Synthesis of pyruvate kinase activators

Abstract

Provided herein are methods for preparing activators of Pyruvate Kinase (PK) or a salt or a hydrate thereof, as well as intermediates useful in the preparation of such compounds or salts or hydrates thereof. Also provided are a number of crystalline forms of select compounds or salts or hydrates disclosed herein.

Description

128748-04620 (AGI-PKR-36WO)SYNTHESIS OF PYRUVATE KINASE ACTIVATORSRELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No.63 / 759,910, filed February 18, 2025, the entire contents of which are incorporated herein by reference.BACKGROUND

[0002] Pyruvate kinase (PK) is a metabolic enzyme that converts phosphoenolpyruvate to pyruvate during glycolysis. Four PK isoforms exist in mammals: the L and R isoforms are expressed in liver and red blood cells, the Ml isoform is expressed in most adult tissues, and the M2 isoform is a splice variant of Ml expressed during embryonic development. A well-known difference between the Ml and M2 isoforms of PK is that M2 is a low-activity enzyme that relies on allosteric activation by the upstream glycolytic intermediate, fructose-1,6-bisphosphate (FBP), whereas Ml is a constitutively active enzyme. PK activators can be used to treat a number of different disorders including PKD (Pyruvate Kinase Deficiency), thalassemia (e.g., alpha and beta-thalassemia), hereditary elliptocytosis, abetalipoproteinemia or Bassen-Kornzweig syndrome, sickle cell disease, paroxysmal nocturnal hemoglobinuria, and various anemias which include congenital anemias (e.g, enzymopathies) and hemolytic anemias (e.g, hereditary and / or congenital hemolytic anemia, acquired hemolytic anemia, chronic hemolytic anemia caused by phosphoglycerate kinase deficiency, anemia due to MDS (myelodysplastic syndromes), non- spherocytic hemolytic anemia and hereditary spherocytosis).SUMMARY

[0003] Provided herein are synthetic methods for preparing pyruvate kinase (PK) activators. Such activators may be prepared using compounds having the Formula (A-2) and / or Formula (A-3):wherein R1, R2, R3, L, L1, Rx, and Ryare as defined herein.1MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0004] Alternatively, such activators may be prepared using compounds having the Formula (A-2) and / or Formula (A-3’):(A-2) (A-3’),wherein R1, R2, R3, L, L1, Rx, and Ryare as defined herein.

[0005] Specific PK activators and various intermediates prepared by and / or used in the synthetic methods described herein are also disclosed.BRIEF DESCRIPTION OF THE FIGURES

[0006] FIG. 1 shows the combined Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) di-tert-butyl 2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)mal onate.

[0007] FIG. 2 shows the X-Ray Powder Diffraction (XRPD) plot for di-tert-butyl 2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate.

[0008] FIG. 3 shows the combined Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) for (2,4-dichlorothiazol-5-yl)(l,3-dioxan-2-yl)methanone.

[0009] FIG. 4 shows the X-Ray Powder Diffraction (XRPD) plot for (2,4-dichlorothiazol-5-yl)(l,3-dioxan-2-yl)methanone.

[0010] FIG. 5 shows the combined Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) for di-tert-butyl 2-(4-chl oro-5 -(1,3 -di oxane-2-carbonyl)thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate.

[0011] FIG. 6 shows the X-Ray Powder Diffraction (XRPD) plot for di-tert-butyl 2-(4-chloro-5-(l,3-dioxane-2-carbonyl)thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate.

[0012] FIG. 7 shows the combined Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) for di-tert-butyl 2-(6-(l,3-dioxan-2-yl)-5-(ethoxycarbonyl)-4-methyl-4H-pyrrolo[2,3-d]thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-1 H-py razol -3 -y l)mal onate .2MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0013] FIG. 8 shows the X-Ray Powder Diffraction (XRPD) plot for di-tert-butyl 2-(6-(l,3-dioxan-2-yl)-5-(ethoxycarbonyl)-4-methyl-4H-pyrrolo[2,3-d]thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate.

[0014] FIG. 9 shows the combined Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) for 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid.

[0015] FIG. 10 shows the X-Ray Powder Diffraction (XRPD) plot for 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid crystalline Form A.

[0016] FIG. 11 shows the X-Ray Powder Diffraction (XRPD) plot for 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid crystalline Form B.

[0017] FIG. 12 shows the X-Ray Powder Diffraction (XRPD) plot for 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid crystalline Form C.

[0018] FIG. 13 shows the X-Ray Powder Diffraction (XRPD) plot for 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid crystalline Form U.

[0019] FIG. 14 shows the X-Ray Powder Diffraction (XRPD) plot for 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid crystalline Form 6.DETAILED DESCRIPTION

[0020] In one embodiment, provided is a method of preparing a compound of Formula (A-l):(A-l),or a salt thereof, whereinR1is hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-C6cyanoalkyl C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C63MEl\59875898.vl128748-04620 (AGI-PKR-36WO)cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN;L and L1are each independently a bond or Ci-Ce alkylene; andR2and R3are each independently C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group;the method comprising reacting a compound of Formula (A-2):R'LZ'N'NH2(A-2) or a salt thereof,with a compound of Formula (A-3):(A-3) or a salt thereof,wherein Rxand Ryare each independently benzyl or Ci-Ce alkyl; to form the compound of Formula (A-l), or a salt thereof.

[0021] In another embodiment, provided is a method of preparing a compound of Formula (A-l):or a salt thereof, whereinR1is hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-C6cyanoalkyl C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN;L and L1are each independently a bond or Ci-Ce alkylene; and4MEl\59875898.vl128748-04620 (AGI-PKR-36WO)R2and R3are each independently C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)?, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group;the method comprising reacting a compound of Formula (A-2):(A-2) or a salt thereof,with a compound of Formula (A-3’):(A-3’) or a salt thereof,wherein Rxand Ryare each independently benzyl or Ci-Ce alkyl; to form the compound of Formula (A-l), or a salt thereof.

[0022] In another embodiment, provided is a method of preparing a compound of Formula (A-l):or a salt thereof, whereinR1is hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN;L and L1are each independently a bond or Ci-Ce alkylene; andR2and R3are each independently C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl,5MEl\59875898.vl128748-04620 (AGI-PKR-36WO)Ci-C6aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)?, CN, and NO?, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group;the method comprising reacting a compound of Formula (A-2):(A-2) or a salt thereof,with a compound of Formula (A-3a):(A-3a) or a salt thereof,wherein T is CN or -C(O)ORX, and Rxand Ryare each independently benzyl or Ci-Ce alkyl; to form the compound of Formula (A-l), or a salt thereof.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure.

[0024] The use of any and all examples or exemplary language (e.g., “for example”, “such as” and “e.g.”) as provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless expressly claimed otherwise. Phrases such as “in one aspect” or “in one embodiment” or “in some embodiments” or “in certain embodiments” or “in further embodiments” and the like should not be construed as indicating that such elements occur or exist in isolation or that such elements are not shared by other aspects or embodiments of the disclosure. Rather, it should be understood that all aspects and embodiments may be freely combined with any and all other aspects and embodiments of the disclosure as described herein. No language in the specification should be construed as indicating that any non-claimed element is essential to the practice of the disclosure.

[0025] The terms “Ci-Ce alkyl” refers to a straight- or branched-chain hydrocarbon group having from 1 to 6 carbon atoms. Examples of Ci-Ce alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-6MEl\59875898.vl128748-04620 (AGI-PKR-36WO)butyl), pentyl (C5) (e.g, n-pentyl, 3-pentyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (Ce) (e.g, n-hexyl).

[0026] The term “Ci-Ce alkylene” refers to a bivalent radical of a saturated, straight or branched chain hydrocarbon. Exemplary alkylene groups include, but are not limited to, Ci-C4 alkylene, C1-C3 alkylene, C1-C2 alkylene, and the corresponding alkylene to any of the other exemplary alkyl groups described above.

[0027] When a range of carbon atoms is used herein, for example, Ci-Ce, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, “C1-C3” includesCi-C3, C1-C2, C2-C3, Ci, C2, and C3.

[0028] As used herein, the term “C2-C6 alkenyl” refers to a straight- or branched-chain group having from 2 to 6 carbon atoms in the group, wherein the group includes at least one carbon-carbon double bond. Examples of C2-C6 alkenyl groups include vinyl (-CH=CH ; C2alkenyl), allyl (-CH -CH=CH2; Csalkenyl), propenyl (-CH=CHCH3; Csalkenyl), isopropenyl (-C(CH3)=CH2; Csalkenyl), butenyl (-CE^CElCEhCEE; C4alkenyl), sec-butenyl (-C(CH3)=CHCH3; C4alkenyl), iso-butenyl (-CH=C(CH3)2; C4alkenyl), and 2-butenyl (-CH2CH=CHCH3; C4alkyl).

[0029] As used herein, the term “C2-C6 alkynyl” refers to a straight- or branched-chain group having from 2 to 6 carbon atoms in the group, and wherein the group includes at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C=CH;C2alkynyl), propargyl (-CH2-OCH; Csalkynyl), propynyl (-OCCH3; Csalkynyl), butynyl (-OCCH2CH3; C4alkynyl), and pentynyl (-OCCH2CH2CH3; Csalkynyl).

[0030] The term “C3-C6 cycloalkyl” refers to cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 6 carbon atoms. Examples of C3-C6 cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), and cyclohexyl (Ce).

[0031] The term “halo” or “halogen,” as used by itself or as part of another group refers to a fluorine, chlorine, bromine, or iodine atom.

[0032] As used herein, the term “Ci-Ce haloalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms which may be the same or different. In some embodiments, the alkyl is substituted by at least one halogen. In other embodiments, the alkyl is substituted by one, two, or three F and / or Cl. Examples of haloalkyl groups include fluoromethyl (CH2F), 1-fluoroethyl (CH(CH3)F), 2-fluoroethyl, difluoromethyl (CHF 2), trifluoromethyl (CF3), pentafluoroethyl, 1,1-difluoroethyl (C(CH3)F2), 2,2-difluoroethyl (CH2CHF2), 2,2,2-trifluoroethyl (CH2CF3), 2-7MEl\59875898.vl128748-04620 (AGI-PKR-36WO)fluoropropan-2-yl (C(CH3)2F), 3, 3 -trifluoropropyl, 4,4,4-trifluorobutyl, trichloromethyl and the like.

[0033] The term “Ci-Ce cyanoalkyl” as used by itself or as part of another group refers to an alkyl as defined herein that is substituted by one or more CN. In some embodiments, the alkyl is substituted by at least one CN. In other embodiments, the alkyl is substituted by one, two, or three CN. Examples of cyanoalkyl groups include CH2CN, CH2CH2CN, CH(CN)CH3, CH2CH2CH2CN, C(CH3)2CN, CH2CH(CN)CH3, CH(CN)CH2CH3, and the like.

[0034] The term “Ci-Ce hydroxyalkyl” as used by itself or as part of another group refers to an alkyl group as defined herein wherein one or more of the hydrogen atoms has been replaced with one or more hydroxyl (z.e., -OH). In some embodiments, the hydroxyalkyl contains one OH. In other embodiments, the hydroxyalkyl contains two OH. In further embodiments, the hydroxyalkyl contains three OH. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxy ethyl (e.g., 1 -hydroxy ethyl, 2 -hydroxy ethyl), 1,2-dihydroxy ethyl, hydroxypropyl (e.g., 2-hydroxypropyl, 3 -hydroxy propyl), hydroxybutyl (e.g., 3-hydroxybutyl, 4-hydroxybutyl), 2-hydroxy-l -methylpropyl, l,3-dihydroxyprop-2-yl, and the like.

[0035] The term “Ci-Ce aminoalkyl” as used by itself or as part of another group refers to an alkyl as defined herein that is substituted by one or more NH2. In some embodiments, the alkyl is substituted by at least one NH2. In other embodiments, the alkyl is substituted by one, two, or three NH2. Examples of cyanoalkyl groups include CH2 NH2, CH2CH2 NH2, CH2CH2CH2NH2, and C(CH3)2NH2.

[0036] The term “6-12 membered aryl” refers to a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 12 carbon atoms in the ring. Examples of aryl groups include phenyl, indenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl.

[0037] The term “5-14 membered heteroaryl” refers to a mono- or bicyclic- aromatic ring structure having 5 to 14 ring atoms that include carbon atoms as well as up to four heteroatoms that are each independently selected from nitrogen, oxygen, or sulfur. Examples of heteroaryl groups include thienyl, benzo[b]thienyl, furanyl, benzofuryl, pyranyl, thiophenyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, quinoxalyl, phthalazinyl, naphthyridinyl, cinnolinyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, quinazolinyl, pteridinyl, pyrimidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, pyrazolo[l,5-a]pyridinyl,8MEl\59875898.vl128748-04620 (AGI-PKR-36WO)pyrazolo[l,5-a]pyridinyl, benzoisothiazolyl, imidazol[l,5-a]pyridinyl, pyrrolo[l,2]pyridazinyl, benzo[d]thiazolyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzoisoxazolyl, isothiazolyl, and tetrahydropyrazolo[l,5-a]pyridinyl.

