 4 carbon atoms. Unless stated otherwise in the specification, an alkoxy group can be optionally substituted by one or more substituents e.g., asdescribed herein for alkyl). The terms “alkenoxy” and “alkynoxy” mirror the above description of “alkoxy” wherein the prefix “alk” is replaced with “alken” or “alkyn” respectively, and the parent “alkenyl” or “alkynyl” terms are as described herein.

[0079] Amide. The term “amide” or “amido” refers to a chemical moiety with formula C(O)N(R’)2, -C(O)N(R’)-, -NR’C(O)R’, or -NR’C(O)-, where each R’ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein, or two R’ can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring.

[0080] Amino: The term “amino” or “amine” refers to a -N(R’)2 group, where each R’ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), unless stated otherwise in the specification, each of which moiety can itself be optionally substituted as described herein, or two R’ can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. In embodiments, an amino group is -NHR’, where R’ is aryl (“arylamino”), heteroaryl (“heteroarylamino”), or alkyl (“alkylamino”).

[0081] Aryl: The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein said ring system has a single point of attachment to the rest of the molecule, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 4 to 7 ring members. In some embodiments, an aryl group has 6 ring carbon atoms (“CG aryl,” c. ., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl,” e.g., naphthyl such as 1 -naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Ci4 aryl,” e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Aryl groups can be unsubstituted or substituted. Exemplary aryls include phenyl, naphthyl, and anthracene. Arylrings can be, for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms. Non-limiting examples of aryl groups include: phenyl, naphthylen-l-yl, naphthylen-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-( , V-diethylamino)phenyl, 2-cyanophenyl, 2.6-di- / c / 7-butylphenyl, 3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-l-yl, and 6-cyano-naphthylen-l-yl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-l,3,5-tri-enyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and / or saturated or partially saturated rings.

[0082] Arylalkyl’. The term “arylalkyl” refers to an -(alkyl ene)-aryl radical where aryl and alkylene are as disclosed herein and which are optionally substituted by one or more of the exemplary substituent groups described herein. The “arylalkyl” group is bonded to the parent molecular structure through the alkylene moiety. The term “arylalkoxy” refers to an -O-[arylalkyl] radical (-O-[(alkylene)-aryl]), which is attached to the parent molecular structure through the oxygen. . Examples of arylalkyl groups include, for example, benzyl, 1 -phenyl ethyl, 2-phenylethyl, 3 -phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.

[0083] Arylene: The term “arylene” as used herein refers to an aryl group that is divalent (that is, having two points of attachment to the molecule). Exemplary arylenes include phenylene (e.g., unsubstituted phenylene or substituted phenylene).

[0084] Carbonyl’. The term “carbonyl” refers to a -C(=O)R’, or -C(=O)- group, where R is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, amino, hydroxyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein.

[0085] Cyclic,’. The term “cyclic” as used herein, refers to any covalently closed structure. Cyclic moieties include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and heterocycloalkyls), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and heterocycloalkyls). In some embodiments, cyclic moieties are optionally substituted. In some embodiments, cyclic moieties form part of a ring system. Cyclic moieties can be unsaturated or saturated.

[0086] Cycloaliphatic: The term “cycloaliphatic” refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen and can be saturated or partially unsaturated. A cycloaliphatic group may be substituted or unsubstituted. Fully saturated cycloaliphatics can be termed “cycloalkyl”. Partially unsaturated cycloalkyl groups can be termed “cycloalkenyl” if the carbocycle contains at least one double bond, or “cycloalkynyl” if the carbocycle contains at least one triple bond. Cycloaliphatic groups include groups having from 3 to 13 ring atoms (e.g, C3-13 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range; e.g., “3 to 10 carbon atoms” means that the cycloaliphatic group (e.g., cycloalkyl) can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 10 carbon atoms. The term “cycloaliphatic” also includes bridged and spiro-fused cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (z.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic cycloaliphatic groups include bicycles, tricycles, tetracycles, and the like. In some embodiments, “cycloalkyl” can be a C3-8 cycloalkyl group. In some embodiments, “cycloalkyl” can be a C3-5 cycloalkyl group. Illustrative examples of cycloaliphatic groups include but are not limited to the following moieties: C3-6 cycloaliphatic groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce) and the like. Examples of C3-7 cycloaliphatic groups include norbomyl (C7). Examples of C3-8 cycloaliphatic groups include the aforementioned C3-7 carbocyclyl groups as well as cycloheptyl (C7), cycloheptadienyl (C7), cyclohept-atrienyl (C7), cyclooctyl (Cs), bicyclo[2.2.1]heptanyl, bicy-clo[2.2.2]octanyl, and the like. Examples of C3-13 cycloaliphatic groups include the aforementioned C3-8 carbocyclyl groups as well as octahydro- 1H indenyl, decahydronaphthal enyl, spiro[4.5]decanyl, and the like. Additional, nonlimiting examples of cycloaliphatic groups (including cycloalkyl groups) include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlo-rocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-l-yl, octahydropentalenyl, octahy-dro-177-indenyl, 3a,4,5,6,7,7a-hexahydro-3 / / -inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]deca-nyl, decahydronaphthal enyl, dodecahydro- 1 7-fluorenyl, bicyclo-[2.1.1]hexanyl, bicyclo [2.2.1 ]heptanyl, bicyclo[3.1.1]heptanyl, l,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]oc-tanyl, and bicyclo[3.3.3]undecanyl. A “bicycloalkyl” group includes bridged cycloalkyl groupssuch as bicyclo[l.l.l]pentyl, bicyclo[2.1.1]heptane, adamantanyl, and norbornanyl; as well as spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane. A “heterobicycloalkyl” group is a bicycloalkyl comprising at least one heteroatom in the ring framework.

[0087] Cyano'. The term “cyano” refers to a -CN group.

[0088] Estev. The term “ester” refers to a group of formula -C(O)OR’ or -R’OC(O)-, where R’ is selected from alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocycloalkyl as described herein.

[0089] Halogen ox Halo. As used herein, the term “halogen” or “halo” means fluorine, chlorine, bromine, or iodine.

[0090] Haloalkyl: The term “haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen. Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF3, CF2CF3). Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, di chloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

[0091] Haloalkoxy: The term “haloalkoxy” refers to the group -O-haloalkyl, wherein the haloalkyl group is as defined above. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and pentafluoroethoxyl.

[0092] Heteroalky . The term “heteroalkyl” is meant a branched or unbranched alkyl, alkenyl, or alkynyl group as defined herein (including groups having from 1 to 14 carbon atoms) which also comprise at least one heteroatom (e.g., 1, 2, 3 or 4 heteroatoms) independently selected from the group consisting of N, O, S, and P. Heteroalkyls include tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphorami dates, sulfonamides, and disulfides. A heteroalkyl group may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. Examples of heteroalkyls include polyethers, such as methoxymethyl and ethoxyethyl. Accordingly, the term “heteroalkoxy” refers to the group -O-heteroalkyl, where the group is attached to the parent molecular structure via the oxygen.

[0093] Heteroalkylene: The term “heteroalkylene,” as used herein, represents a divalent form of a heteroalkyl group as described herein.

[0094] Heteroaryl: The term “heteroaryl,” as used herein, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. In embodiments, “heteroaryl” refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein said ring system has a single point of attachment to the rest of the molecule, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 4 to 7 ring members, and wherein at least one ring atom is a heteroatom such as, but not limited to, nitrogen, oxygen, or sulfur. In heteroaryl groups that include 2 or more fused rings, the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5 / / -cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be unsubstituted or substituted. The term “N-containing heteroaryl” refers to heteroaryl groups which comprise at least one nitrogen in the ring system (e g., a heteroaryl comprising 1, 2, or 3 nitrogen atoms). In some embodiments, the foregoing groups, as derived from the groups listed above, are C-attached or N-attached where such is possible. Further, the term “heteroaryloxy” refers to the group -O-heteroaryl, where the group is attached to the parent molecular structure via the oxygen. Non-limiting examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidi-nyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadia-zolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Non-limiting examples of heteroaryl rings containing a single ring Ide: 1,2,3,4-tetrazolyl, [l,2,3]triazolyl, [l,2,4]triazolyl, triazinyl, thiazolyl, 1 / / -imidazolyl, oxazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7J / -puri-nyl, 9 / / -purinyl, 6-amino-9 / / -purinyl, 5 / / -pyrrolo[3,2-t / ]pyrimidinyl, 7 / / -pyrrolo[2,3-t / ]pyrimidi-nyl, pyrido[2,3- ]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, l / Z-indolyl, 4,5,6,7-tetrahydro-l- / / -indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, 1H-benzo[d]imidazol-2(3H)-inyl, lH-benzo[d]imidazolyl, and isoquinolinyl. One non-limiting example of a heteroaryl group as described above is C1-C5 heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (for example, 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S). Examples of C1-C5 heteroaryl include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-l-yl, l / / -imidazol-2-yl, 177-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyri-din-3-yl, and pyridin-4-yl.

[0095] Heteroarylalkyl'. The term “heteroarylalkyl” refers -o an -(alkylene)-heteroaryl radical where heteroaryl and alkylene are as disclosed herein and which are optionally substituted by one or more of the exemplary substituent groups described herein. The “heteroarylalkyl” group is bonded to the parent molecular structure through the alkylene moiety. The term “heteroarylalkoxy” refers to an -©-[heteroarylalkyl] radical (-O-[(alkylene)-heteroaryl]), which is attached to the parent molecular structure through the oxygen.

[0096] Heterocycloalkyl : The term “heterocycloalkyl” or “heterocyclyl” as used herein, is a nonaromatic ring wherein at least one atom is a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. In embodiments, a “heterocyclo-alkyl” or “heterocyclyl” refers to groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocycle group has from 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. Herein, whenever the number of carbon atoms in a heterocycle is indicated (e. ., Ci-C6-heterocycle), at least one other atom (the heteroatom) must be present in the ring. Designations such as “Ci-Ce-heter-ocycle” refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring. In some embodiments, it is understood that the heterocycle ring has additional heteroatoms in the ring. Designations such as “4-6-membered heterocycle” refer to the total number of atoms that are contained in the ring (i.e., a four, five, or six membered ring, inwhich at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or heteroatoms). In some embodiments, in heterocycles that have two or more heteroatoms, those two or more heteroatoms are the same or different from one another. In some embodiments, heterocycles are optionally substituted. In some embodiments, binding to a heterocycle is at a heteroatom or via a carbon atom (i.e., in some embodiments, the foregoing groups, as derived from the groups listed above, are C-attached or N-at-tached where such is possible). Examples of heterocycloalkyl groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tet-rahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]hep-tanyl, 3H-indolyl and quinolizinyl. In embodiments, heterocyclic moieties having a single ring include: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazoli-dinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-l f-aze-pinyl, 2,3-dihydro-177-indole, and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclic moieties having 2 or more rings include: hexahydro- 17 / -pyrrolizinyl, 3a,4,5,6,7,7a-hexa-hydro-1 7-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-17 / -indolyl, 1,2,3,4-tetrahydroquino-linyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro- 17 / -cycloocta[b]pyrrolyl. The heterocycloalkyl group can be substituted or unsubstituted. The heterocycle groups include benzo-fused ring systems and ring systems substituted with one or two oxo (=0) moieties such as pyrrolidin-2-one. In some embodiments, depending on the structure, a heterocycle group is a monoradical or a diradical (i.e., a heterocyclene group). The heterocycles described herein are substituted or unsubstituted. In embodiments, a heterocycle is substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxy alkylene, mercapto, nitro, amino, and amido moieties.

[0097] Moiety. The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0098] Nitro. The term “nitro” refers to a -NO2 group.

[0099] Phosphoryl'. The term “phosphoryl” refers to a -P(=O)(R’)2, or -P(=O)(R’)- group, where R is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon or through the heteroatom), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon) group, unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein, or two R’ can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-mem-bered ring.

[0100] Sulfonamide. The term “sulfonamide” or sulfonamido” refers to the following groups: -S(=O)2-(R’)2, -N(R’)-S(=O)2-R’, -S(=O)2-N(R’)-, or -N(R’)-S(=O)2-, where each R is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein, or two R’ can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring.

