WO2012078802A1 - PREPARATION OF SUBSTITUTED-4,5-DIHYDROPYRROLO[4,3,2-de][2,6]NAPHTHYRIDIN-3(1H)-ONES - Google Patents

Abstract

Disclosed are materials and methods for preparing substituted 4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-ones of formula (1), Compounds of formula (1) inhibit one or more members of the Janus Kinase (JAK) family of cytoplasmic protein tyrosine kinases, and are useful for treating disorders, diseases, and conditions associated with the immune system, inflammation, and abnormal cell growth.

Description

PREPARATION OF SUBSTITUTED 4,5-DIHYDROPYRROLO[4,3,2- e][2,6]NAPHTHYRIDIN-3(lH)-ONES

FIELD OF THE INVENTION

[0001] This invention relates to materials and methods for preparing substituted 4,5- dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-ones, which inhibit one or more members of the Janus Kinase (JAK) family of cytoplasmic protein tyrosine kinases. Such inhibitors are useful for treating disorders, diseases, and conditions associated with the immune system, inflammation, and abnormal cell growth.

BACKGROUND OF THE INVENTION

[0002] Janus Kinase (JAK) is a family of cytoplasmic protein tyrosine kinases, which include JAK1 , JAK2, JAK3, and TYK2 isoforms. Each of the JAK iso forms is selective for receptors of certain cytokines, though multiple JAK isoforms may be affected by particular cytokine or signaling pathways, including the pathways for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Phosphorylated JAK kinases bind various Signal Transducer and Activator of Transcription (STAT) proteins. STAT proteins are DNA-binding proteins activated by phosphorylation of tyrosine residues and function both as signaling molecules and transcription factors and bind to specific DNA sequences of promoters of cytokine- responsive genes. Cytokines modulate inflammatory and immune responses and influence cell differentiation, proliferation, and activation. Abnormal JAK/STAT signaling is observed in a number of disorders, diseases, and conditions associated with the immune system, inflammation, and undesirable cell growth.

[0003] Co-pending patent applications, US 201 1-0136780 Al ("the '780 application") and WO 2010/144486 Al ("the '486 application"), both filed June 8, 2010, describe various JAK inhibitors, including substituted 4,5-dihydropyrrolo[4,3,2-<ie][2,6]naphthyridin-3(lH)- ones. These compounds may be used to treat a number of disorders, conditions, and diseases involving the immune system, inflammation, and abnormal cell growth, including allergic rhinitis, allergic asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, immune thrombocytopenic purpura, amyotrophic lateral sclerosis, organ transplant rejection, chronic obstructive pulmonary disease, thrombosis, hematological malignancies, such as acute myeloid leukemia, B-cell chronic lymphocytic leukemia, B-cell lymphoma, and T-cell lymphoma, as well as epithelial cancers, such as small cell lung cancer, non-small cell lung cancer, pancreatic cancer, and colon cancer. [0004] The '780 and '486 applications describe useful methods for preparing substituted 4,5-dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-ones at laboratory scale. However, some of these methods may be problematic for pilot- or full-scale production because of efficiency or cost concerns. Thus, improved methods for preparing substituted 4,5- dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-ones would be desirable.

SUMMARY OF THE INVENTION

[0005] The present invention provides comparatively efficient and cost-effective methods for preparing compounds of formula 1 ,

or pharmaceutically acceptable salts thereof, wherein

R¹ is selected from optionally substituted C₃_₈ cycloalkyl, optionally substituted C₃_₆

heterocycloalkyl, optionally substituted C_6-14 aryl, optionally substituted C_1-10 heteroaryl, and optionally substituted Ci_₆ alkyl; and

R² is selected from hydrogen, halo, and Ci_₄ alkyl.

[0006] One aspect of the present invention provides a method for preparing compounds of formula 1 , the method comprising:

(a) reacting a compound of formula 5

with a compound of formula 6,

R¹-NH₂

6

in the presence of a base to give a compound of formula 7,

wherein R¹ in formula 6 and formula 7, and R² in formula 5 and formula 7, are each as defined for formula 1, and X¹ in formula 5 is a leaving group;

(b) reacting the compound of formula 7 under amide bond-forming conditions; and

(c) optionally converting the compound of formula 1 to a pharmaceutically acceptable salt.

[0007] Another aspect of the present invention provides a method for preparing compounds of formula 1, the method comprising:

(a) reacting a compound of formula 11

1 1

with CO in the presence of a palladium catalyst and a base, wherein R¹ and R² in formula 11 are each as defined for formula 1 , R³ is selected from hydrogen and an amine protective group, and X² in formula 11 is halo;

(b) optionally removing the amine protective group; and

(c) optionally converting the compound of formula 1 to a pharmaceutically acceptable salt.

[0008] Another aspect of the invention provides intermediate compounds used in the methods for preparing the compounds of formula 1.

DETAILED DESCRIPTION OF THE INVENTION

[0009] Unless otherwise indicated, this disclosure uses definitions provided below. Some of the definitions and formulae may include a dash ("-") to indicate a bond between atoms or a point of attachment to a named or unnamed atom or group of atoms. Other definitions and formulae may include an equal sign ("=") or an identity symbol ("≡") to indicate a double bond or a triple bond, respectively. Other formulae may include one or more wavy bonds (" ,"). When attached to a stereogenic center, the wavy bonds refer to both stereoisomers, either individually or as mixtures. Likewise, when attached to a double bond, the wavy bonds indicate a Z-isomer, an E-isomer, or a mixture of Z and E isomers. Some formulae may include a dashed bond " " to indicate a single or a double bond.

[0010] The term "substituted," when used in connection with a chemical substituent or moiety {e.g., an alkyl group), means that one or more hydrogen atoms of the substituent or moiety have been replaced with one or more non-hydrogen atoms or groups, provided that valence requirements are met and that a chemically stable compound results from the substitution.

[0011] The terms "about" or "approximately," when used in connection with a

measurable numerical variable, refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval for the mean) or within ±10 percent of the indicated value, whichever is greater.

[0012] The term "C₂_₄ alkenyl" refers to a straight or branched alkenyl chain having from two to four carbon atoms and one or more carbon-carbon double bonds, and includes ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, and the like.

[0013] The term "Ci_₄ alkyl" refers to a straight or branched alkyl chain having from one to four carbon atoms.

[0014] The term "optionally substituted Ci_₄ alkyl" refers to a Ci_₄ alkyl optionally having from 1 to 5 substituents independently selected from the group consisting of amino, Ci_₇ amido, Ci_₈ alkylamino, C₂_₄ alkenyl, Ci_₄ alkoxy, Ci_₄ thioalkoxy, Ci_9 amide, Ci_₅

oxycarbonyl, cyano, C₃_₈ cycloalkyl, C₃_₈ cycloalkoxy, halo, hydroxy, oxo, Ci_₈ sulfonyl, optionally substituted C_1-10 heteroaryl, optionally substituted C₃_₆ heterocycloalkyl, optionally substituted C_1-10 heteroaryl, and optionally substituted phenyl.

[0015] The term "Ci_₆ alkyl" refers to a straight or branched alkyl chain having from one to six carbon atoms.

[0016] The term "optionally substituted Ci_₆ alkyl" refers to a Ci_₆ alkyl optionally having from 1 to 7 substituents independently selected from the group consisting of amino, Ci_₇ amido, Ci_₈ alkylamino, C₂_₄ alkenyl, Ci_₄ alkoxy, Ci_₄ thioalkoxy, C_1-14 amide, Ci_₅

oxycarbonyl, cyano, C₃_₈ cycloalkyl, C₃_₈ cycloalkoxy, halo, hydroxy, oxo, Ci_₈ sulfonyl, optionally substituted C_1-10 heteroaryl, optionally substituted C₃_₆ heterocycloalkyl, optionally substituted C_1-10 heteroaryl, and optionally substituted phenyl. [0017] The term "Ci_g sulfonyl" refers to a sulfonyl linked to a Ci_₆ alkyl group,

C₃_8 cycloalkyl, or an optionally substituted phenyl.

[0018] The term "Ci_₄ alkoxy" refers to a Ci_₄ alkyl attached through an oxygen atom.

[0019] The term "optionally substituted Ci_₄ alkoxy" refers to a Ci_₄ alkoxy optionally having from 1 to 6 substituents independently selected from the group consisting of C₂_₄ alkenyl, Ci_₄ alkoxy, Ci_₉ amide, Ci_₅ oxycarbonyl, cyano, C₃_₈ cycloalkyl, halo, hydroxy, optionally substituted C_1-10 heteroaryl, and optionally substituted phenyl.

[0020] The term "Ci_9 amide" refers to an amide having two groups independently selected from the group consisting of hydrogen and Ci_₄ alkyl, e.g., -CONH₂, -CONHCH₃, and -CON(CH₃)₂.

[0021] The term "C_1-14 amide" refers to an amide (a) having two groups attached to the nitrogen atom which are independently selected from hydrogen and optionally substituted Ci_₄ alkyl, e.g., -CONH₂, -CONHCH₃, and -CON(CH₃)₂; or an amide (b) having a hydrogen and a non-hydrogen substituent on nitrogen, wherein the non-hydrogen substituent is selected from optionally substituted Ci_₄ alkyl, optionally substituted Ci_₄ alkoxy, optionally substituted C₃_g cycloalkyl, optionally substituted C₃_₆ heterocycloalkyl, optionally substituted C_6-14 aryl, and optionally substituted C_1-10 heteroaryl, e.g., -CONH- (cyclopentyl), -CONH-(aryl), -CONH-CH₂-(phenyl), and so on.

[0022] The term "Ci_₇ amido" refers to a -NHC(0)R group in which R is Ci_₆ alkyl.

[0023] The term "Ci_₅ carbamoyl" refers to an O- or N-linked carbamate having a terminal Ci_₄ alkyl.

[0024] The term "Ci_₅ ureido" refers to a urea having a Ci_₄ alkyl.

[0025] The term "Ci_g alkylamino" refers to an amino having one or two Ci_₄ alkyl.

[0026] The term "C_6-14 aryl" refers to a monocyclic or polycyclic unsaturated, conjugated hydrocarbon having aromatic character and having six to fourteen carbon atoms, and includes phenyl, biphenyl, indenyl, cyclopentyldienyl, fluorenyl, and naphthyl.

[0027] The term "optionally substituted C_6-14 aryl" refers to a C_6-14 aryl optionally having

1 to 5 substituents independently selected from the group consisting of amino, Ci_g alkylamino, Ci_₇ amido, Ci_₅ carbamoyl, Ci_₆ sulfonylamido, Co_6 sulfonylamino, Ci_₅ ureido, optionally substituted C_1-4 alkyl, optionally substituted Ci_₄ alkoxy, cyano, halogen, hydroxy, nitro, Ci_₅ oxycarbonyl, and C_1-8 sulfonyl.

[0028] The term "Ci_₅ oxycarbonyl" refers to an oxycarbonyl group (-C0₂H) and Ci_₄ alkyl ester thereof. [0029] The term "C3_8 cycloalkyl" refers to an alkyl ring having from three to eight carbon atoms, and includes cyclopropyl, 2-methyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0030] The term "optionally substituted C3-8 cycloalkyl" refers to a C3-8 cycloalkyl optionally having from 1 to 6 substituents independently selected from the group consisting of optionally substituted Ci_₄ alkyl, C₂_₄ alkenyl, Ci_₄ alkoxy, Ci_₉ amide, Ci_₇ amido, Ci_₈ alkylamino, Ci_₅ oxycarbonyl, cyano, C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C_1-10 heteroaryl, and optionally substituted phenyl.

[0031] The term "C3_8 cycloalkoxy" refers to a C3_8 cycloalkyl attached through an oxygen atom.

[0032] The terms "halogen" and "halo" refer to chloro, fluoro, bromo or iodo.

[0033] The term "C3_₆ heterocycloalkyl" refers to a 4 to 10 membered monocyclic saturated or partially (but not fully) unsaturated ring having one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen and sulfur heteroatoms may optionally be oxidized. For example, the term includes azetidine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran, hexahydropyrimidine, tetrahydropyrimidine, dihydroimidazole, and the like.

[0034] The term "optionally substituted C3-6 heterocycloalkyl" refers to a C3-6

heterocycloalkyl optionally substituted on the ring carbons with 1 to 4 substituents independently selected from the group consisting of optionally substituted Ci_₄ alkyl, C₂_₄ alkenyl, Ci_₄ alkoxy, Ci_9 amide, Ci_₇ amido, Ci_s alkylamino, Ci_₅ oxycarbonyl, cyano, C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, and optionally substituted phenyl; and optionally substituted on any ring nitrogen with a substituent selected from the group consisting of optionally substituted Ci_₄ alkyl, C₂_₄ alkenyl, C3-8 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C_1-10 heteroaryl, optionally substituted phenyl, and Ci_s sulfonyl.

[0035] The term "C_1-10 heteroaryl" refers to a five to twelve membered monocyclic and polycyclic having unsaturated, conjugated ring(s) having aromatic character and having one to ten carbon atoms and one or more, typically one to four, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen and sulfur heteroatoms may optionally be oxidized. For example, the term includes azepine, diazepine, furan, thiophene, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, thiazole, thiadiazole, triazole, tetrazole, benzazepine, benzodiazepine, benzofuran, benzothiophene, benzimidazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, quinazoline, thienopyridine, indolizine, imidazopyridine, quinoline, isoquinoline, indole, isoindole, benzoxazole, benzoxadiazole, benzopyrazole, benzothiazole, and the like.

[0036] The term "optionally substituted C_1-10 heteroaryl" refers to a C_1-10 heteroaryl optionally having 1 to 5 substituents on carbon independently selected from the group consisting of amino, Ci_₇ amido, Ci_g alkylamino, Ci_₅ carbamoyl, Ci_₆ sulfonylamido, Co-6 sulfonylamino,Ci_5 ureido, optionally substituted _₄ alkyl, optionally substituted Ci_₄ alkoxy, cyano, halogen, hydroxy, oxo, nitro, Ci_₅ oxycarbonyl, and Ci_g sulfonyl, and optionally having substituents on each nitrogen independently selected from the group consisting of optionally substituted Q_₄ alkyl, Ci_g sulfonyl, optionally substituted C₃-6 heterocycloalkyl, and optionally substituted phenyl.

