Preparation of imidazo[4,5-b]pyridine AKT1 inhibitors

Abstract

Provided herein are methods and reagents for the preparation of AKT1 modulators and chemical intermediates.

Description

Attorney Docket No. 62619-735601PREPARATION OF IMIDAZO[4,5-B]PYRIDINE AKT1 INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit to U.S. Provisional Patent Application No. 63 / 687,426 filed August 27, 2024, which is incorporated by reference herein in its entirety.BACKGROUND

[0002] AKT is a protein kinase that mediates cell survival and proliferation by inhibiting pathways which promote apoptosis. AKT signaling cascade dysfunction is observed in several cancer types and may be associated with tumor aggressiveness. Additionally, malfunction of AKT typically leads to enhanced proliferation, growth, survival, and resistance to apoptosis. Pharmaceutical agents with the ability to modulate AKT1 activity would be useful in the treatment of disease, such as cancer.BRIEF SUMMARY OF THE INVENTION

[0003] One embodiment provides a process for preparing tert-butyl (l-(4-((3-nitro-6-chloro-pyridin- 2-yl) amino)benzyl)piperidin-4-yl)carbamate (Compound D):(Compound D) comprising contacting a compound having the structure:(tert-butyl (l-(4-aminobenzyl) piperidin-4-yl) carbamate; Compound C) with a compound having the structure:(2,6-dichloro-3-nitro-pyridine; Compound Cl) and a base in the presence of a solvent.

[0004] One embodiment provides a process for preparing tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5- chloro-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (Compound 1):Attorney Docket No. 62619-735601(Compound 1), comprising contacting a compound having the structure:(tert-butyl (l-(4-((3-amino-6-chloropyri din-2 -yl)amino)benzyl)piperidin-4-yl)carbamate;Compound E) with a compound having the structure:(2-aminonicotinaldehyde; Compound El) and an oxidizing agent in the presence of a solvent.

[0005] One embodiment provides a process for preparing tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate(Compound 3):(Compound 3), comprising reacting a compound having the structure:Attorney Docket No. 62619-735601(Compound 1) with a boron-containing heteroaryl compound, a palladium catalyst, and a base in the presence of a solvent.

[0006] One embodiment provides a process for preparing tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5- (5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (Compound 3):(Compound 3), comprising reacting a compound having the structure:(Compound 1) with a borylation reagent, a first base, and a first palladium catalyst in the presence of a first solvent to yield a compound having the structure:Attorney Docket No. 62619-735601(tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)carbamate; Compound 2); and reacting Compound 2 with 2-bromo-5-fluoropyridine (Compound 2a), a second base, and a second palladium catalyst in the presence of a second solvent.

[0007] One embodiment provides a process for the preparation of 3-(3-(4-((4-aminopiperidin-l- yl)methyl)phenyl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine (Compound 4):(Compound 4), or a salt thereof, comprising contacting a compound having the structure:(tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate; Compound 3) with an acid in the presence of a solvent.Attorney Docket No. 62619-735601

[0008] One embodiment provides a process for the preparation of 4-((l-(4-(2-(2-aminopyridin-3-yl)- 5-(5-fluoropyridin-2-yl)-3Z7-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile (Compound 5)(Compound 5) comprising contacting a compound having the structure:(3-(3-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine; Compound 4), or a salt thereof, with a compound having the structure:(Compound 4b) and a base in the presence of a solvent.

[0009] One embodiment provides a process for the preparation of 4-((l-(4-(2-(2-Aminopyridin-3-yl)- 5-(5-fluoropyridin-2-yl)-3Z7-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile maleate (Compound 6)Attorney Docket No. 62619-735601comprising contacting a compound having the structure:(4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3J7-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; Compound 5) with maleic acid in the presence of a solvent.

[0010] One embodiment provides a compound having a structure selected from:Attorney Docket No. 62619-735601

[0011] One embodiment provides a compound having a structure selected from:Attorney Docket No. 62619-735601 or a salt, solvate, or deuteroisotope thereof.INCORPORATION BY REFERENCE

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTION OF THE INVENTION

[0013] As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.Definitions

[0014] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0015] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The termAttomey Docket No. 62619-735601“geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0016] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0017] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0018] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0019] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compoundsAttorney Docket No. 62619-735601 may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N, 160,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0020] In certain embodiments, the compounds disclosed herein have some or all of theJH atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0021] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1- 2), 9-32.

[0022] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0023] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-ds (CD3I), are readily available and may be employed to transfer a deuteriumsubstituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.Attorney Docket No. 62619-735601

[0024] Deuterium-transfer reagents, such as lithium aluminum deuteride (Li AID4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.

[0025] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0026] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeableJH hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0027] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the AKT1 inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0028] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid,Attorney Docket No. 62619-735601 phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0029] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A,A-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A-methylglucamine, glucosamine,Attorney Docket No. 62619-735601 methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0030] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0031] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0032] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” means eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.AKT1 Protein and Function

[0033] AKT, also known as protein kinase B (PKB), is a serine / threonine protein kinase with three isoforms, AKT1, AKT2, and AKT3. While the isoforms are encoded by different genes, they are highly homologous at the protein level and share a conserved domain structure comprising an N-terminal pleckstrin homology (PH) domain, a kinase domain, and a C-terminal regulatory domain comprising a hydrophobic moiety, which includes the regulatory serine residue (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331).Attorney Docket No. 62619-735601

[0034] AKT proteins play a crucial role in major cellular functions including cell cycle progression, cell size, regulation of glucose metabolism, transcription, protein synthesis, genome stability, and neovascularization. AKT proteins can block apoptosis by inactivation of pro-apoptotic proteins, and mediate cellular growth factors, promoting cell survival. AKT is a major downstream effector of nuclear factor-kappaB (NfxB), which may link AKT signaling to the nucleus of a cell.

[0035] AKT1 is ubiquitously expressed, whereas AKT2 is primarily expressed in insulin-responsive tissues, and AKT3 is primarily expressed in brain and testes. A shared phosphorylation site of AKT in the catalytic domain corresponds to a threonine residue; specifically, Thr308 in AKT1, Thr309 in AKT2, and Thr305 in AKT3. A shared phosphorylation site in the C- terminus of the protein cis a serine residue; specifically, Ser473 in AKT1, Ser474 in AKT2, and Ser472 in AKT3.

[0036] AKT is a key downstream mediator of the phosphoinositide-3 -kinase (PI3K) signaling pathway. PI3Ks are activated by different compounds. For example, PI3Ka, PI3KP, and PI3K5, are activated by extracellular ligands binding to a transmembrane glycoprotein with enzymatic activity, receptor tyrosine kinases (RTKs). In contrast, PI3Ky is activated by G- protein-compound receptors (GPCRs) and by RAS family of GTPases.

[0037] The AKT cascade can be activated by RTKs and G-protein-compound receptors (GPCRs), along with other signals including integrins, B cell receptors, T cell receptors, and cytokine receptors.AKT1 Mechanism

[0038] AKT is activated by a second phosphorylation at the regulatory serine residue, Ser473. Known phosphorylating agents of AKT at Ser473 include, but are not limited to PDK-1, integrin- linked kinase (ILK), members of the PI3K-related kinase (PIKK) family, and mammalian target of rapamycin (mTOR) (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331).

[0039] mTOR is a key component in the AKT signaling pathway, which is a downstream member of AKT and an important regulator for cell metabolism and growth. mTOR is also an activator which can directly phosphorylate AKT’s regulatory serine residue, Ser473. mTOR forms a complex with rapamycin-insensitive companion of mTOR (RICTOR) (and other proteins) to form mTOR complex 2 (mT0RC2), which can directly phosphorylate AKT Ser473. AKT can affect cell survival and growth because it can influence the tuberous sclerosis complex (TSC) 1 / 2 along the mTORC signaling pathway and inhibit pro-apoptotic proteins or signals.Attorney Docket No. 62619-735601

[0040] AKT is known as a survival kinase and mediates cell survival and proliferation by inhibiting pathways including, but not limited to Bcl2 and MDM2, which promotes apoptosis. Studies have shown that the AKT signaling cascade has frequent malfunctions in various cancers, and may be associated with tumor aggressiveness (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331). Malfunctions of AKT typically lead to enhanced proliferation, growth, survival, and resistance to apoptosis (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). Malfunction and mis-regulation of AKT may lead to cancers such as but not limited to breast cancer, gastric carcinoma, glioblastoma, gliosarcomas, head and neck squamous cell carcinoma, ovarian cancer, pancreatic cancer, and prostate cancer.

[0041] Additionally, AKT1 has been found to be involved in invasion and migration of cancerous cells (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). Researchers found that silencing the AKT1 isoform can abrogate specific types of cancer cell migration. However, there have been other studies which have demonstrated that activated AKT1 resulted in less metastatic propensity for lung metastatic lesion cells and breast cancer cells. AKT1 has also been identified as a key protein involved in angiogenesis, lung cancer, and tumorigenesis.

[0042] Furthermore, overexpression of AKT has been correlated to resistance to chemotherapeutic agents such as cisplatin, methotrexate, and paclitaxel. Thus, there remains a need to find AKT inhibitors given its role in cell survival and cancer proliferation.

[0043] Recently, it has been found that the AKT1 gene mutation E17K can affect cell growth, proliferation, survival, and migration of breast cancer cells, colorectal cancer cells, and ovarian cancer cells (Chen, Y. et al., Front Cell Dev Biol., 2020; 8: 573599). These mutations in the PH structural domain increase the binding of AKT1 to Phosphatidylinositol-3,4,5- triphosphate (PIP3) lipid ligand, which accelerates transfer of AKT from the cytoplasm to the cell membrane through formation of hydrogen bonds. Transfer of AKT into the cell membrane allows it to be further phosphorylated. Once fully activated, AKT can return to the cytoplasm, or go to the nucleus or other intracellular sites, and phosphorylate other substrate proteins to regulate cell function.

[0044] The E17K mutation enhances migration of breast cancer cells, and also enhances resistance to chemotherapeutic drugs. However, the E17K mutation can also selectively destroy chemoresistant tumor-promoting AKT1 quiescent cancer cells, suggesting that the AKT1(E17K) mutation is crucial in the oncogenic / anti-tumor mechanism.

[0045] A major pathway that activates PI3K-AKT signaling pathway is somatic cell mutations, with the E17K mutation being the highest frequency of AKT1 mutations. It is nearly exclusivelyAttorney Docket No. 62619-735601 present in AKT1. The AKT1(E17K) is a recurrent somatic cell mutation predominantly in breast cancer, ovarian cancer, meningioma, and Proteus syndrome.

[0046] AKT1(E17K) mutations mediate the PI3K-AKT signaling cascade by expanding PIP lipid specificity, which causes conformational changes. This also enhances subcellular localization to accelerate localization of the PH structural domain to the plasma membrane. The E17K mutation increases PIP3 binding specificity by 7-fold and phosphatidylinositol-(4,5)- bisphosphate (PIP2) by 100-fold.

[0047] The AKT1(E17K) mutation also causes rapid conformational changes in the AKT1 PH structural domain. The conformational changes to this domain result in a 4.5-fold increase in its membrane localization, which can result in excessive phosphorylation. The AKT1(E17K) mutation can also result in enhanced subcellular localization by increasing the transient expression.

[0048] Given the conformational and signaling effects of the AKT1(E17K) mutation, this target may be useful for targeted treatment of cancers.Prior Art AKT1 Inhibitors

[0049] Most AKT inhibitors targeting the ATP binding site are non-selective against the three isoforms, as well as having poor to no selectivity against other structurally similar kinases. Thus, there remains a need to develop new and novel AKT inhibitors. These ATP targeting inhibitors are classified as aminofurazans, azepane derivatives, isoquinoline-5-sulfonamides, phenylpyrazole derivatives, thiophene carboxamide derivatives, and thiazole carboxamide derivatives.

[0050] There are also ATP non-competitive AKT inhibitors which are allosteric modulators which have greater specificity than the ATP targeting inhibitors. Many of these allosteric modulator inhibitors are classified as purine derivatives, thiourea derivatives, alkylphospholipids, sulfonamides, 2,3 -diphenylquinoxaline analogs, and indole-3 -carbinol derivatives.Preparation of Compounds

[0051] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester,Attorney Docket No. 62619-735601PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0052] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley &Attorney Docket No. 62619-735601Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0053] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0054] One embodiment provides a process for preparing tert-butyl (l-(4-((3-nitro-6-chloro-pyridin-2-yl) amino)benzyl)piperidin-4-yl)carbamate (Compound D):(Compound D) comprising contacting a compound having the structure:(tert-butyl (l-(4-aminobenzyl) piperidin-4-yl) carbamate; Compound C) with a compound having the structure:(2,6-dichloro-3-nitro-pyridine; Compound Cl) and a base in the presence of a solvent (e.g., dioxane).