[0038] The term “5-14 membered heterocyclyl” as used by itself or as part of another group refers to non-aromatic, saturated or partially unsaturated, e.g., containing one or two double bonds, cyclic groups containing one, two, or three rings having from five to fourteen ring members, wherein at least one carbon atom of one of the rings is replaced with a heteroatom. Each heteroatom is independently selected from oxygen, sulfur, including sulfoxide and sulfone, and / or nitrogen atoms, which can be oxidized or quaternized.Examples of heterocyclyl groups include azetidinyl, dioxanyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, indolinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, aziridinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, thianyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, tetrahydropyranyl, and the like. In some embodiments, the heterocyclyl group includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 6-azaspiro[2.5]octanyl.

[0039] As used herein, the terms “salt”, “salts” and “salt form” refer to an acid addition or base addition salt of a described compound. Acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. It should be understood that the terms “salt”, “salts” and “salt form” refer to all stoichiometries of salts of a described compound, including, for example, bis salts of a described compound. Such bis salts would include, for example, bis acid salts such as a bis hydrochloride salt or bis hydrobromide salt as well as bis basic salts such as a bis sodium salt.

[0040] As used herein, the terms “protecting group” and “PG” refer to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound. For example, in some embodiments the protecting groups protects or blocks the reactivity of the NH of a heteroaryl, such as a pyrazole, while other functional groups on the compound are reacted. Such protecting groups are well known in the art. See for example P. Wuts and T. Greene, 2007, Protective Groups in Organic Synthesis, Chapter 7, J. Wiley & Sons, NJ.9MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0041] As used herein, “crystalline” refers to a solid form of a compound wherein there exists long-range atomic order in the positions of the atoms. The crystalline nature of a solid can be confirmed, for example, by examination of the X-ray powder diffraction pattern. In one embodiment, the crystalline forms described herein are each single crystalline forms.

[0042] A “single crystalline form” means that the recited compound is present as a single crystal or a plurality of crystals in which each crystal has the same crystal form. Percent by weight of a particular crystal form is determined by the weight of the particular crystal form divided by the sum weight of the particular crystal, plus the weight of the other crystal form(s) present plus the weight of amorphous form, if present, multiplied by 100%. In some instances, the crystalline forms described herein are at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% a single crystalline form. “Pure single crystalline form” means that a described crystalline form is present as a single crystal or a plurality of crystals in which each crystal has the same crystal form with no other detectable amounts of other crystal forms and / or amorphous forms present.

[0043] The term “amorphous” refers to a solid that is present in a non-crystalline state or form. Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering. Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).

[0044] The 2-theta (20) values of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly from one instrument to another and also depending on variations in radiation source, instrument calibration, and sample preparation as well as batch to batch variation due to factors such as crystallite size, temperature variation, sample displacement, and the presence or absence of an internal standard. Therefore, unless otherwise defined, the XRPD patterns and peak assignments recited herein are not to be construed as absolute and can vary ± 0.2 degrees (±0.2° 2-theta). It is well known in the art that this variability will account for the above factors without hindering the unequivocal identification of a crystal form. Unless otherwise specified, the 2-theta values provided herein were obtained using Cu Kai radiation (1 = 1.5406 A).

[0045] “Substantially the same XRPD pattern” or “an X-ray powder diffraction pattern substantially similar to” a defined figure means that for comparison purposes, at least about 90% of the peaks shown are present. It is to be further understood that for comparison purposes some variability in peak intensities from those shown are allowed and can depend10MEl\59875898.vl128748-04620 (AGI-PKR-36WO)on one or more factors such as the instrument or radiation source, sample preparation, batch to batch variation, and environmental factors.

[0046] Temperature values, e.g., for DSC peaks herein may vary slightly from one instrument to another and can also depend on variations in sample preparation, batch to batch variation, and environmental factors. Therefore, unless otherwise defined, temperature values recited herein are not to be construed as absolute and can vary ± 5 degrees.

[0047] In some embodiments, R1in the method of preparing Formula (A-l) is Ci-Ce alkyl or Ci-Cehaloalkyl. In some embodiments, R1in the method of preparing Formula (A-l) is C1-C4 alkyl. In some embodiments, R1in the method of preparing Formula (A-l) is methyl.

[0048] In some embodiments, L in the method of preparing Formula (A-l) is Ci-Ce alkylene. In some embodiments, L in the method of preparing Formula (A-l) is -CH2-.

[0049] In some embodiments, L1in the method of preparing Formula (A-l) is Ci-Ce alkylene. In some embodiments, L1in the method of preparing Formula (A-l) is -CH2-.

[0050] In some embodiments, R2in the method of preparing Formula (A-l) is a 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, NH2, -NH(CI-C6 alkyl), N(Ci-Ce alkyl)2, CN, and NO2. In some embodiments, R2in the method of preparing Formula (A-l) is a 5-14 membered heteroaryl optionally substituted with 1 to 3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxy alkyl, hydroxyl, Ci-Ce aminoalkyl, NH2, -NH(Ci-Ce alkyl), N(Ci-Ce alkyl)2, CN, and NO2. In some embodiments, R2in the method of preparing Formula (A-l) is a 5-7 membered heteroaryl optionally substituted with -NH2. In some embodiments, R2in the method of preparing Formula (A-l) is pyridinyl optionally substituted with -NH2. In some embodiments, R2in the method of preparing Formula (A-l) is 2-aminopyridin-6-yl.

[0051] In some embodiments, R3in the method of preparing Formula (A-l) is a 5-14 membered heterocyclyl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, NH2, -NH(CI-C6 alkyl), N(Ci-Ce alkyl)2, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group. In some embodiments, R3in the method of preparing Formula (A-l) is a 5-14 membered heteroaryl, optionally substituted with 1 to 3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, NH2, -NH(CI-C6 alkyl), N(Ci-Ce alkyl)2, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heteroaryl 11MEl\59875898.vl128748-04620 (AGI-PKR-36WO)is optionally substituted with a protecting group. In some embodiments, R3in the method of preparing Formula (A-l) is a 5-7 membered heteroaryl, optionally substituted with 1 to 3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, NH2, -NH(Ci-Ce alkyl), N(Ci-Ce alkyl)?, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-7 membered heteroaryl is optionally substituted with a protecting group. In some embodiments, R3in the method of preparing Formula (A-l) is pyrazolyl optionally substituted with 1 to 3 groups selected from halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, NH?, -NH(CI-C6 alkyl), N(Ci-Ce alkyl)?, CN, and NO?, and wherein one nitrogen atom on said pyrazolyl is optionally substituted with a protecting group. In some embodiments, R3in the method of preparing Formula (A-l) is pyrazolyl and wherein one nitrogen atom on said pyrazolyl is optionally substituted with a protecting group.

[0052] In some embodiments, said protecting group on one nitrogen atom on R3in the method of preparing Formula (A-l) is selected from t-butyloxy carbonyl (BOC), fluorenylmethyloxycarbonyl (FMOC), acetate, benzyl, trityl, tetrahydropyranyl (THP), trichloroethyl chloroformate (Troc), pivaloyl, or tosylate. In some embodiments, said protecting group on one nitrogen on R3in the method of preparing Formula (A-l) is THP.

[0053] In some embodiments, the compound of Formula (A-2) is:or a bis-acid salt thereof. In some embodiments, the compound of Formula (A-2) is:or a salt thereof, wherein PG is a protecting group as defined herein. In some embodiments PG is THP. In some embodiments, the compound of Formula (A-3) is:12MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0055] In some embodiments, the compound of Formula (A-3’) is:or a salt thereof, wherein PG is a protecting group as defined herein. In some embodiments PG is THP. In some embodiments, the compound of Formula (A-3’) is:

[0056] In some embodiments, Rxand Ryin the method of preparing Formula (A-l) are each independently Ci-Ce alkyl. In some embodiments, Rxand Ryin the method of preparing Formula (A-l) are each independently C1-C4 alkyl.

[0057] In some embodiments, the compound of Formula (A-3) is:13MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0058] In some embodiments, the compound of Formula (A-3’) is:, or a salt thereof. In some embodiments, the compound of Formula (A-3’) is:

[0059] In some embodiments, the compound of Formula (A-l) is:defined herein. In some embodiments PG is THP. In some embodiments, the compound of Formula (A-l) is:

[0060] In some embodiments, the compound of Formula (A-l) or a salt thereof is crystalline.

[0061] In some embodiments, the compound of Formula (A-l) or a salt thereof is a hydrate.14MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0062] In some embodiments, the compound of Formula (A-2) or salt thereof is reacted with the compound of Formula (A-3), (A-3’), or (A-3a), or a salt thereof in the presence of one or more acids such as e.g., hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, oxalic acid, tartaric acid, formic acid, methanesulfonic acid or p-toluenesulfonic acid and at least one solvent. In some embodiments, the reaction between the compound of Formula (A-2) or salt and the compound of Formula (A-3), (A-3’), or (A-3a), or a salt thereof further includes the presence of a salt of an acid, such as for example, mono-sodium citrate, sodium dihydrogen citrate, sodium acetate, trisodium citrate, sodium oxalate, sodium tartrate, sodium bitartrate, potassium acetate, or lithium acetate. In some embodiments, the compound of Formula (A-2) or salt thereof is reacted with the compound of Formula (A-3), (A-3’), or (A-3a), or a salt thereof in the presence of citric acid and / or mono-sodium citrate.

[0063] In some embodiments, the compound of Formula (A-2) or salt thereof is reacted with the compound of Formula (A-3), (A-3’), or (A-3a), or a salt thereof in the presence of at least one solvent, e.g., at least one polar protic solvent selected from water, methanol, ethanol, / / -propanol, / -propanol, isopentyl alcohol, / -butanol and / -butanol, or any combination thereof. In some embodiments, the compound of Formula (A-2) or salt thereof is reacted with the compound of Formula (A-3), (A-3’), or (A-3a), or a salt thereof in the presence of ethanol and water.

[0064] In another embodiment, provided is a method of preparing a compound of Formula (A-3):or a salt thereof, whereinR1is hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-C6cyanoalkyl C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN;L1is a C;R3is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from15MEl\59875898.vl128748-04620 (AGI-PKR-36WO)halo, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)?, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group; andRxand Ryare each independently benzyl or Ci-Ce alkyl;the method comprising hydrolyzing a compound of Formula (A-4):(A-4) or a salt thereof,wherein R4is Ci-Ce alkyl to form the compound of Formula (A-4), or a salt thereof.

[0065] In another embodiment, provided is a method of preparing a compound of Formula (A-3’):or a salt thereof, whereinR1is hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN;L1is C;R3is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)?, CN, and NO?, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group; andRxand Ryare each independently benzyl or Ci-Ce alkyl;the method comprising hydrolyzing a compound of Formula (A-4’):16MEl\59875898.vl128748-04620 (AGI-PKR-36WO)(A-4’) or a salt thereof,wherein R4is Ci-Ce alkyl to form the compound of Formula (A-4’), or a salt thereof.

[0066] In another embodiment, provided is a method of preparing a compound of Formula (A-3a):(A-3a),or a salt thereof, whereinR1is hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-C6cyanoalkyl C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN;T is CN or -C(O)ORX;L1is C;R3is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group; andRxand Ryare each independently benzyl or Ci-Ce alkyl;the method comprising hydrolyzing a compound of Formula (A-4a):(A-4a) or a salt thereof,17MEl\59875898.vl128748-04620 (AGI-PKR-36WO)wherein R4is Ci-Ce alkyl to form the compound of Formula (A-4a), or a salt thereof.

[0067] In some embodiments, the compound of Formula (A-4), (A-4’), or (A-4a), or a salt thereof is hydrolyzed in the presence of a base and one or more solvents.

[0068] In some embodiments, the base is selected from lithium hydroxide (LiOH), calcium hydroxide (Ca(OH)2), potassium hydroxide (KOH), sodium hydroxide (NaOH), and barium hydroxide (Ba(OH)2). In some embodiments, the base is NaOH.

[0069] In some embodiments, the compound of Formula (A-4), (A-4’), or (A-4a), or a salt thereof is hydrolyzed in the presence of one or more solvents. In some embodiments the one or more solvents are selected from water, THF, acetonitrile, methanol, ethanol, n-propanol, / -propanol, and / -butanol, or any combination thereof. In some embodiments, the compound of Formula (A-4), (A-4’), or (A-4a), or a salt thereof is hydrolyzed in the presence of water and at least one polar solvent. In some embodiments, the compound of Formula (A-4), (A-4’), or (A-4a), or a salt thereof is hydrolyzed in the presence of water and ethanol. In some embodiments, the compound of Formula (A-4), (A-4’), or (A-4a),or a salt thereof is hydrolyzed in the presence of water and THF.

[0070] In another embodiment, provided herein is a method of preparing a compound of Formula (A-4):or a salt thereof, whereinR1is hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-C6cyanoalkyl C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN;L1is C; andR3is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, CN, and NO2, and wherein one or more nitrogen atoms, if18MEl\59875898.vl128748-04620 (AGI-PKR-36WO)present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group;R4is Ci-C6alkyl; andRxand Ryare each independently benzyl or Ci-Ce alkyl;the method comprising reacting a compound of Formula (A-5):(A-5) or a salt thereof,with acid to form the compound of Formula (A-4), or a salt thereof.