[0037] The term "oxo" refers to an oxygen atom having a double bond to the carbon to which it is attached to form the carbonyl of a ketone, aldehyde, or amide. It is understood that the oxo can be attached to any available position on the group which has the oxo substituent. For example, an acetyl radical (-C(0)CH₃) is contemplated as an oxo substituted alkyl group and a pryidone radical is contemplated as oxo substituted C_1-10 heteroaryl.

[0038] The term "optionally substituted phenyl" refers to a phenyl group optionally having 1 to 5 substituents independently selected from the group consisting of amino, C₂_₄ alkenyl, Q_₄ alkyl, Ci_₄ alkoxy, Ci_9 amide, Ci_g alkylamino, Ci_₅ oxycarbonyl, cyano, halogen, hydrogen, hydroxy, nitro, Ci_g sulfonyl, and trifluoromethyl.

[0039] The term "Ci_₆ sulfonylamido" refers to a -NHS(0)₂-R group wherein R is Ci_₆ alkyl.

[0040] The term "Co-6 sulfonylamino" refers to a -S(0)₂NH-R group wherein R is selected from the group consisting of hydrogen and Ci_₆ alkyl.

[0041] The term "Ci_₄ thioalkoxy" refers to a Ci_₄ alkyl attached through a sulfur atom.

[0042] The term "leaving group" refers to any group that leaves a molecule during a fragmentation process, including substitution reactions, elimination reactions, and addition- elimination reactions. Leaving groups may be nucleofugal, in which the group leaves with a pair of electrons that formerly served as the bond between the leaving group and the molecule, or may be electro fugal, in which the group leaves without the pair of electrons. The ability of a nucleofugal leaving group to leave depends on its base strength, with the strongest bases being the poorest leaving groups. Common nucleofugal leaving groups include sulfonates, including alkylsulfonates (e.g., mesylate), fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), and arylsulfonates (e.g., tosylate, brosylate, closylate, and nosylate). Others include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides.

[0043] The term "opposite enantiomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule, which may be obtained by inverting all of the stereogenic centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R absolute stereochemical configuration. Likewise, if the reference molecule has S,S absolute stereochemical configuration, then the opposite enantiomer has R,R stereochemical configuration, and so on.

[0044] The term "stereoisomers," when used in connection with a compound with given stereochemical configuration refers to the opposite enantiomer of the compound and to any diastereoisomers, including geometrical isomers (ZIE) of the compound. For example, if a compound has S,R,Z stereochemical configuration, its stereoisomers would include its opposite enantiomer having R,S,Z configuration, and its diastereomers having S,S,Z configuration, R,R,Z configuration, S,R,E configuration, R,S,E configuration, S,S,E configuration, and R,R,E configuration. If the stereochemical configuration of a compound is not specified, then "stereoisomers" refers to possible stereochemical configurations of the compound.

[0045] The phrase "substantially pure stereoisomer" and variants thereof refer to a sample containing a stereoisomer which comprises at least about 95% of the sample.

[0046] The phrase "pure stereoisomer" and variants thereof refer to a sample containing a stereoisomer which comprises at least about 99.5% of the sample.

[0047] The phrase "pharmaceutically acceptable" refers to those substances which are within the scope of sound medical judgment suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit-to-risk ratio, and effective for their intended use.

[0048] The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable organic acids and bases or inorganic acids and bases. Examples of

pharmaceutically acceptable salts include the hydrochloride and mesylate salts. [0049] It is understood that, where the terms defined herein mention a number of carbon atoms, that the mentioned number refers to the mentioned group and does not include any carbons that may be present in any optional substituent(s).

[0050] The following abbreviations and acronyms are used throughout the specification: Ac (acetyl); ACN (acetonitrile); HO Ac (acetic acid); AIBN (azo-bis-isobutyronitrile); aq (aqueous); 9-BBN (9-borabicyclo[3.3.1]nonane); Boc (t-butoxycarbonyl); BOP

(benzotriazol- 1 -yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate); z^'-Bu (isobutyl); n- u (normal butyl); Cbz (carbobenzyloxy); DBU (l ,8-diazabicyclo[5.4.0]un- dec-7-ene); DCC (1 ,3-dicyclohexylcarbodiimide); DCE (dichloroethane); DCM

(dichloromethane); DIPEA (N,N-diisopropylethylamine); DMAc (N,N-dimethylacetamide); DMAP (4-dimethylaminopyridine); DMF (N,N-dimethylformamide); DMB (2,4- dimethoxybenzyl); DMSO (dimethylsulfoxide); DMT-MM (4-(4,6-dimethoxy-l ,3,5-triazin- 2-yl)-4-methylmorpholinium chloride); dppf (l ,l '-bis(diphenylphosphino)ferrocene); EDCI (^-(S-dimethylaminopropy^-AT-ethylcarbodiimide); ee (enantiomeric excess); eq

(equivalents); Et (ethyl); Et₃N (triethyl-amine); EtOAc (ethyl acetate); EtOH (ethyl alcohol); FDPP (pentafluorophenyl diphenylphosphinate); HATU (2-(3H- [1 ,2,3]triazolo[4,5-3]pyridin-3-yl)-l , 1 ,3,3-tetramethyluronium hexafluorophosphate(V)); HBTU (2-(lH-benzo[<i] [ 1 ,2,3]triazol- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate^)); HOAt (l-hydroxy-7-azabenzotriazole); HOBt (lH-benzo[<i][l ,2,3]triazol-l-ol); HODhbt (3-hydroxy-3,4-dihydro-4-oxo-l ,2,3-benzotriazine); IPA (isopropyl alcohol); IPE (isopropylether); z^'-Pr (isopropyl); z^'-PrOAc (isopropyl acetate); LAH (lithium aluminum hydride); LDA (lithium diisopropylamide); Me (methyl); MEK (methylethylketone); MeOH (methyl alcohol); MTBE (methyl tertiary butyl ether); NaOt-Bu (sodium tertiary butoxide); NBS (N-bromosuccinimide); NCS (N-chlorosuccinimide); NIS (N-iodosuccinimide); NMM (N-methylmorpholine); NMP (N-methylpyrrolidone); PE (petroleum ether); Ph (phenyl); Pr (propyl); PyBOP (( lH-benzo[<i] [ 1 ,2,3]triazol- 1 -yloxy)tripyrrolidin- 1 -ylphosphonium hexafluorophosphate(V)); RT (room temperature, about 20°C to 25°C); SEM ((2- (trimethylsilyl)ethoxy)methyl); TATU (2-(3H-[ 1 ,2,3]triazolo[4,5-3]pyridin-3-yl)- 1 , 1 ,3,3- tetramethyluronium tetrafluoroborate); TCEP (tns(2-carboxyethyl)phosphine); TFA

(trifluoroacetic acid); THF (tetrahydrofuran); and Ts (tosyl).

[0051] This disclosure concerns materials and methods for preparing compounds of formula 1 , including compounds specifically named in the specification and claims, and their pharmaceutically acceptable complexes, salts, solvates and hydrates. Compounds of formula 1 include the following embodiments.

[0052] a. One embodiment relates to compounds of formula 1 in which R² is selected from the group consisting of hydrogen, halo, and Ci_₄ alkyl.

[0053] b. Another embodiment relates to compounds of formula 1 in which R² is hydrogen.

[0054] c. Another embodiment relates to compounds of formula 1 in which R² is halo.

[0055] d. Another embodiment relates to compounds of formula 1 in which R² is

Ci_₄ alkyl.

[0056] e. Another embodiment relates to compounds of formula 1 in which R² is methyl.

[0057] f. Another embodiment relates to compounds of formula 1 , and optionally any one of the above embodiments a, b, c, d, and e, in which R¹ in formula 1 is optionally substituted C3-8 cycloalkyl.

[0058] g. Another embodiment relates to compounds of formula 1, and optionally any one of the above embodiments a, b, c, d, and e, in which R¹ in formula 1 is optionally substituted C3-6 heterocycloalkyl.

[0059] h. Another embodiment relates to compounds of formula 1 , and optionally any one of the above embodiments a, b, c, d, and e, in which R¹ in formula 1 is a nitrogen containing C₃_6 heterocycloalkyl substituted on a ring carbon with Ci_₄ alkyl and substituted on a ring nitrogen with optionally substituted Ci_₄ alkyl.

[0060] i. Another embodiment relates to compounds of formula 1 , and optionally any one of the above embodiments a, b, c, d, and e, in which R¹ in formula 1 is optionally substituted C_6-14 aryl.

[0061] j. Another embodiment relates to compounds of formula 1, and optionally any one of the above embodiments a, b, c, d, and e, in which R¹ in formula 1 is optionally substituted C_1-10 heteroaryl.

[0062] k. Another embodiment relates to compounds of formula 1 , and optionally any one of the above embodiments a, b, c, d, and e, in which R¹ in formula 1 is optionally substituted Ci_₆ alkyl.

[0063] 1. Another embodiment relates to compounds of formula 1, and optionally any one of the above embodiments a, b, c, d, and e, in which R¹ in formula 1 is Ci_₆ alkyl having an oxo substituent and an optionally substituted C₃_₆ heterocycloalkyl. [0064] m. Another embodiment relates to compounds of formula 1 , and optionally any one of the above embodiments a, b, c, d, and e, in which R¹ in formula 1 is Ci_₆ alkyl having an oxo substituent and an optionally substituted C₃_₆ heterocycloalkyl attached to the same carbon atom of the Ci_₆ alkyl group.

[0065] n. Another embodiment relates to compounds of formula 1 , and optionally any one of the above embodiments a, b, c, d, and e, in which R¹ in formula 1 is Ci_₆ alkyl substituted with Ci_i4 amide.

[0066] The compounds of formula 1 may be prepared using the techniques described below. Some of the schemes and examples may omit details of common reactions, including oxidations, reductions, and so on, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like), and analytical procedures, which are known to persons of ordinary skill in the art of organic chemistry. The details of such reactions and techniques can be found in a number of treatises, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series edited by Michael B. Smith and others, Compendium of Organic Synthetic Methods (1974 et seq.). Starting materials and reagents may be obtained from commercial sources or may be prepared using literature methods. Some of the reaction schemes may omit minor products resulting from chemical transformations (e.g., an alcohol from the hydrolysis of an ester, C0₂ from the decarboxylation of a diacid, etc.). In addition, in some instances, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

[0067] In some of the reaction schemes and examples below, certain compounds can be prepared using protective groups, which prevent undesirable chemical reaction at otherwise reactive sites. Protective groups may also be used to enhance solubility or otherwise modify physical properties of a compound. For a discussion of protective group strategies, a description of materials and methods for installing and removing protecting groups, and a compilation of useful protective groups for common functional groups, including amines, carboxylic acids, alcohols, ketones, aldehydes, and so on, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0068] Generally, the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification may be carried out at about room temperature (RT) and ambient pressure, but depending on reaction kinetics, yields, and so on, some reactions may be run at elevated pressures or employ higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -78°C to 0°C). Any reference in the disclosure to a stoichiometric range, a temperature range, a pH range, etc., whether or not expressly using the word "range," also includes the indicated endpoints.

[0069] Many of the chemical transformations may also employ one or more compatible solvents, which may influence the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane); aromatic hydrocarbons (e.g., benzene, toluene, xylenes); halogenated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-l-ol, propan-2-ol, butan-l-ol, 2-methyl-propan-l-ol, butan-2-ol, 2-methyl-propan-2- ol, pentan-l-ol, 3-methyl-butan-l-ol, hexan-l-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2- butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-butoxy- ethoxy)-ethanol); ethers (e.g., diethyl ether, di-isopropyl ether, dibutyl ether, 1,2- dimethoxy-ethane, 1 ,2-diethoxy-ethane, l-methoxy-2-(2-methoxy-ethoxy)-ethane, 1- ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane); ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (e.g., formamide, N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydro-thiophene- 1,1, -dioxide); and phosphorus-containing solvents (e.g., hexamethylphosphoric triamide).

7

Scheme I

[0070] Scheme I shows a method for preparing compounds of formula 1. The method includes reducing a carboxylic acid moiety of a pyrrolopyridine nitrile (formula 2) to give a primary alcohol (formula 3). Hydrolyzing the nitrile moiety in formula 3 with an acid (e.g., concentrated HC1 at RT to about 60°C) gives a carboxylic acid (formula 4). The conversion of the primary alcohol in formula 4 to a leaving group X¹ in formula 5 allows for subsequent displacement with an appropriately-substituted amine (formula 6), and reacting the resulting amino acid (formula 7) under amide bond-forming conditions gives the desired N-substituted lactam of formula 1. Though not shown, the compound of formula 1 may be optionally converted to a pharmaceutically acceptable salt. Substituent R¹ in formula 6 and 7, and substituent R² in formula 2, 3, 4, 5, and 7, are each as defined for formula 1.

[0071] As noted above, the method shown in Scheme I includes reducing a carboxylic acid moiety of the pyrrolopyridine nitrile (formula 2) to give a primary alcohol (formula 3). The reduction may be carried out via treatment with a reducing agent, typically in a solvent, and often under mild conditions (e.g., at about 0°to RT). Representative reducing agents and solvents include NaBH₄; BH₃-THF; 9-BBN; LiAlH(OCH₃)₃ in THF; LiAlH₄ in diethyl ether; A1H₃ in THF; (z^'-Bu)₂AlH; and NaAlEt₂H₂. Alternatively, the pyrrolopyridine nitrile (formula 2) may be reacted with 1,1 '-carbonyldiimidazole (e.g., at RT to about 50°C) to give an acyl imidazole intermediate, which is subsequently reacted with NaBH₄ in water (e.g., at about 0°C to RT) to give the primary alcohol in formula 3. In another alternative, the pyrrolopyridine nitrile (formula 2) may be reacted with a chlorinating reagent, such as thionyl chloride, oxalyl chloride, and the like, to give an acid chloride intermediate, which is subsequently reacted with NaBH₄ to give the primary alcohol in formula 3. As described, below, the pyrrolopyridine nitrile (formula 2) may be prepared using the method shown in Scheme IV.