[0055] In some embodiments, the base is selected from N,N-Diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, potassium carbonate, trisodium phosphate, tripotassium phosphate, disodium phosphate, dipotassium phosphate, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), tetramethylguanidine, tributylamine, 2,6-lutidine, 2,4,6-collidine, or a combination of two orAttomey Docket No. 62619-735601 more thereof. In some embodiments, the base is DIEA or sodium bicarbonate. In some embodiments, the base is sodium bicarbonate. In some embodiments, the solvent is dioxane. In other embodiments, the solvent is 2-methyltetrahydrofuran or methyl tert-butyl ether (MTBE).

[0056] In some embodiments, the base is NaHCCE or DIEA.

[0057] In some embodiments, Compound D has a chemical purity of 95% or more. In some embodiments, Compound D has a chemical purity of 96% or more. In some embodiments, Compound D has a chemical purity of 97% or more. In some embodiments, Compound D has a chemical purity of 98% or more. In some embodiments, Compound D has a chemical purity of 99% or more. In some embodiments, Compound D has a chemical purity of 99.5% or more.

[0058] In some embodiments, the compound with the structure:is prepared by reducing a compound having the structure:(Compound B).

[0059] In some embodiments, the reduction is conducted in a solvent with a metal and a Bronsted- Lowry acid.

[0060] In some embodiments, the solvent comprises an alcohol (e.g., EtOH) and water, DMSO and water, or DMF and water. In some embodiments, the solvent is EtOH and water.

[0061] In some embodiments, the solvent comprises an alcohol, DMSO, DMF, water or a combination thereof. In some embodiments, the solvent is EtOH and water.

[0062] In some embodiments, the solvent is DMF / water, DMSO / water, or EtOH / water.

[0063] In some embodiments, the metal comprises Fe, Sn, or Zn. In some embodiments, the metal is Fe.

[0064] In some embodiments, the Bronsted-Lowry acid is NH4CI.

[0065] In some embodiments, the compound with the structure:(Compound B) is prepared by a process comprising contacting a compound having the structure:(Compound A)Attorney Docket No. 62619-735601 with a compound having the structure:

[0066] In some embodiments, the base is selected from N-Diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, potassium carbonate, or a combination of two or more thereof. In some embodiments, the base is TEA or potassium carbonate. In some embodiments, the base is potassium carbonate.

[0067] In some embodiments, the solvent is selected from acetone, tetrahydrofuran (THF), acetonitrile (ACN), dimethyl sulfoxide (DMSO), dichloromethane (DCM), Dimethylformamide (DMF), or a combination of two or more thereof. In some embodiments, the solvent is acetone.

[0068] In some embodiments, the solvent is acetone, THF, ACN, DMSO, or DCM.

[0069] In some embodiments, the base is K2CO3 or TEA.

[0070] One embodiment provides a process for preparing tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5- chloro-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (Compound 1):(Compound 1), comprising contacting a compound having the structure:(tert-butyl (l-(4-((3-amino-6-chloropyri din-2 -yl)amino)benzyl)piperidin-4-yl)carbamate;Compound E) with a compound having the structure:(2-aminonicotinaldehyde; Compound El)Attorney Docket No. 62619-735601 and an oxidizing agent (e.g., NH4Fe(SO4)2'12H2O) in the presence of a solvent.

[0071] In some embodiments, the oxidizing agent is an Fe (III) salt, H2O2, Na2S2O8, NaClO, oxone, MnCh, DDQ, Mn(OAc)s, or a combination thereof.

[0072] In some embodiments, the oxidizing agent is an Fe (III) salt, H2O2, NaClO, oxone, MnCh, DDQ, Mn(OAc)s, or a combination thereof.

[0073] In some embodiments, the oxidizing agent is FeCh, NH4Fe(SO4)2"12H2O, H2O2, Na2S2O8, NaClO, oxone, Mn02, DDQ, Mn(OAc)s, or a combination thereof.

[0074] In some embodiments, the oxidizing agent is FeCh, NH4Fe(SO4)2'12H2O, H2O2, NaClO, oxone, Mn02, DDQ, Mn(OAc)s, or a combination thereof.

[0075] In some embodiments, the oxidizing agent is NH4Fe(SO4)2'12H2O, H2O2, Na2S2O8, NaClO, oxone, Mn02, DDQ, Mn(OAc)s, or a combination thereof.

[0076] In some embodiments, the oxidizing agent is NH4Fe(SO4)2'12H2O, H2O2, NaClO, oxone, Mn02, DDQ, Mn(OAc)s, or a combination thereof.

[0077] In some embodiments, the oxidizing agent is FeCh, NH4Fe(SO4)2'12H2O, or a combination thereof. In some embodiments, the oxidizing agent is NH4Fe(SO4)2'12H2O.

[0078] In some embodiments, the solvent is DMF, DMSO, DMA, NMP, w-BuOH, toluene, dioxane, IP A, t-BuOH, or IPA / water. In some embodiments, the solvent is isopropyl alcohol (IP A).

[0079] In some embodiments, the solvent is DMF, DMSO, DMA, NMP, w-BuOH, toluene, dioxane, IP A, t-BuOH, or IPA / water.

[0080] In some embodiments, the solvent is DMF, DMSO, DMA, NMP, w-BuOH, toluene, dioxane, IP A, t-BuOH, water, or a combination thereof.

[0081] In some embodiments, the reagent is FeCh, NH3H2O, an Fe III salt, NH4Fe(SO4)2"12H2O, H2O2, Na2S2O8, NaClO, oxone, MnO2, DDQ, Mn(OAc)3, ZnCl2, or CaCl2.

[0082] In some embodiments, the reagent equivalents are FeCh (0.5 to 5 eq), aq NH (1-6 eq), NH4Fe(SO4)2-12H2O (0.5-3 eq).

[0083] In some embodiments, the temperature is room temperature, 40, 60, or 80 °C.

[0084] In some embodiments, Compound 1 is stable for 3 months at room temperature.

[0085] In some embodiments, Compound 1 has a chemical purity of 95% or more. In some embodiments, Compound 1 has a chemical purity of 96% or more. In some embodiments, Compound 1 has a chemical purity of 97% or more. In some embodiments, Compound 1 has a chemical purity of 98% or more. In some embodiments, Compound 1 has a chemical purity of 99% or more. In some embodiments, Compound 1 has a chemical purity of 99.5% or more.

[0086] In some embodiments, the compound with the structure:Attorney Docket No. 62619-735601(Compound E) is prepared by a process comprising contacting a compound having the structure:(Compound D) with an organocatalyst and reducing agent in the presence of a solvent.

[0087] In some embodiments, the organocatalyst comprises bipyridyl (4,4’-bipyridine).

[0088] In some embodiments, the reducing agent comprises tetrahydroxy diborane.

[0089] In some embodiments, the solvent is methanol (MeOH) and water, ethanol (EtOH) and water, or isopropyl alcohol (IP A). In some embodiments, the solvent is methanol, ethanol, isopropyl alcohol, water, or a combination of two or more thereof. In some embodiments, the solvent is isopropyl alcohol (IP A).

[0090] In some embodiments, the solvent is MeOH / water, EtOH / water, or IPA.

[0091] In some embodiments, the base is K2HPO4, TEA, or a combination thereof.

[0092] In some embodiments, the base is K2HPO4 or TEA.

[0093] In some embodiments, the acid is KHSO4, KH2PO4, citric acid, or acetic acid. In some embodiments, the acid is KHSO4, KH2PO4, citric acid, acetic acid, or a combination thereof.

[0094] One embodiment provides a process for preparing tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5- (5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (Compound 3):(Compound 3), comprising reacting a compound having the structure:Attorney Docket No. 62619-735601(Compound 1) with a boron-containing heteroaryl compound, a palladium catalyst, and a base in the presence of a solvent.

[0095] In some embodiments, the palladium catalyst is selected from Pd(OAc)2, Pd(PPhs)4, and Pd(dppf)Cl2-DCM.

[0096] In some embodiments, the boron-containing heteroaryl compound is a boronic acid, boronate ester, or trifluoroborate.

[0097] In some embodiments, the boron-containing heteroaryl compound is selected from:In some embodiments, the boron-containing heteroaryl compound

[0098] In some embodiments, the base is selected from cesium carbonate, potassium carbonate, potassium phosphate, DIEA, l,8-Diazabicyclo(5.4.0)undec-7-ene (DBU), 2,6-lutidine, TEA, sodium tert-butoxide, or a combination of two or more thereof.Attorney Docket No. 62619-735601

[0099] In some embodiments, the solvent is selected from DMF, dioxane, dimethylacetamide (DMA), toluene, / / -butanol, N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, or a combination of two or more thereof.

[0100] One embodiment provides a process for preparing tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5- (5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (Compound 3):(Compound 3), comprising reacting a compound having the structure:(Compound 1) with a borylation reagent, a first base, and a first palladium catalyst in the presence of a first solvent to yield a compound having the structure:(tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)carbamate; Compound 2); and reacting Compound 2 with 2-bromo-5-fluoropyridine (Compound 2a), a second base, and a second palladium catalyst in the presence of a second solvent.Attorney Docket No. 62619-735601

[0101] In some embodiments, the borylation reagent is pinacolborane, bis(pinacolato)diboron or bis(catecholato)diborane. In some embodiments, the borylation reagent is bis(pinacolato)diboron.

[0102] In some embodiments, the first palladium catalyst and the second palladium catalyst are independently selected from Pd2(dba)s, Pd(dtbpf)C12, Pd(AmPhos)2C12, Pd(OAc)2, Pd(PPhs)4, or Pd(dppf)C12'DCM. In some embodiments, the palladium catalyst is generated in-situ from Pd2(dba)s and a ligand. In some embodiments, the palladium catalyst is generated in-situ from Pd2(dba)s and a phosphine ligand. In some embodiments, the palladium catalyst is generated in-situ from Pd2(dba)3 and PCy3, Ad2(n-Bu)P, or AmgenPHOS. In some embodiments, the palladium catalyst is generated in-situ from Pd2(dba)3 and Ad2(n-Bu)P or AmgenPHOS. In some embodiments, the palladium catalyst is generated in-situ from Pd2(dba)3 and Ad2(n- Bu)P. In some embodiments, the first palladium catalyst and the second palladium catalyst are independently selected from Pd(OAc)2, Pd(PPh3)4, or Pd(dppf)C12'DCM. In some embodiments, the first palladium catalyst and the second palladium catalyst is Pd(dppf)C12'DCM. In some embodiments, the first palladium catalyst is Pd(dppf)C12,DCM. In some embodiments, the second palladium catalyst is generated in-situ from Pd2(dba)3 and a phosphine ligand. In some embodiments, the second palladium catalyst is generated in-situ from Pd2(dba)3 and Ad2(n-Bu)P. In some embodiments, the first palladium catalyst is Pd(dppf)C12'DCM and the second palladium catalyst is generated in-situ from Pd2(dba)3 and Ad2(n-Bu)P.

[0103] In some embodiments, the first base and the second base are independently selected from a carboxylate or carbonate salt. In some embodiments, the first base and the second base are independently selected from a carbonate, acetate, or pivalate salt. In some embodiments, the first base and the second base are independently selected from potassium acetate, potassium pivalate, or cesium carbonate.

[0104] In some embodiments, the first base and the second base are independently selected from potassium acetate, potassium pivalate, cesium carbonate, potassium carbonate, potassium phosphate, DIEA, l,8-Diazabicyclo(5.4.0)undec-7-ene (DBU), 2,6-lutidine, TEA, sodium tert- butoxide, or a combination of two or more thereof. In some embodiments, the first base and the second base are independently selected from potassium acetate, potassium pivalate, cesium carbonate, potassium carbonate, potassium phosphate, DIEA, 1,8- Diazabicyclodiazabicyclo(5.4.0)undec-7-ene (DBU), 2,6-lutidine, TEA, sodium tert-butoxide, or a combination of two or more thereof.Attorney Docket No. 62619-735601

[0105] In some embodiments, the first base and the second base are independently selected from cesium carbonate, potassium carbonate, potassium phosphate, DIEA, 1,8- Diazabicyclo(5.4.0)undec-7-ene (DBU), 2,6-lutidine, TEA, sodium tert-butoxide, or a combination of two or more thereof.

[0106] In some embodiments, the first base is potassium acetate. In some embodiments, the first base is potassium acetate or potassium pivalate. In some embodiments, the first base is potassium pivalate.

[0107] In some embodiments, the second base is cesium carbonate.

[0108] In some embodiments, the first solvent and the second solvent are independently selected from DMF, dioxane, dimethylacetamide (DMA), toluene, / / -butanol, N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, or a combination of two or more thereof. In some embodiments, the first solvent and the second solvent are dioxane. In some embodiments, the first solvent and the second solvent are independently selected from DMF, dioxane, dimethylacetamide (DMA), toluene, / / -butanol, N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, 2-methyl tetrahydrofuran, water, or a combination of two or more thereof. In some embodiments, the first solvent and the second solvent are independently selected from dioxane, 2-methyl tetrahydrofuran, water, or a combination thereof. In some embodiments, the first solvent and the second solvent are independently selected from 2-methyl tetrahydrofuran, water, or a combination thereof. In some embodiments, the first solvent is 2-methyl tetrahydrofuran. In some embodiments, the second solvent is 2-methyl tetrahydrofuran, water, or a combination thereof. In some embodiments, the second solvent is a combination of 2-methyl tetrahydrofuran and water.