[0101] Sulfonyl'. The term “sulfonyl” refers to a -S(=O)2R’, or -S(=O)2- group, where R is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), amino, cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein. For example, in one embodiment, the sulfonyl group is -SO2R’, where R’ is alkyl substituted with a carbonyl group.

[0102] Sulfinyl: The term “sulfinyl” refers to a chemical moiety with formula -S(=O)R’, -S(=O)-, or -S(=O)(=NR’)-, where R is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroaryl alkyl, heterocycloalkyl (bonded through a ring carbon), unless stated other-wise in the specification, each of which moiety can itself be optionally substituted as described herein.

[0103] Ureido: The term “ureido” refers to a chemical moiety with formula -NR’C(O)NR’-, where each R’ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), unless stated otherwise in the specification, each of which moiety can itself be optionally substituted as described herein, or two R’ can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring.

[0104] Whenever a term (e.g, alkyl or aryl) or either of their prefix roots (e.g, alk- or ar-) appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g, arylene is the divalent moiety of aryl, heteroarylene is the divalent moiety of heteroaryl, cycloalkylene is the divalent moiety of cycloalkyl, heterocycloalkylene is the divalent moiety of heterocycloalkyl, or heterocyclylene is the divalent moiety of heterocyclyl. Similarly, affixing the suffix “-oxy” to a group indicates the group is attached to the parent molecular structure through an oxygen atom (-O-) (e.g., cycloalkyloxy, benzyloxy, and the like).

[0105] The term “substituted” is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents as defined herein below and wherein said replacement is with a permissible substituent, e.g., a substituent which upon substitution for the hydrogen results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents. The substituents are capable of replacing one or two hydrogen atoms of a single moiety at a time. Thus, where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit. For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two-hydrogen atom replacement includes carbonyl, oximino, and the like. A two-hydrogen atomreplacement from adjacent carbon atoms includes epoxy, and the like. The term “substituted” is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be replaced. For example, difluoromethyl is a substituted Ci alkyl; trifluoromethyl is a substituted Ci alkyl; 4-hydroxyphenyl is a substituted aromatic ring; (N,N-dimethyl-5-amino)octanyl is a substituted Cs alkyl; 3-guanidinopropyl is a substituted C3 alkyl; and 2-carboxypyridinyl is a substituted heteroaryl.

[0106] A wide variety of substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known. Representative substituents include but are not limited to alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl, heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di- and trihaloalkyl, mono-, di- and trihaloalkoxy, amino, alkylamino, dialkylamino, alkoxy, hydroxy, halo (e.g., — Cl and — Br), nitro, oximino, — COOR50, —COR50, — SO0-2R50, — SO2NR50R51, — NR52SO2R50, =C(R5OR51), =N— OR50, =N— CN, =C(halo)2, =S, =0, — CON(R50R51), — OCOR50, — OCON(R50R51), — N(R52)CO(R50), N(R52)COOR50, N(R52)CON(R50(R51), P(OR50)2, P(O)R50R51, and P(O)OR50OR51, wherein R50, R51and R52may be independently selected from the following: a hydrogen atom and a branched or straight-chain, Ci-6-alkyl, C3-6-cycloalkyl, C4-6-heterocycloal-kyl, heteroaryl and aryl group, with or without substituents. When permissible, R50and R51can be joined together to form a carbocyclic or heterocyclic ring system.

[0107] The following are still further non-limiting examples of substituents which can substitute for hydrogen atoms on a moiety: halogen (chlorine (Cl), bromine (Br), fluorine (F) and iodine®), -CN, -NO2, OXO (=0), -OR’, -SR’, -N(R’)2, -NR’C(O)R’, -SO2R’, -SO2OR’, -SO2N(R’)2, -C(O)R’, -C(O)OR’, -C(0)N(R’)2, C1-C6 alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, C2-Cs alkenyl, C2-Cs alkynyl, C3-C14 cycloalkyl, aryl, heterocycle, or heteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups is optionally substituted with 1-10 (e. , 1-6 or 1-4) groups selected independently from halogen, -CN, -NO2, OXO, and R’; wherein R’, at each occurrence, independently is hydrogen, -OR”, -SR”, -C(O)R”, -C(O)OR”, -C(0)N(R”)2, -SO2R”, S(O)2OR”, -N(R”)2, -NR”C(0)R”, CI-C6alkyl, Ci-Ce haloalkyl, C2-Cs alkenyl, C2-Cs alkynyl, cycloalkyl (e.g., C3-C6 cycloalkyl), aryl, heterocycle, or heteroaryl, or two R’ units taken together with the atom(s) to which they arebound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle has 3 to 7 ring atoms; wherein R”, at each occurrence, independently is hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl (e.g., C3-C6 cycloalkyl), aryl, heterocycle, or heteroaryl, or two R’ ’ units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle has, for example, 3 to 7 ring atoms.

[0108] In embodiments, a substituent is selected from halogen, -COR’, -CO2H, -CO2R’, -CN, -OH, -OR’, -OCOR’, -OCO2R’, -NH2, -NHR’, -N(R’)z, -SR’, and -SO2R’, wherein each instance of R’ independently is C1-C20 aliphatic (e.g., C1-C20 alkyl, C1-C15 alkyl, C1-C10 alkyl, or C1-C3 alkyl). In certain embodiments thereof, R’ independently is an unsubstituted alkyl (e.g., unsubstituted C1-C20 alkyl, C1-C15 alkyl, C1-C10 alkyl, or C1-C3 alkyl). In embodiments, R’ independently is unsubstituted C1-C3 alkyl.

[0109] In some embodiments, the substituents are selected from:i) -OR’”; for example, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3;ii) -C(O)R’”; for example, -COCH3, -COCH2CH3, -COCH2CH2CH3;iii) -C(O)OR’”; for example, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3;iv) -C(O)N(R’”)2; for example, -CONH2, -CONHCH3, -CON(CH3)2;v) -N(R’”)2; for example, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3);vi) halogen: -F, -Cl, -Br, and -I;vii) -CHeXg; wherein X is halogen, m is from 0 to 2, e+g =3; for example, -CH2F, -CHF2, -CF3, -CCI3, or -CBr3;viii) -SO2R’”; for example, -SO2H; -SO2CH3; -SO2C6H5;ix) Ci-Ce linear, branched, or cyclic alkyl;x) Cyanoxi) Nitro;xii) N(R’”)C(O)R’”;xiii) Oxo (=0);xiv) Heterocycle; andxv) Heteroaryl.wherein each R’” is independently hydrogen, optionally substituted CI-CG linear or branched alkyl (e.g., optionally substituted C1-C4 linear or branched alkyl), or optionally substituted C3-C6 cycloalkyl (e.g., optionally substituted C3-C4 cycloalkyl); or two R’” units can be taken together to form a ring comprising 3-7 ring atoms. In certain aspects, each R’” is independently hydrogen, Ci-Ce linear or branched alkyl optionally substituted with halogen or C3-C6 cycloalkyl or C3-C6 cycloalkyl.

[0110] At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-6 alkyl” is specifically intended to individually disclose Ci, C2, C3, C4, C5, Ce, Ci-Ce, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6alkyl.

[0111] Unless otherwise noted, when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R2and R3taken together with the nitrogen (N) to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). The ring can be saturated or partially saturated and can be optionally substituted.

[0112] When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., in N(R9)2, each R9may be the same or different than the other). Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0113] Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula unless specific stereochemistry is otherwise indicated. Thus, any formula given herein is intended to represent a racemate, one ormore enantiomeric forms, one or more diastereomeric forms, one or more atropi someric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (z.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to embrace hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.

[0114] Compounds described herein can comprise an asymmetric atom (also referred as a chiral center), and some of the compounds can comprise one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis and trans isomers of compounds containing alkenyl moi eties (e.g, alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.General Techniques

[0115] Standard chemical laboratory techniques are used to implement the synthetic methods disclosed herein. The exemplary synthetic methods described in the Examples of the disclosure can be used to prepare still other compounds disclosed herein.Processes

[0116] In an aspect, the present disclosure provides a process for preparing Compound C, having the following structure, from Compound SMI, having the following structure, according to Step 1:Compound SMIwherein Step 1 comprises: reacting Compound SMI with a nucleophilic reagent and a first base in a first organic solvent in the presence of a palladium catalyst; wherein: X is selected from Cl, Br, I, and OTf (trifluoromethanesulfonate); R is OR1or NR2R3; R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, phenyl, and benzyl; and R2and R3are independently selected from H, methyl, methoxy, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, secbutyl, phenyl, benzyl, cyclopropyl, and cyclobutyl (or each independently is selected from any subgroup thereof), or R2and R3together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group, for example morpholinyl or piperidinyl. In embodiments, R2is any one of the options listed herein for it and independently R3is any one of the options listed herein for it. In other words, any pair of options for R2and R3is a combination disclosed herein. In embodiments, NR2R3comprises any two of the substituents listed.

[0117] In some embodiments, R is OR1and the nucleophilic reagent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, t-butanol, phenol, benzyl alcohol.

[0118] In some embodiments, R is NR2R3and the nucleophilic reagent is the corresponding HNR2R3amine. In embodiments, the nucleophilic reagent is selected from an alkylamine, a cycloalkylamine, a dialkylamine, and a dicycloalkylamine. In embodiments, the nucleophilic reagent is selected from methoxymethylamine, aniline, benzylamine, piperidine, morpholine, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutyl amine, sec-butyla-mine, benzylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, di-sec-butylamine, dibenzylamine, dicyclopropylamine, and dicyclobutylamine. For example, if R2is H and R3is sec-butyl, then the nucleophilic reagent is sec-butyl-amine. If R2and R3are both methyl, then the nucleophilic reagent is dimethylamine.In some embodiments of Step 1, Compound C has the formula:Compound C-lQrCompound C-2

[0119] In some embodiments of Step 1, the nucleophilic reagent is methanol, and optionally Compound C has the formula:OMeCompound C-l a

[0120] In some embodiments of Step 1, the first base is selected from tetramethylethylenediamine (TMEDA), DIPEA, NaOPh, tri ethyl amine, DBU, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, and NaOMe. In some embodiments of Step 1, the first base is tetramethylethylenediamine (TMEDA). In embodiments of Step 1, the first organic solvent is selected from a polar protic solvent, a polar aprotic solvent, a non-polar solvent, and mixtures thereof. In embodiments of Step 1, the first organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, dimethylformamide, DMSO, DMAc, di chloroethane, chlorobenzene, 1,4-dioxane, 2-MethylTHF, THF, iPrOAc, MEK, toluene, xylene, heptane, and mixtures thereof.

[0121] In embodiments of Step 1, the first organic solvent is a mixture of dimethylformamide and methanol. For example, in some embodiments, the first organic solvent is dimethylforma-mide-methanol in a ratio of from 1:9 to 9:1 vol / vol, such as in a ratio of 1:9 DMF:methanol.

[0122] In embodiments of Step 1, the palladium catalyst is a monodentate phosphine ligand / pal-ladium catalyst or a bidentate phosphine ligand / palladium catalyst. For example, in some embodiments, the palladium catalyst is selected from 1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)C12), (Rac)-BINAP + Pd(OAc)2, and dppb + Pd(OAc)2. In some embodiments, the palladium catalyst is 1 , 1 '-bis(diphe-nylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)C12). In embodiments, the palladium catalyst is PdCE or Pd(OAc)2 and is used with a bidentate phosphine ligand, for example with l,l'-bis(diphenylphosphino)ferrocene (dppf), (Rac)-BINAP, dppb, bis(2-(2-diphenylphospha-nyl)phenyl)ether (DPEphos), l,l-bis(diphenylphosphanyl)methane (dppm), 2,3-bis(diphe-nylphosphanyl)bicyclo[2.2. l]hept-5-ene (norphos), 4, 12-bis(diphenylphosphanyl)-[2.2]-paracy-clophane (phanephos), (R)-2,2’-bis(di-p-tolylphosphanyl)-l,l’-binaphthyl (tol-binap), or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos). In embodiments, a palladium catalyst in combination with a monodentate phosphine ligand is used; for example, the monodentate phosphine ligand / palladium catalyst is Pd(PPhs)4 or Pd(t-Bu3P)2, or a palladium catalyst is used with the monodentate phosphine ligand di-(l-adamantyl)-n-butylphosphine (cataCXium A) and is used with a monodentate phosphine ligand.