[0071] In another embodiment, provided herein is a method of preparing a compound of Formula (A-4’):(A-4’),or a salt thereof, whereinR1is hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-C6cyanoalkyl C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN;L1is C; andR3is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group;R4is Ci-Ce alkyl; andRxand Ryare each independently benzyl or Ci-Ce alkyl;19MEl\59875898.vl128748-04620 (AGI-PKR-36WO)the method comprising reacting a compound of Formula (A-5’):(A-5’) or a salt thereof,with acid to form the compound of Formula (A-4’), or a salt thereof.

[0072] In another embodiment, provided herein is a method of preparing a compound of Formula (A-4a):(A-4a),or a salt thereof, whereinR1is hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-C6cyanoalkyl C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN;T is CN or -C(O)ORX;L1is C; andR3is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group;R4is Ci-Ce alkyl; andRxand Ryare each independently benzyl or Ci-Ce alkyl;the method comprising reacting a compound of Formula (A-5a):20MEl\59875898.vl128748-04620 (AGI-PKR-36WO)(A-5a) or a salt thereof,with acid to form the compound of Formula (A-4a), or a salt thereof, whereinRzaand Rzbare each, independently, Ci-Ce alkyl or benzyl;or Rzaand Rzb, together with the oxygen atoms to which they are attached, form a 5-to 7-membered heterocyclyl optionally substituted by one or more C1-C4 alkyl.

[0073] In some embodiments, the compound of Formula (A-5), (A-5’), or (A-5a), or a salt thereof is reacted with acid in the presence of one or more solvents to form the compound of Formula (A-4), (A-4’), or (A-4a), or a salt thereof. In some embodiments, the acid used in the reaction with the compound of Formula (A-5), (A-5’), or (A-5a), is acetic acid, citric acid, sodium dihydrogen citrate, oxalic acid, tartaric acid, formic acid, or hydrochloric acid. In some embodiments, the acid used in the reaction with the compound of Formula (A-5), (A-5’), or (A-5a), is citric acid. In some embodiments, the one or more solvents used in the reaction with the compound of Formula (A-5), (A-5’), or (A-5a), is selected from ethanol, water, THF and acetonitrile or any combination thereof. In some embodiments, the one or more solvents used in the reaction with the compound of Formula (A-5), (A-5’), or (A-5a), is selected from ethanol, THF water, and acetonitrile or any combination thereof. In some embodiments, the one or more solvents used in the reaction with the compound of Formula (A-5), (A-5’), or (A-5a), is water and THF.

[0074] In another embodiment, provided herein is a method of preparing a compound of Formula (A-5):or a salt thereof, whereinR1is hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce cyanoalkyl C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C621MEl\59875898.vl128748-04620 (AGI-PKR-36WO)cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN;LUs C;R3is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)?, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group;R4is Ci-Ce alkyl; andRxand Ryare each independently benzyl or Ci-Ce alkyl;the method comprising reacting a compound of Formula (A-6):(A-6) or a salt thereof,with a compound of Formula (A-7):(A-7) or a salt thereof,to form the compound of Formula (A-5). In some embodiments R4is Ci-Ce alkyl. In some embodiments R4is ethyl. In some embodiments R1is selected from H and Ci-Ce alkyl. In some embodiments R1is H. In some embodiments R4is ethyl and R1is H.

[0075] In another embodiment, provided herein is a method of preparing a compound of Formula (A-5’):(A-5’),or a salt thereof, wherein22MEl\59875898.vl128748-04620 (AGI-PKR-36WO)R1is hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-C6cyanoalkyl C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN;LUs C;R3is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group;R4is Ci-Ce alkyl; andRxand Ryare each independently benzyl or Ci-Ce alkyl;the method comprising reacting a compound of Formula (A-6’):(A-6’) or a salt thereof,with a compound of Formula (A-7):(A-7) or a salt thereof,to form the compound of Formula (A-5’). In some embodiments R4is Ci-Ce alkyl. In some embodiments R4is ethyl. In some embodiments R1is selected from H and Ci-Ce alkyl. In some embodiments R1is H. In some embodiments R4is ethyl and R1is H.

[0076] In another embodiment, provided herein is a method of preparing a compound of Formula (A-5a):23MEl\59875898.vl128748-04620 (AGI-PKR-36WO)(A-5a),or a salt thereof, whereinR1is hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-C6cyanoalkyl C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN;T is CN or -C(O)ORX;l / is C;R3is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group;R4is Ci-Ce alkyl; andRxand Ryare each independently benzyl or Ci-Ce alkyl;Rzaand Rzbare each, independently, Ci-Ce alkyl or benzyl;or Rzaand Rzb, together with the oxygen atoms to which they are attached, form a 5-to 7-membered heterocyclyl optionally substituted by one or more C1-C4 alkyl;the method comprising reacting a compound of Formula (A-6a):(A-6a) or a salt thereof,with a compound of Formula (A-7):(A-7) or a salt thereof,to form the compound of Formula (A-5a). In some embodiments R4is Ci-Ce alkyl. In some embodiments R4is ethyl. In some embodiments R1is selected from H and Ci-Ce alkyl. In some embodiments R1is H. In some embodiments R4is ethyl and R1is H.24MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0077] In some embodiments, the compound of Formula (A-6), (A-6’), or (A-6a), or a salt thereof and the compound of Formula (A-7) or a salt thereof is reacted with an organic base. In some embodiments, the base is a strong organic base. In some embodiments, the base is selected from l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5,7-Triazabicyclo(4.4.0)dec-5-ene (TBD), 7-Methyl-l,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD), 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN), and 1,1,3,3-Tetramethylguanidine (TMG). In some embodiments, the base is DBU.

[0078] In some embodiments, the compound of Formula (A-6), (A-6’), or (A-6a), or a salt thereof and the compound of Formula (A-7) or a salt thereof is reacted in the presence of at least one solvent. In some embodiments, the at least one solvent is selected from water, acetonitrile, THF, 2-MeTHF, and acetic acid, or any combination thereof. In some embodiments, the at least one solvent is selected from water, acetonitrile, THF and 2-MeTHF, or any combination thereof. In some embodiments, the at least one solvent is selected from water, acetonitrile, and acetic acid, or any combination thereof. In some embodiments, the at least one solvent is selected from water, acetonitrile, and acetic acid, or any combination thereof. In some embodiments the reaction between the compound of Formula (A-6), (A-6’), or (A-6a), or a salt thereof and the compound of Formula (A-7) or a salt thereof is conducted at elevated temperatures.

[0079] In another embodiment, provided is a method of preparing a compound of Formula (A-6):(A-6),or a salt thereof, whereinL1is C; andR3is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)?, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group; andRxand Ryare each independently benzyl or Ci-Ce alkyl;25MEl\59875898.vl128748-04620 (AGI-PKR-36WO)the method comprising reacting a compound of Formula (A-8):(A-8) or a salt thereof,wherein X is halo;with a compound of Formula (A-9):(A-9) or a salt thereof, wherein L1is CH,to form the compound of Formula (A-6). In some embodiments X is chloro.

[0080] In another embodiment, provided is a method of preparing a compound of Formula (A-6’):(A-6’),or a salt thereof, whereinL1is C; andR3is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)?, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group; andRxand Ryare each independently benzyl or Ci-Ce alkyl;the method comprising reacting a compound of Formula (A-8):(A-8) or a salt thereof,26MEl\59875898.vl128748-04620 (AGI-PKR-36WO)wherein X is halo;with a compound of Formula (A-9’):NORyO 'l ,Y or3(A-9’) or a salt thereof, wherein L1is CH,to form the compound of Formula (A-6’). In some embodiments X is chloro.

[0081] In another embodiment, provided is a method of preparing a compound of Formula (A-6a):or a salt thereof, whereinT is CN or -C(O)ORX;L1is C; andR3is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)?, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group; andRxand Ryare each independently benzyl or Ci-Ce alkyl;Rzaand Rzbare each, independently, Ci-Ce alkyl or benzyl;or Rzaand Rzb, together with the oxygen atoms to which they are attached, form a 5-to 7-membered heterocyclyl optionally substituted by one or more C1-C4 alkyl;the method comprising reacting a compound of Formula (A-8a):"(A-8a) or a salt thereof,wherein X is halo;with a compound of Formula (A-9a):27MEl\59875898.vl128748-04620 (AGI-PKR-36WO)(A-9a) or a salt thereof, wherein L1is CH,to form the compound of Formula (A-6a). In some embodiments X is chloro.

[0082] In some embodiments, the compound of Formula (A-8) or (A-8a) or a salt thereof is reacted with the compound of Formula (A-9), (A-9’), or (A-9a), or a salt thereof in the presence of a base, a metal halide salt, and one or more solvents. In some embodiments, the compound of Formula (A-8) or (A-8a) or a salt thereof is reacted with the compound of Formula (A-9), (A-9’), or (A-9a), or a salt thereof in the presence of a base selected from lithium bis(trimethylsilyl)amide (LiHMDS), lithium / -butoxide (LiO / Bu), lithium tert-amoxide (LiO / Am), sodium / -butoxide (NaO / Bu), potassium / -butoxide (KO / Bu), and sodium hydride (NaH). In some embodiments, the compound of Formula (A-8) or (A-8a) or a salt thereof is reacted with the compound of Formula (A-9), (A-9’), or (A-9a), or a salt thereof in the presence of LiO / Bu. In some embodiments the metal halide salt is zinc bromide (ZnBn). In some embodiments the metal halide salt is indium chloride, indium bromide, manganese chloride, manganese bromide, zinc bromide, or zinc chloride. In some embodiments the reaction between the compound of Formula (A-8) or (A-8a) or a salt thereof and the compound of Formula (A-9), (A-9’), or (A-9a), or a salt thereof is conducted at moderate temperatures.

[0083] In some embodiments, the compound of Formula (A-8) or (A-8a) or a salt thereof is reacted with the compound of Formula (A-9), (A-9’), or (A-9a), or a salt thereof in the presence of at least one solvent. In some embodiments, the compound of Formula (A-8) or (A-8a) or a salt thereof is reacted with the compound of Formula (A-9), (A-9’), or (A-9a), or a salt thereof in the presence of at least one non-polar solvent. In some embodiments, the compound of Formula (A-8) or (A-8a) or a salt thereof is reacted with the compound of Formula (A-9), (A-9’), or (A-9a), or a salt thereof in the presence of at least one solvent selected from heptane, THF, dioxane, dichloroethane, benzene, toluene, chlorobenzene, di chlorobenzene, and xylene or any combination thereof. In some embodiments, the compound of Formula (A-8 or (A-8a)) or a salt thereof is reacted with the compound of Formula (A-9), (A-9’), or (A-9a), or a salt thereof in the presence of toluene, THF, and heptane or any combination thereof.

[0084] In another embodiment, provided herein is a method of preparing a compound of Formula (A-8):28MEl\59875898.vl128748-04620 (AGI-PKR-36WO)or a salt thereof, wherein X is halo;the method comprising reacting a compound of Formula (A- 10):(A- 10) or a salt thereof,wherein R5is Ci-Ce alkyl;with a compound of Formula (A-l 1):(A-l 1) or a salt thereof,wherein X is halo, to form the compound of Formula (A-8). In some embodiments X is chloro. In some embodiments R5is ethyl. In some embodiments R5is methyl or ethyl.

[0085] In another embodiment, provided herein is a method of preparing a compound of Formula (A-8):(A-8a),or a salt thereof, wherein:X is halo;Rzaand Rzbare each, independently, Ci-Ce alkyl or benzyl;or Rzaand Rzb, together with the oxygen atoms to which they are attached, form a 5-to 7-membered heterocyclyl optionally substituted by one or more C1-C4 alkyl;the method comprising reacting a compound of Formula (A- 10):<(A- 10a) or a salt thereof,wherein R5is Ci-Ce alkyl;29MEl\59875898.vl128748-04620 (AGI-PKR-36WO)with a compound of Formula (A-l 1):(A-l 1) or a salt thereof,wherein X is halo, to form the compound of Formula (A-8). In some embodiments X is chloro. In some embodiments R5is ethyl. In some embodiments R5is methyl or ethyl.