[0109] In some embodiments, the catalyst is Pd(OAc)2, Pd(PPh3)4, or Pd(dppf)C12'DCM.

[0110] In some embodiments, the ligand is Sphos, Xphos, dppf, dcpp'2HBF4, TED A, TPME, DABCO, DPPP, or a Cy reagent. In some embodiments, the ligand is Sphos, Xphos, dppf, dcpp,2HBF4, TED A, TPME, DABCO, DPPP, PCy3'HBF4, Cy-DPEphos, Cy-cBRIDP, or Cy- biphep. In some embodiments, the ligand is Sphos, Xphos, dppf, dcpp'2HBF4, DPPP, PCy3'HBF4, Cy-DPEphos, Cy-cBRIDP, or Cy-biphep.

[0111] In some embodiments, the base is CS2CO3, K3PO4, K2CO3, DIEA, DBU, 2,6-lutidine, TEA, or Z-BuONa. In some embodiments, the base is CS2CO3, K3PO4, K2CO3, DIEA, DBU, 2,6- lutidine, TEA, Z-BuONa, or a combination thereof.

[0112] In some embodiments, the equivalents of CS2CO3 are from about 1.5 equivalents to about 3 equivalents.Attorney Docket No. 62619-735601

[0113] In some embodiments, the solvent is DMF, dioxane, DMA, toluene, w-BuOH, NMP, or THF.

[0114] Scheme 1. Suzuki Coupling of Compound 1

[0115] In some embodiments, Compound 3 is prepared from Suzuki coupling of Compound 1 and Compound III-l, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9. In some embodiments, Compound 3 is prepared from Suzuki coupling of Compound 1 and Compound III-l. In some embodiments, the Suzuki coupling of Compound 1 and Compound III-l results in low conversion.

[0116] In some embodiments, the equivalents of Compound III-l is from about 1.05 equivalents to about 1.5 equivalents. In some embodiments, the equivalents of Compound III-2 is from about 1.05 equivalents to about 1.5 equivalents. In some embodiments, the equivalents of Compound III- 3 is from about 1.05 equivalents to about 1.5 equivalents. In some embodiments, the equivalents of Compound III-4 is from about 1.05 equivalents to about 1.5 equivalents. In some embodiments, the equivalents of Compound III- 5 is from about 1.05 equivalents to about 1.5 equivalents. In some embodiments, the equivalents of Compound III- 6 is from about 1.05 equivalents to about 1.5 equivalents. In some embodiments, the equivalents of Compound III-7 is from about 1.05 equivalents to about 1.5 equivalents. In some embodiments, the equivalents of Compound III-8 is from about 1.05 equivalents to about 1.5 equivalents. In some embodiments, the equivalents of Compound III-9 is from about 1.05 equivalents to about 1.5 equivalents.

[0117] In some embodiments, Compound 3 is purified using EtOAc, IP A, IP Ac, MTBE, or ACN.

[0118] In some embodiments, Compound 3 has a chemical purity of 95% or more. In some embodiments, Compound 3 has a chemical purity of 96% or more. In some embodiments, Compound 3 has a chemical purity of 97% or more. In some embodiments, Compound 3 has a chemical purity of 98% or more. In some embodiments, Compound 3 has a chemical purity of 99% or more. In some embodiments, Compound 3 has a chemical purity of 99.5% or more. InAttomey Docket No. 62619-735601 some embodiments, Compound 3 is substantially free of impurities. In some embodiments, the impurity comprises:

[0119] In some embodiments, Compound 2 has a chemical purity of 95% or more. In some embodiments, Compound 2 has a chemical purity of 96% or more. In some embodiments, Compound 2 has a chemical purity of 97% or more. In some embodiments, Compound 2 has a chemical purity of 98% or more. In some embodiments, Compound 2 has a chemical purity of 99% or more. In some embodiments, Compound 2 has a chemical purity of 99.5% or more.

[0120] One embodiment provides a process for the preparation of 3-(3-(4-((4-aminopiperidin-l- yl)methyl)phenyl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine (Compound 4):(Compound 4), comprising contacting a compound having the structure:Attorney Docket No. 62619-735601(tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)carbamate; Compound 3) with an acid in the presence of a solvent.

[0121] One embodiment provides a process for the preparation of3-(3-(4-((4-aminopiperidin-l- yl)methyl)phenyl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine(Compound 4):(Compound 4), or a salt thereof, comprising contacting a compound having the structure:(tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)carbamate; Compound 3) with an acid in the presence of a solvent.

[0122] In some embodiments, the acid is selected from HC1, HNO3, H2SO4, HBr, H3PO4, HF, HI, or a combination of two or more thereof. In some embodiments, the acid is HC1.Attorney Docket No. 62619-735601

[0123] In some embodiments, the solvent is selected from ethyl acetate, 2-methyl tetrahydrofuran, methyl tert-butyl ether (MTBE), isopropyl acetate, isopropyl alcohol, methanol, dioxane, or a combination of two or more thereof. In some embodiments, the solvent is isopropyl alcohol or methanol. In some embodiments, the solvent is isopropyl alcohol.

[0124] In some embodiments, the solvent is selected from dichloromethane, ethyl acetate, 2-methyl tetrahydrofuran, methyl tert-butyl ether (MTBE), isopropyl acetate, isopropyl alcohol, methanol, dioxane, water, or a combination of two or more thereof. In some embodiments, the solvent is dichloromethane, water, or a combination thereof. In some embodiments, the solvent is dichloromethane and water.

[0125] In some embodiments, the solvent is IPA or MeOH.

[0126] In some embodiments, the equivalents of HC1 are 5, 8, or 10 equivalents.

[0127] In some embodiments, Compound 4 has a chemical purity of 95% or more. In some embodiments, Compound 4 has a chemical purity of 96% or more. In some embodiments, Compound 4 has a chemical purity of 97% or more. In some embodiments, Compound 4 has a chemical purity of 98% or more. In some embodiments, Compound 4 has a chemical purity of 99% or more. In some embodiments, Compound 4 has a chemical purity of 99.5% or more.

[0128] One embodiment provides a process for the preparation of 4-((l-(4-(2-(2-Aminopyridin-3-yl)- 5-(5-fluoropyridin-2-yl)-3J / -imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile (Compound 5)(Compound 5) comprising contacting a compound having the structure:Attorney Docket No. 62619-735601(3-(3-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine; Compound 4), with a compound having the structure:(Compound 4b) and a base in the presence of a solvent.

[0129] One embodiment provides a process for the preparation of 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3Z7-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile (Compound 5)(Compound 5) comprising contacting a compound having the structure:Attorney Docket No. 62619-735601(3-(3-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine; Compound 4), or a salt thereof, with a compound having the structure:(Compound 4b) and a base in the presence of a solvent.

[0130] In some embodiments, the solvent is selected from dioxane, dimethylacetamide (DMA), N- methyl-2-pyrrolidone (NMP), DMSO, or a combination thereof. In some embodiments, the solvent is dimethylacetamide (DMA).

[0131] In some embodiments, the base is a combination of K3PO4 and K2HPO4. In some embodiments, the base is K3PO4, K2HPO4, or a combination thereof. In some embodiments, the base is K3PO4.

[0132] In some embodiments, the process further comprises purification of Compound 5 from N,N- dimethylacetamide (DMA). In some embodiments, the process further comprises recrystallization of Compound 5 from N,N-dimethylacetamide (DMA).

[0133] In some embodiments, the solvent is DMA, DMF, NMP, or DMSO. In some embodiments, the solvent is DMA, DMF, NMP, DMSO, or a combination thereof.

[0134] In some embodiments, the temperature is 25, 40, 50, 60, or 70 °C.

[0135] In some embodiments, Compound 5 is purified with slurry purification using one or more of EtO Ac, IP A, IP Ac, MTBE, ACN, DCM, MeOH, acetone, EtOH, w-BuOH, or DCM / MeOH. In some embodiments, Compound 5 is purified with slurry purification using EtO Ac, IP A, IP Ac, MTBE, ACN, DCM, MeOH, acetone, EtOH, w-BuOH, N,N-dimethylacetamide (DMA), or a combination thereof. In some embodiments, Compound 5 is purified with slurry purification using N,N-dimethylacetamide (DMA).

[0136] In some embodiments, Compound 5 is purified from N,N-dimethylacetamide (DMA). In some embodiments, Compound 5 is purified with slurry purification using N,N-dimethylacetamide (DMA). In some embodiments, Compound 5 is recrystallized from N,N-dimethylacetamide (DMA). In some embodiments, Compound 5 has a chemical purity of 95% or more. In some embodiments, Compound 5 has a chemical purity of 96% or more. In some embodiments, Compound 5 has a chemical purity of 97% or more. In some embodiments, Compound 5 has a chemical purity of 98% or more. In some embodiments, Compound 5 has a chemical purity ofAttorney Docket No. 62619-73560199% or more. In some embodiments, Compound 5 has a chemical purity of 99.5% or more. In some embodiments, Compound 5 is substantially free of impurities

[0137] In some embodiments, the impurity comprises:

[0138] In some embodiments, Compound 5 is substantially free of impurities, wherein the impurity comprises:Attorney Docket No. 62619-735601

[0139] In some embodiments, Compound 5 is substantially free of impurities, wherein the impurity comprises:

[0140] In some embodiments, Compound 5 has less than 5% of an impurity comprising:

[0141] In some embodiments, Compound 5 has less than 2% of an impurity comprising:

[0142] In some embodiments, Compound 5 has less than 0.5% of an impurity comprising:Attorney Docket No. 62619-735601

[0143] In some embodiments, Compound 5 has less than 5% of an impurity comprising:

[0144] In some embodiments, Compound 5 has less than 2% of an impurity comprising:

[0145] In some embodiments, Compound 5 has less than 0.5% of an impurity comprising:

[0146] In some embodiments, the compound with the structure:prepared by a process comprising contacting a compound having the structure:Attorney Docket No. 62619-735601phase transfer catalyst in the presence of a solvent.

[0147] In some embodiments, the phase transfer catalyst is tetrabutylammonium bromide.

[0148] In some embodiments, solvent is selected from dichloromethane, water, or a combination thereof.

[0149] In some embodiments, Compound 4b (4-chloropyrimidine-2-carbonitrile) is stable for 3 months at room temperature.

[0150] In some embodiments, a salt of Compound 4b (4-chloropyrimidine-2-carbonitrile) is prepared from an acid and a solvent. In some embodiments, the acid is HC1, H2SO4, MSA, TsOH, BSA, L-tartaric acid, H3PO4, formic acid, or oxalic acid. In some embodiments, the solvent is acetone, MTBE, heptane, or THF.

[0151] One embodiment provides a process for the preparation of 4-((l-(4-(2-(2-aminopyridin-3-yl)- 5-(5-fluoropyridin-2-yl)-3Z7-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile maleate (Compound 6)(Compound 6) comprising contacting a compound having the structure:Attorney Docket No. 62619-735601(4-((l-(4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3J7-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; Compound 5) with maleic acid in the presence of a solvent.

[0152] In some embodiments, the solvent is selected from DMSO, an ether, an alcohol, or a combination thereof. In some embodiments, the solvent is selected from DMSO, 2-methyl tetrahydrofuran, EtOH, or a combination thereof.

[0153] One embodiment provides a process for the preparation of 4-((l-(4-(2-(2-aminopyridin-3-yl)- 5-(5-fluoropyridin-2-yl)-3Z7-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile maleate (Compound 6)(Compound 6) comprising contacting a compound having the structure:(4-((l-(4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3Z7-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; Compound 5) with maleic acid in the presence of an alcohol (e.g., ethanol, methanol).

[0154] In some embodiments, the temperature is 50, 60, or 70 °C.

[0155] In some embodiments, the solvent is EtOH or MeOH. In some embodiments, the solvent is EtOH, MeOH, or a combination thereof.Attorney Docket No. 62619-735601

[0156] In some embodiments, Compound 6 has a chemical purity of 95% or more. In some embodiments, Compound 6 has a chemical purity of 96% or more. In some embodiments, Compound 6 has a chemical purity of 97% or more. In some embodiments, Compound 6 has a chemical purity of 98% or more. In some embodiments, Compound 6 has a chemical purity of 99% or more. In some embodiments, Compound 6 has a chemical purity of 99.5% or more.

[0157] One embodiment provides a compound having a structure selected from:or a salt, solvate, or deuteroisotope thereof.

[0158] One embodiment provides a compound having a structure selected from:Attorney Docket No. 62619-735601or a salt, solvate, or deuteroisotope thereof.