[0072] After the nitrile hydrolysis, the primary alcohol (formula 4) is converted to a leaving group (X¹ in formula 5). Useful leaving groups include halogens (e.g., chloro, bromo, iodo) and sulfonate esters, including alkylsulfonates (e.g., mesylate),

fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), and arylsulfonates (e.g., tosylate, brosylate, closylate, and nosylate). Thus, for example, the primary alcohol (formula 4) may be activated by reaction with methanesulfonyl chloride, /?-toluenesulfonyl chloride, and the like, in the presence of a base (e.g., pyridine) to give a compound of formula 5 in which X¹ is mesylate, tosylate, etc. Similarly, the compound of formula 4 may be reacted with phosphorus tribromide or phosphorus triiodide (generated in situ from a mixture of red phosphorus and iodine) to give the corresponding bromide or iodide. As shown in the Examples, the compound of formula 4 may be reacted with thionyl chloride in the presence of a catalyst (DMF) and a solvent (e.g., DCM) at about 0°C to RT to give the corresponding chloride.

[0073] Following the activation of the primary alcohol, the compound of formula 5 is reacted with an appropriately-substituted amine (formula 6) in the presence of a non- nucleophilic base (e.g., DIPEA, Et₃N, CS₂CO₃, etc.) to give an amino acid (formula 7), The reaction is typically carried out at moderate temperatures (e.g., about RT) in the presence of an aprotic polar solvent, such as DMF or acetonitrile, and optionally in the presence of an alcohol as co-solvent (e.g. EtOH). Appropriately-substituted amines (formula 6) include those in which R¹ in formula 6 is any of the substituents attached to the nitrogen atom of the lactam moiety in the compounds described in Examples 1-88 of co-pending patent applications US 2011-0136780 Al and WO 2010/144486 Al, both of which were filed on June 8, 2010 and are herein incorporated by reference.

[0074] The amino acid (formula 7) is subsequently reacted under amide bond-forming conditions to give the compound of formula 1. Such conditions generally include treatment with a coupling agent to activate the carboxy moiety in situ. The reaction is normally carried out at about RT in an aprotic solvent, such as ACN, DMF, DMSO, toluene, DCM, NMP, THF, and mixtures thereof, and often in the presence of a non-nucleophilic base, such as Et₃N, DIPEA, NMM, etc. Useful coupling agents may include DCC, DMT -MM, FDPP, HATU, HBTU, TATU, BOP, PyBOP, EDCI, diisopropyl carbodiimide, isopropenyl chloroformate, isobutyl chloroformate, N,N-bis-(2-oxo-3-oxazolidinyl)-phosphinic chloride, diphenylphosphoryl azide, diphenylphosphinic chloride, diphenylphosphoryl cyanide, and the like. In addition, the reaction may include an optional additive, such as DMAP,

HODhbt, HOBt, and HOAt, which may accelerate the reaction and/or suppress side reactions (e.g., minimize racemization).

[0075] Scheme II shows another method for preparing compounds of formula 1. The method includes halogenating the 3-position of an lH-pyrrolo[2,3-¾]pyridine (formula 8) via treatment at about RT with one equivalent of N-iodosuccinimide, N-bromosuccinimide or N-chlorosuccinimide, in a polar aprotic solvent, such as ACN, THF or DMF. Following the installation of an optional amine protective group, such as Boc, Cbz, DMB, etc., the resulting heteroaryl halide (formula 9 or formula 10) is reacted with an appropriately- substituted amine (formula 6) to give an aminomethyl-heteroaryl halide (formula 11).

Reaction of the aminomethyl-heteroaryl halide (formula 11) with CO in the presence of a palladium catalyst and a base gives the compound of formula 1 or an amino-protected derivative (not shown). For the latter case, removing the optional amine protective group affords the desired N-substituted lactam of formula 1. See T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000) for a description of useful amine protecting groups, their installation and their removal. Though not shown in Scheme II, the compound of formula 1 may be optionally converted to a pharmaceutically acceptable salt. Substituent R¹ in formula 11 and substituent R² in formula 8, 9, 10, and 11, are each as defined for formula 1. Substituent X² in formula 9, 10, and 11 is halo, particularly iodo or bromo, and substituent R³ in formula 10 and 11 is hydrogen or an amine protective group, such as Boc, Cbz or DMB.

1

Scheme II

[0076] As noted above, the heteroaryl halide of formula 9 or formula 10 is reacted with an appropriately-substituted amine (formula 6) to give an aminomethyl-heteroaryl halide (formula 11). The reductive amination may be carried out under a variety of conditions using a reducing agent, such as sodium borohydride, sodium triacetoxyborohydride, zinc/hydrochloric acid, zinc borohydride, sodium cyanoborohydride, and the like. The reaction is carried out in a solvent, such as MeOH or THF, typically at a temperature of about 0°C to 60°C. When using sodium cyanoborohydride, the reaction is carried out in a solvent, such as THF or dichloromethane or mixtures thereof. Alternatively, the reaction may be carried out by hydrogenation over a catalyst, including palladium, platinum or nickel catalysts. Such hydrogenations are carried out in a suitable solvent such as EtOAc, EtOH, MeOH, isopropanol, and the like, at a pressure which may range from about atmospheric pressure to about 300 psi, and at a temperature that may range from about RT to about 100°C.

[0077] Following reductive amination, the aminomethyl-heteroaryl halide (formula 11) is reacted with CO in the presence of a Pd(0) or Pd(II) catalyst to give, upon amide formation, the compound of formula 1 or an amino-protected derivative. Useful palladium catalysts include (PPh₃)₂PdCl₂, Pd(OAc)₂, and (Ph₃P)₄Pd, and are typically used at substrate to catalyst ratios of about 100: 1 to about 20: 1. The reaction is carried out in the presence of a base, such as Et₃N, Na₂C0₃ or K₃P0₄, which is often used at stoichiometric excess (e.g., 2 or 3 eq). The reaction may be carried out at a pressure that may range from atmospheric pressure to about 100 psi and at a temperature that may range from about 50°C to about 100°C. The carbonylation may employ various solvents, including DMF, THF, toluene, water, and mixtures thereof.

[0078] As can be seen in Scheme II, the compound of formula 1 may alternatively be prepared by reacting the heteroaryl halide (formula 9 or formula 10) with carbon monoxide, which is generated in situ in the presence of a palladium catalyst, to give a formyl- heteroaryl acid (formula 12). Conditions for in situ generation of CO include, for example, the use of lithium formate in the presence of lithium chloride, an acid anhydride, such as acetic anhydride, and a non-nucleophilic base, such as Et₃N, DIPEA, etc. Like the conversion of the compound of formula 10 to the compound of formula 11, reacting the formyl-heteroaryl acid (formula 12) with an appropriately-substituted amine (formula 6) gives, via reductive amination, an amino acid (formula 13), which is then cyclized under amide-bond forming conditions to give the desired compound of formula 1 or an amino- protected derivative. The amide bond- forming conditions are described above in connection with the conversion of the amino acid (formula 7) to the compound of formula 1 in Scheme I. Substituent R¹ in formula 13 and substituent R² in formula 12 and formula 13 are each as defined for formula 1. Substituent R³ in formula 12 and formula 13 is hydrogen or an amine protective group, such as Boc, Cbz or DMB.

[0079] As shown in Scheme II, the compound of formula 12 may alternatively be prepared from the compound of formula 4. The method includes esterifying a carboxylic acid moiety via reaction with R⁵OH, for example, in the presence of an acid catalyst, such as H₂S0₄ or HC1, under reflux conditions. Converting a primary alcohol of the resulting ester (formula 14) to a carbonyl group through reaction with an oxidizing agent, such as Dess-Martin periodinane, gives a formyl-heteroaryl ester (formula 15), which is subsequently hydro lyzed to give the formyl-heteroaryl acid (formula 12 with R³ being H). The ester moiety (formula 15) may be hydro lyzed by treatment with an acid (e.g., HC1 or H₂SO₄) and excess H₂0 to give the acid (formula 12) or by treatment with an aqueous inorganic base (e.g., LiOH, KOH, NaOH, CsOH, Na₂C0₃, K₂C0₃, Cs₂C0₃) to give a base addition salt, which may be treated with an acid to generate the free acid. The ester hydrolysis may be carried out at temperatures ranging from RT to reflux. Substituent R² in formula 4, 14, and 15, are each as defined for formula 1, and substituent R⁵ in formula 14 and formula 15 is Ci_₄ alkyl, particularly methyl or ethyl.

[0080] The compound of formula 8 in Scheme II may be prepared using the method shown in Scheme III. According to the method, treating a hydroxymethyl-heteroaryl nitrile (formula 3) with H₂S0₄ (50%) at elevated temperature (e.g., 70°C) cleaves the nitrile moiety. Reacting the resulting hydroxymethyl-heteroaryl compound (formula 16) with an oxidizing agent, such as Dess-Martin periodinane, or treating the compound (formula 16) under Swern-oxidation conditions, gives the desired formyl-heteroaryl compound

(formula a 1.

3 16 8

Scheme III

[0081] Scheme IV shows a method for preparing the compound of formula 2 in Scheme I. As shown in Scheme IV, a chloro-oxoacetate (formula 17) is reacted with an appropriately- substituted alkoxyethene (formula 18) in the presence of a non-nucleophilic base (e.g., Et₃N) and solvent (e.g., dioxane) at a temperature of about 0°C to about 35°C. The resulting intermediate (formula 19) is subsequently reacted with 5-amino-l-fert-butyl-lH-pyrrole-3- carbonitrile (formula 20) in acetic acid at elevated temperature (about 100°C) to give a tert- butyl protected pyrrolopyridine nitrile (formula 21) and a regioisomer (not shown).

Reaction with A1C1₃ in chlorobenzene at elevated temperature (about 80°C to about 125°C) removes the tert-butyl protective group with concomitant ester cleavage to give the desired acid (formula 2). Substituent R² in formula 2, 18, 19, and 21 are each as defined for formula 1. Substituent R⁴ in formula 17, 19, and 21, and substituent R⁵ in formula 18 and formula 19 are each independently Ci_₄ alkyl, and more particularly, methyl or ethyl.

Scheme IV

[0082] As discussed above, the compound of formula 1 can be converted to a

pharmaceutically acceptable salt. For example, a compound of formula 1 may be reacted with an appropriate acid or base to give the desired salt. Alternatively, a precursor of the compound of formula 1 may be reacted with an acid or base to remove an acid- or base- labile protecting group or to open a lactone or lactam group of the precursor. Additionally, a salt of the compound of formula 1 may be converted to another salt through treatment with an appropriate acid or base or through contact with an ion exchange resin. Following reaction, the salt may be isolated by filtration if it precipitates from solution or may be recovered by evaporation. The degree of ionization of the salt may vary from completely ionized to almost non-ionized.

[0083] Useful salts of the compound of formula 1 may include acid addition salts

(including di-acids) and base addition salts. Pharmaceutically acceptable acid addition salts may include nontoxic salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acids, as well nontoxic salts derived from 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. Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

[0084] Useful base addition salts may include nontoxic salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines. Examples of suitable metal cations may include sodium, potassium, magnesium, calcium, zinc, and aluminum cations. Examples of suitable amines may include arginine, N,1ST- dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, olamine, 2- amino-2-hydroxymethyl-propane-l ,3-diol, and procaine.

[0085] The compounds of formula 1 may exist in both unsolvated and solvated forms, and as other types of complexes besides salts and solvates in which the compound and at least one other component are present in stoichiometric or non-stoichiometric amounts.

Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together. See, e.g., O. Almarsson and M. J. Zaworotko, Chem. Commun. (2004) 17: 1889-1896. For a general review of multi-component complexes, see J. K. Haleblian, J. Pharm. Sci. (1975)

64(8): 1269-88.

[0086] Certain compounds described herein may have stereoisomers. These compounds may exist as single enantiomers (enantiopure compounds) or mixtures of enantiomers (enriched and racemic samples), which depending on the relative excess of one enantiomer over another in a sample, may exhibit optical activity. Such stereoisomers, which are non- superimposable mirror images, possess a stereogenic axis or one or more stereogenic centers (i.e., chirality). Other compounds may be stereoisomers that are not mirror images. Such stereoisomers, which are known as diastereoisomers, may be chiral or achiral (contain no stereogenic centers). They include molecules containing an alkenyl or cyclic group, so that cisltrans (or ZIE) stereoisomers are possible, or molecules containing two or more stereogenic centers, in which inversion of a single stereogenic center generates a

corresponding diastereoisomer. [0087] Unless stated or otherwise clear (e.g., through use of stereobonds, stereocenter descriptors, etc.) the scope of the invention and disclosure generally includes the reference compound and its stereoisomers, whether they are each pure (e.g., enantiopure), substantially pure or mixtures (e.g., enantiomerically enriched or racemic).

[0088] Geometrical {cisl trans) isomers may be separated by conventional techniques such as chromatography and fractional crystallization.

[0089] Individual enantiomers of compounds may be prepared via chiral synthesis from a suitable optically pure precursor or isolated via resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral HPLC. Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable enantiomerically pure compound (e.g., acid or base) to yield a pair of diastereoisomers, each composed of a single enantiomer, which are separated via, say, fractional recrystallization or chromatography. The desired enantiomer is subsequently regenerated from the appropriate diastereoisomer. Often, the desired enantiomer may be further enriched by recrystallization in a suitable solvent (e.g., ACN) when it is it available in sufficient quantity (e.g., typically not much less than about 85% ee, and in some cases, not much less than about 90% ee). For a further discussion of techniques for separating stereoisomers, see E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds (1994).