[0086] In some embodiments, the compound of Formula (A-10) or (A-lOa) or a salt thereof is reacted with the compound of Formula (A-l 1) or a salt thereof in the presence of a base and one or more solvents. In some embodiments, the compound of Formula (A-10) or (A-lOa) or a salt thereof is reacted with the compound of Formula (A-l 1) or a salt thereof in the presence of a base selected from lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium tetramethylpiperidide (LiTMP), and sodium hydride (NaH). In some embodiments, the compound of Formula (A-10) or (A-lOa)or a salt thereof is reacted with the compound of Formula (A-l 1) or a salt thereof in the presence of LDA. In some embodiments, the compound of Formula (A-10) or (A-lOa)or a salt thereof is reacted with the compound of Formula (A-l 1) or a salt thereof in the presence of LiTMP. In some embodiments, the compound of Formula (A-10) or (A-lOa)or a salt thereof is reacted with the compound of Formula (A-l 1) or a salt thereof in the presence of at least one solvent. In some embodiments, the compound of Formula (A-10) or (A-lOa)or a salt thereof is reacted with the compound of Formula (A-l 1) or a salt thereof in the presence of at least one solvent selected from THF, 2-MeTHF, heptane, dioxane, di chloroethane, benzene, toluene, chlorobenzene, di chlorobenzene, and xylene or any combination thereof. In some embodiments, the compound of Formula (A-10) or (A-lOa)or a salt thereof is reacted with the compound of Formula (A-l 1) or a salt thereof in the presence of at least one solvent selected from THF, 2-MeTHF, heptane, dioxane, benzene, toluene, and xylene or any combination thereof. In some embodiments, the compound of Formula (A-10) or (A-lOa)or a salt thereof is reacted with the compound of Formula (A-l 1) or a salt thereof in the presence of THF. In some embodiments, the compound of Formula (A-10) or (A-lOa)or a salt thereof is reacted with the compound of Formula (A-l 1) or a salt thereof in the presence of 2-MeTHF. In some embodiments, the reaction between the compound of Formula (A-10) or (A-lOa)or a salt and the compound of Formula (A-l 1) or a salt thereof is conducted at low temperature. In some embodiments, the reaction between the compound of Formula (A-10) or (A-lOa)or a salt and30MEl\59875898.vl128748-04620 (AGI-PKR-36WO)the compound of Formula (A-l 1) or a salt thereof further includes the addition of an acid in the presence of one or more solvents. In some embodiments, the acid is acetic acid. In some embodiments, at least one solvent is selected from iPAc, THF, heptane, dioxane, di chloroethane, benzene, toluene, chlorobenzene, di chlorobenzene, and xylene or any combination thereof. In some embodiments, the acid is acetic acid. In some embodiments, at least one solvent is selected from iPAc, THF, heptane, dioxane, benzene, toluene, and xylene or any combination thereof.

[0087] In another embodiment, provided herein is a method of preparing a compound of Formula (A-9):(A-9),or a salt thereof, whereinL1is CH;R3is, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, , Ci-Ce aminoalkyl, -N(Ci-Ce alkyl)?, CN, and NO?, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group; andRxand Ryare each independently benzyl or Ci-Ce alkyl;the method comprising reacting a compound of Formula (A- 12):ORyORXO^L1^O(A-12) or a salt thereof, wherein L1is CH2,with a compound of Formula (A-13):X1R3(A-13) or a salt thereof,wherein X1is halo, to form the compound of Formula (A-9).

[0088] In another embodiment, provided herein is a method of preparing a compound of Formula (A-9a):31MEl\59875898.vl128748-04620 (AGI-PKR-36WO)(A-9a),or a salt thereof, whereinL1is CH;T is CN or -C(O)ORX;R3is, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, Ci-Ce alkyl, Ci-Cehaloalkyl, , Ci-Ce aminoalkyl, -N(Ci-Ce alkyl)?, CN, and NO?, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group; andRxand Ryare each independently benzyl or Ci-Ce alkyl;the method comprising reacting a compound of Formula (A-12a):(A-12a) or a salt thereof, wherein L1is CH2,with a compound of Formula (A-13):X1R3(A-13) or a salt thereof,wherein X1is halo, to form the compound of Formula (A-9a).

[0089] In some embodiments, the compound of Formula (A-12) or (A-12a) or a salt thereof is reacted with compound of Formula (A-13) or a salt thereof in the presence of a catalyst, a ligand, a base, and one or more solvents. In some embodiments, the ligand is 2-picolinic acid, benzoic acid, 1,10-phenanthroline, 1,3 -benzoxazole, pipecolic acid, orL-proline. In some embodiments, the base is potassium carbonate, cesium carbonate, potassium phosphate tribasic, sodium Zc / V-butoxide, lithium ZcvZ-butoxide, potassium ZcvZ-butoxide or lithium hexamethyldisilazide. In some embodiments, the compound of Formula (A-12) or (A-12a) or a salt thereof is reacted with compound of Formula (A-13) or a salt thereof in the presence of a copper catalyst, 2-picolinic acid, cesium carbonate, potassium ZcvZ-butoxide and one or more solvents. In some embodiments, the compound of Formula (A-12) or (A-12a) or a salt thereof is reacted with compound of Formula (A-13) or a salt thereof in the presence of a copper catalyst, 2-picolinic acid, potassium ZcvZ-butoxide and one or more solvents. In some32MEl\59875898.vl128748-04620 (AGI-PKR-36WO)embodiments, the compound of Formula (A-12) or (A-12a) or a salt thereof is reacted with compound of Formula (A-13) or a salt thereof in the presence of a copper iodide, copper(I) chloride, or copper(I) bromide. In some embodiments, the compound of Formula (A-12) or (A-12a) or a salt thereof is reacted with compound of Formula (A-13) or a salt thereof in the presence of a copper iodide. In some embodiments the one or more solvents are selected from THF, heptane, dioxane, di chloroethane, benzene, toluene, chlorobenzene, di chlorobenzene, DMSO, 2-MeTHF, acetonitrile, and xylene or any combination thereof. In some embodiments the one or more solvents are selected from THF, dioxane, benzene, toluene, DMSO, 2-MeTHF, and xylene or any combination thereof. In some embodiments, the compound of Formula (A-12) or a salt thereof is reacted with compound of Formula (A-13) or a salt thereof in the presence of dioxane. In some embodiments, the compound of Formula (A-12) or (A-12a) or a salt thereof is reacted with compound of Formula (A-13) or a salt thereof in the presence of Me-THF.

[0090] In some embodiments, R1in the present methods is Ci-Ce alkyl or Ci-Ce haloalkyl. In some embodiments, wherein R1in the present methods is C1-C4 alkyl. In some embodiments, wherein R1in the present methods is methyl.

[0091] In some embodiments, R4in the present methods is ethyl.

[0092] In some embodiments, R3in the present methods is a 5-14 membered heterocyclyl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, NH2, -NH(Ci-Ce alkyl), N(Ci-Ce alkyl)?, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heterocyclyl or 5-14 membered heteroaryl is optionally substituted with a protecting group. In some embodiments, R3in the present methods is a 5-14 membered heteroaryl, optionally substituted with 1 to 3 groups selected from halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, NH2, -NH(Ci-Ce alkyl), N(Ci-Ce alkyl)?, CN, and NO?, and wherein one or more nitrogen atoms, if present, on said 5-14 membered heteroaryl is optionally substituted with a protecting group. In some embodiments, R3in the present methods is a 5-7 membered heteroaryl, optionally substituted with 1 to 3 groups selected from halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, NH?, -NH(CI-C6 alkyl), N(Ci-Ce alkyl)?, CN, and NO2, and wherein one or more nitrogen atoms, if present, on said 5-7 membered heteroaryl is optionally substituted with a protecting group. In some embodiments, R3in the present methods is pyrazolyl optionally substituted with 1 to 3 groups selected from halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, hydroxyl, Ci-Ce aminoalkyl, NH?, - 33MEl\59875898.vl128748-04620 (AGI-PKR-36WO)NH(Ci-Ce alkyl), N(Ci-Ce alkyl)?, CN, and NO2, and wherein one nitrogen atom on said pyrazolyl is optionally substituted with a protecting group. In some embodiments, R3in the present methods is pyrazolyl and wherein one nitrogen atom on said pyrazolyl is optionally substituted with a protecting group.

[0093] In some embodiments, said protecting group (or PG) in the present methods is an alcohol or an amine protecting group. In some embodiments, said protecting group (or PG) in the present methods is selected from / -butyl, methoxymethyl, allyl, Z-butyldiphenylsilyl, t-butyldimethylsilyl, benzyloxycarbonyl (Cbz), / -butyl oxy carbonyl (BOC), fluorenylmethyloxycarbonyl (FMOC), acetate, trifluoroacetate, benzyl, trityl, tetrahydropyranyl (THP), tri chloroethyl chloroformate (Troc), pivaloyl, or tosylate. In some embodiments, said protecting group (or PG) in the present methods is selected from t-butyloxycarbonyl (BOC), fluorenylmethyloxycarbonyl (FMOC), acetate, benzyl, trityl, tetrahydropyranyl (THP), pivaloyl, or tosylate. In some embodiments, said protecting group (or PG) in the present methods is THP.

[0094] In some embodiments, T in the present methods is CN. In some embodiments, T in the present methods is C(O)ORX.

[0095] In some embodiments, Rxand Ryin the present methods are each independently Ci-Ce alkyl. In some embodiments, Rxand Ryin the present methods are each independently C1-C4 alkyl.

[0096] In some embodiments Rzaand Rzbin the present methods are each independently Ci-Cealkyl. In embodiments, Rzaand Rzbin the present methods are each benzyl. In some embodiments, Rzaand Rzbin the present methods are each independently Ci-C4alkyl. In some embodiments, Rzaand Rzbin the present methods are each independently Ci-C2alkyl.

[0097] In some embodiments, Rzaand Rzbin the present methods, together with the oxygen atoms to which they are attached, form a 5- to 7-membered heterocyclyl optionally substituted by one or more Ci-C4alkyl. In some embodiments, Rzaand Rzbin the present methods, together with the oxygen atoms to which they are attached, form a 5- or 6-membered heterocyclyl optionally substituted by one or more Ci-C4alkyl. In some embodiments, Rzaand Rzbin the present methods, together with the oxygen atoms to which they are attached, form a 5- or 6-membered heterocyclyl optionally substituted by one or two Ci-C4alkyl.

[0098] In some embodiments, X in the present methods is chloro.

[0099] In some embodiments, X1in the present methods is iodo.34MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0100] In some embodiments, R5in the present methods is ethyl. In other embodiments, R5in the present methods is methyl.

[0101] In some embodiments, the compound of Formula (A-3) is

[0102] In some embodiments, the compound of Formula (A-4) is

[0103] In some embodiments, the compound of Formula (A-5) is

[0104] In some embodiments, the compound of Formula (A-6) issalt thereof.

[0105] In some embodiments, the compound of Formula (A-7) issalt thereof.35MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0106] In some embodiments, compound of Formula (A-7) is

[0107] In some embodiments, the compound of Formula (A-8) is

[0108] In some embodiments, the compound of Formula (A-9) issalt thereof.

[0109] In some embodiments, the compound of Formula (A-10) issalt thereof.

[0110] In some embodiments, the compound of Formula (A-l 1) issalt thereof.

[0111] In some embodiments, the compound of Formula (A-12) issalt thereof.

[0112] In some embodiments, the compound of Formula (A-13) issalt thereof.

[0113] Also provided is a compound having the structural formula:36MEl\59875898.vl128748-04620 (AGI-PKR-36WO)salt thereof.

[0114] In some embodiments, the compound having the structural formula:salt thereof,is crystalline. In some embodiments, the compound is crystalline and is characterized by three or more x-ray powder diffraction peaks at 20 angles selected from 8.95° ± 0.2° 20, 8.98° ± 0.2° 20, 13.46° ± 0.2° 20, 17.05° ± 0.2° 20, and 20.07° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 8.95° ± 0.2° 20, 8.98° ± 0.2° 20, 13.46° ± 0.2° 20, 17.05° ± 0.2° 20, and 20.07° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 8.95° ± 0.2° 20, 8.98° ± 0.2° 20, 13.46° ± 0.2° 20, 17.05° ± 0.2° 20, and 20.07° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by x-ray powder diffraction peaks at 20 angles at 8.95° ± 0.2° 20, 8.98° ± 0.2° 20, 13.46° ± 0.2° 20, 17.05° ± 0.2° 20, and 20.07° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by x-ray powder diffraction peaks at 20 angles at 8.95° ± 0.2° 20, 8.98° ± 0.2° 20, 10.48° ± 0.2° 20, 12.38° ± 0.2° 20, 13.46° ± 0.2° 20, 15.74° ± 0.2° 20, 16.49° ± 0.2° 20, 17.05° ± 0.2° 20, 17.99° ± 0.2° 20, 18.86° ± 0.2° 20, 19.45° ± 0.2° 20, 20.07° ± 0.2° 20, 20.44° ± 0.2° 20, and 21.18° ± 0.2° 20.

[0115] Also provided is a compound having the structural formula:

[0116] In some embodiments, the compound having the structural formula:MEl\59875898.vl128748-04620 (AGI-PKR-36WO)salt thereof,is crystalline. In some embodiments, the compound is crystalline and is characterized by three or more x-ray powder diffraction peaks at 20 angles selected from 9.78° ± 0.2° 20, 12.76° ± 0.2° 20, 19.35° ± 0.2° 20, 24.43° ± 0.2° 20, and 25.81° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 9.78° ± 0.2° 20, 12.76° ± 0.2° 20, 19.35° ± 0.2° 20, 24.43° ± 0.2° 20, and 25.81° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 9.78° ± 0.2° 20, 12.76° ± 0.2° 20, 19.35° ± 0.2° 20, 24.43° ± 0.2° 20, and 25.81° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by x-ray powder diffraction peaks at 20 angles at 9.78° ± 0.2° 20, 12.76° ± 0.2° 20, 19.35° ± 0.2° 20, 24.43° ± 0.2° 20, and 25.81° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by x-ray powder diffraction peaks at 20 angles at 9.78° ± 0.2° 20, 12.76° ± 0.2° 20, 19.35° ± 0.2° 20, 24.43° ± 0.2° 20, 25.5° ± 0.2° 20, 25.57° ± 0.2° 20, 25.81° ± 0.2° 20, 29.05° ± 0.2° 20, 38.96° ± 0.2° 20, and 38.96° ± 0.2° 20.