[0123] In embodiments of Step 1, X is Br.

[0124] In embodiments of Step 1, the reaction proceeds under an atmosphere of carbon monoxide (CO). For example, the reaction proceeds under an atmosphere of CO wherein the CO pressure is from 0.2 to 2 MPa, 0.3 to 0.6 MPa, 0.34 to 1.5 MPa, 0.3 to 0.4 MPa, 0.4 to 0.5 MPa, or 0.5 to 0.6 MPa.

[0125] In embodiments of Step 1, the reaction proceeds at a temperature of from about 75°C to about 85°C, or at a temperature of from about 70°C to about 80°C, from about 75°C to about 85°C, from about 80°C to about 90°C, or at a temperature of about 80°C, e g., at 80°C.

[0126] In an aspect, the present disclosure provides a process for preparing Compound D, having the following structure, from Compound C, having the following structure, according to Step 2:R Compound C Compound Dwherein Step 2 comprises reacting Compound C with a first reducing agent in a second organic solvent; wherein R is OR1or NR2R3; R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, phenyl, and benzyl; and R2and R3are independently selected from H, methyl, methoxy, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, and cyclobutyl (or each independently is selected from any subgroup thereof), or R2and R3together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group, for example morpholinyl or piperidinyl. In embodiments, R2is any one of the options listed herein for it and independently R3is any one of the options listed herein for it. In other words, any pair of options for R2and R3is a combination disclosed herein. In embodiments, NR2R3comprises any two of the substituents listed. In embodiments of Step 2, R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, phenyl, and benzyl, e.g., R1is methyl. In embodiments of Step 2, the first reducing agent is selected from DIBAL-morpholine, DIBAL, Cp2ZrHCl, lithium aluminum hydride, DIB AL -H, NaBHiCN, sodium bis(2-methoxy-ethoxy)aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, lithium tritertbutoxyalumnium hydride (LTBA), poly(methylhydrosiloxane) + TiCp2F2, TiCU / NaBRi, and EtsSiH + (2,6-difluorophenyl)bis(2,3,5,6-tetrafluorophenyl)borane catalyst. In embodiments of Step 2, the first reducing agent is selected from DIBAL-morpholine, sodium bi s(2-m ethoxy -ethoxy)aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, and lithium tritertbutoxyalumnium hydride (LTBA); for example, the first reducing agent is DIBAL-morpholine. In embodiments of Step 2, in Compound C, R is NR2R3and the first reducing agent is (Cp2ZrHCl). In some embodiments, R2is Me, R3is OMe and the reducing agent is a hydride source, for example lithium aluminum hydride, DIBAL-H, LTBA and NaBHiCN.

[0127] In embodiments of Step 2, the second organic solvent is selected from a non-polar solvent, a polar aprotic solvent, and mixtures thereof. In embodiments of Step 2, the second organic solvent is selected from toluene, heptane, hexanes, cyclohexane, THF, 2-MeTHF, 1,4-dioxane, dichloromethane, CPME, and mixtures thereof. In embodiments of Step 2, the second organic solvent is a mixture of THF and toluene; in some embodiments, the ratio of THF to toluene is from 1:1 to 2:1 vol / vol, or from 1:1 to 1.5:1 vol / vol, or from about 1.2:1 vol / vol to about 1.4:1 vol / vol, e.g., from 1.2:1 vol / vol to 1.4:1 vol / vol.

[0128] In embodiments of Step 2, the reaction proceeds at a temperature of from -15°C to 5°C, or from -10°C to 10°C, or at a temperature of -15°C, -10°C, -5°C, 0°C, 5°C, or 10°C.

[0129] In an aspect, the present disclosure provides a process for preparing a compound of Formula (1), comprising the step of combining Compound D with Compound SM21 according to Step 3 :HNZCompound D (1)wherein Step 3 comprises reacting Compound D with Compound SM21 under suitable conditions for reductive amination.

[0130] In embodiments of Step 3, Compound D is reacted with Compound SM21 in the presence of a reducing agent and an additive in a solvent, e.g. in the presence of the reducing agent STAB (sodium triacetoxyborohydride) and the additive acetic acid (AcOH). In embodiments of Step 3, Compound D is reacted with Compound SM21 in the presence of a reductive aminase enzyme and NADPH, or Compound D is reacted with Compound SM21 under catalytic reductive amination conditions e.g. in the presence of palladium catalyst, platinum catalyst or nickel catalyst under a hydrogen atmosphere. In embodiments of Step 3, the reducing agent is selected from sodium triacetoxyborohydride (STAB) and sodium cyanoborohyride. The reducing agent may also be sodium borohydride, optionally sodium borohydride in combination with acetic acid. In addition, in embodiments, the additive is selected from acetic acid, DIPEA, and Ti(O-iPr)4. In some embodiments, the additive is acetic acid. In embodiments, the solvent is a polar aprotic solvent. For example, the solvent may be selected from NMP, DMAc, DMF, pyridine, and mixtures thereof. In some embodiments, the solvent is NMP.

[0131] In embodiments of Step 3, the reaction proceeds at about 25°C to about 45°C, for example, from about 30°C to about 40°C, e.g. at about 35°C or at 35°C.

[0132] In embodiments of Step 3, the reaction is quenched with a suitable solvent. In some embodiments, the quenching solvent is or comprises, for example, methanol or water or a mixture thereof.

[0133] In an aspect, the present disclosure provides a process for preparing a bis(tartrate) salt of the compound of Formula (I), having the following structure, from the compound of Formula (I), having the following structure, according to Step 4:bis(tartrate) salt of (I) wherein Step 4 comprises: (i) combining the compound of Formula (I) and L-(+)-tartaric acid in a solvent; (ii) seeding the mixture of (i) with the bis(tartrate) salt of the compound of Formula (I); and (iii) adding a solvent to the mixture of (ii). In embodiments of Step 4, the solvent in (i) is selected from acetic acid, water, and mixtures thereof. In embodiments of Step 4, the solvent in (iii) is ethyl acetate or IPA or acetone.

[0134] In an aspect, the present disclosure provides a process for preparing Compound D, having the following structure, from Compound SMI, having the following structure, according to Steps 1 and 2:Compound SMI Compound C-l Compound Dwherein Step 1 comprises: reacting Compound SMI with a nucleophilic reagent and a first base in a first organic solvent in the presence of a palladium catalyst; wherein X is selected from Cl, Br, I, and OTf; and R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-bu-tyl, phenyl, and benzyl; and Step 2 comprises: reacting Compound C-l with a first reducing agent in a second organic solvent.

[0135] In embodiments of the process for preparing Compound D, Step 1 takes place under one or more of the following conditions:(i) the nucleophilic reagent is selected from methanol, ethanol, n-propanol, isopropanol, n- butanol, 2-butanol, t-butanol, phenol, and benzyl alcohol;(ii) the first base is selected from tetramethylethylenediamine (TMEDA), DIPEA, NaOPh, triethylamine, DBU, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, and NaOMe, optionally wherein the first base is tetramethylethylenediamine (TMEDA);(iii) the first organic solvent is selected from a polar protic solvent, a polar aprotic solvent, a non-polar solvent, and mixtures thereof, orthe first organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-buta- nol, 2-butanol, dimethylformamide, DMSO, DMAc, di chloroethane, chlorobenzene, 1,4-di- oxane, 2-MethylTHF, THF, iPrOAc, MEK, toluene, xylene, heptane, and mixtures thereof, or the first organic solvent is a mixture of dimethylformamide and methanol that optionally is 1:9 dimethylformamide-methanol;(iv) the palladium catalyst is a bidentate phosphine ligand / palladium catalyst, optionally wherein the palladium catalyst is selected from l,l'-bis(diphenylphosphino)ferrocene)palla- dium(II) dichloride (Pd(dppf)C12), (Rac)-BINAP + Pd(OAc)2, and dppb + Pd(OAc)2, or the palladium catalyst is l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)C12);(v) the palladium catalyst is PdCE or Pd(OAc)2 and is used with a bidentate phosphine ligand, for example with l,l'-bis(diphenylphosphino)ferrocene (dppf), (Rac)-BINAP, dppb, bis(2-(2-diphenylphosphanyl)phenyl)ether (DPEphos), l,l-bis(diphenylphosphanyl)methane (dppm), 2,3-bis(diphenylphosphanyl)bicyclo[2.2.1]hept-5-ene (norphos), 4,12-bis(diphe- nylphosphanyl)-[2.2]-paracyclophane (phanephos), (R)-2,2’-bis(di-p-tolylphosphanyl)-l,r- binaphthyl (tol-binap), or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos);(vi) a palladium catalyst in combination with a monodentate phosphine ligand is used; for example, the monodentate phosphine ligand / palladium catalyst is Pd(PPha)4 or Pd(t-BusP)2, or a palladium catalyst is used with the monodentate phosphine ligand di-(l-adamantyl)-n-bu- tylphosphine (cataCXium A) and is used with a monodentate phosphine ligand;(vii) X is Br;(viii) the reaction proceeds under an atmosphere of CO, optionally wherein the CO pressure is 0.34 MPa to 1.5 MPa; and(ix) the reaction proceeds at a temperature of from about 75°C to about 85°C.

[0136] In embodiments of the process for preparing Compound D, the nucleophilic reagent is methanol. In embodiments of the process for preparing Compound D, the nucleophilic reagent is methanol and Compound C-l has the formula:OMeCompound C-l a

[0137] In embodiments of the process for preparing Compound D, Step 2 takes place under one or more of the following conditions:(i) the first reducing agent is selected from DIB L-morpholine, DIBAL, Cp2ZrHCl, lithium aluminum hydride, DIBAL-H, NaBHsCN. sodium bis(2-methoxyethoxy)aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert- butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, lithium tritertbutoxyalumnium hydride (LTBA), poly(methylhydrosiloxane) + TiCp2F2, TiCL / NaBHr, and EtsSiH + (2,6-difluoro- phenyl)bis(2,3,5,6-tetrafluorophenyl)borane catalyst, orthe first reducing agent is selected from DIBAL-morpholine, sodium bi s(2-methoxy ethoxy )aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, and lithium tritertbutoxyalumnium hydride (LTBA), orthe first reducing agent is DIBAL-morpholine; and(ii) the second organic solvent is selected from a non-polar solvent, a polar aprotic solvent, and mixtures thereof, or the second organic solvent is selected from toluene, heptane, hexanes, cyclohexane, THF, 2-MeTHF, 1,4-dioxane, dichloromethane, CPME, and mixtures thereof, orthe second organic solvent is a mixture of THF and toluene.

[0138] In an aspect, the present disclosure provides a process for preparing a bis(tartrate) salt of the compound of Formula (I), having the following structure, from Compound SMI, having the following structure, according to Steps 1-4:bis(tartrate) salt of (I)wherein:(i) Step 1 comprises reacting Compound SMI with a nucleophilic reagent and a first base in a first organic solvent in the presence of a palladium catalyst, wherein X is selected from Cl, Br, I, and OTf (trifluoromethanesulfonate); and R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, phenyl, and benzyl;(ii) Step 2 comprises: reacting Compound C-l with a first reducing agent in a second organic solvent;(iii) Step 3 comprises reacting Compound D with Compound SM21 under suitable conditions for reductive amination, and(iv) Step 4 comprises: (a) combining the compound of Formula (T) and L-(+)-tartaric acid in a fourth solvent; (b) seeding the mixture of (i) with the bis(tartrate) salt of the compound of Formula (I); and (c) adding to the mixture of (b) a fifth solvent.