[0159] One embodiment provides a compound having a structure selected from:

[0160] One embodiment provides a compound having a structure selected from:deuteroisotope thereof.

[0161] One embodiment provides a compound having a structure selected from:Attorney Docket No. 62619-735601salt, solvate, or deuteroisotope thereof.

[0162] One embodiment provides a compound having a structure selected from:, or a salt, solvate, or deuteroisotope thereof.

[0163] One embodiment provides a compound having a structure selected from:, or a salt, solvate, or deuteroisotope thereof.

[0164] One embodiment provides a compound having a structure selected from:salt, solvate, or deuteroisotope thereof.Alternative Synthetic Routes

[0165] One embodiment provides a process for the preparation of 4-((l-(4-(2-(2-Aminopyridin-3-yl)- 5-(5-fluoropyridin-2-yl)-3Z7-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile (Compound 5)Attorney Docket No. 62619-735601(Compound 5) comprising contacting a compound having the structure:(3-(3-(4-(chloromethyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyri din-2- yl)pyridin-2-amine; 1-5) with a compound having the structure:(piperidin-4-ylamino)pyrimidine-2-carbonitrile; 1-8) and a base in the presence of a solvent.

[0166] One embodiment provides a process for the preparation of 4-(piperidin-4-ylamino)pyrimidine- 2-carbonitrile (Compound 1-8) g a compound having the structure:(tert-butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-l -carboxylate; 1-7) with an acid in the presence of a solvent.Attorney Docket No. 62619-735601

[0167] One embodiment provides a process for the preparation of tert-butyl 4-((2-cyanopyrimidin-4- yl)amino)piperidine-l -carboxylate (Compound 1-7) g a compound having the structure:(tert-butyl 4-aminopiperidine-l -carboxylate; 1-6) with a compound having the structure:(4-chloropyrimidine-2-carbonitrile; Compound 4b) and a base in the presence of a solvent.

[0168] Scheme 2. Synthesis of Compound 5

[0169] Scheme 3. Synthesis of Intermediate 1-1Attorney Docket No. 62619-735601

[0170] One embodiment provides a process for preparing a compound, or a salt, solvate, or deuteroisotope thereof, having a structure presented in Table 1.Table 1Attorney Docket No. 62619-735601

[0171] One embodiment provides a compound, or a salt, solvate, or deuteroisotope thereof, having a structure presented in Table 2.Table 2Attorney Docket No. 62619-735601

[0172] In some embodiments, a solvent described herein is any suitable solvent, such as a polar aprotic solvent, water, an alcohol, a halocarbon, or a combination thereof. In some embodiments, a solvent described herein is selected according to its characteristics, such as boiling point, ability to solubilize a composition provided herein, polarity, pH, or the like. In some embodiments, a solvent provided herein has a boiling point of about 30 °C or more. In some embodiments, a solvent provided herein has a boiling point of about 70 °C or more. In certain embodiments, a solvent provided herein has a boiling point of about 120 °C or more. In some embodiments, a solvent provided herein has a boiling point of about 240 °C or less. In some embodiments, a solvent described herein is a polar solvent. In some embodiments, the polar solvent is a polar protic solvent. In some embodiments, the polar solvent is a polar aprotic solvent. In some embodiments, a solvent described herein is a nonpolar solvent. In some embodiments, the solvent is acetonitrile, propionitrile, butyronitrile, toluene, 1,2- di chlorobenzene, chlorobenzene, fluorobenzene, 1,2-difluorobenzene, di chloroethane, trifluorotoluene, chloroform, sulfolane, DMF, DMSO, tert-butanol, tert-amyl alcohol, water, or combinations thereof.

[0173] In some embodiments, a base described herein is any suitable base, such as an organic base, an inorganic base, a monoprotic base, a polyprotic base, or combinations thereof. In some embodiments, the base is an alkylamine base. In some embodiments, the base comprises aAttorney Docket No. 62619-735601 carbonate, bicarbonate, acetate, or phosphate anion. In some embodiments, the base is selected from N,N-diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, lithium hydroxide, sodium hydroxide, calcium carbonate, cesium carbonate, sodium carbonate, potassium acetate, potassium carbonate, sodium acetate, sodium bicarbonate, calcium bicarbonate, potassium bicarbonate, potassium phosphate, trisodium phosphate, tripotassium phosphate, disodium phosphate, dipotassium phosphate, sodium tert-butoxide, potassium tert-butoxide, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), tetramethylguanidine, tributylamine, 2,6-lutidine, 2,4,6-collidine, or combinations thereof.

[0174] In some embodiments, an oxidizing agent described herein is any suitable oxidizing agent. In some embodiments, the oxidizing agent comprises dichromate, hypochlorite, persulfate, permanganate, perchlorate, dithionite, peroxide, manganese, or benzoquinone. In some embodiments, the oxidizing agent comprises an iron (III) salt, manganese (III) salt, manganese (IV) salt, or manganese (VII) salt.

[0175] In some embodiments, a reducing agent described herein is any suitable reducing agent. In some embodiments, the reducing agent comprises hydrogen, an alkali metal, formic acid, oxalic acid, diborane, or the like.

[0176] In some embodiments, an organocatalyst described herein is any suitable organocatalyst, such as a chiral organocatalyst, an achiral organocatalyst, a Lewis base, a Lewis acid, a Bronsted base, or a Bronsted acid. In some embodiments, the organocatalyst comprises proline, imidazolidinone, urea, thiourea, l,l'-Bi-2-naphthol (BINOL), bipyridine, or the like.

[0177] In some embodiments, a palladium catalyst described herein is any suitable palladium catalyst, such as an organopalladium complex. In some embodiments, the organopalladium complex is a palladium-phosphine complex. In some embodiments, a palladium catalyst described herein is selected according to its characteristics, such as stability, oxidation state, solubility, stereoselectivity, or the like. In some embodiments, the palladium catalyst is Pd(dppf)C12, PdCh, Pd(OAc)2, Pd(PhsP)4, Pd2(dba)s, orPd / C. In some embodiments, the palladium catalyst is Pd(dppf)C12, Pd(dppf)Ch,DCM, PdCh, Pd(OAc)2, Pd(PhsP)4, Pd2(dba)s, orPd / C. In some embodiments, the palladium catalyst is generated in-situ from a palladium source and a ligand. In some embodiments, the palladium catalyst is generated in-situ from Pd2(dba)s and a phosphine ligand. In some embodiments, the palladium catalyst is generated in-situ from Pd2(dba)s and PCys or Ad2(n-Bu)P. In some embodiments, the palladium catalyst is Pd(dppf)Ch"DCM.Attorney Docket No. 62619-735601

[0178] In some embodiments, a borylation reagent described herein is any suitable borylation reagent, such as an organoboron compound. In some embodiments, the organoboron compound is a boronic acid or a boronic ester. In some embodiments, the borylation reagent is pinacol borane (HBPin), bis(pinacolato)diboron (B2Pin2), or bis(catecholato)diborane (B2Cat2).