[0117] Also provided is a compound having the structural formula:salt thereof, wherein PG is a protecting group as defined herein. In some embodiments PG is THP.

[0118] Also provided is a compound having the structural formula:salt thereof.

[0119] In some embodiments, the compound having the structural formula:38MEl\59875898.vl128748-04620 (AGI-PKR-36WO)salt thereof,is crystalline. In some embodiments, the compound is crystalline and is characterized three or more x-ray powder diffraction peaks at 20 angles selected from 10.55° ± 0.2° 20, 12.22° ± 0.2° 20, 16.05° ± 0.2° 20, 16.4° ± 0.2° 20, and 19.27° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 10.55° ± 0.2° 20, 12.22° ± 0.2° 20, 16.05° ± 0.2° 20, 16.4° ± 0.2° 20, and 19.27° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 10.55° ± 0.2° 20, 12.22° ± 0.2° 20, 16.05° ± 0.2° 20, 16.4° ± 0.2° 20, and 19.27° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by x-ray powder diffraction peaks at 20 angles at 10.55° ± 0.2° 20, 12.22° ± 0.2° 20, 16.05° ± 0.2° 20, 16.4° ± 0.2° 20, and 19.27° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by x-ray powder diffraction peaks at 20 angles at 9.5° ± 0.2° 20, 10.55° ± 0.2° 20, 10.89° ± 0.2° 20, 11.03° ± 0.2° 20, 11.85° ± 0.2° 20, 12.22° ± 0.2° 20, 14.15° ± 0.2° 20, 14.6° ± 0.2° 20, 15.61° ± 0.2° 20, 16.05° ± 0.2° 20, 16.4° ± 0.2° 20, 16.88° ± 0.2° 20, 17.89° ± 0.2° 20, 18.39° ± 0.2° 20, 18.97° ± 0.2° 20, 19.27° ± 0.2° 20, 19.53° ± 0.2° 20, 19.98° ± 0.2° 20, 21.59° ± 0.2° 20, 21.82° ± 0.2° 20, 23.13° ± 0.2° 20, 23.8° ± 0.2° 20, and 27.85° ± 0.2° 20.

[0120] Also provided is a compound having the structural formula:

[0121] Also provided is a compound having the structural formula:39MEl\59875898.vl128748-04620 (AGI-PKR-36WO)wherein PG is a protecting group as defined herein. In some embodiments PG is THP.

[0122] Also provided is a compound having the structural formula:

[0123] Also provided is a compound having the structural formula:

[0124] Also provided is a compound having the structural formula:

[0125] In some embodiments, the compound having the structural formula:40MEl\59875898.vl128748-04620 (AGI-PKR-36WO)salt thereof, is crystalline. In some embodiments, the compound is crystalline and is characterized by three or more x-ray powder diffraction peaks at 20 angles selected from 9.16° ± 0.2° 20, 10.64° ± 0.2° 20, 15.48° ± 0.2° 20, 18.34° ± 0.2° 20, and 20.37° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 9.16° ± 0.2° 20, 10.64° ± 0.2° 20, 15.48° ± 0.2° 20, 18.34° ± 0.2° 20, and 20.37° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 9.16° ± 0.2° 20, 10.64° ± 0.2° 20, 15.48° ± 0.2° 20, 18.34° ± 0.2° 20, and 20.37° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by x-ray powder diffraction peaks at 20 angles at 9.16° ± 0.2° 20, 10.64° ± 0.2° 20, 15.48° ± 0.2° 20, 18.34° ± 0.2° 20, and 20.37° ± 0.2° 20. In some embodiments, the compound is crystalline and is characterized by x-ray powder diffraction peaks at 20 angles at 9.16° ± 0.2° 20, 10.32° ± 0.2° 20, 10.64° ± 0.2° 20, 11.79° ± 0.2° 20, 13.02° ± 0.2° 20, 13.28° ± 0.2° 20, 15.48° ± 0.2° 20, 16.56° ± 0.2° 20, 16.71° ± 0.2° 20, 18.34° ± 0.2° 20, 19.14° ± 0.2° 20, 20.37° ± 0.2° 20, 20.54° ± 0.2° 20, and 21.15° ± 0.2° 20.

[0126] Also provided is a compound having the structural formula:salt thereof.

[0127] Also provided is a compound having the structural formula:41MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0128] In some embodiments, the compound having the structural formula:is crystalline.

[0129] In some embodiments, the compound is crystalline Form A, characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 9.74° ± 0.2° 20, 15.63° ± 0.2° 20, 15.80° ± 0.2° 20, 19.54° ± 0.2° 20, and 22.75° ± 0.2° 20. In some embodiments, the compound is crystalline Form A, characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 9.74° ± 0.2° 20, 15.63° ± 0.2° 20, 15.80° ± 0.2° 20, 19.54° ± 0.2° 20, and 22.75° ± 0.2° 20. In some embodiments, the compound is crystalline Form A, characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 9.74° ± 0.2° 20, 15.63° ± 0.2° 20, 15.80° ± 0.2° 20, 19.54° ± 0.2° 20, and 22.75° ± 0.2° 20. In some embodiments, the compound is crystalline Form A, characterized by x-ray powder diffraction peaks at 20 angles at 9.74° ± 0.2° 20, 15.63° ± 0.2° 20, 15.80° ± 0.2° 20, 19.54° ± 0.2° 20, and 22.75° ± 0.2° 20. In some embodiments, the compound is crystalline Form A, characterized by x-ray powder diffraction peaks at 20 angles at 9.74° ± 0.2° 20, 10.05° ± 0.2° 20, 11.12° ± 0.2° 20, 11.45° ± 0.2° 20, 15.63° ± 0.2° 20, 15.80° ± 0.2° 20, 17.49° ± 0.2° 20, 19.54° ± 0.2° 20, 19.92° ± 0.2° 20, 20.08° ± 0.2° 20, and 22.75° ± 0.2° 20.

[0130] In some embodiments, the compound is crystalline Form B, characterized by three or more x-ray powder diffraction peaks at 20 angles selected from 5.25° ± 0.2° 20, 15.9° ± 0.2° 20, 16.19° ± 0.2° 20, 18.37° ± 0.2° 20, and 21.08° ± 0.2° 20. In some embodiments, the compound is crystalline Form B, characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 5.25° ± 0.2° 20, 15.9° ± 0.2° 20, 16.19° ± 0.2° 20, 18.37° ± 0.2° 20, and 21.08° ± 0.2° 20. In some embodiments, the compound is crystalline Form B,42MEl\59875898.vl128748-04620 (AGI-PKR-36WO)characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 5.25° ± 0.2° 20, 15.9° ± 0.2° 20, 16.19° ± 0.2° 20, 18.37° ± 0.2° 20, and 21.08° ± 0.2° 20. In some embodiments, the compound is crystalline Form B, characterized by x-ray powder diffraction peaks at 20 angles 5.25° ± 0.2° 20, 15.9° ± 0.2° 20, 16.19° ± 0.2° 20, 18.37° ± 0.2° 20, and 21.08° ± 0.2° 20. In some embodiments, the compound is crystalline Form B, characterized by x-ray powder diffraction peaks at 20 angles 5.25° ± 0.2° 20, 9.91° ± 0.2° 20, 10.49° ± 0.2° 20, 10.74° ± 0.2° 20, 11.2° ± 0.2° 20, 12.49° ± 0.2° 20, 13.65° ± 0.2° 20, 13.95° ± 0.2° 20, 14.08° ± 0.2° 20, 15.76° ± 0.2° 20, 15.9° ± 0.2° 20, 16.19° ± 0.2° 20, 16.36° ± 0.2° 20, 17.86° ± 0.2° 20, 18.37° ± 0.2° 20, 18.89° ± 0.2° 20, 20.02° ± 0.2° 20, 20.15° ± 0.2° 20, 20.7° ± 0.2° 20, 20.81° ± 0.2° 20, 21.08° ± 0.2° 20, 21.48° ± 0.2° 20, 22.36° ± 0.2° 20, 24.23° ± 0.2° 20, 26.42° ± 0.2° 20, 27.27° ± 0.2° 20, and 28.09° ± 0.2° 20.

[0131] In some embodiments, the compound is crystalline Form C, characterized by three or more x-ray powder diffraction peaks at 20 angles selected from 8.43° ± 0.2° 20, 10.03° ± 0.2° 20, 10.74° ± 0.2° 20, 13° ± 0.2° 20, and 20.57° ± 0.2° 20. In some embodiments, the compound is crystalline Form C, characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 8.43° ± 0.2° 20, 10.03° ± 0.2° 20, 10.74° ± 0.2° 20, 13° ± 0.2° 20, and 20.57° ± 0.2° 20. In some embodiments, the compound is crystalline Form C, characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 8.43° ± 0.2° 20, 10.03° ± 0.2° 20, 10.74° ± 0.2° 20, 13° ± 0.2° 20, and 20.57° ± 0.2° 20. In some embodiments, the compound is crystalline Form C, characterized by x-ray powder diffraction peaks at 20 angles 8.43° ± 0.2° 20, 10.03° ± 0.2° 20, 10.74° ± 0.2° 20, 13° ± 0.2° 20, and 20.57° ± 0.2° 20. In some embodiments, the compound is crystalline Form C, characterized by x-ray powder diffraction peaks at 20 angles 8.43° ± 0.2° 20, 10.03° ± 0.2° 20, 10.74° ± 0.2° 20, 10.9° ± 0.2° 20, 11.68° ± 0.2° 20, 12.39° ± 0.2° 20, 13° ± 0.2° 20, 13.79° ± 0.2° 20, 16.72° ± 0.2° 20, 16.77° ± 0.2° 20, 16.89° ± 0.2° 20, 18.91° ± 0.2° 20, 19.82° ± 0.2° 20, 20.14° ± 0.2° 20, 20.57° ± 0.2° 20, 21.58° ± 0.2° 20, 21.86° ± 0.2° 20, and 26.16° ± 0.2° 20.

[0132] In some embodiments, the compound is crystalline Form U, characterized by three or more x-ray powder diffraction peaks at 20 angles selected from 4.54° ± 0.2° 20, 7.16° ± 0.2° 20, 7.65° ± 0.2° 20, 11.65° ± 0.2° 20, and 13.55° ± 0.2° 20. In some embodiments, the compound is crystalline Form U, characterized at least three x-ray powder diffraction peaks at 20 angles selected from 4.54° ± 0.2° 20, 7.16° ± 0.2° 20, 7.65° ± 0.2° 20, 11.65° ± 0.2° 20, and 13.55° ± 0.2° 20. In some embodiments, the compound is crystalline Form U,43MEl\59875898.vl128748-04620 (AGI-PKR-36WO)characterized x-ray powder diffraction peaks at 20 angles 4.54° ± 0.2° 20, 5.54° ± 0.2° 20, 7.16° ± 0.2° 20, 7.65° ± 0.2° 20, 8.05° ± 0.2° 20, 11.65° ± 0.2° 20, 13.2° ± 0.2° 20, 13.55° ± 0.2° 20, 14.34° ± 0.2° 20, and 22.03° ± 0.2° 20.

[0133] In some embodiments, the compound is crystalline Form 6, characterized by three or more x-ray powder diffraction peaks at 20 angles selected from 8.96° ± 0.2° 20, 11.71° ± 0.2° 20, 11.98° ± 0.2° 20, 14.19° ± 0.2° 20, and 20.95° ± 0.2° 20. In some embodiments, the compound is crystalline Form 6, characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 8.96° ± 0.2° 20, 11.71° ± 0.2° 20, 11.98° ± 0.2° 20, 14.19° ± 0.2° 20, and 20.95° ± 0.2° 20. In some embodiments, the compound is crystalline Form 6, characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 8.96° ± 0.2° 20, 11.71° ± 0.2° 20, 11.98° ± 0.2° 20, 14.19° ± 0.2° 20, and 20.95° ± 0.2° 20. In some embodiments, the compound is crystalline Form 6, characterized by x-ray powder diffraction peaks at 20 angles 8.96° ± 0.2° 20, 11.71° ± 0.2° 20, 11.98° ± 0.2° 20, 14.19° ± 0.2° 20, and 20.95° ± 0.2° 20. In some embodiments, the compound is crystalline Form 6, characterized by x-ray powder diffraction peaks at 20 angles 8.27° ± 0.2° 20, 8.96° ± 0.2° 20, 10.92° ± 0.2° 20, 11.71° ± 0.2° 20, 11.98° ± 0.2° 20, 14.01° ± 0.2° 20, 14.19° ± 0.2° 20, 14.8° ± 0.2° 20, 16.27° ± 0.2° 20, 17.06° ± 0.2° 20, 17.89° ± 0.2° 20, and 20.95° ± 0.2° 20.