[0090] The compounds of formula 1 may exist as tautomers, which refer to structural isomers that are interconvertible via a low energy barrier. Tautomeric isomerism

(tautomerism) may take the form of proton tautomerism in which the compound contains, for example, an imino, keto, or oxime group, or valence tautomerism in which the compound contains an aromatic moiety.

EXAMPLES

[0091] The following examples are intended to be illustrative and non-limiting, and represent specific embodiments of the present invention.

[0092] 1H Nuclear magnetic resonance (NMR) spectra were obtained for many of the compounds in the following examples. Characteristic chemical shifts (δ) are given in parts- per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks, including s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), spt (septet) and br (broad). The mass spectra (m/z) were recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). The following abbreviations are used for common solvents: CDCI₃ (deuterochloroform), DMSO-<¾ (deuterodimethylsulfoxide), CD₃OD (deuteromethanol), and THF-<¾

(deuterotetrahydrofuran). "Ammonia" refers to a concentrated solution of ammonia in water possessing a specific gravity of 0.88.

[0093] Where indicated, products of certain preparations and examples are purified by mass-triggered HPLC (e.g., Pump: Waters™ 2525; MS: ZQ™; Software: MassLynx™), flash chromatography or preparative thin layer chromatography (TLC). Preparative HPLC is carried out using either acidic or basic conditions. Acid conditions are typically gradients in Solvent A (water with 0.05% TFA) and Solvent B (acetonitrile with 0.035% TFA); basic conditions are typically gradients in Solvent A (10 mM NH₄HCO₃ in water) and Solvent B (10 mM NH₄HCO₃ in 20/80 (v/v) water/acetonitrile). Preparative TLC is typically carried out on silica gel 60 F254 plates. After isolation by chromatography, the solvent is removed and the product is obtained by drying in a centrifugal evaporator (e.g., Gene Vac™), rotary evaporator, evacuated flask, lyophilizer, etc. Reactions in an inert (e.g., nitrogen) or reactive (e.g., H₂, CO) atmosphere are typically carried out at a pressure of about 1 atmosphere (14.7 psi) or greater (e.g., up to about 100 psi).

[0094] EXAMPLE 1 : l-(tert-Butoxycarbonyl)-4-formyl-5-methyl-lH-pyrrolo[2,3- £]pyridine-3-carboxylic acid

[0095] A. 5-Methyl-lH-pyrrolo[2,3-¾]pyridine-4-carbaldehyde

[0096] 5-Chloro-lH-pyrrolo[2,3- yridine-4-carbaldehyde (100 g) and

trimethylboroxine (156 mL, 2 eq), were slurried in dioxane/water (1.1 L, 9:1). The system was degassed with 3 pump/purge cycles followed by bubbling nitrogen sub-surface for at least 30 minutes. Sodium carbonate (176 g, 3 eq) was added and the reaction mixture was sparged a second time with N₂ for at least 20 minutes. Next, PdCl₂(dppf)^»CH₂Ci₂ (22 g, 5 mol%>) was added and the reaction mixture was degassed by 3 pump/purge cycles prior to being heated to 90°C. After the starting material was consumed, the hot reaction mixture was filtered through silica (400 g) and washed sequentially with dioxane (500 mL), MeOH (500 mL) and EtOAc (500 mL). The filtrates were concentrated to remove the organic solvents and were then slurried in IP A (200 mL) and water (300 mL) for a minimum of 10 minutes. The slurry was cooled to 0-5°C and stirred for 10 minutes. The solids were collected by filtration, washed with IP A/water (300 mL, 1 : 1.5) and dried in a vacuum oven at 40-45°C for 24 hours to give the title compound (62.9 g, 71% crude yield, 88 wt% by NMR). 1H NMR (400 MHz, DMSO-d₆) δ ppm 2.7 (s, 3H), 6.99 (m, 1H), 7.70 (m, 1H), 8.24 (s, 1H), 10.69 (s, 1H), 11.95 (s br, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ ppm 15.04, 99.37, 116.62, 126.18, 129.29, 130.09, 145.07, 149.26, 193.62.

[0097] B. 3-Iodo-5-methyl-lH-pyrr -¾]pyridine-4-carbaldehyde

[0098] 5-M ethyl- lH-pyrrolo[2,3-£]pyridine-4-carbaldehyde (60 g) was slurried in CH₃CN (1.08 L) and N-iodosuccinimide (84.6 g, 1 eq) was added in one portion. After the reaction was deemed complete by HPLC (typically <1 hour) the resulting slurry was filtered to collect the solids, washed with CH₃CN (2 x 20 mL) and dried under vacuum at 30°C to give the title compound (96.1 g, 90% crude yield, 80 wt% by NMR). 1H NMR (400 MHz, DMSO-de δ ppm 2.56 (s, 3H), 8.01 (s, 1H), 8.34 (s, 1H), 11.60 (s, 1H), 12.51 (s, 1H).

[M+H] calc'd for Ci₇Hi₄N₂0₅S, 287; found, 287.

[0099] C. tert- utyl 4-formyl-3-iodo-5-methyl-lH-pyrrolo[2,3-¾]pyridine-l-carboxylate

[0100] 3-Iodo-5-methyl-lH-pyrrolo[2,3-¾]pyridine-4-carbaldehyde (39.6 g, 1 eq) was slurried in THF (200 mL) followed be the addition of Et₃N (23 mL, 1.2 eq) and DMAP (0.18 g, 0.01 eq). Di-tert-butyl dicarbonate (36.7 g, 1.2 eq) was then added and the reaction mixture was stirred at 25°C. After the reaction was deemed complete by HPLC (typically 2 hours), MeOH (370 mL) was added, followed by a slow addition of water (370 mL). The slurry was cooled to 10°C and held for 1 hour. The solids were filtered off, washed with MeOH (370 mL), and dried to give the title compound (44.3 g, 83% crude yield, 98 wt% by NMR). 1H NMR (500 MHz, DMSO- ₆) δ ppm 1.61 (s, 9H), 11.46 (s, 1H), 2.47 (s, 3H), 8.16 (s, 1H), 8.44 (s, 1H). [M+H] calc'd for Ci₄Hi₅IN₂0₃, 387; found 387.

[0101] D. l-(tert-Butoxycarbonyl)-4-formyl-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3- carboxylic acid

[0102] Lithium chloride (3.95 g, 93.0 mmol) and lithium formate monohydrate (7.46 g, 93.0 mmol) were combined in a dry sealed flask under nitrogen. DMF (70 mL), tert-butyl 4- formyl-3-iodo-5-methyl-lH-pyrrolo[2,3-¾]pyridine-l-carboxylate (12.0 g, 31.1 mmol), acetic anhydride (5.87 mL, 62.1 mmol) and palladium acetate (698 mg, 3.11 mmol) were added. Diisopropylethylamine (10.82 mL, 62.1 mmol) was added, and the reaction tube was immediately sealed. The reaction mixture was stirred for 4.5 hours at 28°C. The black mixture was diluted with 20% MeOH/DCM and filtered to remove the black palladium material. The red solution was concentrated and then taken up in 10% MeOH/DCM and washed with 0.1 N citric acid solution. The aqueous layer was extracted with 10%>

MeOH/DCM (2 x). The organic phases were combined, dried over MgS0₄, and

concentrated in vacuo. Purification by silica gel chromatography (8%-10% MeOH/DCM), and then precipitation from cold MeOH and collection by filtration gave the title compound as a pale yellow solid (4.76 g, 50%). 1H NMR (500 MHz, DMSO- ₆) δ ppm 1.63 (s, 9H), 2.43 (s, 3H), 8.39 (s, 1H), 8.46 (s, 1H), 10.75 (s, 1H), 13.11 (s, 1H). [M+H] calc'd for Ci₅Hi₆N₂0₅, 305; found 305.

[0103] EXAMPLE 2: (R)-ierf-Butyl 1 -(3 -cyanoazetidin-l-yl)-3 -methyl- l-oxobutan-2- ylcarbamate

[0104] Method A: To (i?)-2-(tert-Butoxycarbonylamino)-3-methylbutanoic acid (100 g, 460 mmol) in DCM (1.08 L) was added azetidine-3-carbonitrile hydrochloride (54.6 g, 46 mmol), lH-benzo[d][l,2,3]triazol-l-ol (6.22 g, 46.0 mmol), Et₃N (64.2 mL, 460 mmol), and -((ethylimino)methylene)-N3,N3-dimethylpropane- 1 ,3 -diamine hydrochloride (97 g, 506 mmol). The resulting white suspension was stirred at room temperature for 3 hours. The reaction was subsequently quenched with water (360 mL). The organic layer was washed with water (360 mL), concentrated, and dried in a vacuum oven at 40°C for 16 hours. The crude material was suspended in isopropyl acetate (360 mL) at 65°C for 90 minutes. The suspension was cooled and stirred at room temperature for 1 hour. Hexanes (180 mL) were added to the suspension over a 15 minute period, and the reaction mixture was stirred for 2 hours at 0°C. The solid was filtered and washed with isopropyl acetate/hexanes (1 :1, 100 mL) and dried in a vacuum oven at 40°C for 16 hours to give the title compound as a white solid (119.2 g, 92%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 0.75-0.94 (m, 6H), 1.30-1.47 (m, 9H), 1.74-1.95 (m, 1H), 3.64 (m, J=8.0 Hz, 1H), 3.73-3.89 (m, 1H), 4.00 (ddd, J=12.3, 9.7, 6.1 Hz, 1H), 4.15 (dt, J=18.6, 9.3 Hz, 1H), 4.34 (dd, J=8.5, 5.9 Hz, 1H), 4.40-4.60 (m, 1H), 7.05 (dd, J=12.9, 8.3 Hz, 1H). [M+H] calc'd for C₁₄H₂₃N₃O₃, 282; found, 282.

[0105] Method B: A 100 L jacketed reactor was charged with azetidine-3-carbonitrile hydrochloride (2.29 kg, 20.0 mol), HOBt (261 g, 1.7 mol), EDCI (4.08 kg, 26.3 mol), IPA (21.0 L), and NMM (4.5 L, 40.6 mol) via an addition pump, which was rinsed with additional IPA (4.2 L). Next, a solution of (i?)-2-(tert-butoxycarbonylamino)-3- methylbutanoic acid (4.20 kg, 20.0 mol) in IPA (8.4 L) was prepared in a 20 L glass carboy and was added over 1.1 hours with vigorous stirring. An exotherm raised the temperature from 18°C to 30°C. The carboy was rinsed with IPA (8.4 L) and the rinse was transferred into the reactor. After stirring the reaction mixture for 19.5 hours at 20-30°C, water (42.0 L) was added to the reactor while maintaining the temperature at 15-25°C by the addition rate and jacket temperature. The quenched suspension was stirred at 15-25°C for 30 minutes, cooled to 15°C, stirred at 5-15°C for another 30 minutes, and then filtered. The reactor was rinsed with 20% ACN in water (20.0 L) and the rinse was transferred onto the filter. The cake was conditioned for 40 hours under vacuum and then transferred to an oven and dried under reduced pressure at 50°C until a constant weight was achieved. This afforded the title compound as a white powder (3.90 kg, 72%>).

[0106] EXAMPLE 3 : (R)- 1 -(2-Amino-3-methylbutanoyl)azetidine-3-carbonitrile, TFA salt

[0107] Method A : (R)-tert-Butyl 1 -(3 -cyanoazetidin- 1 -yl)-3 -methyl- 1 -oxobutan-2- ylcarbamate (119.2 g, 424 mmol) was dissolved in anhydrous DCM (700 mL). The solution was cooled in an ice bath, and trifluoroacetic acid (326 mL) was added dropwise over the course of 70 minutes. The reaction mixture was stirred at 0°C for 1 hour and at RT for 5 hours. The solution was concentrated in vacuo to an oil. The oil was triturated in diethyl ether (1.6 L) to produce a white precipitate, which was then filtered, washed with ether (300 mL) and dried in vacuo to afford the title compound as a white solid (104.7 g, 89%). 1H NMR (500 MHz, DMSO-d₆) δ ppm 0.86-1.02 (m, 6H), 2.01 (m, 1H), 3.73 (m, 1H), 3.88 (m, 1H), 4.12 (m, 1H), 4.24 (m, 1H), 4.48 (s, 2H), 8.09 (m, 2H). [M+H] calc'd for C₉Hi₅N₃0, 182; found, 182.

[0108] Method B: To a 5 L round bottom flask equipped with a mechanical stirrer and a dry ice-acetone cooling bath was added trifluoroacetic acid (1.94 L) under an atmosphere of nitrogen. The flask was cooled to an internal temperature of -15°C. Anhydrous dimethyl sulfoxide (590 mL) was added slowly over 30 minutes via an addition funnel, while maintaining the internal temperature between -9°C and -18°C. After 15 minutes, (R)-tert- butyl 1 -(3 -cyanoazetidin-l-yl)-3 -methyl- l-oxobutan-2-ylcarbamate (590 g) was added in small portions (10 to 20 g each) over the course of 2.3 hours at a rate which maintained the internal temperature between -11.8°C and -20°C. Following the addition, the reaction mixture was allowed to gradually warm to 0°C (1.5 hours) to 10°C (3 hours). After stirring for approximately 12 hours at RT, the reaction mixture was transferred to a 22-L round bottom flask with mechanical stirring and cooled with an ice-water bath. MTBE (12 L) was added within 54 minutes via an addition funnel while maintaining the temperature between 15°C and 23°C. A white precipitate began to form after approximately one-third of the MTBE was added. The resulting slurry was stirred for 2 hours at RT and then filtered using a glass filter. The cake was washed with MTBE (4 L) and then dried under vacuum at 40-45°C overnight to give the title compound as a white powder (460 g, 74%).