[0139] In embodiments of the process for preparing a bis(tartrate) salt of the compound of Formula (I) from Compound SMI, Step 1 takes place under one or more of the following conditions:(i) the nucleophilic reagent is selected from methanol, ethanol, n-propanol, isopropanol, n- butanol, 2-butanol, t-butanol, phenol, and benzyl alcohol;(ii) the first base is selected from tetramethylethylenediamine (TMEDA), DIPEA, NaOPh, triethylamine, DBU, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, and NaOMe, optionally wherein the first base is tetramethylethylenediamine (TMEDA);(iii) the first organic solvent is selected from a polar protic solvent, a polar aprotic solvent, a non-polar solvent, and mixtures thereof, orthe first organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-buta- nol, 2-butanol, dimethylformamide, DMSO, DMAc, di chloroethane, chlorobenzene, 1,4-di- oxane, 2-MethylTHF, THF, iPrOAc, MEK, toluene, xylene, heptane, and mixtures thereof, or the first organic solvent is a mixture of dimethylformamide and methanol that optionally is 1:9 dimethylformamide-methanol;(iv) the palladium catalyst is a bidentate phosphine ligand / palladium catalyst, optionally wherein the palladium catalyst is selected from l,l'-bis(diphenylphosphino)ferrocene)palla- dium(II) dichloride (Pd(dppf)C12), (Rac)-BINAP + Pd(OAc)2, and dppb + Pd(OAc)2, or the palladium catalyst is l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Cl2);(v) the palladium catalyst is PdCh or Pd(OAc)2 and is used with a bidentate phosphine ligand, for example with l,l'-bis(diphenylphosphino)ferrocene (dppf), (Rac)-BINAP, dppb, bis(2-(2-diphenylphosphanyl)phenyl)ether (DPEphos), l,l-bis(diphenylphosphanyl)methane (dppm), 2,3-bis(diphenylphosphanyl)bicyclo[2.2.1]hept-5-ene (norphos), 4,12-bis(diphe- nylphosphanyl)-[2.2]-paracyclophane (phanephos), (R)-2,2’-bis(di-p-tolylphosphanyl)-l,r- binaphthyl (tol-binap), or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos); (vi) a palladium catalyst in combination with a monodentate phosphine ligand is used; for example, the monodentate phosphine ligand / palladium catalyst is Pd(PPhs)4 or Pd(t-BusP)2, or a palladium catalyst is used with the monodentate phosphine ligand di-(l-adamantyl)-n-bu- tylphosphine (cataCXium A) and is used with a monodentate phosphine ligand;(vii) X is Br;(viii) the reaction proceeds under an atmosphere of CO, optionally wherein the CO pressure is 0.34 MPa to 1.5 MPa; and(ix) the reaction proceeds at a temperature of from about 75°C to about 85°C.

[0140] In embodiments of the process for preparing a bis(tartrate) salt of the compound of Formula (I) from Compound SMI, the nucleophilic reagent is methanol. In embodiments of the process for preparing a bis(tartrate) salt of the compound of Formula (I) from Compound SMI (e g. Compound SMl-la (7-bromo-3,6-difluoropyrazolo[l,5-a]quinoxalin-4(5H)-one)), thenucleophilic reagent is methanol and Compound C-la (methyl 3,6-difluoro-4-oxo-4,5-dihydro-pyrazolo[l,5-a]quinoxaline-7-carboxylate) has the formula:OMeCompound C-la

[0141] In embodiments of the process for preparing a bis(tartrate) salt of the compound of Formula (I) from Compound SMI, Step 2 takes place under one or more of the following conditions:(i) the first reducing agent is selected from DIBAL-morpholine, DIBAL, Cp2ZrHCl, lithium aluminum hydride, DIBAL-H, NaBHsCN. sodium bis(2-methoxyethoxy)aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert- butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, lithium tritertbutoxyalumnium hydride (LTBA), poly(methylhydrosiloxane) + TiCp2F2, TiCh / NaBFL, and EtsSiH + (2,6-difluoro- phenyl)bis(2,3,5,6-tetrafluorophenyl)borane catalyst,or the first reducing agent is selected from DIBAL-morpholine, sodium bi s(2 -methoxy ethoxy )aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, and lithium tritertbutoxyalumnium hydride (LTBA),or the first reducing agent is DIBAL-morpholine; and(ii) the second organic solvent is selected from a non-polar solvent, a polar aprotic solvent, and mixtures thereof, or the second organic solvent is selected from toluene, heptane, hexanes, cyclohexane, THF, 2-MeTHF, 1,4-dioxane, dichloromethane, CPME, and mixtures thereof,or the second organic solvent is a mixture of THF and toluene.

[0142] In embodiments of the process for preparing a bis(tartrate) salt of the compound of Formula (I) from Compound SMI, in Step 3, Compound D is reacted with a reducing agent, an additive, and Compound SM21 in a solvent. In embodiments, Compound D is reacted with areducing agent, an additive, and Compound SM21 in a solvent under one or more of the following conditions:(i) the second reducing agent is selected from sodium triacetoxyborohydride (STAB) and sodium cyanoborohyride;(ii) the additive is selected from acetic acid, DIPEA, and Ti(O-iPr)4, optionally wherein the additive is acetic acid;(iii) the third solvent is a polar aprotic solvent, or the third solvent is selected from NMP, DMAc, DMF, pyridine, and mixtures thereof, or the third solvent is NMP; and(iv) the reaction proceeds at about 35°C.

[0143] In embodiments of the process for preparing a bis(tartrate) salt of the compound of Formula (I) from Compound SMI, Step 4 takes place under one or more of the following conditions:(i) the fourth solvent is selected from acetic acid, water, and mixtures thereof, and(ii) the fifth solvent is ethyl acetate or acetone.

[0144] In embodiments, the starting material SMI may be prepared, for example, as described in WO2023169226A1, the relevant parts of which (see, e.g., Scheme 8 at page 75 and pages 121-123) are incorporated herein in their entirety.

[0145] In an aspect, the present disclosure provides a compound having the following structure:Compound D ,or a sah thereof.

[0146] In an aspect, the present disclosure provides a process for preparing Compound 6-B, having the following structure, from Compound 6-A, having the following structure, according to Step 1:wherein Step 1 comprises reacting Compound 6-A with an electrophilic reagent in a first organic solvent, forming a first intermediate; and reacting the first intermediate with methylamine and hydrochloric acid.

[0147] In some embodiments of the process for preparing Compound 6-B, Step 1 takes place under one or more of the following conditions:(i) the electrophilic reagent is N, N'-carbonyldiimidazole N, 2-(lH-benzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate, oxalyl chloride, trichlorotria- zine and N-methylmorpholine, hexafluorophosphate azabenzotri azole tetramethyl uronium, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1 -ethyl-3- (3-dimethylaminopropyl)carbodiimide, propylphosphonic anhydride, or diphe- nylphosphinic chloride;(ii) the first organic solvent is dichloromethane, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethylformamide, acetonitrile, or dioxane; and(iii)the reaction proceeds at about 15±5 °C.

[0148] In an aspect, the present disclosure provides a process for preparing Compound 6-C, having the following structure, from Compound 6-B, having the following structure, according to Step 2:Compound 6-Cwherein Step 2 comprises reacting Compound 6-B with an oxidizing agent and an activator in a second organic solvent.

[0149] In some embodiments of the process for preparing Compound 6-C, Step 2 takes place under one or more of the following conditions:(i) the oxidizing agent and activator are hydrogen peroxide-urea and trifluoroacetic anhydride, hydrogen peroxide and acetic acid, or m eta-chl or operoxy benzoic acid and acetic acid;(ii) the second organic solvent is dichloromethane, acetonitrile, acetic acid, or ethyl acetate; and(iii) the reaction proceeds at about 15±5 °C.

[0150] In an aspect, the present disclosure provides a process for preparing Compound 6-C-l, having the following structure, from Compound 6-C, having the following structure, according to Step 3 :Compound 6-CFCompound 6-C-lwherein Step 3 comprises reacting Compound 6-C with 1-boc-piperazine in the presence of a palladium catalyst and a base in a third organic solvent.

[0151] In some embodiments of the process for preparing Compound 6-C-l, Step 3 takes place under one or more of the following conditions:(i) the palladium catalyst is Ruphos PdG3, palladium (II) acetate or Tris(dibenzyli- deneacetone)dipalladium(O) with 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, 1,1- bis(diphenylphosphino)ferrocene, or XPhos;(ii) the base is potassium phosphate, cesium carbonate, or sodium tert-butoxide;(iii) the third organic solvent is dioxanedimethylformamide, toluene, tetrahydrofuran, acetonitrile, N-methyl-2-pyrrolidone, 2-methyl tetrahydrofuran, isopropyl alcohol, cyclopentyl methyl ether, isopropyl acetate, dimethyl sulfoxide, di chloroethane, dimethylacetamide, or dimethyl ether; and(iv) the reaction proceeds at about 85±5 °C.

[0152] In an aspect, the present disclosure provides a process for preparing Compound 6-D-2, having the following structure, from Compound 6-C-l, having the following structure, according to Step 4:OCompound 6-C-l Compound 6-D-2wherein Step 4 comprises reacting Compound 6-C-l with an organic base and an acid anhydride or oxalyl chloride in a fourth organic solvent.

[0153] In some embodiments of the process for preparing Compound 6-D-2, Step 4 takes place under one or more of the following conditions:(i) the organic base is trimethyl amine;(ii) the acid anhydride is tri fluoroacetic anhydride, p-toluenesulfonic anhydride, or methanesulfonic anhydride;(iii) the fourth organic solvent is tetrahydrofuran; and(iv) the reaction proceeds at about 15±5 °C.

[0154] In an aspect, the present disclosure provides a process for preparing Compound 6-5, hav-ing the following structure, from Compound 6-D-2, having the following structure, according to Step 5:OCompound 6-D-2 Compound 6-5wherein Step 5 comprises reacting Compound 6-D-2 with an organic fluoride source in a fifth organic solvent.

[0155] In some embodiments of the process for preparing Compound 6-5, Step 5 takes place under one or more of the following conditions:(i) the organic fluoride source is tetrabutylammonium fluoride;(ii) the fifth organic solvent is acetonitrile; and(iii) the reaction proceeds at about 60±5 °C.

[0156] In an aspect, the present disclosure provides a process for preparing Compound SM21, having the following structure, from Compound 6-5, having the following structure, according to Step 6:Compound 6-5 Compound SM21wherein Step 6 comprises reacting Compound 6-5 with an acid in a sixth organic solvent.

[0157] In some embodiments of the process for preparing Compound SM21, Step 6 takes place under one or more of the following conditions:(i) the acid is hydrochloric acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, or p-toluenesulfonic acid;(ii) the sixth organic solvent is dioxane, dichloromethane, or a mixture of dioxane and dichloromethane; and(iii) the reaction proceeds at about 40±5 °C.

[0158] In some aspects, provided are individual synthetic reactions. In some aspects, provided is a multi-step process for preparing Compound SM21.

[0159] In an aspect, the present disclosure provides a process for preparing Compound SM21, having the following structure, from Compound 6-A, having the following structure, according to Steps 1-6:Step 1 Step 2Compound 6-A Compound 6-BStep 3 Step 4 Compound 6-C-lCompound 6-D-2Compound 6-5 Compound SM21wherein:(i) Step 1 comprises:reacting Compound 6-A with an electrophilic reagent in a first organic solvent, forming a first intermediate; andreacting the first intermediate with methylamine and hydrochloric acid;(ii) Step 2 comprises reacting Compound 6-B with an oxidizing agent and an activator in a second organic solvent;(iii) Step 3 comprises reacting Compound 6-C with 1-boc-piperazine in the presence of a palladium catalyst and a base in a third organic solvent, and (iv) Step 4 comprises reacting Compound 6-C-l with an organic base and an acid anhydride or oxalyl chloride in a fourth organic solvent;(v) Step 5 comprises reacting Compound 6-D-2 with an organic fluoride source in a fifth organic solvent; and(vi) Step 6 comprises reacting Compound 6-5 with an acid in a sixth organic solvent.