[0134] Also provided is a compound having the structural formula:salt thereof.EXEMPLIFICATION

[0135] While a number of embodiments have been described, the scope of this disclosure is to be defined by the appended claims, and not by the specific embodiments that have been represented by way of example. The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

[0136] Typical abbreviations used are outlined below.44MEl\59875898.vl128748-04620 (AGI-PKR-36WO)Solvents / ReagentsName AbbreviationCopper Iodide CuiAcetic acid AcOHTert-butyloxycarbonyl Bocsulfuric acid H2SO4Potassium iodide KISodium nitrite NaNCh Dihydropyran DHPHydrochloric acid HC1 dichloromethane DCMCesium carbonate CS2CO3Lithium diisopropylamide LDAtetrahydrofuran THFIsopropyl acetate iPAcLithium tert-butoxide LiOtBuZinc bromide ZnBl,8-Diazabicyclo[5.4.0]undec-7-ene DBUacetonitrile ACN, MeCNEthanol EtOHSodium hydroxide NaOHn-butanol n-BuOHn-Butylmagnesium n-BuMgn-Butyllithium n-BuLi Palladium(II) acetate Pd(OAc)2methanol MeOHPalladium on carbon Pd / CDimethyl sulfoxide DMSOGeneral Methods

[0137] Mass spectra were recorded using a Waters Acquity QDA using high performance liquid chromatography with electrospray mass spectroscopy (HPLC ESI Single45MEl\59875898.vl128748-04620 (AGI-PKR-36WO)quadrupole / MS). Samples were ionized using electrospray ionization (ESI) in positive mode. The mass range was set from m / z 50.0 to 800.0.

[0138] 'H-NMR spectra were recorded on a 400 or 600 MHz spectrometer using their respective deuterated solvent as indicated on the peak summary. Chemical shifts (6) are reported in ppm relative to the deuterated solvent peak.

[0139] XRPD patterns were obtained using a Bruker D22ndGen Phaser diffractometer with Cu Kai radiation (1 = 1.5406 A). Data were collected over a 29 range of 4° to 40° with a step size of 0.026°.

[0140] Melting points were collected through the analysis of DSC performed using a TA Instruments Q2000 DSC. Samples (2-5 mg) were sealed in aluminum pans and heated from 35 °C to 260 °C at a rate of 10 °C / min under nitrogen atmosphere.Preparation of Compounds

[0141] Compounds described herein can be prepared by the following schemes, and also by methods described in WO 2025 / 010390 and WO 2019 / 035864, the entire contents of which are incorporated herein by reference.Scheme 1:46MEl\59875898.vl128748-04620 (AGI-PKR-36WO)toluene, 110°CH2SO4, NaNO2,Step 1 KI, H2OTHP LiOtBu:ZnBr Step 3 Step 52Toluene:THF, 35-40°C; Toluene / Heptane recryst.2.4 eq.Alternative Scheme 1:47MEl\59875898.vl128748-04620 (AGI-PKR-36WO)nediol.24,tolueneH2SO4, NaNO2,Step 1 KI HOu:nBr2Step 3 THPStep 5 Toluene:THF Toluene / IPA recryst.2.4 eq.Scheme 2:Step 9tert-Butyl carbamate,Pd(OAC2),Step 8 Toluene, n-BuOH,1.n-BuMg / n-BuLi K3PO4, Xantphos, H2NNHBOC2.n-Formylmorpline Na-Ascorbate-MeOH Toluene, -20~-10°CNaHSO3, NaOH H 40-50 °C48MEl\59875898.vl128748-04620 (AGI-PKR-36WO)Alternative Scheme 2:Step 9tert-Butyl carbamate,Pd(OAC2),Step 8 Toluene, n-BuOH,1.n-BuMg / n-BuLi f| q K2CO3, Xantphos, H2NNHBOC2.n-Formylmorpline O Na-AscorbateBr N ►MeOH Toluene, -20-10°C NaHSO3, NaOH H 40-50 °C>

[0142] Procedure for Step 3

[0143] In a 3 L round bottom flask, under nitrogen flush, was placed 3 -iodo- 1- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole (300 g, 1.0 eq, 1.08 mol), 2-picolinic acid (26.6 g, 0.2 eq, 0.216 mol), cesium carbonate (1054 g, 3.0 eq, 3.24 mol), cuprous iodide (41.1 g, 0.2 eq, 0.216 mol), di- / c / 7-butyl mal onate (483 mL, 2.0 eq, 2.16 mol) and 1,4-di oxane (1.50 L, 5 vol, pre-purged with N2). The resulting reaction mixture was then heated to 50-55°C with vigorous stirring. The mixture was allowed to stir for 42 h before being transferred to a large quench vessel where saturated NH4CI (3.0 L, 10 vol), water (12.0 L, 40 vol) and ethyl acetate (3.0 L, 10 vol) were added. The organic layer was separated and the aqueous later extracted with ethyl acetate (3.0 L, 10 vol) twice. The organic layers were combined, dried with anhydrous sodium sulfate (-200 g) for 4 h, filtered and concentrated to get the crude product. To the crude product was added n-heptane (1.8 L, 6 vol) at 30°C and the mixture was slowly cooled to -10°C over 2 h. The solution was allowed to stand at -10°C for 3 h whereupon it was filtered and the wet cake washed with cold n-heptane (300 mL, 1 vol). The solids were then dried under vacuum at 45 °C for 12 h to yield di-tert-butyl 2-(l-(tetrahydro-2H-pyran-2- yl)-lH-pyrazol-3-yl)malonate.

[0144] Alternative Conditions for Step 3

[0145] In a 3 L round bottom flask, under nitrogen flush, was placed 3 -iodo- 1- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole (300 g, 1.0 eq, 1.08 mol), 2-picolinic acid (26.6 g,49MEl\59875898.vl128748-04620 (AGI-PKR-36WO)0.2 eq, 0.216 mol), potassium Zc / V-butoxide (248 g, 2.05 eq, 2.21 mol), cuprous iodide (41.1 g, 0.2 eq, 0.216 mol), 2-MeTHF (3.0 L, 10 vol, pre-purged with N2) and di-Zc / V-butyl malonate (483 mL, 2.0 eq, 2.16 mol) . The resulting reaction mixture was then heated to 50-60°C with vigorous stirring. The mixture was allowed to stir for 42 h and then cooled to 20-25°C. Acetic acid (130 mL, 2.1 eq, 2.27 mol) was added to quench the reaction. 10% sodium thiosulfate (1.2 L, 4 vol) was added to the mixture and the organic layer was separated while the aqueous layer was discarded. The organic layer was further neutralized with 5% sodium bicarbonate (0.9 L, 3 vol). The organic layer was separated and concentrated to get the crude product. To the crude product was added n-heptane (1.5 L, 5 vol) at 30°C and the mixture was slowly cooled to -10°C over 3 h. The mixture was allowed to stand at -10°C for 3 h whereupon it was filtered and the wet cake washed with cold n-heptane (300 mL, 1 vol). The solids were then dried under vacuum at 45 °C for 12 h to yield di -tert-butyl 2-(l-(tetrahydro-2H-pyran-2-yl)-1 H-py razol -3 -y l)mal onate .

[0146] 'H NMR (400 MHz, DMSO-tL) 67.82 (d, J= 2.4 Hz, 1H), 6.27 (d, J= 2.5 Hz, 1H), 5.34 (dd, J= 10.0, 2.3 Hz, 1H), 4.50 (s, 1H), 3.96 - 3.84 (m, 1H), 3.60 (ddd, J= 14.0, 7.2, 5.0 Hz, 1H), 2.13 - 1.99 (m, 1H), 1.97 - 1.81 (m, 2H), 1.72 - 1.58 (m, 1H), 1.57 - 1.47 (m, 2H), 1.42 (s, 18H). Melting point: 65.7°C (FIG. 1). MS m / z: [M + H]+ Calcd for C19H30N2O5 367.22; Found 367.21.

[0147] FIG. 2 shows the XRPD plot for di-tert-butyl 2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)mal onate, and the XRPD peak list is shown in the table below:50MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0148] Procedure for Step 4

[0149] To a nitrogen-flushed 3.0 L three-necked round bottom flask was added anhydrous THF (900 mL, 6 vol) and diisopropylamine (108.4 g, 150.2 mL, 1.10 eq, 1.071 mol), which was cooled to about -60°C using an acetone-dry ice bath. N-butyllithium (66.76 g, 416.9 mL, 2.5 M, 1.07 eq, 1.042 mol) was added dropwise (over about 4 min) ensuring that the temperature of the mixture remains about -60°C. To the reaction mixture was added a solution of 2,4-dichlorothiazole (150.0 g, 1 eq, 974.0 mmol) in THF (360.0 mL, 2.4 vol) over about 30 min, while ensuring that the reaction temperature remained between -70°C and -60°C. It should be noted that the dissolution of 2,4-dichlorothiazole (150.0 g, 1 eq, 974.0 mmol) in THF was endothermic. The resulting mixture was allowed to stir for about 75 min at -70°C to -60°C, whereupon ethyl l,3-dioxane-2-carboxylate (163.8 g, 1.05 eq, 1.023 mol) was added over about 15 min while maintaining a reaction temperature between -70°C and -60°C. The resulting mixture was allowed to stir for 30 min at -70°C to -60°C and was quenched with the addition of acetic acid (117.0 g, 111.5 mL, 2.0 eq, 1.948 mol) over 5 min at -60°C. An exotherm was observed which warmed the reaction to about -40°C. After the addition was complete, the mixture was allowed to warm to -15 to -10°C and then water (600 mL, 4 vol) was added. The reaction mixture was allowed to reach 20°C and was stirred for 10 min before the organic layer was separated. The aqueous later was extracted with IP Ac (350.0 mL, 2.3 vol) once. The organic layers were combined, filtered and concentrated (-100 mL) and a precipitate formed. Fresh IP Ac (150.0 mL, 1 vol) was added and the mixture was heated to 70°C. n-Heptane (450 mL, 3 vol) was added over 1 min causing the temperature to drop to 50°C and a precipitate formed. The mixture was re-heated to 70°C, and all solids dissolved. Additional n-heptane was added slowly (300.0 mL, 2 vol) over 5 min and the mixture heated to 76°C to ensure everything was fully dissolved. The mixture was allowed to slowly cool to 20°C over 4 h and the mixture was allowed to stir at 20°C for 16 h. The solids were recovered by filtration, washed with n-heptane (100.0 mL, 0.66 vol), allowed to air dry for 3 h before being transferred to a crystallization dish and then dried in a vacuum oven at 30-35°C for 16 h to provide (2,4-dichlorothiazol-5-yl)(l,3-dioxan-2-yl)methanone.

[0150] Alternative Conditions for Step 451MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0151] To a nitrogen-flushed 3.0 L three-necked round bottom flask was added of 2,4-dichlorothiazole (150.0 g, 1 eq, 974.0 mmol) and anhydrous THF (750 mL, 6 vol). The mixture was cooled to about -60°C using an acetone-dry ice bath. Lithium diisopropylamide solution (487 mL, 2.0 M, 1.1 eq, 1.07 mol) was added dropwise (over about 4 min) ensuring that the temperature of the mixture remains about -60°C. The resulting mixture was allowed to stir for about 30 min at -70°C to -60°C, whereupon methyl l,3-dioxane-2-carboxylate (149 g, 1.05 eq, 1.023 mol) was added over about 15 min while maintaining a reaction temperature between -70°C and -60°C. The resulting mixture was allowed to stir for 75 min at -70°C to -60°C and was quenched with the addition of acetic acid (117.0 g, 111.5 mL, 2.0 eq, 1.948 mol) over 5 min at -60°C. An exotherm was observed which warmed the reaction to about -40°C. After the addition was complete, the mixture was allowed to warm to -15 to -10°C and then water (60 mL, 0.4 vol) and THF (150 mL, 1.0 vol.) was added. The reaction mixture was allowed to reach 20°C and was stirred with activated carbon (24 g, 0.16 wts) for Ih. The mixture was filtered over celite to remove the activated carbon. The filtrate was added water (750 mL, 5.0 vol) and concentrated to 8.4 vol (-420 mL). The mixture was allowed to slowly cool to 20°C over 30 min and the mixture was allowed to stir at 20°C for 16 h. The solids were recovered by filtration, washed with water (300 mL, 2.0 vol), allowed to air dry for 3 h before being transferred to a crystallization dish and then dried in a vacuum oven at 30-35°C for 16 h to provide (2,4-dichlorothiazol-5-yl)(l,3-dioxan-2-yl)methanone.