[0179] In some embodiments, a phase transfer catalyst described herein is any suitable phase transfer catalyst, such as a quaternary ammonium salt, phosphonium salt, crown ether, or polyether. In some embodiments, the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium fluoride, 12-crown-4, 15-crown-5, 18-crown-6, 21 -crown-7, tetrabutylphosphonium bromide, or polyethylene glycol.Numbered EmbodimentsSome numbered examples of embodiments follow.(1) A process for preparing Tert-butyl (l-(4-((3-nitro-6-chloro-pyri din-2 -yl) amino)benzyl)piperidin-4-yl)carbamate (Compound D):(Compound D) comprising contacting a compound with the structure:(Tert-butyl (l-(4-aminobenzyl) piperidin-4-yl) carbamate; Compound C) with a compound with the structure:(2,6-dichloro-3-nitro-pyridine; Compound Cl) and a base in the presence of a solvent.(2) The process of embodiment 1, wherein the base is selected from N,N- Diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, potassium carbonate, trisodium phosphate, tripotassium phosphate, disodium phosphate, dipotassium phosphate, 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), tetramethylguanidine, tributylamine, 2,6-lutidine, 2,4,6-collidine, or a combination of two or more thereof.Attorney Docket No. 62619-735601(3) The process of any one of embodiments 1-2, wherein the base is DIEA or sodium bicarbonate.(4) The process of any one of embodiments 1-3, wherein the base is sodium bicarbonate.(5) The process of any one of embodiments 1-4, wherein the solvent is dioxane.(6) The process of any one of embodiments 1-5, wherein Compound D has a chemical purity of 95% of more. (7) The process of any one of embodiments 1-6, wherein Compound D has a chemical purity of 96% of more. (8) The process of any one of embodiments 1-7, wherein Compound D has a chemical purity of 97% of more. (9) The process of any one of embodiments 1-8, wherein Compound D has a chemical purity of 98% of more. (10) The process of any one of embodiments 1-9, wherein Compound D has a chemical purity of 99% of more. (11) The process of any one of embodiments 1-10, wherein Compound D has a chemical purity of 99.5% of more.(12) The process of any one of embodiments 1-11, wherein the compound with the structure:(Compound C) is prepared by reducing a compound with the structure:(Compound B).(13) The process of embodiment 12, wherein the reduction is conducted in a solvent with a metal and a Bronsted-Lowry acid. (14) The process of embodiment 13, wherein the solvent comprises an alcohol and water, DMSO and water, or DMF and water. (15) The process of any one of embodiments 13-14, wherein the solvent is EtOH and water. (16) The process of any one of embodiments 13-15, wherein the metal comprises Fe, Sn, or Zn. (17) The process of embodiment 16, wherein the metal is Fe. (18) The process of any one of embodiments 13- 17, wherein the Bronsted-Lowry acid is NH4CI. (19) The process of any one of embodiments 12-18, wherein the compound with the structure: O^2NNHBOC (Compound B) is prepared by a process comprising contacting a compound with the structure:XjXBr^2N(Compound A) with a compound with the structure:Attorney Docket No. 62619-735601(Compound Al) in the presence of a base and a solvent.(20) The process of embodiment 19, wherein the base is selected from N- Diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, potassium carbonate, or a combination of two or more thereof. (21) The process of embodiment 19 or 20, wherein the base is TEA or potassium carbonate.(22) The process of any one of embodiments 19-21, wherein the base is potassium carbonate.(23) The process of any one of embodiments 19-22, wherein the solvent is selected from acetone, tetrahydrofuran (THF), acetonitrile (ACN), dimethyl sulfoxide (DMSO), dichloromethane (DCM), Dimethylformamide (DMF), or a combination of two or more thereof. (24) The process of any one of embodiments 19-23, wherein the solvent is acetone.(25) A process for preparing Tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-chloro-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (Compound 1):(Compound 1), comprising contacting a compound with the structure:(Tert-butyl (l-(4-((3-amino-6-chloropyridin-2-yl)amino)benzyl)piperidin-4-yl)carbamate;Compound E) with a compound with the structure:(2-aminonicotinaldehyde; Compound El) and an oxidizing agent in the presence of a solvent.Attorney Docket No. 62619-735601(26) The process of embodiment 25, wherein the oxidizing agent is FeCh, NH3H2O, an Fe (III) salt, NH4Fe(SO4)2.12H2O, H2O2, Na2S2O8, NaClO, oxone, MnO2, DDQ, Mn(OAc)3,ZnCh, or CaCh. (27) The process of embodiment 25 or 26, wherein the oxidizing agent is NH4Fe(SO4)2.12H2. (28) The process of any one of embodiments 25-27, wherein the solvent is DMF, DMSO, DMA, NMP, w-BuOH, toluene, dioxane, IP A, t-BuOH, or IPA / water. (29) The process of any one of embodiments 25-28, wherein the solvent is isopropyl alcohol (IP A).(30) The process of any one of embodiments 25-29, wherein Compound 1 has a chemical purity of 95% of more. (31) The process of any one of embodiments 25-30, wherein Compound 1 has a chemical purity of 96% of more. (32) The process of any one of embodiments 25-31, wherein Compound 1 has a chemical purity of 97% of more. (33) The process of any one of embodiments 25-32, wherein Compound 1 has a chemical purity of 98% of more. (34) The process of any one of embodiments 25-33, wherein Compound 1 has a chemical purity of 99% of more. (35) The process of any one of embodiments 25-34, wherein Compound 1 has a chemical purity of 99.5% of more. (36) The process of any one of embodiments 25-35, wherein the compound with the structure:(Compound E) is prepared by a process comprising contacting a compound with the structure:(Compound D) with an organocatalyst and reducing agent in the presence of a solvent.(37) The process of embodiment 36, wherein the organocatalyst comprises bipyridyl (4,4’- bipyridine). (38) The process of embodiment 36 or embodiment 37, wherein the reducing agent comprises tetrahydroxydiborane. (39) The process of any one of embodiments 36-38, wherein the solvent is methanol (MeOH) and water, ethanol (EtOH) and water, or isopropyl alcohol (IP A). (40) The process of any one of embodiments 36-39, wherein the solvent is isopropyl alcohol (IP A). (41) A process for preparing Tert-butyl (l-(4-(2-(2-aminopyri din-3 - yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (Compound 3):Attorney Docket No. 62619-735601(Compound 3), comprising reacting a compound with the structure:(Compound 1) a boron-containing heteroaryl compound, a palladium catalyst, and a base in the presence of a solvent.(42) The process of embodiment 41, wherein the palladium catalyst is selected from Pd(OAc)2, Pd(PPhs)4, and Pd(dppf)C12.DCM. (43) The process of embodiment 41 or embodiment 42, wherein the boron-containing heteroaryl compound is a boronic acid, boronate ester, or trifluoroborate. (44) The process of any one of embodiments 41-43, wherein the boron-containing heteroaryl compound is selected from:Attorney Docket No. 62619-735601(45) The process of embodiment 44, wherein the boron-containing heteroaryl compoundThe process of any one of embodiments 41-45, wherein the base is selected from cesium carbonate, potassium carbonate, potassium phosphate, DIEA, l,8-Diazabicyclo(5.4.0)undec-7-ene (DBU), 2,6-lutidine, TEA, sodium tert- butoxide, or a combination of two or more thereof. (47) The process of any one of embodiments 41-46, wherein the solvent is selected from DMF, dioxane, Dimethylacetamide(DMA), toluene, / / -butanol, N-Methyl-2-pyrrolidone (NMP), tetrahydrofuran, or a combination of two or more thereof. (48) A process for preparing Tert-butyl (l-(4-(2-(2- aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin- 4-yl)carbamate (Compound 3):(Compound 3), comprising reacting a compound with the structure:(Compound 1) with a borylation reagent, a first base, and a first palladium catalyst in the presence of a first solvent to yield a compound with the structure:Attorney Docket No. 62619-735601(tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)carbamate; Compound 2); and reacting Compound 2 with 2-bromo-5-fluoropyridine (Compound 2a), a second base, and a second palladium catalyst in the presence of a second solvent. (49)The process of embodiment 48, wherein the borylation reagent is pinacolborane, bis(pinacolato)diboron or bis(catecholato)diborane. (50) The process of embodiment 48 or 49, wherein the borylation reagent is bis(pinacolato)diboron. (51) The process of any one of embodiments 48-50, wherein the first palladium catalyst and the second palladium catalyst are selected from Pd(OAc)2, Pd(PPhs)4, or Pd(dppf)C12.DCM. (52) The process of any one of embodiments 48- 51, wherein the first palladium catalyst and the second palladium catalyst is Pd(dppf)C12.DCM. (53) The process of any one of embodiments 48-52, wherein the first base and the second base is selected from cesium carbonate, potassium carbonate, potassium phosphate, DIEA, l,8-Diazabicyclo(5.4.0)undec-7-ene (DBU), 2,6-lutidine, TEA, sodium tert- butoxide, or a combination of two or more thereof. (54) The process of any one of embodiments 48-53, wherein the first base is potassium acetate. (55) The process of any one of embodiments 48-54, wherein the second base is cesium carbonate. (56) The process of any one of embodiments 48-55, wherein the first solvent and the second solvent is selected from DMF, dioxane, Dimethylacetamide (DMA), toluene, / / -butanol, N-Methyl-2-pyrrolidone (NMP), tetrahydrofuran, or a combination of two or more thereof. (57) The process of any one of embodiments 48-56, wherein the first solvent and the second solvent is dioxane. (58) The process of any one of embodiments 48-57, wherein Compound 3 has a chemical purity of 95% of more. (59) The process of any one of embodiments 48-58, wherein Compound 3 has a chemical purity of 96% of more. (60) The process of any one of embodiments 48-59, wherein Compound 3 has a chemical purity of 97% of more. (61) The process of any one of embodiments 48-60, wherein Compound 3 has a chemical purity of 98% of more. (62) TheAttorney Docket No. 62619-735601 process of any one of embodiments 48-61, wherein Compound 3 has a chemical purity of 99% of more. (63) The process of any one of embodiments 48-62, wherein Compound 3 has a chemical purity of 99.5% of more. (64) The process of any one of embodiments 48-63, wherein Compound 2 has a chemical purity of 95% of more. (65) The process of any one of embodiments 48-64, wherein Compound 2 has a chemical purity of 96% of more. (66) The process of any one of embodiments 48-65, wherein Compound 2 has a chemical purity of 97% of more. (67) The process of any one of embodiments 48-66, wherein Compound 2 has a chemical purity of 98% of more. (68) The process of any one of embodiments 48-67, wherein Compound 2 has a chemical purity of 99% of more. (69) The process of any one of embodiments 48-68, wherein Compound 2 has a chemical purity of 99.5% of more. (70) The process of any one of embodiments 48-69, wherein Compound 3 is substantially free of impurities, wherein the impurity comprises:process for the preparation of 3-(3-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-5-(5- fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Compound 4):Attorney Docket No. 62619-735601(Compound 4), comprising contacting a compound with the structure:(Tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate; Compound 3) with an acid in the presence of a solvent.(72) The process of embodiment 71, wherein the acid is selected from HC1, HNO3, H2SO4, HBr, H3PO4, HF, HI, or a combination of two or more thereof. (73) The process of any one of embodiments 71-72, wherein the acid is HC1. (74) The process of any one of embodiments 71- 73, wherein the solvent is selected from ethyl acetate, 2-methyl tetrahydrofuran, methyl tertbutyl ether (MTBE), isopropyl acetate, isopropyl alcohol, methanol, dioxane, or a combination of two or more thereof. (75) The process of any one of embodiments 71-74, wherein the solvent is isopropyl alcohol or methanol. (76) The process of any one of embodiments 71-75, wherein the solvent is isopropyl alcohol. (77) The process of any one of embodiments 71-76, wherein Compound 4 has a chemical purity of 95% of more. (78) The process of any one of embodiments 71-77, wherein Compound 4 has a chemical purity of 96% of more. (79) The process of any one of embodiments 71-78, wherein Compound 4 has a chemical purity of 97% of more. (80) The process of any one of embodiments 71-79, wherein Compound 4 has a chemical purity of 98% of more. (81) The process of any one of embodiments 71-80, wherein Compound 4 has a chemical purity of 99% of more. (82) TheAttorney Docket No. 62619-735601 process of any one of embodiments 71-81, wherein Compound 4 has a chemical purity of 99.5% of more. (83) A process for the preparation of 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5- fluoropyridin-2-yl)-3J / -imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2- carbonitrile (Compound 5)(Compound 5) comprising contacting a compound with the structure:(3-(3-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine; Compound 4) with a compound with the structure:(Compound 4b) and a base in the presence of a solvent.(84) The process of embodiment 83, wherein the solvent is selected from dioxane, dimethylacetamide (DMA), N-Methyl-2-pyrrolidone (NMP), DMSO, or combinations thereof.(85) The process of embodiment 83 or embodiment 84, wherein the base is a combination of KjPCU and K2HPO4. (86) The process of any one of embodiments 83-85, wherein CompoundAttorney Docket No. 62619-7356015 has a chemical purity of 95% of more. (87) The process of any one of embodiments 83-86, wherein Compound 5 has a chemical purity of 96% of more. (88) The process of any one of embodiments 83-87, wherein Compound 5 has a chemical purity of 97% of more. (89) The process of any one of embodiments 83-88, wherein Compound 5 has a chemical purity of 98% of more. (90) The process of any one of embodiments 83-89, wherein Compound 5 has a chemical purity of 99% of more. (91) The process of any one of embodiments 83-90, wherein Compound 5 has a chemical purity of 99.5% of more. (92) The process of any one of embodiments 83-91, wherein Compound 5 is substantially free of impurities, wherein the impurity comprises:embodiments 83-92, wherein the compound with the structure:Attorney Docket No. 62619-735601N ^N(Compound 4b) is prepared by a process comprising contacting a compound with the structure:(Compound 4a) with NaCN and a phase transfer catalyst in the presence of a solvent.(94) The process of embodiment 93, wherein the phase transfer catalyst is Tetrabutylammonium bromide. (95) The process of embodiment 93 or embodiment 94, wherein the solvent is selected from dichloromethane, water, or combination thereof. (96) A process for the preparation of 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3JT- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile maleate (Compound 6)(Compound 6) comprising contacting a compound with the structure:(4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3J7-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; Compound 5)Attorney Docket No. 62619-735601 with a maleic acid in the presence of an alcohol. (97) The process of embodiment 96, wherein Compound 6 has a chemical purity of 95% of more. (98) The process of embodiment 96 or 97, wherein Compound 6 has a chemical purity of 96% of more.(99) The process of any one of embodiments 96-98, wherein Compound 6 has a chemical purity of 97% of more. (100) The process of any one of embodiments 96-99, wherein Compound 6 has a chemical purity of 98% of more. (101) The process of any one of embodiments 96-100, wherein Compound 6 has a chemical purity of 99% of more. (102) The process of any one of embodiments 96-101, wherein Compound 6 has a chemical purity of 99.5% of more.(103) A compound having a structure selected from:or a salt, solvate, or deuteroisotope thereof.EXAMPLESI. Chemical SynthesisAttorney Docket No. 62619-735601

[0180] In some embodiments, the AKT1 inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:ACN acetonitrile Ad2(n-Bu)P Di(l-adamantyl)-n-butylphosphine AmgenPHOS bis(di-tert-butyl)-4-dimethylaminophenylphosphine BSA bis(trimethylsilyl)acetamide CaCl2calcium chloride CaCO3calcium carbonate Ca(HCO3)2calcium bicarbonate CH3COOK potassium acetate (CH3)3CONa sodium tert-butoxide CS2CO3 cesium carbonate Cy-DPEphos bis(2-dicyclohexylphosphinophenyl)ether Cy-cBRIDP l-(Dicyclohexylphosphino)-2,2-Diphenyl-l -methylcyclopropane Cy-biphep 2,2'-Bis(dicyclohexylphosphino)- 1 , 1 '-biphenyl °C degrees Celsius 5H chemical shift in parts per million downfield from tetramethylsilaneDABCO l,4-diazabicyclo[2.2.2]octane DBU l,8-Diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane (CH2Q2) dcpp'2HBF4 1.3-Bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) DDQ 2.3-Dichloro-5,6-dicyano-l,4-benzoquinone DIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMA dimethylacetamide DMF dimethylformamide DMSO dimethylsulfoxide dppf 1 , 1 '-Bi s(diphenylphosphino)ferrocene dppp 1 ,3 -Bi s(diphenylphosphino)propane EA ethyl acetate EtOAc ethyl acetate ESI electrospray ionization Et ethyl EtOH ethanol FeCl3iron (III) chloride g gram(s) h hour(s) H2O water H2O2 hydrogen peroxide HC1 hydrochloric acidAttorney Docket No. 62619-735601HNO3nitric acid H2SO4 sulfuric acid H3PO4 phosphoric acid HPLC high performance liquid chromatography Hz hertz IPA isopropanol IP Ac isopropyl acetate coupling constant (in NMR spectrometry)KOAc potassium acetate KOPiv potassium pivalate KHSO4 potassium bi sulfate K2CO3 potassium carbonate K2HPO4 dipotassium phosphate K3PO4 tripotassium phosphate LCMS liquid chromatography mass spectrometry micro m multiplet (spectral); meter(s); milli M molar M+parent molecular ion MnCh manganese dioxide Mn(OAc)3 manganese (III) acetate Me methyl MeOH methanol MsCl methanesulfonyl chloride MTBE methyl tert-butyl ether MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliter MS mass spectrometry w-BuOH n-butyl alcohol Na2CO3sodium carbonate NaHCOs sodium bicarbonate Na2HPO4 di sodium phosphate Na3PO4 trisodium phosphate Na2SO4sodium sulfate NaCN sodium cyanide NaClO sodium hypochlorite NH4CI ammonium chlorideNH4Fe(SO4)2-12H2O ammonium iron(III) sulfateNMP N-Methyl-2-pyrrolidone nm nanometer(s)NMR nuclear magnetic resonanceAttorney Docket No. 62619-735601Pd(OAc)2palladium (II) acetatePd(PPh3)4Tetrakis(triphenylphosphine)palladiumPd(AmPhos)2Cl2Bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II)Pd2(dba)3Tris(dibenzylideneacetone)dipalladium(0)Pd(dppf)Cl2-DCM l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethanePd(dtbpf)Cl2[1 J'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solutionPE petroleum ether RT room temperature s singlet (spectral) t triplet (spectral) SiO2silicon dioxide SFC Supercritical fluid chromatography Sphos Dicy clohexyl(2 6 '-dimethoxy [1,1 '-biphenyl] -2-yl)phosphane T temperature t-BuOH tert-butyl alcohol TBA tributylamine TBAB tetrabutylammonium bromide TEA triethylamine TEDA tri ethyl enedi amine TEAA triethylammonium acetate TFA trifluoroacetic acid THF tetrahydrofuran 2-MeTHF 2-Methyltetrahydrofuran TPP Triphenylphosphine Xphos Dicyclohexyl[2',4',6'-tris(propan-2-yl)[l,l'-biphenyl]-2-yl]phosphane ZnCl2Zinc chlorideAttorney Docket No. 62619-735601Experimental Procedures

[0181] Scheme 4. Synthesis of Compound 5 and Compound 6 for Batch 1 and Batch 2

[0182] Table 3. Summary of BatchesAttorney Docket No. 62619-735601

[0183] Table 4. Reagents for Batch 1 and Batch 2Batch 1 and Batch 2: Experimental Procedures for Compound 1 and Compound 4b

[0184] Step a: Preparation of Compound B

[0185] To a mixture of Compound Al (1.0 eq) in acetone (15 vol) was added K2CO3 (1.5 eq) followed by Compound A (2.7 kg) in portions at RT over a period of 2 h. The reaction mixture was held at RT for 5 h and monitored by LC-MS. The reaction mixture was filtered and washed with acetone (2 x 4 vol). The resulting filtrate was concentrated to ~2 vol and diluted with / / -heptane (5.5 vol) to afford a slurry. After 2 h at RT, the slurry was filtered,Attorney Docket No. 62619-735601 washed with / / -heptane (2 x 0.5 vol) and dried under vacuum to afford 3.9 kg (93%) of Compound B (99.1% AUC by HPLC) as a white solid.