[0160] In some embodiments of the process for preparing Compound SM21, Step 1 takes place under one or more of the following conditions:(i) the electrophilic reagent is N, N'-carbonyl diimidazole, 2-(lH-benzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate, oxalyl chloride, tri chloro tri a- zine and N-methylmorpholine, hexafluorophosphate azabenzotri azole tetramethyl uronium, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, l-ethyl-3- (3-dimethylaminopropyl)carbodiimide, propylphosphonic anhydride, or diphe- nylphosphinic chloride;(ii) the first organic solvent is dichloromethane, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethylformamide, acetonitrile, or dioxane; and(iii)the reaction proceeds at about 15±5 °C.

[0161] In some embodiments of the process for preparing Compound SM21, Step 2 takes place under one or more of the following conditions:(i) the oxidizing agent and activator are hydrogen peroxide-urea and trifluoroacetic anhydride, hydrogen peroxide and acetic acid, or meta-chloroperoxybenzoic acid and acetic acid;(ii) the second organic solvent is dichloromethane, acetonitrile, acetic acid, or ethyl acetate; and(iii) the reaction proceeds at about 15±5 °C.

[0162] In some embodiments of the process for preparing Compound SM21, Step 3 takes place under one or more of the following conditions:(i) the palladium catalyst is Ruphos PdG3, palladium (II) acetate or Tris(dibenzyli- deneacetone)dipalladium(O) with 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, 1,1- bis(diphenylphosphino)ferrocene, or XPhos;(ii) the base is potassium phosphate, cesium carbonate, or sodium tert-butoxide;(iii) the third organic solvent is dioxanedimethylformamide, toluene, tetrahydrofuran, acetonitrile, N-methyl-2-pyrrolidone, 2-methyl tetrahydrofuran, isopropyl alcohol, cyclopentyl methyl ether, isopropyl acetate, dimethyl sulfoxide, di chloroethane, dimethyl acetamide, or dimethyl ether; and(iv) the reaction proceeds at about 85±5 °C.

[0163] In some embodiments of the process for preparing Compound SM21, Step 4 takes place under one or more of the following conditions:(i) the organic base is trimethyl amine;(ii) the acid anhydride is trifluoroacetic anhydride, p-toluenesulfonic anhydride, or methanesulfonic anhydride;(iii) the fourth organic solvent is tetrahydrofuran; and(iv) the reaction proceeds at about 15±5 °C.

[0164] In some embodiments of the process for preparing Compound SM21, Step 5 takes place under one or more of the following conditions:(i) the organic fluoride source is tetrabutylammonium fluoride;(ii) the fifth organic solvent is acetonitrile; and(iii) the reaction proceeds at about 60±5 °C.

[0165] In some embodiments of the process for preparing Compound SM21, Step 6 takes place under one or more of the following conditions:(i) the acid is hydrochloric acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, or p-toluenesulfonic acid;(ii) the sixth organic solvent is dioxane, dichloromethane, or a mixture of dioxane and dichloromethane; and(iii) the reaction proceeds at about 40±5 °C.Procedure for preparation of the bis-tartrate salt of the compound of Formula (I)

[0166] Step 1 : Preparation of Compound C-la as diagrammed above may be performed as follows. A solution of SMl-la (1.0 eq.), TMEDA (2eq.) and Pd(dppf)C12 (0.05 eq.) in 20-50 V of DMF:MeOH=l:9 is stirred 12-24 h at 75~85°C under CO (0.34-1.5 MPa) flow. After completion monitored by HPLC, the reaction solution is concentrated at 50°C under vacuum to 18-20 V. After filtration and drying, Compound C-la as dark brown solid is obtained with 95.5% purity in 85.5% yield corrected by assay.

[0167] Step 2: Preparation of Compound D from Compound C-la may be performed via flow chemistry as follows: The solution of Compound D is obtained via flow chemistry. A solution of Compound C, morpholine, and DIB AL -H in THF is charged into reactor, charge 5V EA, concentrated to 20-25V below 50°C under vacuum. Then 40V 4M HC1 is charged at 0-25°C and stirred at 5-15 °C for 2 hr. The mixture is filtered and washed with water (5V) and EA (5V) to get a wet cake. After drying, Compound D is obtained as a light brown solid with about 95% purity.

[0168] Step 3: First, compound SM21 is prepared from compound SM2 (SM2F3HC1): 1.0 eq. of Compound SM2, 5V H2O, 6mol / L NaOH solution are combined, pH is adjusted to 12, the material is held at 15-25°C for 0.5-1 h, then the solution is extracted with DCM. Product Compound SM21 is obtained as almost white solid with about 99% purity in about 82% assay yield. Compound SM2 may be prepared using conventional methods well-documented in the art for analogous intermediates.

[0169] Then, 1.0 eq. of Compound D, 1.2 eq. of Compound SM21, 1.5 eq. of STAB, 25 V of NMP are combined and maintained at 30-40°C for about 20 hours. The compound of Formula (I) is obtained as an off-white solid.

[0170] In more detail: to a solution of Compound D (1.0 eq.) (dissolved in 20V NMP) is added CH3COOH (5.0 eq). STAB (1.5 eq) in NMP (5V) is added over 20 hours at 35-45 °C. The mixture is stirred at 35-45 °C for 1 hr. After completion monitored by HPLC, the reaction solution is quenched with MeOH (40 V) and stirred for 16-20 hours at -10-0°C. After filtration, the wet cake is charged into a reactor and stirred for 3-10 hours at 10-25°C in 1% NaOH / THF (1:10, 25V). After filtration, the wet cake is charged into a reactor and stirred for 1-5 hours at 20-30°C in water (25V) with CH3COOH (5 equivalents). After filtration, the wet cake is charged into a reactor and crystalized in EA / AcOH system. After filtration, the wet cake is charged into a reactor and stirred for 3-10 hours at 20-30°C in water (25V). After filtration and drying, the compound of Formula (I) as almost white solid is obtained with >99% purity in 37.0% yield corrected by assay.

[0171] Step 4: Preparation of bis-tartrate salt of Compound of Formula (I) from Compound of Formula (I): To a 1 liter beaker, the compound of Formula (I) (25g, 1.0 eq.), AcOH (250mL 10V) and H2O (10 mL, 0.4V) are added and stirred until compound of Formula (I) is fully dissolved. The solution is filtered into a 2L jacketed flask, tartaric acid (19.9g, 2.5eq. in 0.6V H2O) solution and the seed is added at 35-45°C, EA (750mL, 30V) is added slowly at 35-45°C over 15h. The resulting material is cooled at 0-10°C, filtered and dried. 40g of the bis-tartrate salt of the compound of Formula (I) is obtained with >99% purity. The crude yield is >98%.

[0172] Preparation of bis-tartrate salt of compound of Formula (I) from compound of Formula (I): 400.3 mg compound of Formula (I) and 382.3 mg L(+)-tartaric acid are weighed into a 20-mL vial followed by addition of 10.0 mL acetone to obtain a suspension. The mixture is slurried at roomtemperature for 4 days, then centrifuged at 10,000 rpm for 2 minutes. The solid material is dried under vacuum at 50°C for 4 hours. The solid is collected (625.0 mg) and tested by XRPD. The product is the bis-tartrate salt of the compound of Formula (I).EXAMPLESThe following abbreviations are used herein.Abbreviation Full name(Rac)-BINAP racemic 2,2' -bis(diphenylphosphino)-l,l ' - binaphthyl2-MeTHF 2-MethyltetrahydrofuranBoc tert-butyl oxy carb ony 1CDI carbonyldiimidazoleCPME cyclopentyl methyl etherDBU 1,8-Diazabicyclo [5.4.0]undec-7-eneDCM di chloromethaneDIBAL di-isobutyl aluminum hydrideDIPEA N,N-DiisopropylethylamineDMAc N,N-DimethylacetamideDMF dimethylformamideEA Ethyl acetateEt3SiH tri ethyl silaneIPA isopropyl alcohol or isopropanoliPrOAc Isopropyl acetateIPAc isopropyl acetateMBTE methyl tert-butyl etherMEK Methyl ethyl ketoneMPa (unit of presmegapascalsure)MeCN acetonitrileNaOMe sodium methoxideNaOPh Sodium phenoxidenBuLi n-butyllithiumNMP A-methyl-2-pyrrolidoneOTf trifluoromethanesulfonateAbbreviation Full nameSTAB sodium triacetoxyborohydrideTBAF tetrabutyl ammonium fluorideTFAA trifluoroacetic anhydrideTHF tetrahydrofuranTi(O-iPr)4titanium isopropoxideUHP urea hydrogen peroxideExample 1. Step 1.

[0173] An example of Step 1 of the synthetic procedure as disclosed herein is disclosed and described below. A diagram of the exemplary synthetic procedure follows.1) 0.05 eq. Pd(dppf)Cl2 / 2.0 eq. TMEDA2) DMF / MeOH (1:9)3) CO4) 75-85°C stir 12-24h5) Filter and concentrate6) Filter and dry.OMe Compound SMI -la Step 1Compound C- 1 a

[0174] Compound SMl-la (7-bromo-3,6-difluoropyrazolo[l,5-a]quinoxalin-4(5H)-one) may be prepared, for example, as described in WO2023169226A1 , the relevant parts of which (including but not limited to Scheme 8 at pages 74-75 and pages 121-123) are incorporated herein in their entirety.

[0175] Preparation of Compound C-la (methyl 3,6-difluoro-4-oxo-4,5-dihydropyrazolo[l,5-a]quinoxaline-7-carboxylate) as diagrammed above was performed as follows. A solution of SMl-la (1.0 eq.),TMEDA (2eq.) and Pd(dppf)Cl2(0.05 eq.) in 20-50 V of DMF:MeOH=l:9 was stirred 12-24 h at 75~85°C under CO (0.34-1.5 MPa) flow. After completion monitored by HPLC, the reaction solution was concentrated at 50°C under vacuum to 18-20 V. After filtration and drying, Compound C-la as dark brown solid was obtained with 95.5% purity in 85.5% yield corrected by assay.Example 2, Step 2,

[0176] An example of Step 2 of the synthetic procedure as disclosed herein is disclosed and described below. A diagram of the exemplary synthetic procedure follows.1) Reaction via flow chemistry 2) Charge 4M HC1 solution (40V) at 0-25°C 3) Stir for 2hrat 5-15°C _ 4) Filter and wash with H2O (5V)and EA (5 V) 5) DryStep 2Compound C-la Compound D

[0177] The solution of Compound D (3,6-difluoro-4-oxo-4,5-dihydropyrazolo[l,5-a]quinoxa-line-7-carbaldehyde) was obtained via flow chemistry. A solution of Compound C-la, morpholine, and DIBAL-H in THF was charged into reactor, charge 5V EA, concentrated to 20-25V below 50°C under vacuum. Then 40V 4M HC1 was charged at 0-25°C and stirred at 5-15°C for 2 hr. The mixture was filtered and washed with water (5 V) and EA (5 V) to get a wet cake. After drying, Compound D was obtained as a light brown solid with 95.28% purity.Example 3 , Step 3 ,

[0178] An example of Step 3 of the synthetic procedure as disclosed herein is disclosed and described below. Diagrams of the exemplary synthetic procedures follow.

[0179] Step 3A. Preparation of Compound SM21HhKNaOHWater Compound SM21 Compound SM2 Step 3A

[0180] For the preparation of Compound SM21 (6-fluoro-N-methyl-5-(piperazin-l-yl)pico-linamide), reaction conditions were optimized, resulting in the following stoichiometry: 1.0 eq. of Compound SM2 (6-fluoro-N-methyl-5-(piperazin-l-yl)picolinamide) as the 1.5 HC1 salt (see diagram above), 5V FEO, 6mol / L NaOH solution, adjust pH=12, 15-25°C / 0.5-1 h, extract thesolution with DCM. Following the optimized process, product Compound SM21 was obtained as almost white solid with 98.9% purity in 82.2% assay yield.

[0181] Step 3A. 4.3 kg scale1) Charge Compound SM2 (1.0 eq.)and H2O (5V) into Rl.2) Charge 6M NaOH solution (7V)into Rl (pH=12). HN^ 3) Stir Rl for 0.5 hr at 15-25°C.4) Extract Rl with DCM (4V) four times.5) Extract the organic phase witfTH2O(4V).Compound SM216) Concentrate the organic phase.Step 3 A

[0182] Step 3. Preparation of the compound of Formula (I) from Compound D.