[0152] 'H NMR (600 MHz, DMSO-t / 6) 85.27 (s, IH), 4.23 - 4.08 (m, 5H), 3.98 - 3.90 (m, 5H), 2.07 (m, 2H), 1.52 (d, J= 13.7 Hz, IH). Melting point: 99.4°C (FIG. 3). MS m / z: [M + H]+Calcd for C8H7CI2NO3S 267.95; Found 267.92

[0153] FIG. 4 shows the XRPD plot for (2,4-dichlorothiazol-5-yl)(l,3-dioxan-2-yl)methanone, and the XRPD peak list is shown in the table below:52MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0154] Procedure for Step 5

[0155] Under nitrogen in a round bottom flask (Flask A) was placed lithium 2-methylpropan-2-olate (15.73 g, 1.2 eq, 196.5 mmol) in a mixture of THF (50.0 mL, 0.833 vol) and toluene (60.0 mL, 1.0 vol). The mixture was heated to 40-45°C and zinc bromide (22.12 g, 0.6 eq, 98.24 mmol) was added in small portions. The resulting reaction mixture was stirred for 1.5 h to provide a colorless transparent mixture. In a second round bottom flask (Flask B) was placed di -tert-butyl 2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate (60.00 g, 1 eq, 163.7 mmol) and (2,4-dichlorothiazol-5-yl)(l,3-dioxan-2-yl)methanone (46.09 g, 1.05 eq, 171.9 mmol), toluene (456 mL, 7.6 vol) and THF (24.0 mL, 0.4 vol). The second reaction mixture (Flask B) was stirred for 1.5 h at ambient temperature before being added to the mixture in Flask A (which was maintained at 40°C). The resulting combination was stirred at 40-45°C for 2 h before being cooled to ambient temperature. Once cooled, toluene (300 mL, 5 vol), acetic acid (11.80 g, 11.25 mL, 1.2 eq, 196.5 mmol) in water (327.0 mL, 6 vol) were added to yield a mixture with a pH ~ 4-5. The organic layer was separated and the aqueous layer extracted with toluene (240 mL, 4 vol). The organic layers were combined and concentrated to dryness to give a yellow solid. The crude product was dissolved in toluene (108.0 mL, 1.8 vol) at 70°C whereupon n-heptane (102.0 mL, 1.7 vol) was added over 5 min and the mixture was allowed to stir for 3 h while cooling to 20°C. The solution was filtered to give a pale yellow-off-white solid, which was washed with a solution of n-heptane Toluene (100.0 mL, 1.6 vol, 4:1 ratio) and dried in a high vacuum oven at 30-35°C for 19 h to provide di-tert-butyl 2-(4-chloro-5-(l,3-dioxane-2-carbonyl)thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate.

[0156] Alternative Conditions for Step 5

[0157] Under nitrogen in a round bottom flask (Flask A) was placed lithium 2-methylpropan-2-olate (7.71 g, 1.2 eq, 96.3 mmol) in a mixture of THF (30.0 mL, 1.0 vol) and toluene (255 mL, 8.5 vol). The mixture was heated to 40-45°C and zinc bromide (10.8 g, 0.6 eq, 48.1 mmol) was added in small portions. The resulting reaction mixture was stirred for 1 h to provide a colorless near-transparent mixture. Di-tert-butyl 2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate (30.00 g, 1 eq, 80.2 mmol) and (2,4-dichlorothiazol-5-yl)(l,3-53MEl\59875898.vl128748-04620 (AGI-PKR-36WO)dioxan-2-yl)methanone (23.3 g, 1.05 eq, 84.2 mmol) were added sequentially. The mixture was stirred at 40-45°C for 3.5 h before being cooled to ambient temperature. Once cooled, acetic acid (10.0 mL, 2.2 eq, 176.5 mmol) and water (90.0 mL, 3 vol) were added to yield a mixture with a pH ~ 4-5. The organic layer was separated and the aqueous layer was discarded. The organic layer was concentrated to 3.33 vol (100 mL) at 30°C whereupon isopropanol (340 mL, 11.5 vol) was added and the mixture was concentrated to 5.8 vol (175 mL) at 60°C. A second potion of isopropanol (340 mL, 11.5 vol) was added to the mixture and stirred at ambient temperature for 19 h. The mixture was filtered to give a pale yellow-off-white solid, which was washed with isopropanol (60 mL, 2 vol) and dried in a high vacuum oven at 35-45°C for 7 h to provide di-tert-butyl 2-(4-chl oro-5 -(1,3 -di oxane-2-carbonyl)thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate.

[0158] 'HNMR (400 MHz, DMSO-t / 6) 87.86 (d, J= 2.5 Hz, 1H), 6.41 (d, J= 2.5 Hz, 1H), 6.09 (s, 3H), 5.36 (dd, J= 9.5, 2.5 Hz, 1H), 5.33 (s, 1H), 4.17 (ddd, J= 12.0, 5.0, 1.6 Hz, 2H), 3.94 (td, J= 12.0, 2.6 Hz, 3H), 3.89 - 3.82 (m, 1H), 3.71 (s, 10H), 3.59 (ddd, J = 11.5, 9.0, 4.4 Hz, 1H), 2.12 - 1.95 (m, 2H), 1.94 - 1.80 (m, 2H), 1.63 (ddt, J= 17.3, 9.3, 5.9 Hz, 1H), 1.51 (dt, J= 12.0, 2.6 Hz, 3H), 1.45 (s, 9H), 144 (s, 9H). Melting point: 149.5°C (FIG. 5). MS m / z: [M + H]+ Calcd for C27H36CIN3O8S 598.19; Found 598.19

[0159] FIG. 6 shows the XRPD plot for di-tert-butyl 2-(4-chloro-5-(l,3-dioxane-2-carbonyl)thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate, and the XRPD peak list is shown in the table below:54MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0160] Procedure for Step 6

[0161] To a nitrogen-flushed 400.0 mL reactor was added di-tert-butyl 2-(4-chloro-5-(l,3-dioxane-2-carbonyl)thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate (30.00 g, 1.0 eq, 50.2 mmol), methylamino-acetic acid ethyl ester hydrochloride (18.49 g, 2.4 eq, 120.4 mmol) and anhydrous acetonitrile (48.0 mL, 1.6 vol). The resulting mixture was heated to 75°C and then l,8-Diazabicyclo[5.4.0]undec-7-ene (18.33 g, 18.00 mL, 2.4 eq, 120.4 mmol) was added over 4 h. The reaction was allowed to stir at 75°C for 20 h and additional l,8-Diazabicyclo[5.4.0]undec-7-ene (16.04 g, 15.75 mL, 2.1 eq, 105.3 mmol) was added. The reaction mixture was kept at 75°C for an additional 23 h before adding acetonitrile (18.0 mL, 0.6 vol) and cooling the reaction to 45-50°C. The mixture was allowed to stir for 10 min before the addition of acetic acid (6.33 g, 6.03 mL, 2.1 eq, 105.3 mmol) which was exothermic (48 to 50°C). The reaction was allowed to stir for 10 min before the dropwise addition of water (20.0 mL, 0.66 vol) over 5 min. Solid started to crystallize out about 30 s after the addition was complete. The reaction was allowed to cool to 20°C over 6 h and allowed to age for 19 h. Solids were collected using a frit and vacuum setup. The solids were washed with 3:1 (v / v) acetonitrile:water (60.0 mL, 2 vol), allowed to air dry for 1 h and then dried under vacuum for 19 h to provide the desired product.

[0162] Alternative Conditions for Step 655MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0163] To a nitrogen-flushed 100.0 mL reactor was added methylamino-acetic acid ethyl ester hydrochloride (6.15 g, 2.4 eq, 40.0 mmol) and anhydrous acetonitrile (12.0 mL, 1.2 vol). The resulting mixture was stirred at ambient temperature and then 1,8-Diazabicyclo[5.4.0]undec-7-ene (6.09 g, 5.97 mL, 2.4 eq, 40.0 mmol) was added over 20 min. The resulting mixture was heated to 60 to 70°C for 15 min and then di -tert-butyl 2-(4-chloro-5-(l,3-dioxane-2-carbonyl)thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate (10.5 g, 1 eq, 16.7 mmol) was added. The reaction was allowed to stir at 75°C for 20 h and additional l,8-Diazabicyclo[5.4.0]undec-7-ene ( 5.33 g, 5.23 mL, 2.1 eq, 35.0 mmol) was added. The reaction mixture was kept at 75°C for an additional 20 h before adding acetonitrile (18.0 mL, 0.6 vol) and cooling the reaction to 45-50°C. The mixture was allowed to stir for 10 min before the addition of acetic acid (2.10 g, 2.00 mL, 2.1 eq, 35.0 mmol) which was exothermic (48 to 50°C). The reaction was allowed to stir for 10 min before the dropwise addition of water (20.0 mL, 0.66 vol) over 20 min. Solid started to crystallize out after the addition was complete. The reaction was allowed to cool to 20°C over 4 h and allowed to age for 19 h. Solids were collected using a frit and vacuum setup. The solids were washed with 3:1 (v / v) acetonitrile:water (13.3 mL, 1.33 vol), allowed to air dry for 1 h and then dried under vacuum for 19 h to provide the desired product.

[0164] 'HNMR (600 MHz, CD3CN) 87.61 (d, J= 2.5 Hz, 1H), 6.43 (d, J= 2.5 Hz, 1H), 6.06 (s, 1H), 5.28 (dd, J= 9.9, 2.5 Hz, 1H), 4.33 (q, J=1A Hz, 2H), 4.14 (ddd, J= 12.0, 5.0, 1.4 Hz, 2H), 4.01 (s, 3H), 3.99 - 3.92 (m, 3H), 3.63 (ddd, J= 11.4, 10.0, 3.7 Hz, 1H), 2.15 -2.01 (m, 2H), 1.98 - 1.88 (m, 3H), 1.71 - 1.52 (m, 2H), 1.50 (s, 18H), 1.43 - 1.36 (m, 5H). Melting point: 174.60°C (FIG. 7). MS m / z: [M + H]+ Calcd for C32H44N4O9S 661.28; Found 661.29.

[0165] FIG. 8 shows the XRPD plot for di-tert-butyl 2-(6-(l,3-dioxan-2-yl)-5-(ethoxycarbonyl)-4-methyl-4H-pyrrolo[2,3-d]thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate, and the XRPD peak list is shown in the table below:56MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0166] Procedure for Step 7

[0167] To a 250 mL round bottom flask was added di-tert-butyl 2-(6-(l,3-dioxan-2-yl)-5-(ethoxycarbonyl)-4-methyl-4H-pyrrolo[2,3-d]thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate (7.60 g, 1.0 eq, 0.012 mol) and acetonitrile (76.0 mL, 10 vol). The resulting mixture was allowed to stir as aqueous citric acid (0.88 g, 0.5 eq, 0.006 mol in water, 22.8 mL, 3 vol) was added dropwise over 30 min. The resulting reaction mixture was heated to 40°C and allowed to stir for 5-6 h. The mixture was then cooled to 0-5°C and aqueous NaOH (2.3 M, 4.5 eq, 22.8 mL, 3 vol) was added dropwise. The reaction was allowed to stir for 18 h at 20°C before adjusting the pH to 4-5 with AcOH (3.29 mL, 5.0 eq, 0.058 mol). The pH was monitored using pH paper. The reaction mixture was then extracted with ethyl acetate (38.0 mL, 5 vol) which was concentrated to obtain a yellow foam. The yellow foam was dissolved in EtOH (22.8 mL, 3 vol) at 70°C whereupon water (114.0 mL, 15 vol) was added dropwise over 30 min while maintaining the reaction at 70°C. The mixture was allowed to cool to 10°C gradually over 3 h and then filtered to recover the solids that formed. The solids were dried under vacuum at 40°C for 16 h to provide 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid.

[0168] Alternative Conditions for Step 7

[0169] To a 100 mL round bottom flask was added di-tert-butyl 2-(6-(l,3-dioxan-2-yl)-5-(ethoxycarbonyl)-4-methyl-4H-pyrrolo[2,3-d]thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)malonate (5.0 g, 1.0 eq, 7.57 mmol) and THF (15.0 mL, 3 vol). The resulting mixture was added citric acid (0.727 g, 3.0 eq, 3.78 mol) and water (10.0 mL, 2 vol). The resulting reaction mixture was heated to 40°C and allowed to stir for 20-24 h. The mixture was then cooled to 15-20°C and aqueous NaOH (4.54 M, 5.0 mL, 3.0 eq, 1 vol) was added dropwise. The reaction was allowed to stir for 4 h at 25-30°C before adjusting the pH57MEl\59875898.vl128748-04620 (AGI-PKR-36WO)to 5-6 with AcOH (1.30 mL, 3.0 eq, 22.7 mmol). The pH was monitored using pH paper. The mixture was heated to 45-50°C and water (40.0 mL, 8 vol) was added dropwise over 1 h while maintaining the reaction at 45°C. Seeds of di-tert-butyl 2-(6-(l,3-dioxan-2-yl)-5-(ethoxycarbonyl)-4-methyl-4H-pyrrolo[2,3-d]thiazol-2-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)- lH-pyrazol-3-yl)malonate (0.05 g, 0.01 eq, 0.076 mmol) was added to the reaction mixture followed by addition of water (10.0 mL, 2 vol) dropwise over 1 h while maintaining the reaction at 45°C. The mixture was allowed to cool to 15-20°C gradually over 6 h and then held at 15-20°C for 16h. The mixture was filtered to recover the solids that formed, and the solids were rinsed with water (5 mL, 1 vol) twice. The solids were dried under vacuum at 50°C for 24 h to provide 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid.