[0109] EXAMPLE 4: (i?)-l-(2-Amino-3-methylbutanoyl)azetidine-3-carbonitrile, HC1 salt

[0110] Method A: A 50 mL flask was charged with (R)-tert-butyl l-(3-cyanoazetidin-l- yl)-3 -methyl- l-oxobutan-2-ylcarbamate (2 g, 7.11 mmol), followed by acetonitrile (12 mL) under a nitrogen atmosphere. A white suspension was obtained. Next, 4 N HCI solution in dioxane (8.89 mL, 35.5 mmol) was added via syringe without external cooling, resulting in a clear solution. The reaction mixture was stirred for 3 hours at RT. MTBE (about 15 mL) was added, followed by toluene (about 25 mL). Upon continued stirring, a white precipitate formed, which was granulated for 45 minutes at RT. The solids were filtered, rinsed with MTBE (about 20 mL) and dried to give the title compound as a white solid (1.534 g, 99%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 0.95 (m, 6 H), 2.05 (m, 1H), 3.63 (br s, 1H), 3.87 (m, 1H), 4.09 (m, 1H), 4.18-4.27 (m, 2H), 4.36 (m, 0.5H), 4.45 (m, 0.5H), 4.58 (m, 0.5H), 4.70 (m, 0.5H), 8.41 (br s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ ppm 16.81, 17.25, 17.86, 17.97, 29.12, 51.28, 53.30, 53.60, 53.89, 120.23, 120.51, 168.24.

[0111] Method B: A 50 mL flask was charged with (R)-tert-butyl l-(3-cyanoazetidin-l- yl)-3 -methyl- l-oxobutan-2-ylcarbamate (2.006 g, 7.13 mmol) followed by acetonitrile (8 mL) under a nitrogen atmosphere. A white suspension was obtained. Next, 4 N HCl solution in dioxane (8.91 mL, 35.6 mmol) was added via syringe without external cooling, resulting in a clear solution. After stirring at RT for about 45 minutes, toluene (20 mL) was added, followed by a few seed crystals. After about 20 minutes, more toluene was added (about 8 mL) and the mixture was stirred at RT, at which time white solids began to precipitate. After granulating for about 3 hours, the suspension was filtered, the solids rinsed with MTBE (12 mL) and dried to obtain the title compound as a white solid (1.488 g, 96%).

[0112] Method C: In a 2 L flask, (R)-tert-butyl l-(3-cyanoazetidin-l-yl)-3-methyl-l- oxobutan-2-ylcarbamate (90. Og, 320 mmol) was suspended in acetonitrile (360 ml). Next, 4 N HCl solution in dioxane (239.9 mL, 960 mmol) was added at RT over a 9 minute period without external cooling. After about 60 minutes, toluene (450 mL) was added and the solution was stirred at RT for about 30 minutes. Seed crystals were added, and the mixture was stirred overnight at RT, during which a white precipitate had formed. Additional toluene (630 mL) was added, and the mixture was stirred for one hour. The precipitate was filtered, rinsed with MTBE (450mL), and dried for about 28 hours at 50°C under vacuum to give the title compound as a white solid (59.6 g, 86%>).

[0113] Method D: (R)-tert- utyl 1 -(3 -cyanoazetidin-l-yl)-3 -methyl- l-oxobutan-2- ylcarbamate (4.27 kg, 15.2 mol) was charged to a 100 L jacketed reactor. Acetonitrile (17.2 L) was added and the reactor was flushed with nitrogen. HCl (4 N) in dioxane (11.5 L, 45.9 mol) was added over a 37 minute period, while maintaining the temperature at 15-25°C. The batch was stirred for 1.2 hours at 20-30°C and seed crystals (3 g, 0.001 eq) were added. Over the course of one hour, the product slowly crystallized. Toluene (68.0 L) was added over a 35 minute period, and the resulting suspension was stirred at 15-25°C for 17.5 hours, and then filtered. The reactor was rinsed with MTBE (25.0 L) and the rinse was transferred onto the filter cake. The filter cake was subsequently charged back to the reactor, suspended in MTBE (25.0 L), stirred for two hours, and then filtered. The reactor was rinsed with MTBE (26.0 L) and the rinse was transferred onto the filter cake. The filter cake was conditioned under vacuum for 22 hours, then transferred to an oven and dried under reduced pressure at 50°C until a constant weight was achieved. This afforded the title compound as a white static solid (3.37 kg, 101%).

[0114] EXAMPLE 5: (i?)-l-(3-Methyl-2-(6-methyl-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

[0115] A. (R)- 1 -(tert-Butoxycarbonyl)-4-((l-(3-cyanoazetidin- 1 -yl)-3 -methyl- 1 - oxobutan-2-ylamino)methyl)-5 -methyl- lH-pyrrolo [2,3 -¾]pyridine-3 -carboxylic acid

[0116] Sodium triacetoxyborohydride (5.29 g, 25.0 mmol) and (i?)-l-(2-amino-3- methylbutanoyl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate (7.47 g, 25.0 mmol) were stirred in DCM (120 mL) for 30 minutes. The solution was cooled to 0°C and l-(tert- butoxycarbonyl)-4-formyl-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylic acid (4.75 g, 15.6 mmol) was added. The solution was stirred for 1 hour and then concentrated in vacuo to give the title compound, which was used in the next step without further purification. [0117] B. (R)-ierf-Butyl 4-( 1 -(3 -cyanoazetidin-l-yl)-3 -methyl- 1 -oxobutan-2-yl)-6- methyl-3-oxo-4,5-dihydropyrrolo[4,3 - e][2,6]naphthyridine-l(3H)-carboxylate

[0118] Crude (R)- 1 -(tert-butoxycarbonyl)-4-((l -(3-cyanoazetidin- 1 -yl)-3 -methyl- 1 - oxobutan-2-ylamino)methyl)-5-methyl- lH-pyrrolo[2,3-¾]pyridine-3-carboxylic acid was taken up in THF (100 mL). 2-(3H-[l,2,3]Triazolo[4,5-¾]pyridin-3-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate(V) (8.90 g, 23.4 mmol) and 4-methylmorpholine (2.60 mL, 23.4 mmol) were added, and the reaction mixture was stirred at 50°C for 2 hours. Additional HATU (2.97 g, 7.8 mmol) and 4-methylmorpholine (0.87 mL, 7.8 mmol) were added. The reaction mixture was stirred for an additional 1 hour, then cooled, diluted with EtOAc, and washed with brine. The organic phase was dried over MgS0₄ and concentrated in vacuo. The residue was purified by a first silica gel chromatography (3% MeOH/DCM) and then a second silica gel chromatography (75% EtOAc/Hexanes) to give the title compound as a yellow foam/oil (4.24 g, 60% for Steps A and B). 1H NMR (500 MHz, DMSO-de) δ ppm 0.88-0.95 (m, 3H), 1.01-1.08 (m, 3H), 1.67 (d, J=3.0 Hz, 9H), 2.33 (d, J=7.5 Hz, 3H), 2.46-2.55 (m, 1H), 3.40-3.55 (m, 1H), 4.19-4.40 (m, 2H), 4.55-4.82 (m, 3H), 5.05-5.22 (m, 2H), 8.04 (d, J=18.5 Hz, 1H), 8.34 (d, J=10.0 Hz, 1H). [M+H] calc'd for C₂₄H₂9N₅0₄, 452; found 452.

[0119] C. (i?)-l-(3-Methyl-2-(6-methyl-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin- 4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

[0120] TFA (5 mL) was added slowly to a solution of (i?)-tert-butyl-4-[l-(3- cyanoazetidin-l-yl)-3-methyl-l-oxobutan-2-yl]-6-methyl-3-oxo-4,5-dihydropyrrolo[4,3,2- <ie][2,6]naphthyridine-l(3H)-carboxylate in DCM (5 mL) at 0°C. The solution was stirred for 2 hours at 0°C and then for 30 minutes while warming the reaction mixture to RT. The solution was concentrated in vacuo and purified by silica gel chromatography (l%>-20%> EtOH in 1 :1 EtOAc/DCM). The desired fractions were concentrated and crystallized from cold MeOH. The solid was collected by filtration and dried for 2 days in vacuo to give the title compound as an off-white solid (1.98 g, 60%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 0.77-0.80 (m, 3H), 0.90-0.98 (m, 3H), 2.25 (d, J=3.6 Hz, 3H), 2.33-2.49 (m, 1H), 3.65-3.82 (m, 1H), 4.02-4.52 (m, 4H), 4.72-5.08 (m, 3H), 7.83 (dd, J=6.4, 2.4 Hz, 1H), 8.11 (d, J=3.6 Hz, 1H), 12.11 (br s, 1H). [M+H] calc'd for Ci₉H₂iN₅0₂, 352; found, 352.

[0121] EXAMPLE 6: (i?)-l-(3-Methyl-2-(6-methyl-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

[0122] A.

4-((l -(3 -cyanoazetidin-l-yl)-3 -methyl- l-oxobutan-2- ylamino)methyl)-3-iodo-5-methyl-l -pyrrolo[2,3-¾]pyridine-l -carboxylate

[0123] Method A: tert-Butyl 4-formyl-3-iodo-5-methyl-7H-pyrrolo[2,3-¾]pyridine-l- carboxylate (5.0 g, 12.9 mmol), (i?)-l-(2-amino3-methylbutanoyl)azetidine-3-carbonitrile, TFA salt (4.6 g, 1.2 eq) and Et₃N (1.8 mL, 1 eq) were stirred in THF (50 mL) at 20-25°C for 60 minutes. Sodium cyanoborohydride (0.85 g, 1 eq) was added and the reaction mixture was stirred at RT. The reaction was complete after 1 hour (by HPLC) and was quenched with saturated aq NaHC0₃ (50 mL) and stirred until all bubbling ceased. The mixture was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water (50 mL), dried over MgS0₄ (5 g) and Darco-G60 (1.5 g, 30 wt%), stirred for 30 minutes, filtered through Celite, and concentrated under vacuum to give the title compound (crude) as a foam (8.51 g, 77 wt% by NMR, 80.9%). 1H NMR (500 MHz, CDC1₃) δ ppm 0.85-0.96 (m, 6H), 1.66 (s, 9H), 1.73-1.82 (m, 1H), 2.48 (s, 3H), 2.82- 2.88 (m, 1H), 3.44-3.53 (m, 1H), 4.12-4.44 (m, 6H), 7.81 (d, J=11.5 Hz, 1H), 8.36 (s, 1H). [M+H] calc'd for C₂3H₃oIN₅03, 552; found, 552.

[0124] Method B: In a 500 mL round bottom flask, tert-butyl 4-formyl-3-iodo-5-methyl- lH-pyrrolo[2,3-¾]pyridine-l-carboxylate (20.0 g, 51.8 mmol) and (i?)-l-(2-amino3- methylbutanoyl)azetidine-3-carbonitrile, TFA salt (23.0 g, 78 mmol) were combined in DCE (200 mL). The solution was allowed to stir at 50°C under N₂ atmosphere for 4 hours. Sodium triacetoxyborohydride (14.6 g, 68.9 mmol) was divided into 4 portions, and one portion was added every 20 minutes. The solution was stirred for 20 minutes after the final portion was added, and was then diluted with DCM and washed with 1 N NaHCC>3 aq solution. The organics were dried over Na₂S0₄, concentrated in vacuo, and purified by silica gel chromatography (50-80% EtOAc/Hexanes) to give the title compound as a white solid (23.46 g, 82%).

[0125] Method C: tert- utyl 4-formyl-3-iodo-5-methyl-lH-pyrrolo[2,3-¾]pyridine-l- carboxylate (1.0 kg), (i?)-l-(2-amino3-methylbutanoyl)azetidine-3-carbonitrile, TFA salt (0.92 kg, 1.2 eq), and Et₃N (360 mL, 1 eq) were stirred in THF (7.5 L) at 20-25°C for 3 hours. Sodium triacetoxyborohydride (160 g, 1 eq) was added in portions, while maintaining an internal temperature less than 30°C. An additional portion of sodium triacetoxyborohydride (20 g) was added after 2.5 hours. The reaction was quenched with aqueous saturated sodium bicarbonate (8 L) and stirred until all bubbling had ceased. The mixture was diluted further with water (8 L) and extracted with z^'-PrOAc (2 x 8 L). The combined organic layers were washed with water (8 L) and then treated with magnesium sulfate (1 kg) and Darco-G60 (300 g). The mixture was stirred for 15 minutes, filtered through silica (2 kg), and concentrated under vacuum to give the title compound as a foam (1.57 kg, 108%, 76 wt % by NMR).

[0126] B. (i?)-l-(3-Methyl-2-(6-methyl-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin- 4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

[0127] Method A : To a steel reaction vessel equipped with a magnetic stirrer were added (R)-tert-butyl 4-(( 1 -(3 -cyanoazetidin- 1 -yl)-3 -methyl- 1 -oxobutan-2-ylamino)methyl)-3 -iodo- 5-methyl-lH-pyrrolo[2,3-£]pyridine-l-carboxylate (16.6 g, 30.1 mmol), PdCl₂(PPh₃)₂ (634 mg, 0.90 mmol), and DMF (70 mL), followed by Et₃N (12.6 mL, 90.0 mmol). The reaction vessel was charged with N₂ (50 psi) and vacuum purged. Following three N₂ fill-vacuum purge cycles, the reaction vessel was charged with carbon monoxide (50 psi). The reaction mixture was stirred at 68°C for 3 hours and subsequently heated at 98°C for 16 hours. The reaction mixture was allowed to cool and was filtered. The reaction vessel and filter solids were rinsed with DCM. The filtrate was collected in a round bottom flask and was concentrated in vacuo. Toluene was added, and the solution was concentrated again. The residue was taken up in 5% MeOH/DCM and was washed with a 1 : 1 solution of saturated aq NaHC0₃ and brine. The aqueous layer was back-extracted once with 5% MeOH/DCM. The combined organic phases were dried over MgS0₄ and concentrated in vacuo to give a brown oily foam, which was purified by silica gel chromatography (2-10% MeOH in 3: 1 DCM/EtOAc). The resulting yellow solid (9.16 g) was crystallized from cold MeOH, collected, and dried under vacuum to give the title compound as a white solid (7.74 g, 73%). 1H NMR (400 MHz, DMSO- ₆) δ ppm 0.77-0.80 (m, 3H), 0.90-0.98 (m, 3H), 2.25 (d, J=3.6 Hz, 3H), 2.33-2.49 (m, 1H), 3.65-3.82 (m, 1H), 4.02-4.52 (m, 4H), 4.72-5.08 (m, 3H), 7.83 (dd, J=6.4, 2.4 Hz, 1H), 8.11 (d, J=3.6 Hz, 1H), 12.11 (br s, 1H). [M+H] calc'd for

Ci9H₂iN₅0₂, 352; found, 352.