[0183] For the preparation of the compound of Formula (I), reaction conditions were optimized, resulting in the following stoichiometry: 1.0 eq. of Compound D (3,6-difluoro-4-oxo-4,5-dihy-dropyrazolo[l,5-a]quinoxaline-7-carbaldehyde), 1.2 eq. of Compound SM21 (6-fluoro-N-me-thyl-5-(piperazin-l-yl)picolinamide), 1.5 eq. of STAB, 25 V ofNMP, 30-40°C, 20 hours. Fol-lowing the optimized process, product compound of Formula (I) was obtained as off-white solid.Compound D Compound SM211) Charge D (1.0 eq.), SM21 (l.leq.) NMP (20V), CH3COOH (5eq.)2) Charge STAB (1.5 eq) in NMP (5V) over 20hr at 35-45°C3) Stir for 1 hr at 35-45°C4) Charge MeOH (40V) and stir over 1 hr5) Stir for 16-20 hi’ at at -10-0°C6) Filter and wet cake return reactor7) Charge 1% NaOH / THF (1:10. 25V) and stir at 10-25°C for 3-10 hr8) Filter and wet cake return reactor9) Charge progress water (25V), CH3COOH (5eq.) and stir at 20-30°C for 1-5 hr10) Filter and wet cake return reactor11) Charge CH3COOH (10V)12) Charge EA (40V) at 10-25°C for 2-6 hr13) Adjust to 0-10°C over 3 hr and stir at 0-10°C for 2-10 hr14) Filter and wet cake return reactor15) Charge progress water (25V) and stir at 20-30°C for 3-10 hr16) Filter and drySTEP 3

[0184] To a solution of Compound D (1.0 eq.) (dissolved in 20V NMP) was added CH3COOH (5.0 eq). STAB (1.5 eq) in NMP (5V) was added over 20 hours at 35-45 °C. The mixture was stirred at 35-45 °C for 1 hr. After completion monitored by HPLC, the reaction solution was quenched with MeOH (40 V) and stirred for 16-20 hours at -10-0°C. After filtration, the wet cake was charged into reactor and stirred for 3-10 hours at 10-25 °C in 1% NaOH / THF (1:10,25V). After filtration, the wet cake was charged into reactor and stirred for 1-5 hours at 20-30 °C in water (25V) with CH3COOH (5 equivalents). After filtration, the wet cake was charged into reactor and crystalized in EA / AcOH system. After filtration, the wet cake was charged into reactor and stirred for 3-10 hours at 20-30°C in water (25V). After filtration and drying, the com-pound of Formula (I) (5-(4-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[l,5-a]quinoxalin-7-yl)me-thyl)piperazin-l-yl)-6-fluoro-N-methylpicolinamide) as almost white solid was obtained with 99.8% purity in 37.0% yield corrected by assay.Example 4, Step 4, Preparation of bis-tartrate salt of Compound of Formula (I) from Compound of Formula (I)

[0185] An example of Step 4 of the synthetic procedure as disclosed herein is disclosed and described below. Diagrams of the exemplary synthetic procedures follow.

[0186] (Prepare seed of bis-tartrate salt of Compound of Formula (I): Total -230 g crystal seed was obtained by jet milling.)1) Charge Compound of Formula (I)(l.Oeq.), AcOH (10V) and H2O (0.4V) into Rl.2) Filter the suspension and transfer the liquor into Rl3) Charge tartaric acid (19.9g, 2.5 eq. in 0.6V H2O) solution into Rl 4) Charge 0.05X seed. 5) Charge (30.000 V) into Rl dropwise over 15 hr at 35~45°C 6) Adjust 0-10°C and stir 2 hours.7) Filter.Step 4bis(tartrate) salt of (I)

[0187] To a 1 liter beaker, compound of Formula (I) (25g, 1.0 eq.), AcOH (250mL 10V) and H2O (10 mb, 0.4V) were added and stirred until compound of Formula (I) was fully dissolved. The solution was filtered into a 2L jacketed flask, tartaric acid (19.9g, 2.5eq. in 0.6V H2O) solu-tion and the seed was added at 35-45°C, EA (750mL, 30V) was added slowly at 35-45°C over 15h. After cooled at 0-10°C, filtered and dried. 40g of the bis-tartrate salt of the compound of Formula (I) was obtained with 99.77% purity. The crude yield is 98.5%.

[0188] Brief summary of the production activities: One batch on 1.98 kg scale was conducted to manufacture the bis-tartrate salt of the compound of Formula (I). The IPC of XRPD was typical. After work up, 3.144 kg of the salt was obtained with 99.77% purity and 98.1% assay. Theoverall yield from compound of Formula (I) to bis-tartrate salt of the compound of Formula (I) was about 95%.Example 5, Preparation of bis-tartrate salt of compound of Formula (I) from compound of Formula (1)

[0189] 400.3 mg compound of Formula (I) and 382.3 mg L(+)-tartaric acid were weighed into a 20-mL vial followed by addition of 10.0 mb acetone to obtain a suspension. The mixture was slurried at room temperature for 4 days, then centrifuged at 10,000 rpm for 2 minutes. The solid material was dried under vacuum at 50°C for 4 hours. The solid was collected (625.0 mg) and tested by XRPD. The product was the bis-tartrate salt of the compound of Formula (I).Example 6, Alternative Preparation of Compound SM21

[0190] One route to SM2, used in Step 3A of Example 2, is shown in Scheme 1.Scheme 1. Route to SM2.4

[0191] Several challenges were identified with this route, including:• Step 1 bromination: poor regioselectivity resulting in mixed isomers that add complexity to subsequent separation and purification procedures• Step 2 Balz-Shi emann reaction: hazardous conditions that pose challenges and safety concerns with scale-up• Step 3 Buchwald-Hartiwig coupling: high cost due to excessive catalyst loading and the expense of CS2CO3• Steps 1-3 are low yielding• Raw material methyl 6-aminopicolinate is expensive with poor availability and limited suppliers• Column chromatography used for purifications

[0192] The following route to SM21 mitigates the above process challenges (Scheme 2).Scheme 2. Second-generation route to SM21.

[0193] Advantages to the new route include:• Significant overall yield improvement (32.5% vs 7.0%)• Replaces strong and dangerous HF pyridine with milder TBAF for fluorination step • Cost-optimized Buchwald-Hartwig coupling that uses a lower catalyst loading (3% vs 18%)o Replaces expensive CS2CO3 with K3PO4• Most intermediates are isolable via crystallization, lending to more control and better purity by purging impurities• The starting raw material 5-bromopicolinic acid is more cost effective and readily available commerciallyStep 1. Preparation of Compound 6-B

[0194] This step was conducted on a scale of 85 kg of input Compound 6-A to give 600.3 kg of Compound 6-B as a solution in dichloromethane with 98.8% HPLC purity, 12.1% assay, and 91% yield.Scheme 3. Synthetic Scheme to Compound 6-BCDI.DCM MeNH2HCI6-A-1 6-BSolution in DCMProcess DescriptionReaction:

[0195] Charge di chloromethane (10 V) to R1 at room temperature. Charge 5-bromo-2-pyridine-carboxylic acid (Compound 6-A) (1.0 eq., 1.0 X) at 1T=15±5 °C followed by of N, N'-carbon-yldiimidazole (1.5 eq.). Stir reaction mixture at IT=15±5 °C for 2 hours. Sample contents for IPC-1 (A 1 mL sample of the reaction mixture was pulled and dimethylamine (2M, in THF) was added dropwise for derivatization.) Requirement: 6-A / (6-A+6-A-l) < 3%.

[0196] Maintain the temperature at IT=15±5 °C and add methylamine hydrochloride (1.5 eq ). Stir the mixture at IT=15±5 °C for 8 h. Sample contents for IPC-2. Requirement: 6-A-l / (6-B+6-A-l) < 3%.

[0197] Maintain the temperature at 15±5°C and add methylamine hydrochloride (1.5 eq.). After the addition is finished, stir at 15±5 °C for 8 hours and sample contents for IPC. The second stage of the reaction is deemed complete when Compound 6-A is < 3%.Work-up:

[0198] Add 5% aqueous sodium carbonate solution (5 V) to Rl, stir for 0.5 hours, and allow phase separation. Extract the aqueous phase once with dichloromethane (3 V). Combine the organic phases, then add water (5 V) to the combined organic phases, stir for 0.5 hours, and separate the phases. Add water (5 V) to the organic phase again, stir for 0.5 hours, and perform phase separation. Concentrate the organic phase under reduced pressure at IT=40±10 °C / 100 mbar to a volume of 6~8 V to obtain Compound 6-B as a solution in dichloromethane.Step 2. Preparation of Compound 6-C

[0199] This step was conducted on a scale of 72.6 kg of input Compound 6-B to give 66.1 kg of Compound 6-C with 99.1% HPLC purity, 95.6% assay, and 81% yield.Scheme 4. Synthetic Scheme to Compound 6-CUHP, TFAA, MeCNMeHN6-B 6-CProcess DescriptionReaction:

[0200] At room temperature, add the di chloromethane solution of Compound 6-B (1.0 eq ). Control the temperature at 1T=15±5 °C and add urea peroxide (1.3 eq.). Maintain the temperature at IT=15±5 °C, then dropwise add trifluoroacetic anhydride (1.4 eq.). Upon completion of the addition, stir at IT=15±5 °C for 12 hours. IPC-1 sample was taken and sent for HPLC analysis. Requirement: 6-B / (6-B+6-C) < 3%.Work-up:

[0201] Add 10% aqueous sodium sulfite solution (4 V) to Rl, stir for 0.5 hours, and allow phase separation. Extract the aqueous phase once with di chloromethane (3 V). Combine the organic phases, then add 6% aqueous sodium carbonate solution (5 V) to the combined organic phases, stir for 0.5 hours, and separate the phases. Concentrate the organic phase under reduced pressure IT=40±10 °C / 100 mbar to a volume of 3~4 V. Add 1,4-dioxane (5 V) and concentrate under reduced pressure to 3~5 V. Add 1,4-dioxane (6 V) and heptane (8V) then filter to yield Compound 6-C.Step 3. Preparation of Compound 6-C-l

[0202] This step was conducted on a scale of 66 kg of input Compound 6-C to give 69 kg of Compound 6-C-l with 99.5% HPLC purity, 98.2% assay, and 73% yield.Scheme 5. Synthetic Scheme to Compound 6-C-lBuchwald-Hartwig16-C 6-C-1 ! 3-1Process DescriptionReaction:

[0203] To R1 combine Compound 6-C (1.0 eq.) and 1,4-dioxane (6 V), followed by Boc-pipera-zine (1.3 eq.), and potassium phosphate (2.5 eq.) at room temperature. Upon completion of the addition, purge with high-purity nitrogen for 0.5 hours and perform nitrogen replacement 3 times. Add Ruphos Pd G3 (0.0275 eq.). After the addition, perform high-purity nitrogen replacement 3 times. Heat the system to IT=85±5 °C and stir for 25 hours. IPC-1 samples were taken and sent for HPLC analysis. Requirement: 6-C / (6-C+6-C-1) <2%.Work-up:

[0204] Control the temperature below 55 °C and concentrate the system to 2-3 X. Maintain the temperature at 20-30 °C, then add water (15 V) dropwise. Stir at 20-30 °C for 0.5 hours and filter. Rinse the filter cake with water (1 V). Dissolve the filter cake in dichloromethane (12 V), add water (3 V), stir for 0.5 hours, and separate the phases. Extract the aqueous phase once with dichloromethane (3 V). Combine the organic phases, add modified resin (0.25 X), stir at 20~30°C for 12 hours, and filter through a pad of diatomaceous earth (0.2 X). Rinse with dichloromethane (1 V). Concentrate the filtrate under reduced pressure at JT=40±l 0 °C and 100 mbar to 2-4 X. Add ethyl acetate (2 V) and / / -heptane (8 V), stir at 20-30 °C for 6-8 hours, and filter. Rinse the filter cake with / / -heptane: ethyl acetate (4:1, 1 V). Dry the filter cake under reduced pressure at 40-50 °C to give Compound 6-C-l.Step 4. Preparation of Compound 6-D-2