[0170] 'H NMR (600 MHz, DMSO-t / 6) 8 10.39 (s, 1H), 7.82 (d, J= 2.5 Hz, 1H), 6.41 (d, J= 2.5 Hz, 1H), 5.36 (dd, J= 9.5, 2.5 Hz, 1H), 4.09 (s, 3H), 3.90 - 3.83 (m, 1H), 3.59 (ddd, J = 11.4, 9.4, 4.1 Hz, 1H), 2.02 (dddd, J= 15.9, 13.0, 9.4, 3.7 Hz, 1H), 1.95 - 1.83 (m, 2H), 1.68 - 1.58 (m, 1H), 1.54 - 1.49 (m, 2H), 1.47 (s, 20H). Melting point: 180.7°C (FIG. 9). MS m / z: [M + H]+Calcd for C27H34N4O8S 575.21; Found 575.17

[0171] Several crystalline forms were discovered for 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid.

[0172] FIG. 10 shows the XRPD plot for 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid, crystalline Form A and the XRPD peak list is shown in the table below:58MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0173] FIG. 11 shows the XRPD plot for 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid, crystalline Form B and the representative XRPD peak list is shown in the table below:59MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0174] FIG. 12 shows the XRPD plot for 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid, crystalline Form C and the representative XRPD peak list is shown in the table below:60MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0175] FIG. 13 shows the XRPD plot for 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid, crystalline Form U and the representative XRPD peak list is shown in the table below:

[0176] FIG. 14 shows the XRPD plot for 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid, crystalline Form 6 and the representative XRPD peak list is shown in the table below:61MEl\59875898.vl128748-04620 (AGI-PKR-36WO)

[0177] Procedure for Step 12

[0178] To a nitrogen-flushed 250 mL round bottom flask was added 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid (2.00 g, 1.0 eq, 3.48 mmol), 6-(hydrazineylmethyl)pyridin-2-amine dihydrochloride (0.810 g, 1.1 eq, 3.83 mmol), sodium dihydrogen citrate (1.49 g, 2.0 eq, 6.96 mmol), citric acid (0.334 g, 0.5 eq, 1.74 mmol), and anhydrous nitrogen- sparged ethanol (44.0 mL, 22 vol). The resulting mixture was heated to 80°C and allowed to stir for 16 h. The reaction mixture was cooled to 60°C and concentrated HC1 (5.81 mL, 20.0 eq, 7.0 mmol) was added to the reaction mixture dropwise. The reaction mixture was kept at 60°C for an additional 24 h. Nitrogen-sparged isopropyl acetate (80.0 mL, 40.0 vol) was added to the reaction mixture while stirring to precipitate the HC1 salt of the desired product and the mixture was filtered to recover the solids that formed. The resulting solids were dissolved in nitrogen-sparged water (40.0 mL, 20.0 vol) and neutralized with ammonium hydroxide dropwise until the pH reached neutral (pH ~ 7) to precipitate the crude product and then filtered to recover the solids that formed. To the resulting solids were added to nitrogen-sparged n-propanol (25.5 mL, 12.875 vol.) and nitrogen-sparged water (2.25 mL, 2.25 vol). The resulting mixture was heated to 85°C until all the solids dissolved. The mixture was allowed to cool to 5°C gradually over 3 h and was filtered to recover the solids that formed. The solids were dried under vacuum at 35°C for 24 h to provide the desired product.

[0179] Alternative Conditions for Step 12

[0180] To a nitrogen-flushed 250 mL round bottom flask was added 2-(l,3-di-tert-butoxy-l,3-dioxo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)propan-2-yl)-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid (2.00 g, 1.0 eq, 3.48 mmol), 6-(hydrazineylmethyl)pyridin-2-amine dihydrochloride (0.810 g, 1.1 eq, 3.83 mmol), sodium dihydrogen citrate (1.49 g, 2.0 eq, 6.96 mmol), citric acid (0.334 g, 0.5 eq, 1.74 mmol), and anhydrous nitrogen- sparged ethanol (10.0 mL, 5 vol). The resulting mixture was heated to 70°C and allowed to stir for 3 h. The reaction mixture was cooled to 60°C and concentrated HC1 (2.91 mL, 10.0 eq, 35.0 mmol) was added to the reaction mixture dropwise. The reaction mixture was kept at 60°C for an additional 16 h. Nitrogen-sparged isopropyl acetate (10.0 mL, 5.0 vol) was added to the reaction mixture while stirring to precipitate the HC1 salt of the62MEl\59875898.vl128748-04620 (AGI-PKR-36WO)desired product and the mixture was filtered to recover the solids that formed. The resulting solids were dissolved in nitrogen-sparged water (16.0 mL, 8.0 vol) and neutralized with ammonium hydroxide dropwise until the pH reached neutral (pH ~ 7) to precipitate the crude product and then filtered to recover the solids that formed. To the resulting solids were added to nitrogen-sparged n-propanol (20.4 mL, 10.2 vol.) and nitrogen- sparged water (3.60 mL, 1.8 vol). The resulting mixture was heated to 85°C until all the solids dissolved. The mixture was allowed to cool to 5°C gradually over 3 h and was filtered to recover the solids that formed. The solids were dried under vacuum at 35°C for 24 h to provide the desired product.63MEl\59875898.vl

Claims

128748-04620 (AGI-PKR-36WO)CLAIMSListing of Claims:A compound having the structural formula:

2. The compound of Claim 1, wherein the compound is crystalline.

3. The compound of Claim 1 or 2, wherein the compound is crystalline and is characterized by three or more x-ray powder diffraction peaks at 20 angles selected from 9.78° ± 0.2° 20, 12.76° ± 0.2° 20, 19.35° ± 0.2° 20, 24.43° ± 0.2° 20, and 25.81° ± 0.2° 20.

4. The compound of any one of Claims 1 to 3, wherein the compound is crystalline and is characterized by x-ray powder diffraction peaks at 20 angles at 9.78° ± 0.2° 20, 12.76° ± 0.2° 20, 19.35° ± 0.2° 20, 24.43° ± 0.2° 20, 25.5° ± 0.2° 20, 25.57° ± 0.2° 20, 25.81° ± 0.2° 20, 29.05° ± 0.2° 20, 38.96° ± 0.2° 20, and 38.96° ± 0.2° 20.

5. A compound having the structural formula:salt thereof, wherein PG is defined herein.A compound having the structural formula:salt thereof.64MEl\59875898.vl128748-04620 (AGI-PKR-36WO)7. The compound of Claim 6, wherein the compound is crystalline.

8. The compound of Claim 6 or 7, wherein the compound is crystalline and is characterized by three or more x-ray powder diffraction peaks at 20 angles selected from 10.55° ± 0.2° 20, 12.22° ± 0.2° 20, 16.05° ± 0.2° 20, 16.4° ± 0.2° 20, and 19.27° ± 0.2° 20.

9. The compound of any one of Claims 6 to 8, wherein the compound is crystalline and is characterized by x-ray powder diffraction peaks at 20 angles at 9.5° ± 0.2° 20, 10.55° ± 0.2° 20, 10.89° ± 0.2° 20, 11.03° ± 0.2° 20, 11.85° ± 0.2° 20, 12.22° ± 0.2° 20, 14.15° ± 0.2° 20, 14.6° ± 0.2° 20, 15.61° ± 0.2° 20, 16.05° ± 0.2° 20, 16.4° ± 0.2° 20, 16.88° ± 0.2° 20, 17.89° ± 0.2° 20, 18.39° ± 0.2° 20, 18.97° ± 0.2° 20, 19.27° ± 0.2° 20, 19.53° ± 0.2° 20, 19.98° ± 0.2° 20, 21.59° ± 0.2° 20, 21.82° ± 0.2° 20, 23.13° ± 0.2° 20, 23.8° ± 0.2° 20, and 27.85° ± 0.2° 20.

10. A compound having the structural formula:salt thereof.

11. A compound having the structural formula:salt thereof, wherein PG is defined herein.

12. A compound having the structural formula:65MEl\59875898.vl128748-04620 (AGI-PKR-36WO)13. A compound having the structural formula:salt thereof.

14. A compound having the structural formula:

15. The compound of Claim 14, wherein the compound is crystalline.

16. The compound of Claim 14 or 15, wherein the compound is crystalline and is characterized by three or more x-ray powder diffraction peaks at 20 angles selected from 9.16° ± 0.2° 20, 10.64° ± 0.2° 20, 15.48° ± 0.2° 20, 18.34° ± 0.2° 20, and 20.37° ± 0.2° 20.

17. The compound of any one of Claims 14 to 16, wherein the compound is crystalline and is characterized by x-ray powder diffraction peaks at 20 angles at 9.16° ± 0.2° 20, 10.32° ± 0.2° 20, 10.64° ± 0.2° 20, 11.79° ± 0.2° 20, 13.02° ± 0.2° 20, 13.28° ± 0.2° 20,66MEl\59875898.vl128748-04620 (AGI-PKR-36WO)15.48° ± 0.2° 20, 16.56° ± 0.2° 20, 16.71° ± 0.2° 20, 18.34° ± 0.2° 20, 19.14° ± 0.2° 20, 20.37° ± 0.2° 20, 20.54° ± 0.2° 20, and 21.15° ± 0.2° 20.

18. A compound having the structural formula:

19. A compound having the structural formula:

20. The compound of Claim 19, wherein the compound is crystalline.

21. The compound of Claim 20, wherein the compound is crystalline Form A, B, C, U, or22. A compound having the structural formula:

23. A compound having the structural formula:67MEl\59875898.vl128748-04620 (AGI-PKR-36WO)salt thereof.

24. A method of making a compound of Formula (A-l) or a salt or a hydrate thereof, wherein the compound of Formula (A-l) has the following structural formula:said method comprising at least one compound of Claims 1-23 or a salt thereof.

25. A compound of Formula (A-3) having the structural formula:salt thereof, wherein R1, Rx, Ryand PG are as defined herein.

26. A compound of Formula (A-l) having the structural formula:salt thereof, wherein PG is defined herein.

27. A method of making a compound of Formula (A-l) or a salt thereof, wherein the compound of Formula (A-l) has the following structural formula:68MEl\59875898.vl128748-04620 (AGI-PKR-36WO)said method comprising at least one compound of Claims 1-22 or Claim 25 or a salt thereof and wherein PG is defined herein.

28. A method of making a compound having the structural formula:salt thereof,said method comprising at least one of the procedures disclosed herein.

29. A method of making a compound having the structural formula:salt thereof,said method comprising at least one of the procedures disclosed herein.

30. A method of making a compound having the structural formula:salt thereof,said method comprising at least one of the procedures disclosed herein.

31. A method of making a compound having the structural formula:salt thereof69MEl\59875898.vl128748-04620 (AGI-PKR-36WO)said method comprising at least one of the procedures disclosed herein.

32. A method of making a compound having the structural formula:salt thereof, said method comprising at least one of the procedures disclosed herein.

33. A method of making a compound having the structural formula:salt thereof, said method comprising at least one of the procedures disclosed herein.

34. A method of making a compound having the structural formula:salt thereof, said method comprising at least one of the procedures disclosed herein.

35. A method of making a compound having the structural formula:salt thereof, said method comprising at least one of the procedures disclosed herein.70MEl\59875898.vl128748-04620 (AGI-PKR-36WO)36. A method of making a compound having the structural formula:salt or a hydrate thereof, said method comprising at least one compound of Claims 1-9, 11, 12, 14-17, 19-21, or 25 or a salt thereof and at least one of the procedures disclosed herein.

37. A method of making a compound of Formula (A-3) having the structural formula:salt thereof, wherein R1, Rx, Ryand PG are as defined herein, said method comprising at least one of the procedures described herein.

38. A method of making a compound of Formula (A-l) having the structural formula:said method comprising at least one of the procedures described herein.

39. A method of making a compound of Formula (A-l) or a salt thereof, wherein the compound of Formula (A-l) has the following structural formula:said method comprising at least one compound of Claims 1-22 or 25 or a salt thereof and at least one of the procedures described herein.71MEl\59875898.vl128748-04620 (AGI-PKR-36WO)40. The method of Claim 37 wherein at least one of the procedures comprises at least one of the following compounds:salt thereof.

41. The method of Claim 29 wherein at least one of the procedures comprises the compound of Claim 1 or a salt thereof.

42. The method of Claim 31 wherein at least one of the procedures comprises the compound of Claim 6 or a salt thereof.

43. The method of Claim 33 wherein at least one of the procedures comprises the compound of Claim 19 or a salt thereof.

44. The method of Claim 24 or Claim 36 wherein the compound is a salt.

45. The method of Claim 24 or Claim 36 wherein the compound is a hydrate.72MEl\59875898.vl

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