[0128] Method B: (R)-tert-Butyl 4-((l-(3-cyanoazetidin-l-yl)-3-methyl-l-oxobutan-2- ylamino)methyl)-3-iodo-5-methyl-lH-pyrrolo[2,3-¾]pyridine-l-carboxylate (1.55 kg) and PdCl₂(PPh₃)₂ (99 g, 5 mol %) were charged to a 20 L pressure reactor followed by the addition of a solution of DMF (anhydrous, 6.2 L ) and Et₃N (anhydrous, 1.18L). DMF (1.5 L) was used as a rinse and was added to the reactor. The autoclave was sealed and successively purged with nitrogen (3x) and carbon monoxide (3x), then pressurized to 100 psi with carbon monoxide and heated to 70°C for 2.5 hours, resulting in complete conversion (>99%). Next, ammonium hydroxide (29% solution, 2.33 L) was added to the yellow reaction mixture. Upon conversion, water (23.5 L) was added to the reactor and the contents were extracted with DCM (3 x 7.75 L). The combined organic phases were washed with a mixture of 10% citric acid and brine (540 g and 1.18 kg, respectively, in 8.17 L of water), then with water (8 L), and successively treated with MgS0₄ (790 g) and charcoal (Darco G-60, 800 g). After filtration, the mixture was concentrated and co-evaporated with z^'-PrOAc (3.9 L) to give an oil, which was diluted with additional z^'-PrOAc (7.8 L) over a 30 minute period. The mixture was subsequently stirred for 60 minutes, and the crude product was collected by filtration, rinsed with z^'-PrOAc (3 L), and dried to afford a light yellow solid (557 g, 56%). The crude product (550 g) was then slurried in MeOH/THF (1 : 1 , 11 L) and heated to 50°C to obtain a solution. SiliaBond-DMT resin (423 g) was added and the slurry was stirred at 50°C for 16 hours and then filtered hot through a coarse frit. The organic solvents were removed under reduced pressure. THF (550 mL), MeOH (550 mL), and water (8 L) were added. The resulting slurry was stirred at 50°C for 30 minutes and then cooled to room temperature. The solids were isolated by filtration, washed with water (2 x 1.3 L), and dried at 45-50°C to afford the title compound (493 g, 89%).

[0129] EXAMPLE 7. 5-Amino-l-tert-butyl-lH-pyrrole-3-carbonitrile

[0131] To a 12 L 4-neck flask equipped with an overhead stirrer was charged, in order, succinonitrile (366 g, 457 mmol), toluene (1500 mL), ethyl formate (462 mL, 571 mmol), and tert-butanol (300 mL). The solution was cooled in an acetone/ice-bath to 3°C. A 1M potassium tert-butoxide in tert-butanol solution (4800 mL) was added via an addition funnel over a period of 2.5 hours, which maintained an internal temperature of about 5-10°C.

Shortly after the addition of the KOt-Bu/t-BuOH solution, a precipitate began to form. Once the addition was complete, the ice-bath was removed and the yellow suspension was stirred overnight while warming to RT. The reaction mixture was subsequently filtered and the filter cake was rinsed with EtOH (600 mL) and MTBE (1500 mL). The wet cake was dried at 60-65°C in a vacuum oven overnight to give the title compound as a yellow solid (674.39 g, 101%).

[0132] B. 2-((tert-Butylamino)methylene)succinonitrile

[0133] Method A: To a 1000-mL 3-neck round bottom flask equipped with reflux condenser, overhead stirrer, and thermocouple was added potassium 2,3-dicyanoprop-l-en- 1-olate (45.20 g, 309 mmol) followed by toluene (480 mL). Stirring was started and tert- butyl amine (33.3 mL, 315 mmol) was added. Next, the flask was placed in an ice-bath, and acetic acid (44.2 mL, 773 mmol) was added via addition funnel over about an 8 minute period. An exotherm was observed during the addition of the first 50% of HO Ac. After complete addition of HO Ac, the ice-bath was removed, and the mixture was heated to about 105°C (internal temperature) using a heating mantle. Upon reaching an internal temperature of about 104°C, the suspension had dissolved and a dark solution was obtained. After 50 minutes of heating (internal temperature 105.1°C), the heating was halted and the reaction mixture was stirred overnight while cooling to RT. A solution of NaCl (32 g) in H₂0 (160 mL) was subsequently added and the mixture was stirred vigorously. A dark brown biphasic mixture was obtained, which contained undissolved solids. More water (100 mL) was added. The mixture was concentrated on a rotavap (40°C water-bath temperature) to remove toluene, and the resulting suspension was filtered and rinsed with H₂0 (about 250 mL) to afford a crude wet cake (48.33 g), which was dried in vacuo at 60°C to give the title compound (35.23 g 69.8%).

[0134] Method B: The jacket of a 300 gallon glass-lined reactor (reactor #1) was heated to approximately 40°C. 7¾rt-butanol (335.1 kg) was charged and the contents were heated to approximately 40°C. While agitating, potassium tert-butoxide was charged in two portions (20.1 kg and 40.6 kg) within approximately 30 minutes. The maximum temperature recorded during the addition was 45°C. Upon complete addition, the contents were agitated for approximately 1 hour at about 45°C. Separately, succinonitrile (38.95 kg), toluene (133 kg), and ethyl formate (38.17 kg) were charged to a 500 gallon glass-lined reactor (reactor #2) and the contents were cooled to approximately -14°C. Next, the contents of reactor #1 were transferred into reactor #2 over 3 hours and 45 minutes while maintaining the internal temperature below -5°C. Reactor #1 was washed with tert- uOH (2 x 25.1 kg) and the washes were transferred to reactor #2. The contents of reactor #2 were stirred between -10 and -5 °C for 13 to 14 hours. Next, tert-BuNH₂ (36.2 kg) was charged to reactor #2, followed by a rinse of the transfer lines with toluene (9 kg). The internal temperature was adjusted to -5°C, and acetic acid (77.0 kg) was charged to reactor #2 over approximately 1.5 hours at a rate which maintained the internal temperature below 10°C. After rinsing the transfer lines with toluene (7.5 kg), the contents of reactor #2 were heated at approximately 82°C for about 2.5 hours. The internal temperature was subsequently decreased to 78°C. Once in-process monitoring indicated the reaction was complete, the contents of reactor #2 were cooled to 6°C, H₂0 (500 kg) was charged, and the contents were stirred for 20 minutes at approximately 7°C. The contents of reactor #2 were then distilled under vacuum at a temperature of 35 ± 5°C until a distillate volume of approximately 800 L was obtained. The final batch temperature was 20°C. The temperature of the remaining contents in reactor #2 was adjusted to 25°C, and the solids were collected by filtration using a stainless steel Nutsche filter. Reactor #2 was rinsed with H₂0 (380 kg) and the rinse was transferred in 3 portions (60 kg, 200 kg, 120 kg) onto the filter cake. The filter cake was dried by suction, then transferred to an oven and dried at approximately 60°C under vacuum until loss on drying was less than 1% to afford the title compound as an off-white powder (60.8 kg, 76.5%).

[0135] C. 5-Amino-l-tert-butyl-lH-pyrrole-3-carbonitrile

[0136] Method A: In a 5-L flask, potassium hydroxide (82 g, 1243 mmol) was dissolved in EtOH (1708 mL) and stirred until an opalescent solution was obtained. Solid 2-((tert- butylamino)methylene)succinonitrile (111.50 g, 683 mmol) was added in portions over 5 minutes, then the reaction mixture was stirred at RT overnight. The mixture was filtered through Celite to remove insoluble brown fine particles and the flask and filter cake were rinsed with EtOH (3 x 50 mL). The filtrate was concentrated at 35°C by vacuum distillation. Once the distillation subsided, H₂0 (1 L) was added to the thick mixture, which was cooled in an ice-bath, forming a precipitate. After 3 hours, the cold mixture was filtered and the filter cake was rinsed with H₂0 (500 mL). The cake was dried by suction overnight to give the title compound as an amber-colored, free-flowing, granular solid (98.64 g, 88%).

[0137] Method B: To a 300 gallon glass-lined reactor (reactor #2) was charged KOH (45.0 kg) followed by methanol (386.0 kg). The temperature of the contents of reactor #2 was adjusted to 30°C. Separately, 2-((tert-butylamino)methylene)succinonitrile (60.0 kg) was charged to a 500 gallon glass-lined reactor (reactor #1). The contents of reactor #2 were transferred to reactor #1, and the contents of reactor #1 were agitated for at least 12 hours at 20 to 25°C. Once the reaction was complete, the contents of reactor #1 were distilled at a temperature of 35 ± 5°C under vacuum until the batch volume reached the minimum possible stir volume (-175 L). Then, H₂0 (820 kg) was charged to reactor #1 and the contents were agitated for 12 hours at an internal temperature of about 5°C. The solids were collected by filtration using a stainless steel Nutsche filter. Reactor #1 was rinsed with H₂0 (327 kg) and the rinse was transferred onto the filter cake in three portions. The filter cake was dried by suction, then transferred to an oven and dried at ambient temperature under vacuum to afford the title compound (57.14 kg, 94.1%; > 98% purity by 1H NMR).

[0138] EXAMPLE 8: (E)-Ethyl 4-ethoxy-3-methyl-2-oxobut-3-enoate

[0139] Method A : A 5 L round bottom flask, equipped with an overhead stirrer, was dried with a heat gun under N₂ flush. Triethylamine (490 mL, 3483 mmol) and anhydrous dioxane (735 mL) were added to the flask. With stirring, 1-ethoxyprop-l-ene (643 mL, 5805 mmol) was added, and the resulting clear solution was cooled in an ice-bath. At a temperature of 6.7°C, ethyl 2-chloro-2-oxoacetate (258 mL, 2322 mmol) was added via addition funnel over an 11 minute period. A yellow precipitate formed during the addition. Initially, an exotherm was observed, which subsided as the addition progressed. The ice- bath was removed and the yellow suspension warmed to RT. After about 30 minutes, another exotherm was observed, which was controlled by cooling the mixture in an ice-bath such that the internal temperature did not exceed 35°C. Once the exotherm subsided, the mixture was stirred at RT overnight. The suspension was filtered and rinsed with EtOAc (3 x 250 mL). The filtrate was concentrated at 35°C. Water (1 L) was added to the concentrate, followed by MTBE (1 L). The bi-phasic mixture was stirred vigorously, and then the phases were separated. The aqueous phase was extracted with MTBE (1 x 500 mL), dried over MgSC^, filtered, rinsed with MTBE, and concentrated on a rotary evaporator at 35-40°C. The concentrate was dried under high vacuum for 2-3 days to give the title compound as a low viscosity orange syrup (371.18 g, 86%). 1H NMR (400 MHz, DMSO- de) 5 ppm 1.26-1.30 (m, 6H), 1.62 (m, 3H), 4.24-4.31 (m, 2H), 7.59 (s, 1H); ¹³C NMR (100 MHz, DMSO- e) δ ppm 6.97, 13.78, 15.24, 61.57, 71.08, 112.55, 164.69, 166.80, 186.92.

[0140] Method B: To a 200 gallon glass-lined reactor were charged Et₃N (60.1 kg), 1,4- dioxane (129.2 kg), and 1-ethoxyprop-l-ene (84.7 kg). The reactor contents were cooled to about 1°C and within 12 minutes, ethyl chlorooxoacetate (53.5 kg) was added while maintaining the internal temperature below 10°C. Upon completing the addition, the internal temperature was maintained at 20-25°C, and the reactor contents were agitated at this temperature for about 16 hours. The precipitated solids were collected by filtration. The reactor was rinsed with EtOAc (180 kg) and the rinse was transferred onto the filter cake. The combined filtrates (including rinse) were transferred into a 200 gallon glass-lined reactor and the contents of this reactor were subsequently concentrated by vacuum distillation at < 35°C batch temperature until no more distillate was observed. To the residue was added H₂0 (170 kg), followed by MTBE (125.9 kg), and the contents were agitated for about 20 minutes at approximately 25°C. After phase separation, the aqueous layer was separated and washed with MTBE (62.9 kg) using a 200 gallon glass-lined reactor. The layers were separated again. The aqueous layer was discarded and the organic layers were combined. The two reactors were rinsed with MTBE (20 kg each) and the two rinses were combined with the organic layers from the extraction. The combined organic layers were dried over MgS0₄ (20.0 kg). The drying agent was filtered off and the organics were subsequently concentrated by vacuum distillation at < 35°C batch temperature until no more distillate was observed. The residue in the reactor was collected to afford the title compound, which was used without further purification (61.78 kg, 84.7%).