[0205] This step was conducted on a scale of 35 kg of input Compound 6-C-l to give 49 kg of Compound 6-D-2 with 99.6% HPLC purity, 87.0% assay, and 84% yield.Scheme 6. Synthetic Scheme to Compound 6-D-26-C-1 6-D-2Process DescriptionReaction:

[0206] Charge tetrahydrofuran (10 V) and C-l (1.0 eq.) to Rl. Purge and replace with nitrogen, then add trimethylamine in tetrahydrofuran solution (2M in THF, 5.0 eq.) and stir. Cool the system to IT=15±5 °C, then dropwise add trifluoroacetic anhydride (1.85 eq.) while maintaining IT=15±5 °C. After finishing the dropwise addition, hold the temperature at 15±5 °C for 8 h. IPC- 1 samples were taken and sent for HPLC analysis. Requirements: 6-C-l / (6-C-l + 6-D-2) < 2%. Work-np:

[0207] Add z?-heptane (30 V) dropwise to the reaction system while controlling IT=20±5 °C and stir for 30 minutes. Filter the mixture. Add tetrahydrofuran (5 V) and the filter cake (1 X) to R2 with stirring. Heat to IT=45±5 °C to dissolve the filter cake then cool to IT=20±5 °C. Add MTBE (15 V) dropwise while maintaining IT=20±5 °C. Stir for another 30 minutes, then filter to obtain 6-D-2 as a white powder. 6-D-2 was directly used in the next reaction step.Step 5. Preparation of Compound 6-5

[0208] This step was conducted on a scale of 95 kg of input Compound 6-D-2 to give 48 kg of Compound 6-5 with 99.2% HPLC purity, 99.0% assay, and 84% yield.Scheme 7. Synthetic Scheme to Compound 6-5O6-D-2 6-5Process DescriptionReaction:

[0209] Charge acetonitrile (5 V) and D-2 (1 eq.) to Rl with stirring. Add tetrabutylammonium fluoride trihydrate (2.5 eq.) at room temperature. Heat the system to IT=60±5 °C and stir for 2hours. IPC-1 samples were taken and sent for HPLC analysis. Requirements: 6-5 / (6-5+6-D-2) < 1%.Work-up:

[0210] Cool the system to IT=20±5 °C and add ethyl acetate (5 V) and water (5 V) to the reaction mixture, stir for 10 minutes, let stand for 20 minutes for phase separation. Discharge the aqueous phase. Add water (3 V) and stir for 10 minutes, let stand for 20 minutes for phase separation. Discharge the aqueous phase. Add water (3 V) and stir for 10 minutes, let stand for 20 minutes for phase separation. Discharge the aqueous phase. Add water (3 V) and stir for 10 minutes, let stand for 20 minutes for phase separation. Discharge the aqueous phase. Allow the organic phase to stand. Combined the aqueous phases and wash with ethyl acetate (5 V), let stand for 20 minutes for phase separation. Discharge the aqueous phase. Combine the organic phases and concentrate at JT=45±5 °C / 100 mbar until no more distillate to give crude Compound 6-5.

[0211] Add water (2 V) to R2 with stirring, add crude Compound 6-5 (1 X), and stir at room temperature for 1 hour. Filter the mixture and rinse with water (1 V) to obtain the wet cake. Dry the wet cake at JT=50±5 °C / 100 mbar to give Compound 6-5.Step 6. Preparation of SM21

[0212] This step was conducted on a scale of 48 kg of input Compound 6-5 to give 28 kg of SM21 with 99.7% HPLC purity, 97.6% assay, and 80% yield.Scheme 8. Synthetic Scheme to SM216-5 SM21Process DescriptionReaction:

[0213] Add dichloromethane (2 V) to R1 followed by Compound 6-5 (1.0 eq.) with stirring. Dropwise add a dioxane solution of hydrogen chloride (5 V) at IT=25±5 °C. Heat the system to an IT= 40±5 °C and stir for 2 hours. IPC-1 samples were taken and sent for HPLC analysis. Requirements: 6-5 / (6-5+SM21) < 2%.Work-up:

[0214] Cool the system to IT=25±5 °C then filter and rinse the filter cake with ethyl acetate (2 V) to obtain crude SM21.

[0215] Add dichloromethane (10 V) to R2 followed by crude SM21 (1.0 X) and sodium carbonate (1.0 X) with stirring. Stir at room temperature for 3 hours, filter to obtain Cake-2, and rinse Cake-2 with dichloromethane (1 V). Store Filtrate-2 temporarily. Add dichloromethane (10 V) to R3 followed by Cake-2 with stirring. Stir at room temperature for 2 hours, filter to obtain Cake-3, and rinse Cake-3 with dichloromethane (1 V) to obtain Filtrate-3.

[0216] Combine Filtrate-2 and Filtrate-3 and concentrate at JT=45±5 °C / 100 mbar until no more distillate to give SM21.

[0217] SM21 can be slurried in MTBE (10 V) at room temperature to further purify.

Claims

WHAT IS CLAIMED IS;1. A process for preparing Compound C, having the following structure, from Compound SMI, having the following structure, according to Step 1 :Compound SMI Compound Cwherein Step 1 comprises:reacting Compound SMI with a nucleophilic reagent and a first base in a first organic solvent in the presence of a palladium catalyst;whereinX is selected from Cl, Br, I, and OTf (trifluoromethanesulfonate);R is OR1or NR2R3;R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, phenyl, and benzyl; andR2and R3are independently selected from H, methyl, methoxy, ethyl, n-propyl, n- butyl, isopropyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, and cyclobutyl, or R2and R3together with the N atom to which they are attached form a 4- to 6- membered heterocyclyl group, optionally wherein the 4- to 6-membered heterocy- clyl group is morpholinyl or piperidinyl.

2. The process of claim 1, wherein:i) R is OR1and the nucleophilic reagent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, t-butanol, phenol, benzyl alcohol, orii) R is NR2R3and the nucleophilic reagent is selected from an alkylamine, a cycloalkylamine, a dialkylamine, and a dicycloalkylamine, or is selected from methoxymethylamine, aniline, benzylamine, piperidine, morpholine, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, sec-butylamine, benzylamine, dimethylamine,diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, di-sec-butyl- amine, dibenzylamine, dicyclopropylamine, and dicyclobutylamine.

3. The process of claim 1 or 2, wherein Compound C has the formula:Compound C-lQrCompound C-24. The process of claim 1 or 2, wherein the nucleophilic reagent is methanol.

5. The process of claim 4, wherein Compound C has the formula:OMeCompound C-l a6. The process of any one of claims 1-5, wherein the first base is selected from tetramethylethylenediamine (TMEDA), DIPEA, NaOPh, triethylamine, DBU, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, and NaOMe.

7. The process of any one of claims 1-6, wherein the first base is tetramethylethylenediamine (TMEDA).

8. The process of any one of claims 1-7, wherein the first organic solvent is selected from a polar protic solvent, a polar aprotic solvent, a non-polar solvent, and mixtures thereof.

9. The process of any one of claims 1-8, wherein the first organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, dimethylformamide, DMSO,DMAc, di chloroethane, chlorobenzene, 1,4-dioxane, 2-MethylTHF, THF, iPrOAc, MEK, toluene, xylene, heptane, and mixtures thereof.

10. The process of any one of claims 1-9, wherein the first organic solvent is a mixture of dimethylformamide and methanol.

11. The process of any one of claims 1-10, wherein the palladium catalyst is a monodentate phosphine ligand / palladium catalyst or a bidentate phosphine ligand / palladium catalyst.

12. The process of any one of claims 1-11, wherein the palladium catalyst is selected from 1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Ch), (Rac)-BINAP + Pd(OAc)2, and dppb + Pd(OAc)2.

13. The process of any one of claims 1-12, wherein the palladium catalyst is 1, l'-bis(diphe- nylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)C12).

14. The process of any one of claims 1-13, wherein X is Br.

15. The process of any one of claims 1-14, wherein the reaction proceeds under an atmosphere of CO.

16. The process of any one of claims 1-15, wherein the reaction proceeds at a temperature of from about 75 to about 85°C.

17. A process for preparing Compound D, having the following structure, from Compound C, having the following structure, according to Step 2:R Compound C Compound Dwherein Step 2 comprises:reacting Compound C with a first reducing agent in a second organic solvent; whereinR is OR1or NR2R3;R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, phenyl, and benzyl; andR2and R3are independently selected from H, methyl, methoxy, ethyl, n-propyl, n- butyl, isopropyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, and cyclobutyl, or R2and R3together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group, optionally wherein the 4- to 6-membered heterocyclyl group is morpholinyl or piperidinyl.

18. The process of claim 17, wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, n- butyl, 2-butyl, t-butyl, phenyl, and benzyl.

19. The process of claim 17 or 18, wherein R1is methyl.

20. The process of any one of claims 17-19, wherein the first reducing agent is selected from DIBAL-morpholine, DIBAL, Cp2ZrHCl, lithium aluminum hydride, DIB AL -H, NaBHsCN, sodium bi s(2 -methoxy ethoxy )aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxy- aluminum hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, lithium tritertbutoxyalumnium hydride (LTBA), titanium chloride with sodium borohydride, poly(methylhydrosiloxane) + TiCp2F2, TiCl NaBEL, and EtsSiH + (2,6- difluorophenyl)bis(2,3,5,6-tetrafluorophenyl)borane catalyst.

21. The process of any one of claims 17-20, wherein the first reducing agent is selected from DIBAL-morpholine, sodium bi s(2-methoxy ethoxy )aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, and lithium tritertbutoxyalumnium hydride (LTBA).

22. The process of any one of claims 17-21, wherein the first reducing agent is DIBAL-morpholine.

23. The process of any one of claims 17-22, wherein the second organic solvent is selected from a non-polar solvent, a polar aprotic solvent, and mixtures thereof.

24. The process of any one of claims 17-23, wherein the second organic solvent is selected from toluene, heptane, hexanes, cyclohexane, THF, 2-MeTHF, 1,4-di oxane, dichloromethane, CPME, and mixtures thereof.

25. The process of any one of claims 17-24, wherein the second organic solvent is a mixture of THF and toluene.

26. The process of any one of claims 17-25, wherein the reaction proceeds at a temperature of 0°C.

27. A process for preparing a compound of Formula (I), comprising the step of combining Com- pound D with Compound SM21 according to Step 3:HNCompound D wherein Step 3 comprises:reacting Compound D with Compound SM21 under suitable conditions for reductive amination.

28. The process of claim 27, wherein Compound D is reacted with a second reducing agent, an additive, and Compound SM21 in a third solvent.

29. The process of claim 28, wherein the second reducing agent is selected from sodium tri- acetoxyborohydride (STAB) and sodium cyanoborohyride.

30. The process of claim 28 or 29, wherein the additive is selected from acetic acid, DIPEA, and Ti(O-iPr)4.

31. The process of any one of claims 28-30, wherein the additive is acetic acid.

32. The process of any one of claims 28-31, wherein the third solvent is a polar aprotic solvent.

33. The process of any one of claims 28-32, wherein the third solvent is selected from NMP, DMAc, DMF, pyridine, and mixtures thereof.

34. The process of any one of claims 28-33, wherein the third solvent is NMP.

35. The process of any one of claims 28-34, wherein the reaction proceeds at about 35°C.

36. A process for preparing a bis(tartrate) salt of the compound of Formula (I), having the following structure, from the compound of Formula (I), having the following structure, according to Step 4:bis(tartrate) salt of (I) wherein Step 4 comprises:(i) combining the compound of Formula (I) and L-(+)-tartaric acid in a fourth solvent;(ii) seeding the mixture of (i) with the bis(tartrate) salt of the compound of Formula (I); and(iii) adding to the mixture of (ii) a fifth solvent.