[0186] Step b: Preparation of Compound C

[0187] To a mixture of Compound B (3.9 kg) in 4: 1 EtOH / water (10 vol) was added NH4CI (0.75 eq) at RT. The mixture was heated to 75 °C and Fe (4.5 eq) was added portion-wise over 4 h maintaining the temperature below 80 °C. After 1.5 h, the reaction mixture cooled to RT, filtered and washed with EtOH (2 x 3 vol). The resulting filtrate was concentrated to ~2 vol and adjusted to pH 9-10 to afford a slurry. The slurry was filtered and washed with water (2 x 1 vol). After drying under vacuum, the solids were slurried in MTBE (3 vol) at RT for 4 h, filtered, washed with MTBE (2 x 0.5 vol) and dried under vacuum to afford 2.66 kg (74%) of Compound C (92.2% AUC by HPLC) as a white solid.

[0188] Step c: Preparation of Compound D

[0189] To a mixture of Compound Cl (1.05 eq) and NaHCCL (3.0 eq) in dioxane (10 vol) was added Compound C (2.7 kg) at RT. The mixture was heated to 75-80 °C for 6 h and monitored by LC-MS. The reaction mixture cooled to RT, concentrated to ~2 vol and diluted with water (15 vol). The slurry was held for 5 h at RT, filtered and washed with water (2 x 1 vol). After drying under vacuum, the solids were slurried in MTBE (15 vol) at RT for 5 h, filtered, washed with MTBE (2 x 1 vol) and dried under vacuum to afford 2.9 kg (71%) of Compound D (94.5% AUC by HPLC) as a red solid.

[0190] Step d: Preparation of Compound 1

[0191] To a mixture of Compound D (3.5 kg) in IPA (15 vol) was added bipyridyl (0.1 eq) and the mixture was heated to 55-60 °C. Tetrahydroxydiborane (3.5 eq) was then added in portions over 6 h at 60-65 °C and the mixture was held at 60 °C for 8 h. LC-MS analysis indicated Compound D was no longer present and Compound E was present. The mixture was combined with Compound El (1.0 eq) followed by NH4Fe(SO4)2'12H2O (3.0 eq) at 60 °C. The reaction mixture was heated to 80 °C, held for 40 h and LC-MS indicated 45.0% of Compound 1 was observed as well as 41.6% of boc deprotected Compound 1. The reaction mixture was cooled to RT and adjusted to pH 9 using aqueous K2CO3. Boc anhydride (3.3 kg) was then added and the mixture was held until LC-MS analysis indicated 1.2% of boc deprotected Compound 1 remained. The reaction mixture was filtered and washed with DCM (2 x 7.5 vol). The resulting filtrate was separated, washed with brine (10 vol), dried over Na2SO4, and filtered. The filtrate was concentrated to ~3 vol, diluted with MTBE (5 vol) and held at RT for 3 h. The slurry was filtered, washed with MTBE (2 x 1.5 vol) and dried underAttorney Docket No. 62619-735601 vacuum. The solids were dissolved in DCM (15 vol), treated with activated carbon (30 wt%) for 16 h at RT. The mixture was filtered, washed with DCM (2 x 2 vol) and concentrated to ~2 vol. The mixture was diluted with ^-heptane (3 vol) and held at RT for 3 h. The slurry was filtered, washed with ^-heptane (2 x 0.5 vol), and dried under vacuum to afford 1.65 kg (41%) of Compound D (99.7% AUC by HPLC) as a pink solid.

[0192] Step f: Preparation of Compound 4b

[0193] To a mixture of Compound 4a (1 kg) in water (5 vol) and DCM (5 vol) at RT was added TBAB (0.1 eq) and the mixture was held for 0.25 h. NaCN (1.05 eq) was then added and the mixture was held at RT for 1 h and an LC-MS analysis indicated the reaction was complete. The reaction was diluted with DCM (3 vol) and the phases were separated. The aqueous phase was extracted with DCM (3 vol) and the combined DCM layers were washed with water (3 vol), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by SiCh chromatography (6: 1 / / -heptane / EtOAc) to afford 510 g (70%) of Compound 4b (99.3% by HPLC) as a colorless oil.Batch 3 and Batch 4: Experimental Procedures for Compound 1

[0194] Step a: Preparation of Compound B

[0195] To a mixture of Compound Al (1.0 eq) in acetone (15 vol) was added K2CO3 (1.5 eq) followed by Compound A (6.0 kg) in portions (0.3 kg / 0.25 h) at RT. The reaction mixture was held at RT for 6 h and monitored by HPLC. The reaction mixture was filtered and washed with acetone (2 x 4 vol). The resulting filtrate was concentrated to ~2 vol and diluted with ice / water (5 vol) to afford a slurry. After 5 h at RT, the slurry was filtered, washed with water (2 x 0.5 vol) and dried under vacuum at 40 °C to afford 8.93 kg (96%) of Compound B (99.9% AUC by HPLC) as a white solid.

[0196] Step b: Preparation of Compound C

[0197] To a mixture of Compound B (8.9 kg) in 4: 1 EtOH / water (10 vol) was added NH4CI (1.0 eq) at RT. The mixture was heated to 75 °C and Fe (4.5 eq) was added portion-wise (100 g / 0.25 h) maintaining the temperature below 80 °C. After 1.5 h, HPLC analysis indicated Compound B was no longer present, 93.5% of Compound C was observed along with 2.1% of a dimer impurity. The reaction was deemed complete, cooled to RT, filtered and washed with EtOH (2 x 3 vol). The resulting filtrate was concentrated to ~2 vol and adjusted to pH 9-10 with aqueous ISfeCCh (~2 vol) to afford a slurry. The slurry was held at RT for 4 h, filtered and washed with water (2 x 1 vol). After drying under vacuum, the solids were slurried in MTBE (3 vol) at RT for 4 h, filtered, washed with MTBE (2 x 0.5 vol) and dried under vacuum toAttorney Docket No. 62619-735601 afford 7.48 kg (92%) of Compound C (97.5% AUC by HPLC containing 1.6% of the dimer impurity) as a white solid.

[0198] Step c: Preparation of Compound D

[0199] To a mixture of Compound C (7.4 kg) and NaHCO3 (3.0 eq) in dioxane (10 vol) was added Compound Cl (0.95 eq) at RT. The mixture was heated to 75-80 °C for 6 h and HPLC analysis indicated Compound C was no longer present and 91.1% of Compound D was observed. The reaction mixture cooled to RT, concentrated to ~2 vol and diluted with water (15 vol). The slurry was held for 5 h at RT, filtered and washed with water (2 x 1 vol). After drying under vacuum, the solids were slurried in MTBE (15 vol) at RT for 5 h, filtered, washed with MTBE (2 x 1 vol) and dried under vacuum to afford 10.5 kg (93%) of Compound D (98.0% AUC by HPLC) as a red solid.

[0200] Step d: Preparation of Compound 1

[0201] To a mixture of Compound D (10.5 kg) in IPA (15 vol) was added bipyridyl (0.1 eq) and the mixture was heated to 55-60 °C. Tetrahydroxydiborane (3.5 eq) was then added in portions (100 g / 0.25 h) and the mixture was held at 60 °C for 2 h. HPLC analysis indicated Compound D was no longer present and 98.9% of Compound E was observed. The mixture was combined with Compound El (1.0 eq) followed by NH4Fe(SO4)2'12H2O (3.0 eq) at 60 °C. The reaction mixture was heated to 80 °C, held for 16 h and HPLC indicated 66.4% of Compound 1, 11.2% of a Compound 1 intermediate and 13.0% of Compound El was observed. The reaction mixture was cooled to 70 °C. FeCh (1.0 eq) was added and the mixture was held at 80 °C for 6 h until HPLC analysis indicated 85.0% of Compound 1, 1.3% of a Compound 1 intermediate, 9.9% of Compound El and 1.0% of boc deprotected Compound 1 was observed. The reaction mixture was cooled to RT and adjusted to pH 9 using aqueous K2CO3. Boc anhydride (0.5 eq) was then added and the mixture was held at RT for 1 h until HPLC analysis indicated 87.9% of Compound 1, 0.7% of a Compound 1 intermediate, 5.4% of Compound El and <0.1% of boc deprotected Compound 1 was observed. The reaction mixture was filtered and washed with DCM (2 x 7.5 vol). The resulting filtrate was separated, washed with brine (10 vol) and concentrated to ~3 vol. The mixture diluted with MTBE (10 vol) and held at RT for 16 h. The slurry was filtered and dried under vacuum to afford 6.3 kg (52%) of Compound 1 (97.8% AUC by HPLC) as a brown solid.

[0202] Steps a-d were repeated on 4 kg scale to afford another 5.2 kg of Compound 1. The two batches of Compound 1 (11.5 kg) were combined with DCM (25 vol) and treated withAttorney Docket No. 62619-735601 activated carbon (20 wt%) at 25 °C for 16 h. The mixture was filtered, washed with DCM (5 vol) and resulting filtrate was concentrated to ~2 vol. n-Heptane (10 vol) was added and the resulting slurry was held at 25 °C for 2 h, filtered, washed with n-heptane (2 vol) and dried under vacuum to afford 10.2 kg of Compound 1 (99.3% AUC by HPLC) as a pink solid. Batch 1: Experimental Procedures for Compound 6

[0203] Step 1 and Step 2: Preparation of Compound 3

[0204] To a solution of Compound 1 (650 g) in dioxane (10 vol) was added KOAc (2.0 eq) and bis(pinacolato)diboron (1.1 eq) at 25 °C. The mixture was thoroughly purged with nitrogen and Pd(dppf)C12'DCM (0.075 eq) was added. The mixture was heated to 100 °C for 8 h when an LC-MS analysis indicated Compound 1 no longer remained. The reaction was cooled to 60 °C and Compound 2a (1.5 eq), CS2CO3 (2.0 eq) and additional dioxane (5 vol) were added. The mixture was thoroughly purged with nitrogen, Pd(dppf)C12'DCM (0.1 eq) was added and the mixture was heated to 80 °C for 30 h when an LC-MS analysis indicated the reaction was complete. The mixture was cooled to 50 °C, concentrated to ~3 vol and diluted with EtOAc (10 vol). The mixture was filtered and washed with EtOAc (5 vol). The resulting filtrate was diluted with 0.3 N HC1 (18 vol) and held for 0.5 h at RT. The phases were separated and the aqueous phase was washed with EtOAc (2 x 10 vol). The aqueous phase was adjusted to pH ~9 using aq. K2CO3 and then extracted with DCM (2 x 10 vol). The combined DCM layers were dried over Na2SO4 and treated with activated carbon (20 wt%) and Silica Thiol (40 wt% at RT for 16 h. The mixture was filtered and washed with DCM (2 x 2.5 vol). The resulting filtrate was concentrated to ~2 vol, diluted with ACN (5 vol), and heated to 50 °C for 6 h. The resulting slurry was cooled to RT, filtered, washed with ACN (2 x 1.5 vol) and dried under vacuum to afford 500 g (69%) of Compound 3 (97.1% AUC by HPLC) as a light yellow solid.

[0205] Step 3 : Preparation of Compound 4

[0206] A mixture of Compound 3 (520 g) was combined with dioxane (2 vol) and HC1 in dioxane (10 eq) and held at RT for 8 h. The mixture was concentrated to ~2 vol and diluted with ACN (10 vol). The resulting slurry was held at RT for 16 h, filtered, washed with ACN (2 x 2 vol) and dried under vacuum at 40 °C to afford 637 g (>100%) of crude Compound 4-3HC1 (95.5% AUC by HPLC) as a yellow solid.