[0141] EXAMPLE 9: 4-(Hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3- carboxylic acid

[0142] A. Ethyl l-tert-butyl-3-cyano-5-methyl-lH-pyrrolo[2,3-¾]pyridine-4-carboxylate

[0143] Method A: Into a 500 mL flask was charged 5-amino-l-tert-butyl-lH-pyrrole-3- carbonitrile (29.95 g, 183 mmol), followed by (E)-ethyl 4-ethoxy-3-methyl-2-oxobut-3- enoate (37.6 g, 202 mmol) and HO Ac (92 mL). The mixture was heated to 100°C and kept at that temperature for 20 hours. The mixture was subsequently allowed to cool to RT, and a mixture of H₂0/EtOH (5: 1, 180 mL) was added to the thick slurry. The orange slurry was granulated for about 2 hours, then cooled to about 7°C, filtered, rinsed with H₂0/EtOH (5: 1, 90 mL), and dried by suction overnight. The crude product (44.00 g) was reconstituted in EtOH (220 mL) and the mixture heated until a clear solution was obtained. The solution was cooled to RT, which formed a precipitate. The slurry was kept at 4°C overnight, filtered, and the solids were rinsed with EtOH (100 mL) to afford the title compound (23.97 g, 45.8%). 1H NMR (DMSO- e) δ ppm 1.37 (t, J=7.07 Hz, 3H), 1.76 (s, 9H), 2.42 (s, 3H), 4.43 (q, J=7.24 Hz, 2H), 8.41 (s, 1H), 8.57 (s, 1H); ¹³C NMR (DMSO-d₆) δ ppm 13.83, 15.65, 28.48, 58.67, 61.32, 80.77, 115.18, 116.20, 123.94, 131.06, 137.78, 145.75, 145.78, 165.38.

[0144] Method B: To a 200 gallon glass-lined reactor were charged 5-amino-l-tert-butyl- lH-pyrrole-3-carbonitrile (49.2 kg), (E)-ethyl 4-ethoxy-3-methyl-2-oxobut-3-enoate (61.7 kg), and acetic acid (159.3 kg). The contents were heated to 95-100°C within about 50 minutes and then kept at that temperature for 6 hours. Next, the contents were cooled to about 20°C within 2.5 hours, and a separately prepared, cold (~5°C) mixture of ethanol (42.8 kg) and H₂0 (218.2 kg) was added. After completing the addition, the contents were cooled to about 7°C. The mixture was stirred at this temperature for 2 hours and then filtered through a stainless steel Nutsche filter. The reactor was rinsed with a mixture of EtOH (23.9 kg) and H₂0 (121 kg) and the rinse was transferred onto the filter cake. The filter cake was transferred to an oven and dried at approximately 40°C under vacuum to afford crude product (69.49 kg) as a mixture of regioisomers. The undesired regioisomer was removed via recrystallization. Crude product (69.49 kg) and EtOH (269.1 kg) were heated to 65-70°C and kept at this temperature for 20 minutes to form a clear solution. Next, the reactor contents were cooled to about 24°C over a period of 23-24 hours, and the resulting solids were filtered through a stainless steel Nutsche filter. The reactor was rinsed with EtOH (97 kg) and the rinse was transferred onto the filter cake. The filter cake was dried by suction, then transferred to an oven and dried at 35°C under vacuum to afford the title compound (33.45 kg, 39%; >99 % purity by 1H NMR).

[0145] B. 3-Cyano-5-methyl-lH-pyrrolo[2,3-¾]pyridine-4-carboxylic acid

[0146] Method A: Into a 3 L 3-neck flask, equipped with an overhead stirrer and thermocouple was added aluminum trichloride (83 g, 619 mmol) followed by

chlorobenzene (300 mL). The suspension was cooled in an acetone/ice-bath. Under an atmosphere of nitrogen and while stirring, ethyl l-tert-butyl-3-cyano-5-methyl-lH- pyrrolo[2,3-£]pyridine-4-carboxylate (58.89 g, 206 mmol) was added in portions over a 10 minute period via a powder funnel, which kept the internal temperature between -6°C and 0°C. After the addition was complete, the ice-bath was removed, and the suspension was warmed to RT over a 2 hour period. More chlorobenzene (50 mL) was added, and the amber suspension was carefully heated to an internal temperature of 80-85°C over a 40 minute period. After adding more chlorobenzene (50 mL), the suspension was heated at an internal temperature of about 85°C for 100 minutes. The internal temperature was subsequently raised to 125°C, and the mixture was kept at this temperature for 3-4 hours. After completion of the reaction, the mixture was cooled to RT, then to 10-15°C. The cold mixture was slowly poured into a cold (about 3°C) solution of citric acid (119 g, 619 mmol) in H₂0 (600 mL) portion-wise in a fine stream over a 20 minute period. The addition was stopped whenever a brown color persisted in the light-yellow suspension and was not resumed until the brown color disappeared. Following the addition, the reaction flask was rinsed with a solution of citric acid (30 g, 156 mmol) in H₂0 (150 mL), which was added to the quenched reaction mixture. MTBE (250 mL) was added, followed by aq NaOH (50%, 190 mL, 2807 mmol) resulting in a pH=8.2. More H₂0 (1 L) was added and the phases were separated. Water (500 mL) and MTBE (500 mL) were added to the organic phase, and the phases were separated again. The combined aqueous phases were washed with MTBE (250 mL). After phase separation, the aqueous phase was transferred into a 5 L 3 -neck flask. Concentrated HC1 was added until the pH=2.75. A white precipitate formed, which was granulated at RT overnight. The suspension was filtered and the filter cake was rinsed with water (2 x 120 mL) and dried in vacuo at 45°C for several days to afford the title compound (42.09 g, 101%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 2.44 (s, 3H), 8.34 (s, 1H), 8.49 (s, 1H), 12.93 (s, 1H), 13.93 (br s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ ppm 16.00, 82.92, 113.97, 115.28, 123.42, 132.48, 137.31, 146.79, 146.91, 167.00.

[0147] Method B: To a 200 gallon glass-lined reactor (reactor #1) was charged aluminum chloride (36 kg) followed by chlorobenzene (79 kg), and the contents of the reactor were cooled to about -10°C. Ethyl l-tert-butyl-3-cyano-5-methyl-lH-pyrrolo[2,3-¾]pyridine-4- carboxylate (33.4 kg) and chlorobenzene (146 kg) were charged to a second 200 gallon glass-lined reactor (reactor #2). The contents of reactor #2 were kept at a temperature of 15- 20°C. Within 1 hour, while agitating, the contents of reactor #2 were slowly transferred to reactor #1. The maximum temperature during the addition was -3.0°C. Reactor #2 was rinsed with chlorobenzene (3.50 kg) and the rinse was transferred to reactor #1. The contents of reactor #1 were subsequently agitated for about 1 hour at 25-30°C, heated to 70°C within about 1 hour, kept at about 70°C for 2 hours, heated further to about 120°C within about 75 minutes, kept at about 120°C for 13-14 hours, and finally cooled to 10- 15°C. In reactor #2, an aqueous solution of potassium hydroxide (66 kg) in H₂0 (208 kg) was prepared and cooled to 5.0°C (23 kg of this solution were set aside). The contents of reactor #1 were slowly transferred to reactor #2 within 2 hours (the maximum temperature recorded was 31.0°C). Reactor #1 was rinsed with 10 kg of the aqueous KOH solution, which was set aside above, and the rinse was transferred to reactor #2. Reactor #1 was rinsed with chlorobenzene (12.5 kg) and the rinse was transferred to reactor #2. Next, Celite (23.0 kg) was charged to reactor #2. Separately, a stainless steel Nutsche filter was conditioned with Celite (3.0 kg) and H₂0 (20 kg) and the solids in reactor #2 were collected by filtration using the Nutsche filter. Reactor #2 was rinsed with some of the aqueous KOH solution (10 kg) that was set aside above, and the rinse was sent through the pad of Celite on the Nutsche filter. The filtrates (including rinse) were combined in reactor #1. MTBE (12.5 kg) was added to reactor #1 and the contents were agitated for 10 minutes at 25±5°C. Upon stopping the agitation, the layers were allowed to separate for 15 minutes. The product- containing aqueous layer was transferred from reactor #1 to reactor #2. After discarding the organic layer, reactor #1 was washed with H₂0 (50 kg) and the aqueous wash was discarded as well. MTBE (13.7 kg) was charged to reactor #2, and the contents were agitated for 30 minutes at 25±5°C. Upon stopping the agitation, the layers were allowed to separate for 20 minutes, and the aqueous layer was transferred from reactor #2 to reactor #1. After discarding the organic layer, reactor #2 was washed with H₂0 (100 kg) and the aqueous wash was discarded as well. The contents of reactor #1 were cooled to about 15°C. In reactor #2, a solution of citric acid monohydrate (76 kg) in H₂0 (150 kg) was prepared. The acidic solution of reactor #2 (-200 L) was added to reactor #1 over the course of 25 minutes, resulting in pH=2.8. The maximum internal temperature recorded was 15.5°C. After agitating the contents of reactor #1 at 25±5°C for approximately 12 hours, the solids in reactor #1 were collected by filtration using a stainless steel Nutsche filter. Reactor #1 was rinsed with H₂0 (12.5 kg) and the rinse was transferred onto the filter cake.

[0148] The wet filter cake was charged to a 500 gallon glass-lined reactor. Water (130 kg) was added and the mixture was stirred at about 20°C for approximately 4 hours. The solids in the reactor were collected by filtration using a stainless steel Nutsche filter. The reactor was rinsed with H₂0 (30 kg) and the rinse was transferred onto the filter cake. The filter cake was dried by suction, then transferred to an oven and dried at 45±5°C under vacuum. This afforded the title compound as an off-white solid (8.42 kg). Further product was recovered by a rework of the Celite pad. For that purpose, solutions of KOH (40 kg) in H₂0 (160 kg) and of citric acid monohydrate (51 kg) in H₂0 (102 kg) were prepared. Next, the Celite was transferred into a 500 gallon glass-lined reactor. The aqueous KOH solution (174.24 kg) was charged to the reactor, and the contents were agitated for 2 hours and 15 minutes. The reactor contents were collected by filtration using a stainless steel Nutsche filter. The reactor was rinsed with the aqueous KOH solution (10 kg), and the rinse was transferred onto the filter cake. The filtrates were collected in another 500 gallon glass-lined reactor, and the citric acid monohydrate solution was charged to the filtrates, maintaining an internal temperature of 20-25°C. After stirring the contents of the reactor at 20-25°C for about 2 hours, the solids were collected by filtration using a stainless steel Nutsche filter. The reactor was rinsed with H₂0 (10 kg), and the rinse was transferred onto the filter cake. The filter cake was dried by suction, then transferred to an oven and dried at 45±5°C under vacuum to afford a second batch of the title compound as an off-white solid (12.79 kg). The total amount of isolated 3-cyano-5-methyl-lH-pyrrolo[2,3-¾]pyridine-4-carboxylic acid was 21.21 kg (91%).

[0149] C. 4-(Hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carbonitrile

[0150] Method A: 3-Cyano-5-methyl-lH-pyrrolo[2,3-¾]pyridine-4-carboxylic acid (49 g, 244 mmol) and Ι,Γ-carbonyldiimidazole (55.3 g, 341 mmol) were charged to a 2 L flask at RT. THF (490 mL) was added and the resulting suspension was heated at about 50°C for about 60 minutes at which point the formation of the acyl imidazole intermediate was complete. Heating was halted and the fine yellow suspension was stirred while cooling to RT. Separately, in a 3 L 3-neck flask, a solution of NaBH₄ (23.03 g, 609 mmol) in H₂0 (490 mL) was prepared and cooled to 0-5°C. Next, the mixture containing the acyl imidazole intermediate was transferred into the cold aqueous sodium borohydride solution via a Teflon transfer tube at a rate which maintained the internal temperature <15°C. Upon complete transfer, the remaining solids were rinsed into the cold aqueous sodium

borohydride solution with THF (2 x 50 mL). The cooling bath was removed and the reaction mixture was stirred overnight while warming to RT. Concentrated HC1 was subsequently added (about 200 mL) to adjust the pH of the mixture to 0-1, at which point a clear solution was obtained. The solution was stirred at RT overnight. The reaction mixture was then concentrated by vacuum distillation (80-130 mbar), maintaining the internal temperature below 35°C. Once the distillation subsided, the mixture was cooled in an ice- bath and aq NaOH (50%, about 100 mL) was added to adjust the pH to 8-9, while maintaining the internal temperature below 25°C. The off-white suspension was stirred at RT overnight and filtered. The isolated wet cake was dispersed in H₂0 (100 mL), filtered, rinsed with H₂0 (4 x 10 mL), and dried in vacuo at about 60°C until no further weight loss was observed to afford the title compound (55.6 g, 95%; 22% water by Karl Fischer titration). 1H NMR (DMSO-d₆) δ ppm 2.43 (s, 3H), 4.90 (s, 2H), 5.25 (br s, 1H), 8.21 (s, 1H), 8.38 (s, 1H), 12.66 (br s, 1H); ¹³C NMR (DMSO-d₆) δ ppm 15.12, 56.13, 82.19, 117.07, 117.14, 125.88, 136.09, 139.61, 146.69, 146.81.

[0151] Method B: To a 200 gallon glass-lined reactor (reactor #1) were charged 3-cyano- 5-methyl-lH-pyrrolo[2,3-¾]pyridine-4-carboxylic acid (21.06 kg), 1,1-carbonyldiimidazole (25.5 kg), DMAc (4.71 kg), and THF (140.52 kg). The contents of reactor #1 were heated to 50-55°C over a 1 hour period, during which gas evolution was observed. The mixture was kept at this temperature for an additional 3-4 hours and was subsequently cooled to 20- 25°C. A second 200 gallon glass-lined reactor (reactor #2) was charged with NaBH₄ (10.3 kg). A solution of NaOH (0.64 kg) in H₂0 (80.8 kg) was slowly transferred to reactor #2 in portions over about 90 minutes using a transfer pump. Gas evolution was observed during the transfer. Upon completing the transfer, the internal temperature of reactor #2 was adjusted to about 25°C. Next, the contents of reactor #2 were slowly pressure-transferred to reactor #1 over about 1 hour period, keeping reactor #1 under a nitrogen purge. After stirring the contents of reactor #1 at 20-25°C for 12-13 hours, a solution of NaBH₄ (1.54 kg) in H₂0 (12.6 kg) was charged to reactor #1, and the contents were stirred at 20-25°C for an additional 2-3 hours. While still under a nitrogen purge, concentrated HCl (50.54 kg) was slowly charged to reactor #1 over 45 minutes using a pump, resulting in pH=4.60. The maximum temperature recorded was 30.5°C (an exotherm and large amounts of hydrogen gas evolution were observed). Additional concentrated HCl (10 kg) was charged to reactor #1, which resulted in pH=1.43. Next, the contents of reactor #1 were heated to about 45°C and kept at this temperature for about 4 hours, after which additional concentrated HCl (1.0 kg) was added. The contents of reactor #1 were stirred for 13-15 hours at about 45°C and then cooled to about 25°C. The contents of reactor #1 were vacuum distilled until the THF was removed, and the batch was held at about 25°C under vacuum for about 30 minutes. The pH of the contents of reactor #1 was adjusted by charging a solution of KOH (23 kg) in H₂0 (46 kg) to reactor #1 over a 1 hour period, while maintaining an internal temperature of 15-20°C. This resulted in pH=8.03. The contents of reactor #1 were agitated at 20-25°C for approximately 4 hours before the solids in reactor #1 were collected by filtration using a stainless steel Nutsche filter. The reactor was rinsed with H₂0 (40 kg), and the rinse was transferred onto the filter cake. The wet filter cake was dried by suction, then transferred to an oven and dried at about 40°C under vacuum to afford the title compound (17.83 kg, 91%).