37. The process of claim 36, wherein the fourth solvent is selected from acetic acid, water, and mixtures thereof.

38. The process of claim 36 or 37, wherein the fifth solvent is ethyl acetate or IPA or acetone.

39. A process for preparing Compound D, having the following structure, from Compound SMI, having the following structure, according to Steps 1 and 2:Compound SMI Compound C-l Compound Dwherein Step 1 comprises:reacting Compound SMI with a nucleophilic reagent and a first base in a first organic solvent in the presence of a palladium catalyst;whereinX is selected from Cl, Br, I, and OTf; andR1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, phenyl, and benzyl; andStep 2 comprises:reacting Compound C-l with a first reducing agent in a second organic solvent.

40. The process of claim 39, wherein Step 1 takes place under one or more of the following conditions:(i) the nucleophilic reagent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, t-butanol, phenol, and benzyl alcohol;(ii) the first base is selected from tetramethylethylenediamine (TMEDA), DIPEA, NaOPh, triethylamine, DBU, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, and NaOMe, optionally wherein the first base is tetramethylethylenediamine (TMEDA);(iii) the first organic solvent is selected from a polar protic solvent, a polar aprotic solvent, a non-polar solvent, and mixtures thereof, orthe first organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, dimethylformamide, DMSO, DMAc, di chloroethane,chlorobenzene, 1,4-di oxane, 2-MethylTHF, THF, iPrOAc, MEK, toluene, xylene, heptane, and mixtures thereof, orthe first organic solvent is a mixture of dimethylformamide and methanol that optionally is 1:9 dimethylformamide-methanol;(iv) the palladium catalyst is a bidentate phosphine ligand / palladium catalyst, optionally wherein the palladium catalyst is selected from 1, l'-bis(diphe- nylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Ch), (Rac)-BINAP + Pd(OAc)2, and dppb + Pd(OAc)2, orthe palladium catalyst is l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Ch);(v) X is Br;(vi) the reaction proceeds under an atmosphere of CO, optionally wherein the CO pressure is 0.34 MPa to 1.5 MPa;(vii) the reaction proceeds at a temperature of from about 75°C to about 85°C.

41. The process of claim 39 or claim 40, wherein the nucleophilic reagent is methanol.

42. The process of claim 41, wherein Compound C-l has the formula:OMeCompound C-l a43. The process of any one of claims 39-42, wherein Step 2 takes place under one or more of the following conditions:(i) the first reducing agent is selected from DIB AL-morpholine, DIBAL, Cp2ZrHCl, lithium aluminum hydride, DIB AL -H, NaBLLCN, sodium bi s(2 -methoxy eth- oxy)aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminumhydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, lithium tritertbutoxyalumnium hydride (LTBA), poly(methylhy- drosiloxane) + TiCp2F2, TiCh / NaBH^ and EtsSiH + (2,6-difluoro- phenyl)bis(2,3,5,6-tetrafluorophenyl)borane catalyst, orthe first reducing agent is selected from DIBAL-morpholine, sodium bis(2-meth- oxyethoxy)aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, and lithium tritertbutoxyalumnium hydride (LTBA), orthe first reducing agent is DIBAL-morpholine;(ii) the second organic solvent is selected from a non-polar solvent, a polar aprotic solvent, and mixtures thereof, or the second organic solvent is selected from toluene, heptane, hexanes, cyclohexane, THF, 2-MeTHF, 1,4-di oxane, di chloromethane, CPME, and mixtures thereof, orthe second organic solvent is a mixture of THF and toluene.

44. A process for preparing a bis(tartrate) salt of the compound of Formula (I), having the following structure, from Compound SMI, having the following structure, according to Steps 1- 4:Compound SMI Compound C-l Compound Dbis(tartrate) salt of (I)wherein:(i) Step 1 comprises:reacting Compound SMI with a nucleophilic reagent and a first base in a first or- ganic solvent in the presence of a palladium catalyst;whereinX is selected from Cl, Br, I, and OTf; andR1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-bu- tyl, phenyl, and benzyl;(ii) Step 2 comprises:reacting Compound C-l with a first reducing agent in a second organic solvent; (iii) Step 3 comprises reacting Compound D with Compound SM21 under suitable conditions for reductive amination, and(iv) Step 4 comprises:(a) combining the compound of Formula (I) and L-(+)-tartaric acid in a fourth solvent;(b) seeding the mixture of (i) with the bis(tartrate) salt of the compound of Formula (I); and(c) adding to the mixture of (b) a fifth solvent.

45. The process of claim 44, wherein Step 1 takes place under one or more of the following conditions:(i) the nucleophilic reagent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, t-butanol, phenol, and benzyl alcohol;(ii) the first base is selected from tetramethylethylenediamine (TMEDA), DIPEA, NaOPh, triethylamine, DBU, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, and NaOMe, optionally wherein the first base is tetramethylethylenediamine (TMEDA);(iii) the first organic solvent is selected from a polar protic solvent, a polar aprotic solvent, a non-polar solvent, and mixtures thereof, orthe first organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, dimethylformamide, DMSO, DMAc, dichloroethane, chlorobenzene, 1,4-di oxane, 2-MethylTHF, THF, iPrOAc, MEK, toluene, xylene, heptane, and mixtures thereof, orthe first organic solvent is a mixture of dimethylformamide and methanol that optionally is 1:9 dimethylformamide-methanol;(iv) the palladium catalyst is a bidentate phosphine ligand / palladium catalyst, optionally wherein the palladium catalyst is selected from 1, l'-bis(diphe- nylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Ch), (Rac)-BINAP + Pd(OAc)2, and dppb + Pd(OAc)2, orthe palladium catalyst is l,r-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Ch);(v) X is Br;(vi) the reaction proceeds under an atmosphere of CO, optionally wherein the CO pressure is 0.34 MPa to 1.5 MPa; and(vii) the reaction proceeds at a temperature of from about 75°C to about 85°C.

46. The process of claim 44 or claim 45, wherein the nucleophilic reagent is methanol.

47. The process of claim 46, wherein Compound C-l has the formula:KAHoOMeCompound C- 1 a48. The process of any one of claims 44-47, wherein Step 2 takes place under one or more of the following conditions:(i) the first reducing agent is selected from DIBAL-morpholine, DIBAL, Cp2ZrHCl, lithium aluminum hydride, DIB AL -H, NaBH CN, sodium bi s(2 -methoxy eth- oxy)aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyaluminum hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIBAL-nBuLi, lithium tritertbutoxyalumnium hydride (LTBA), poly(methylhy- drosiloxane) + TiCp2F2, TiCh / NaBPL, and EtsSiH + (2,6-difluoro- phenyl)bis(2,3,5,6-tetrafluorophenyl)borane catalyst, orthe first reducing agent is selected from DIBAL-morpholine, sodium bis(2-meth- oxyethoxy)aluminum dihydride (Red-Al), sodium diisobutyl-tert-butoxyalumi- num hydride (SDBBA), lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), DIB L-nBuLi, and lithium tritertbutoxyalumnium hydride (LTBA), orthe first reducing agent is DIBAL-morpholine; and(ii) the second organic solvent is selected from a non-polar solvent, a polar aprotic solvent, and mixtures thereof, or the second organic solvent is selected from toluene, heptane, hexanes, cyclohexane, THF, 2-MeTHF, 1,4-di oxane, di chloromethane, CPME, and mixtures thereof, orthe second organic solvent is a mixture of THF and toluene.

49. The process of any one of claims 44-48, wherein, in Step 3, Compound D is reacted with a second reducing agent, an additive, and Compound SM21 in a third solvent.

50. The process of claim 49, wherein Step 3 takes place under one or more of the following conditions:(i) the second reducing agent is selected from sodium triacetoxyborohydride (STAB) and sodium cyanoborohyride;(ii) the additive is selected from acetic acid, DIPEA, and Ti(O-iPr)4, optionally wherein the additive is acetic acid;(iii) the third solvent is a polar aprotic solvent, or the third solvent is selected from NMP, DMAc, DMF, pyridine, and mixtures thereof, or the third solvent is NMP; and(iv) the reaction proceeds at about 35°C.

51. The process of any one of claims 44-50, wherein Step 4 takes place under one or more of the following conditions:(i) the fourth solvent is selected from acetic acid, water, and mixtures thereof, and (ii) the fifth solvent is ethyl acetate or acetone.

52. A compound having the following structure:Compound Dor a salt thereof.

53. A process for preparing Compound SM21, having the following structure, from Compound 6-A, having the following structure, according to Steps 1-6:Step 1 Step 2Compound 6-AStep 3Step 4 Compound 6-C-lCompound 6-D-2Compound 6-5 Compound SM21wherein:(i) Step 1 comprises:reacting Compound 6-A with an electrophilic reagent in a first organic solvent, forming a first intermediate; andreacting the first intermediate with methylamine and hydrochloric acid;(ii) Step 2 comprises reacting Compound 6-B with an oxidizing agent and activator in a second organic solvent;(iii) Step 3 comprises reacting Compound 6-C with 1-boc-piperazine in the presence of a palladium catalyst and a base in a third organic solvent, and(iv) Step 4 comprises reacting Compound 6-C-l with an organic base and an acid anhydride or oxalyl chloride in a fourth organic solvent;(v) Step 5 comprises reacting Compound 6-D-2 with an organic fluoride source in a fifth organic solvent; and(vi) Step 6 comprises reacting Compound 6-5 with an acid in a sixth organic solvent.

54. The process of claim 53, wherein Step 1 takes place under one or more of the following conditions:(i) the electrophilic reagent is N, N'-carbonyldiimidazole, 2-(lH-benzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate, oxalyl chloride, trichlorotria- zine and N-methylmorpholine, hexafluorophosphate azabenzotri azole tetramethyl uronium, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, l-ethyl-3- (3-dimethylaminopropyl)carbodiimide, propylphosphonic anhydride, or diphe- nylphosphinic chloride;(ii) the first organic solvent is dichloromethane, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethylformamide, acetonitrile, or dioxane;(iii)the reaction proceeds at about 15±5 °C.

55. The process of claim 53 or 54, wherein Step 2 takes place under one or more of the following conditions:(i) the oxidation system is hydrogen peroxide-urea and trifluoroacetic anhydride, hydrogen peroxide and acetic acid, or meta-chloroperoxybenzoic acid and acetic acid; (ii) the second organic solvent is dichloromethane, acetonitrile, acetic acid, or ethyl acetate; and(iii) the reaction proceeds at about 15±5 °C.

56. The process of any one of claims 53-55, wherein Step 3 takes place under one or more of the following conditions:(i) the palladium catalyst is Ruphos PdG3, palladium (II) acetate or Tris(dibenzyli- deneacetone)dipalladium(O) with 2,2'-bis(diphenylphosphino)-l,T-binaphthyl, 1,1- bis(diphenylphosphino)ferrocene, or XPhos;(ii) the base is potassium phosphate, cesium carbonate, or sodium tert-butoxide;(iii) the third organic solvent is dioxane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile, N-methyl-2-pyrrolidone, 2-methyl tetrahydrofuran, isopropyl alcohol, cyclopentyl methyl ether, isopropyl acetate, dimethyl sulfoxide, di chloroethane, dimethylacetamide, or dimethyl ether; and(iv) the reaction proceeds at about 85±5 °C.

57. The process of any one of claims 53-56, wherein Step 4 takes place under one or more of the following conditions:(i) the organic base is trimethyl amine;(ii) the acid anhydride is trifluoroacetic anhydride, p-toluenesulfonic anhydride, or methanesulfonic anhydride;(iii) the fourth organic solvent is tetrahydrofuran; and(iv) the reaction proceeds at about 15±5 °C.

58. The process of any one of claims 53-57, wherein Step 5 takes place under one or more of the following conditions:(i) the organic fluoride source is tetrabutylammonium fluoride;(ii) the fifth organic solvent is acetonitrile; and(iii) the reaction proceeds at about 60±5 °C.

59. The process of any one of claims 53-58, wherein Step 6 takes place under one or more of the following conditions:(i) the acid is hydrochloric acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, or p-toluenesulfonic acid;(ii) the sixth organic solvent is dioxane, dichloromethane, or a mixture of dioxane and dichloromethane; and(iii) the reaction proceeds at about 40±5 °C.

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