[0207] Step 4: Preparation of Compound 5

[0208] To a mixture of Compound 4-3HC1 (600 g) in DMSO (10 vol) was added K3PO4 (3.0 eq) and K2HPO4 (2.0 eq) followed by Compound 4b (0.83 eq) at RT. The reaction mixture was held at RT for 16 h and monitored by LC-MS. The reaction mixture was diluted with water (50 vol)Attomey Docket No. 62619-735601 to afford a slurry. The slurry was filtered, washed with water (2 x 1.5 vol) and dried under vacuum at 40 °C to afford 435 g of crude Compound 5. The solids were combined with 1 :2 DCM / MeOH (30 vol) and heated to 40 °C for 16 h. The mixture was cooled to RT, filtered, washed with 1 :2 DCM / MeOH (2 x 1.5 vol) and dried under vacuum at 40 °C to afford 300 g of Compound 5 (95.9% AUC by HPLC) as a yellow solid. The batch was further purified by SiO? chromatography to afford 210 g (43%) of Compound 5 (97.1% AUC by HPLC) as a yellow solid.

[0209] Note: the DCM / MeOH mother liquor was concentrated to dryness and further purified by SiO? chromatography to afford 60 g (12%) of Compound 5 with an HPLC purity of 96.5%.

[0210] Step 5: Preparation of Compound 6

[0211] To a solution of maleic acid (1.1 eq) in EtOH (20 vol) at 70 °C was added Compound 5 (210 g + 60 g). The reaction mixture was held at 70 °C for 40 h. The mixture was cooled to RT, filtered and washed with EtOH (2 x 4 vol). The solids were dried under vacuum at 40 °C for 6 h and then combined with MeOH (15 vol) at 65 °C for 16 h. The mixture was cooled to RT, filtered and washed with MeOH (2 x 2.5 vol) and dried under vacuum at 40 °C to afford 257 g (80%) of Compound 6 (98.2% by HPLC) as a light yellow solid.Batch 2: Experimental Procedures for Compound 6

[0212] Step 1 and Step 2: Preparation of Compound 3

[0213] To a solution of Compound 1 (950 g) in dioxane (10 vol) was added KOAc (2.0 eq) and bis(pinacolato)diboron (1.2 eq) at 25 °C. The mixture was thoroughly purged with nitrogen and Pd(dppf)C12'DCM (0.075 eq) was added. The mixture was heated to 100 °C for 8 h when an LC-MS analysis indicated Compound 1 no longer remained. The reaction was cooled to 60 °C and Compound 2a (1.5 eq), CS2CO3 (1.5 eq) and IPA (5 vol) were added. The mixture was thoroughly purged with nitrogen, Pd(dppf)C12'DCM (0.1 eq) was added and the mixture was heated to 80 °C for 16 h when an LC-MS analysis indicated the reaction was complete. The mixture was cooled to 40 °C, filtered and washed with EtOAc (5 vol). The filtrate was concentrated to ~3 vol and diluted with EtOAc (10 vol) and 0.3 N HC1 (18 vol) and held for 0.5 h at RT. The phases were separated and the aqueous phase was washed with EtOAc (2 x 10 vol). The aqueous phase was adjusted to pH ~9 using aq. K2CO3 and then extracted with DCM (2 x 10 vol). The combined DCM layers were dried over Na2SO4 and treated with activated carbon (20 wt%) and Silica Thiol (40 wt% at RT for 16 h. The mixture was filtered and washed with DCM (2 x 2.5 vol). The resulting filtrate was concentrated to ~2 vol, diluted with ACN (5 vol) and heated to 50 °C for 6 h. The resulting slurry was cooled to RT, filtered,Attorney Docket No. 62619-735601 washed with ACN (2 x 1.5 vol) and dried under vacuum to afford 720 g (68%) of Compound3 (95.5% AUC by HPLC) as a yellow solid.

[0214] Step 3: Preparation of Compound 4

[0215] Compound 3 (725 g) was combined with IPA (5 vol) and 4 M HC1 in IPA (5 vol) and held at RT for 16 h. The mixture was concentrated to dryness, diluted with water (5 vol) and adjusted to pH 8-9 using K2CO3. The mixture was extracted with 3 : 1 DCM / IPA (2 x 10 vol) and the combined organic phases are concentrated to ~1 vol. The mixture was diluted with MTBE (5 vol), held at RT for 16 h, filtered, washed with MTBE (2 x 2 vol) and dried under vacuum at 40 °C to afford 556 g (92%) of Compound 4 (95.6% AUC by HPLC) as a yellow solid. The solids were slurried in MeOH (5 vol) for 15 h at 50 °C, filtered, washed with MeOH (1 vol) and dried under vacuum at 40 °C for 24 h to afford 510 g (85%) of Compound 4 (96.6% AUC by HPLC) as a yellow solid.

[0216] Step 4: Preparation of Compound 5

[0217] To a mixture of Compound 4 (500 g) in DMA (10 vol) was added K3PO4 (1.2 eq) followed by Compound 4b (1.05 eq) at RT. The reaction mixture was held at RT for 16 h and monitored by HPLC to show <1% of Compound 4 remained. The reaction mixture was diluted with water (70 vol) to afford a slurry. The slurry was filtered, washed with water (2 x 1.5 vol) and dried under vacuum at 40 °C to afford 520 g of crude Compound 5. The solids were combined with 1 :2 DCM / MeOH (20 vol) and heated to 40 °C for 16 h. The mixture was cooled to RT, filtered, washed with 1 :2 DCM / MeOH (2 x 1.5 vol) and dried under vacuum at 40 °C to afford 455 g (75%) of Compound 5 (97.2% AUC by HPLC) as a yellow solid.

[0218] Step 5: Preparation of Compound 6

[0219] A mixture of Compound 5 (450 g) and maleic acid (1.1 eq) in 3:7 DMSO / 2-MeTHF (10 vol) at 50 °C was added to a suspension of Compound 6 seeds (4.5 g) in EtOH (20 vol) over a period of 10 h at 50 °C. The resulting solution was cooled to 0 °C over 4 h and held for 30 h. The mixture was heated to 50 °C over 1.5 h, held for 2 h, cooled to 0 °C over 4 h and held for4 h. The slurry was filtered, washed with EtOH (3 vol) and dried under vacuum at 40 °C to afford 445 g (81%) of Compound 6 (98.4% by HPLC) as a light yellow solid.Attorney Docket No. 62619-735601

[0220] Scheme 5. Synthesis of Compound 6: Selected ConditionsAttorney Docket No. 62619-735601Step 1 + Step 2: Synthesis of Compound 3:

[0221] Scheme 6. Synthesis of Compound 3 by Step 1 + Step 2Compound 3

[0222] Selected Conditions from High-Throughput Screening of Step 1 + Step 2Attorney Docket No. 62619-735601

[0223] Selected Conditions for Step 1 + Step 2

[0224] Step 1 + Step 2: Kilogram-Scale Synthetic ProcedureAttorney Docket No. 62619-735601Attorney Docket No. 62619-735601Attorney Docket No. 62619-735601Attorney Docket No. 62619-735601Step 1 + Step 2: Kilogram-Scale Synthesis: Selected Impurities in Compound 3 WetCakeAttorney Docket No. 62619-735601Step 3: Synthesis of Compound 4:

[0225] Scheme 7. Synthesis of Compound 4 by Step 3Attorney Docket No. 62619-735601Step 3: Kilogram-Scale Synthetic ProcedureAttorney Docket No. 62619-735601Attorney Docket No. 62619-735601Step 3: Kilogram-Scale Synthesis: Selected Impurities in Compound 3 Wet CakeStep f: Synthesis of Compound 4b:

[0226] Scheme 8. Synthesis of Compound 4b by Step fStep fCompound 4a Compound 4bCompound 4b was prepared from compound 4a at a 10.2 kg scale to produce 5.77 kg ofCompound 4b with a 99.55% HPLC purity and 78% molar yield.Step f: Kilogram-Scale Synthetic ProcedureAttorney Docket No. 62619-735601Attorney Docket No. 62619-735601Attorney Docket No. 62619-735601Step 4: Synthesis of Compound 5:

[0227] Scheme 9. Synthesis of Compound 5 by Step 4Step 4: Kilogram-Scale Synthetic ProcedureAttorney Docket No. 62619-735601Attorney Docket No. 62619-735601Summary of Step 4 and Subsequent Purification with DMA1. 19.1 kg Compound 4 was converted to Compound 5 in plant.2. After 6 vol water added, residual Compound 5 in supernatant was 0.1%w / w, resulting in ~2% yield loss. Purity of the wet cake was 98.55%. After rinsing with 43 kg DMA / H2O=2 / 1, 35.15 kg wet cake was obtained with 98.8% purity.3. After the wet cake was re-slurried in water and dried, 24.1 kg dried cake was obtainedAttorney Docket No. 62619-735601 with KF<0.1% w / w. Purity was 98.7%.4. After purification in DMA, 20.7 kg wet cake has a purity of 99.5%. (l,3-bis(l-(4-(2-(2- aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)urea = 0.23%).5. After drying, 15.94 kg product was obtained. KF was 0.1% w / w, DMA was 0.21% w / w. Purity was 99.5%, assay was 99.4% w / w. Isolated yield = 70%.

[0228] Effect of Water Content: Purification of Compound 5 in DMA eliminated impurities most efficiently when Compound 5 exhibited NMT 30% w / w water content. Purification of Compound 5 with higher water content was less efficient at purging most impurities. Purification of Compound 5 is efficient with <5% w / w water and most efficient with <1% w / w water.Procedure for Purification of Compound 5 in DMAAttorney Docket No. 62619-735601Impurity Profiles of Compound 5 and Major Identified Impurities Throughout DMAPurification (Purity (%) determined by HPLC)Attorney Docket No. 62619-735601Attorney Docket No. 62619-735601

[0229] Note: Imp4-8 (shown below) was typically present in quantities of <0.2%, and often <0.05%, in Compound 5 as a crude starting solid and after purification in DMA.Attorney Docket No. 62619-735601Step 5: Synthesis of Compound 6:

[0230] Scheme 10. Synthesis of Compound 6 by Step 5Step 5Compound 5 Compound 6Step 5: Kilogram-Scale Synthetic ProcedureAttorney Docket No. 62619-735601Attorney Docket No. 62619-735601Attorney Docket No. 62619-735601Attorney Docket No. 62619-735601Table 5. NMR Characterization Data for Selected Compounds:Attorney Docket No. 62619-735601Attorney Docket No. 62619-735601

[0231] Summary of the Kilogram-Scale synthesis of Compound 6Attorney Docket No. 62619-735601

[0232] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

Attorney Docket No. 62619-735601CLAIMSWe claim:

1. A process for preparing tert-butyl (l-(4-((3-nitro-6-chloro-pyridin-2-yl) amino)benzyl)piperidin-4-yl)carbamate (Compound D):(Compound D) comprising contacting a compound having the structure:(tert-butyl (l-(4-aminobenzyl) piperidin-4-yl) carbamate; Compound C) with a compound having the structure:(2,6-dichloro-3-nitro-pyridine; Compound Cl) and a base in the presence of a solvent.

2. The process of claim 1, wherein the base is selected from N,N-diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, potassium carbonate, trisodium phosphate, tripotassium phosphate, disodium phosphate, dipotassium phosphate, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), tetramethylguanidine, tributylamine, 2,6-lutidine, 2,4,6-collidine, or a combination of two or more thereof.

3. The process of any one of claims 1-2, wherein the base is DIEA or sodium bicarbonate.

4. The process of any one of claims 1-3, wherein the base is sodium bicarbonate.

5. The process of any one of claims 1-4, wherein the solvent is dioxane.

6. The process of any one of claims 1-5, wherein Compound D has a chemical purity of 95% or more.

7. The process of any one of claims 1-6, wherein Compound D has a chemical purity of 96% or more.

8. The process of any one of claims 1-7, wherein Compound D has a chemical purity of 97% or more.Attorney Docket No. 62619-7356019. The process of any one of claims 1-8, wherein Compound D has a chemical purity of 98% or more.

10. The process of any one of claims 1-9, wherein Compound D has a chemical purity of 99% or more.

11. The process of any one of claims 1-10, wherein Compound D has a chemical purity of 99.5% or more.

12. The process of any one of claims 1-11, wherein the compound with the structure:(Compound C) is prepared by reducing a compound having the structure:(Compound B).

13. The process of claim 12, wherein the reduction is conducted in a solvent with a metal and a Bronsted-Lowry acid.

14. The process of claim 13, wherein the solvent comprises an alcohol and water, DMSO and water, or DMF and water.

15. The process of any one of claims 13-14, wherein the solvent is EtOH and water.

16. The process of any one of claims 13-15, wherein the metal comprises Fe, Sn, or Zn.

17. The process of claim 16, wherein the metal is Fe.

18. The process of any one of claims 13-17, wherein the Bronsted-Lowry acid is NH4CI.

19. The process of any one of claims 12-18, wherein the compound with the structure:JOTNHBOC (Compound B) is prepared by a process comprising contacting a compound having the structure: nr^2N(Compound A) with a compound having the structure:(Compound Al) in the presence of a base and a solvent.

20. The process of claim 19, wherein the base is selected from N-diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, potassium carbonate, or a combination of two or more thereof.Attorney Docket No. 62619-73560121. The process of claim 19 or 20, wherein the base is TEA or potassium carbonate.

22. The process of any one of claims 19-21, wherein the base is potassium carbonate.

23. The process of any one of claims 19-22, wherein the solvent is selected from acetone, tetrahydrofuran (THF), acetonitrile (ACN), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dimethylformamide (DMF), or a combination of two or more thereof.

24. The process of any one of claims 19-23, wherein the solvent is acetone.

25. A process for preparing tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (Compound 1):(Compound 1), comprising contacting a compound having the structure:(tert-butyl (l-(4-((3-amino-6-chloropyri din-2 -yl)amino)benzyl)piperidin-4-yl)carbamate;Compound E) with a compound having the structure: , H2N ^=0(2-aminonicotinaldehyde; Compound El) and an oxidizing agent in the presence of a solvent.

26. The process of claim 25, wherein the oxidizing agent is an Fe (III) salt, H2O2, Na2S20s,NaClO, oxone, MnCE, DDQ, or Mn(OAc)3.

27. The process of claim 25 or 26, wherein the oxidizing agent is NH4Fe(SO4)2"12H2O or FeCh.

28. The process of claim 25 or 26, wherein the oxidizing agent is NFUFe^O^nEEO.

29. The process of any one of claims 25-28, wherein the solvent is DMF, DMSO, DMA, NMP, n-BuOH, toluene, dioxane, IP A, t-BuOH, water, or a combination thereof.

30. The process of any one of claims 25-29, wherein the solvent is isopropyl alcohol (IP A).Attorney Docket No. 62619-73560131. The process of any one of claims 25-30, wherein Compound 1 has a chemical purity of 95% or more.

32. The process of any one of claims 25-31, wherein Compound 1 has a chemical purity of 96% or more.

33. The process of any one of claims 25-32, wherein Compound 1 has a chemical purity of 97% or more.

34. The process of any one of claims 25-33, wherein Compound 1 has a chemical purity of 98% or more.

35. The process of any one of claims 25-34, wherein Compound 1 has a chemical purity of 99% or more.

36. The process of any one of claims 25-35, wherein Compound 1 has a chemical purity of 99.5% or more.

37. The process of any one of claims 25-36, wherein the compound with the structure:(Compound E) is prepared by a process comprising contacting a compound having the structure:(Compound D) with an organocatalyst and reducing agent in the presence of a solvent.

38. The process of claim 37, wherein the organocatalyst comprises bipyridyl (4,4’ -bipyridine).

39. The process of claim 37 or claim 38, wherein the reducing agent comprises tetrahydroxy diborane.

40. The process of any one of claims 37-39, wherein the solvent is methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IP A), water, or a combination of two or more thereof.

41. The process of any one of claims 37-40, wherein the solvent is isopropyl alcohol (IP A).

42. A process for preparing tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (Compound 3):Attorney Docket No. 62619-735601(Compound 3), comprising reacting a compound having the structure:(Compound 1), a boron-containing heteroaryl compound, a palladium catalyst, and a base in the presence of a solvent.

43. The process of claim 42, wherein the palladium catalyst is selected from Pd(OAc)2, Pd(PPhs)4, and Pd(dppf)C12'DCM.

44. The process of claim 42 or 43, wherein the boron-containing heteroaryl compound is a boronic acid, boronate ester, or trifluoroborate.

45. The process of any one of claims 42-44, wherein the boron-containing heteroaryl compound is selected from:Attorney Docket No. 62619-73560146. The process of claim 45, wherein the boron-containing heteroaryl compound is47. The process of any one of claims 42-46, wherein the base is selected from cesium carbonate, potassium carbonate, potassium phosphate, DIEA, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 2,6-lutidine, TEA, sodium tert-butoxide, or a combination of two or more thereof.

48. The process of any one of claims 42-47, wherein the solvent is selected from DMF, dioxane, dimethylacetamide (DMA), toluene, / / -butanol, N-Methyl-2-pyrrolidone (NMP), tetrahydrofuran, or a combination of two or more thereof.

49. A process for preparing tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (Compound 3):(Compound 3), comprising reacting a compound having the structure:(Compound 1)Attorney Docket No. 62619-735601 with a borylation reagent, a first base, and a first palladium catalyst in the presence of a first solvent to yield a compound having the structure:(tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)carbamate; Compound 2); and reacting Compound 2 with 2-bromo-5-fluoropyridine (Compound 2a), a second base, and a second palladium catalyst in the presence of a second solvent.

50. The process of claim 49, wherein the borylation reagent is pinacolborane, bis(pinacolato)diboron or bis(catecholato)diborane.

51. The process of claim 49 or 50, wherein the borylation reagent is bis(pinacolato)diboron.

52. The process of any one of claims 49-51, wherein the first palladium catalyst and the second palladium catalyst are independently selected from Pd(OAc)2, Pd(PPhs)4, Pd(dppf)C12'DCM, or Pd2(dba)s; each optionally further comprising an exogenous ligand.

53. The process of any one of claims 49-52, wherein the first palladium catalyst and the second palladium catalyst is Pd(dppf)C12'DCM.

54. The process of any one of claims 49-52, wherein the first palladium catalyst is Pd(dppf)Cl2-DCM.

55. The process of any one of claims 49-52 or 54, wherein the second palladium catalyst is generated in-situ from Pd2(dba)s and Ad2(n-Bu)P.

56. The process of any one of claims 49-55, wherein the first base and the second base are independently selected from potassium acetate, potassium pivalate, cesium carbonate, potassium carbonate, potassium phosphate, DIEA, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 2,6-lutidine, TEA, sodium tert-butoxide, or a combination of two or more thereof.

57. The process of any one of claims 49-56, wherein the first base is potassium acetate or potassium pivalate.

58. The process of any one of claims 49-56, wherein the second base is cesium carbonate.Attorney Docket No. 62619-73560159. The process of any one of claims 49-58, wherein the first solvent and the second solvent are independently selected from DMF, dioxane, dimethylacetamide (DMA), toluene, / / -butanol, N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, 2-methyl tetrahydrofuran, water, or a combination of two or more thereof.

60. The process of any one of claims 49-59, wherein the first solvent and the second solvent are independently selected from dioxane, 2-methyl tetrahydrofuran, water, or a combination thereof.

61. The process of any one of claims 49-60, wherein Compound 3 has a chemical purity of 95% or more.

62. The process of any one of claims 49-61, wherein Compound 3 has a chemical purity of 96% or more.

63. The process of any one of claims 49-62, wherein Compound 3 has a chemical purity of 97% or more.

64. The process of any one of claims 49-63, wherein Compound 3 has a chemical purity of 98% or more.

65. The process of any one of claims 49-64, wherein Compound 3 has a chemical purity of 99% or more.

66. The process of any one of claims 49-65, wherein Compound 3 has a chemical purity of 99.5% or more.

67. The process of any one of claims 49-66, wherein Compound 2 has a chemical purity of 95% or more.

68. The process of any one of claims 49-67, wherein Compound 2 has a chemical purity of 96% or more.

69. The process of any one of claims 49-68, wherein Compound 2 has a chemical purity of 97% or more.

70. The process of any one of claims 49-69, wherein Compound 2 has a chemical purity of 98% or more.

71. The process of any one of claims 49-70, wherein Compound 2 has a chemical purity of 99% or more.

72. The process of any one of claims 49-71, wherein Compound 2 has a chemical purity of 99.5% or more.

73. The process of any one of claims 49-72, wherein Compound 3 is substantially free of impurities, wherein the impurity comprises:Attorney Docket No. 62619-73560174. A process for the preparation of 3-(3-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-5-(5- fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Compound 4):(Compound 4), or a salt thereof, comprising contacting a compound having the structure:Attorney Docket No. 62619-735601(tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)carbamate; Compound 3) with an acid in the presence of a solvent.

75. The process of claim 74, wherein the acid is selected from HC1, HNO3, H2SO4, HBr, H3PO4, HF, HI, or a combination of two or more thereof.

76. The process of any one of claims 74-75, wherein the acid is HC1.

77. The process of any one of claims 74-76, wherein the solvent is selected from dichloromethane, ethyl acetate, 2-methyl tetrahydrofuran, methyl tert-butyl ether (MTBE), isopropyl acetate, isopropyl alcohol, methanol, dioxane, water, or a combination of two or more thereof.

78. The process of any one of claims 74-77, wherein the solvent is isopropyl alcohol or methanol.

79. The process of any one of claims 74-77, wherein the solvent is dichloromethane, water, or a combination thereof.

80. The process of any one of claims 74-79, wherein Compound 4 has a chemical purity of 95% or more.

81. The process of any one of claims 74-80, wherein Compound 4 has a chemical purity of 96% or more.

82. The process of any one of claims 74-81, wherein Compound 4 has a chemical purity of 97% or more.

83. The process of any one of claims 74-82, wherein Compound 4 has a chemical purity of 98% or more.

84. The process of any one of claims 74-83, wherein Compound 4 has a chemical purity of 99% or more.

85. The process of any one of claims 74-84, wherein Compound 4 has a chemical purity of 99.5% or more.Attorney Docket No. 62619-73560186. A process for the preparation of 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)- 3J / -imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (Compound 5)(Compound 5) comprising contacting a compound having the structure:(3-(3-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine; Compound 4), or a salt thereof, with a compound having the structure:and a base in the presence of a solvent.

87. The process of claim 86, wherein the solvent is selected from dioxane, dimethylacetamide (DMA), N-Methyl-2-pyrrolidone (NMP), DMSO, or a combination thereof.

88. The process of claim 86, wherein the solvent is dimethylacetamide (DMA).

89. The process of any one of claims 86-88, wherein the base is K3PO4, K2HPO4, or a combination thereof.

90. The process of any one of claims 86-89, wherein the base is a K3PO4.Attorney Docket No. 62619-73560191. The process of any one of claims 86-90, further comprising recrystallization of Compound 5 from N,N-dimethylacetamide (DMA).

92. The process of any one of claims 86-91, wherein Compound 5 has a chemical purity of 95% or more.

93. The process of any one of claims 86-92, wherein Compound 5 has a chemical purity of 96% or more.

94. The process of any one of claims 86-93, wherein Compound 5 has a chemical purity of 97% or more.

95. The process of any one of claims 86-94, wherein Compound 5 has a chemical purity of 98% or more.

96. The process of any one of claims 86-95, wherein Compound 5 has a chemical purity of 99% or more.

97. The process of any one of claims 86-96, wherein Compound 5 has a chemical purity of 99.5% or more.

98. The process of any one of claims 86-91, wherein Compound 5 is substantially free of impurities, wherein the impurity comprises at least one compound selected from the group consisting of:Attorney Docket No. 62619-73560199. The process of any one of claims 86-98, wherein the compound with the structure:CN(Compound 4b) is prepared by a process comprising contacting a compound having the structure:(Compound 4a) with NaCN and a phase transfer catalyst in the presence of a solvent.

100. The process of claim 99, wherein the phase transfer catalyst is tetrabutylammonium bromide.

101. The process of claim 99 or claim 100, wherein the solvent is selected from dichloromethane, water, or a combination thereof.

102. A process for the preparation of 4-((l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)- 3J / -imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile maleate (Compound 6)Attorney Docket No. 62619-735601comprising contacting a compound having the structure:(4-((l-(4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3J / -imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; Compound 5) with maleic acid in the presence of a solvent.

103. The process of claim 102, wherein the solvent is selected from DMSO, an ether, an alcohol, or a combination thereof.

104. The process of claim 102 or claim 103, wherein the solvent is selected from DMSO, 2-methyl tetrahydrofuran, EtOH, or a combination thereof.

105. The process of any one of claims 102-104, wherein Compound 6 has a chemical purity of 95% or more.

106. The process of any one of claims 102-105, wherein Compound 6 has a chemical purity of 96% or more.

107. The process of any one of claims 102-106, wherein Compound 6 has a chemical purity of 97% or more.

108. The process of any one of claims 102-107, wherein Compound 6 has a chemical purity of 98% or more.Attorney Docket No. 62619-735601109. The process of any one of claims 102-108, wherein Compound 6 has a chemical purity of 99% or more.

110. The process of any one of claims 102-109, wherein Compound 6 has a chemical purity of99.5% or more.

111. A compound having a structure selected from:or a salt, solvate, or deuteroisotope thereof.

112. The compound of claim 111, wherein the compound has a structure selected from:Attorney Docket No. 62619-735601, or a salt, solvate, or deuteroisotope thereof.

Images