[0152] D. 4-(Hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylic acid

[0153] Method A: To a 250-mL 3-neck flask equipped with overhead stirrer, condenser, and thermocouple was added 4-(hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3- carbonitrile (18.99 g; contains 22 wt% H₂0) followed by concentrated HC1 (120 mL). The reaction mixture was stirred at RT for 3 hours. More concentrated HC1 (30 mL) was added and the mixture was stirred at RT for 1 hour before it was slowly heated to 45°C. Shortly after the reaction mixture reached 45°C, precipitation was observed. Water (150 mL) was added and the reaction mixture was heated at 60°C overnight. Heating was stopped and the reaction mixture was slowly cooled to <10°C with a water/ice bath. Next, a solution of K₃PO₄ (197g, 928 mmol) in water (200 mL) was added to the reaction mixture until the internal pH was 3-3.5, targeting a pH of about 3.2. Once the pH had stabilized, the mixture was stirred at RT for 1 hour, and then filtered. The filter cake was washed with water (2 x 40 mL) and air dried for 3 days. The filter cake was subsequently dispersed in H₂0 with overhead stirring, and the pH was adjusted to about 10 using 50% NaOH solution, upon which a clear solution was obtained. Then, the pH was adjusted back to pH=3-3.5 using 85% H₃PO₄ (about 40 mL). The internal temperature was kept below 30°C. The final pH was 3.36. The mixture was stirred for 1 hour before filtering and washing the solids with water. The solids were dried in a vacuum oven at 60°C overnight to give the title compound a light pink solid (14.12g, 87%). 1H NMR (DMSO-d₆) δ ppm 2.48 (s, 3H), 5.13 (s, 2H), 8.21 (s, 1H), 8.26 (s, 1H), 9.26 (br s), 12.85 (br s, 1H); ¹³C NMR (DMSO-d₆) δ ppm 15.79, 57.61, 107.46, 118.23, 126.26, 135.70, 141.45, 144.80, 145.23, 165.75.

[0154] Method B: 4-(Hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carbonitrile (10.0 kg, 53.4 mol) was charged to a 100 gallon reactor. Concentrated HC1 (70.0 L) was added and the temperature was adjusted to 55-65°C. A precipitate started to form within ten minutes and the mixture was held at 55-65°C for 50 minutes. Water (70.0 L) was added over 55 minutes and the suspension was stirred for 16 hours at 55-65°C. Additional water (60.0 L) was added over 35 minutes and the temperature was adjusted to 20-25°C. The batch was filtered and washed with water (2 x 20 L). The cake was conditioned under vacuum for three days and was subsequently dried under reduced pressure at 40°C until a constant weight was achieved. This afforded an HCl-salt of the title compound as an off- white solid (11.33 kg, 87%; 92.8% AUC purity by HPLC; 0.57% water by Karl Fischer titration).

[0155] EXAMPLE 10: 4-Formyl- -methyl-7H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

[0156] A. Methyl 4-(hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylate

[0157] To a 50 mL flask were added, in sequence and with magnetic stirring, 4- (hydroxymethyl)-5 -methyl- lH-pyrrolo[2,3-¾]pyridine-3-carboxylic acid hydrochloride (1.00 g, 4.12 mmol), MeOH (20 mL, 494 mmol), and concentrated sulfuric acid (0.659 mL, 12.36 mmol). The reaction mixture was heated at reflux (about 65°C) overnight. The resulting homogeneous solution was cooled to RT and was slowly added to ice water (50 mL). Following the addition, the pH of the mixture was about 1. The mixture was subsequently cooled in an ice bath. While maintaining the internal temperature below 10°C, saturated aq NaHC0₃ was added until the pH was about 7. The mixture was filtered at about 8°C to isolate a solid precipitate, which was washed with water (2 x 5 mL), air dried for 1 hour, and then dried in a vacuum oven at 70°C overnight to afford the title compound as a white crystalline solid (0.75 g, 83%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 2.44 (s, 3H), 3.79 (s, 3H), 4.78 (t, J=5.9 Hz, 1H), 5.09 (d, J=6.1 Hz, 2H), 8.14 (s, 1H), 8.19 (s, 1H), 12.38 (br s, 1H); ¹³C NMR (DMSO-d₆) δ ppm 15.8, 51.2, 57.6, 105.5, 116.2, 125.9, 134.5, 140.9, 145.8, 148.6, 164.8.

[0158] B. Methyl 4-formyl-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylate

[0159] To a 15 mL flask equipped with magnetic stir bar and thermocouple was added methyl 4-(hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylate (612 mg, 2.78 mmol) followed by dimethylacetamide (DMAc) (6 mL). The mixture was stirred for 5 minutes in an ice bath (internal temperature 1.2°C). Dess-Martin Periodinane (1.41 g, 3.33 mmol) was added as solid, after which solids precipitated from the reaction solution. The ice bath was removed and the reaction mixture was stirred at RT for 1 hour and then cooled in an ice-bath. A mixture of saturated aq Na₂C0₃ (2 mL) and Na₂S₂0₃ (2 mL) was added slowly over a 5 minute period. A light yellow solid precipitated and gas evolution was observed. Following the work-up, the pH of the mixture was about 10. The mixture was stirred for 1 hour at RT and then filtered. The filter cake was washed with water (2 x 3 mL), and then dried under high vacuum at RT overnight to afford the title compound as a white solid (551 mg, 91%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 2.44 (s, 3H), 3.78 (s, 3H), 8.32 (s, 1H), 8.38 (s, 1H), 10.91 (s, 1H), 12.83 (br s, 1H); ¹³C NMR (DMSO-d₆) δ ppm 16.7, 51.3, 105.0, 114.8, 124.3, 134.3, 135.6, 146.9, 148.8, 164.5, 196.0.

[0160] C. 4-Formyl-5-methyl-7H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

[0161] Methyl 4-formyl-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylate (200 mg, 0.917 mmol), water (1.5 mL), and MeOH (1.5 mL) were added to a 20 mL flask equipped with a magnetic stir bar. The mixture was stirred at RT and well-ground lithium hydroxide (110 mg, 4.58 mmol) was added. The addition of LiOH resulted in the dissolution of most of the solids and produced a deep-orange reaction mixture. The reaction mixture was stirred at 45°C overnight and subsequently cooled in an ice-bath to a temperature below 5°C. A IN HC1 solution was added while maintaining the internal temperature below 10°C. At about pH 7, a solid precipitate formed. When the pH of the mixture reached about 2, the mixture was stirred for 30 minutes in an ice bath. The mixture was subsequently filtered to isolate the solids, which were dried under high vacuum at RT overnight to afford the title compound as light pink solid (124 mg, 66%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 2.45 (s, 3H), 8.30 (s, 1H), 10.98 (s, 1H), 8.31 (d, J=3.0 Hz, 1H), 12.69 (br s, 1H); ¹³C NMR (DMSO-d₆) 6 ppm 16.8, 106.1, 115.1, 124.0, 134.2, 135.6, 146.6, 148.9, 165.6, 196.2.

[0162] EXAMPLE 11 : (i?)-l-(3-Methyl-2-(6-methyl-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

[0163] To a 4 mL reaction vial equipped with magnetic stir bar and screw cap was added 4-formyl-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylic acid (100 mg, 0.490 mmol), followed by DMF, Et₃N (49.6 mg, 0.490 mmol), and (i?)-l-(3-cyanoazetidin-l-yl)-3- methyl-l-oxobutan-2-aminium 2,2,2-trifluoroacetate (174 mg, 0.588 mmol). The resulting solution was stirred at RT for 1 hour. Once the imine formation was complete (monitored by 1H NMR), NaCNBH₃ (36.9 mg, 0.588 mmol) was added. The desired intermediate was formed slowly and additional NaCNBH₃ (9.23 mg, 0.147 mmol) was added within the next hour to ensure the completion of the reductive amination step. After reductive amination was complete, EDCI (94 mg, 0.490 mmol) was added directly to the mixture. After 1 hour, more EDCI (50 mg) was added and the reaction mixture was stirred at RT for 3 days. Following reaction, water (1.0 mL) was added while stirring at RT. The pH of the aqueous layer was adjusted to about 7 with saturated aq NH₄C1 solution (3 mL). The resulting mixture was extracted with DCM (2 x 10 mL). The combined organic layers were washed with water (10 mL) and evaporated to dryness to afford crude product as a deep orange- brown foam (crude yield 163 mg, 95%). Purification by flash chromatography

(EtOAc/MeOH = 98.5/1.5) provided the title compound as a light brown solid (55 mg, 32%).

[0164] EXAMPLE 12: (i?)-l-(3-Methyl-2-(6-methyl-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

[0165] A. 4-(Chloromethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylic acid

[0166] Method A: 4-(Hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylic acid (20.64 g, 100 mmol) was suspended in DCM (300 niL). DMF (2.325 mL, 30.0 mmol) was added, and the suspension was stirred at RT for 10 minutes, and then cooled to 0°C. Thionyl chloride (29.2 mL, 400 mmol) was added over a 5 minute period. The reaction mixture was stirred at 0°C for 5 hours and was warmed to RT and stirred for 24 hours. Once the level of unreacted starting material was below 2%, MTBE (200 mL) was added. The reaction mixture was cooled to 5°C and stirred for 60 minutes. The solids were collected by filtration, washed with MTBE (30 mL), and then air-dried on the funnel for 30 minutes by vacuum suction. The solids were then suspended in H₂0 (210 mL) and stirred for 3 hours. The mixture was cooled to 5°C. Aqueous NaOH (20%) was added to adjust the pH of the mixture to 2, while maintaining the internal temperature between 6°C and 10°C. After the pH adjustment, the mixture was stirred at 10°C for 20 minutes and then filtered. The solids were washed with H₂0 (150 mL) and dried under high vacuum at 60°C overnight to afford the title compound (19.35 g, 86%). 1H NMR (400 MHz, DMSO- ₆) δ ppm 2.47 (s, 3H),

5.69 (s, 2H), 8.2 (s, 1H), 8.22 (s, 1H), 12.13 (s br, 1H), 12.44 (s, 1H); ⁱC NMR (400 MHz, DMSO- ₆) 6 ppm 15.2, 41.35, 106.17, 116.00, 126.19, 135.11, 136.61, 146.65, 148.76,

165.38.

[0167] Method B: 4-(Hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylic acid hydrochloride (11.24 kg, 46.3 mol) was charged to a 100 gallon reactor, followed by dichloromethane (101.0 L) and N,N-dimethylformamide (17.9 L, 231.6 mol). The temperature was adjusted to 35-45°C and thionyl chloride (13.0 L, 178.1 mol) was added over 1.2 hours. The batch was held at 35-45°C for 20 hours, then cooled to 13°C and transferred into a clean 200 L polypropylene drum. Dichloromethane (18.0 L) was used to rinse the remainder of the reaction mixture into the drum. Water (112.0 L) was pre-cooled to 5°C and charged to the 100 gallon reactor. The reaction batch in the 200 L drum was transferred over 50 minutes to the reactor containing the cold water while maintaining the temperature <15°C. Dichloromethane (7.0 L) was used to rinse the remainder in the drum back into the 100 gallon reactor. The batch temperature was adjusted to 0-10°C, held for one hour, and then filtered. The cake was washed with water (2 x 22.5 L) and the wet cake was returned to the reactor. Water (112.0 L) and acetonitrile (11.3 L) were added. The resulting suspension was stirred for two hours at 15-25°C and filtered. The cake was washed with water (2 x 22.5 L). The filter cake was conditioned for 17 hours and was subsequently transferred to trays and dried under reduced pressure at 50°C until a constant weight was achieved. This afforded the title compound as an off-white solid (8.36 kg, 80%; 95.9% AUC purity by HPLC; 0.17% water by Karl Fischer titration).

[0168] B. (i?)-l-(3-Methyl-2-(6-methyl-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin- 4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

[0169] Method A : (R)- 1 -(2- Amino-3 -methylbutanoyl)azetidine-3 -carbonitrile

hydrochloride (2.91 g, 13.35 mmol) was suspended in MeCN (30 mL). Next, 4- (chloromethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylic acid (3 g, 13.35 mmol) was added, followed by DIPEA (6.06 mL, 34.7 mmol). The reaction mixture was stirred at RT for 24 hours. Then, M-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (3.07 g, 16.03 mmol) was added, and the reaction mixture was stirred for another 16 hours at RT. The reaction mixture was then concentrated to about one third of its original volume. Aqueous sodium chloride solution (10%>, 66 g) was added. The mixture was cooled to 4°C, stirred for 60 minutes, and then filtered. The solids were washed with cold water (30 mL) and dried under high vacuum at 60°C for 20 hours to afford crude product (3.315 g), which was suspended in THF (53 mL) and MeOH (13 mL) and heated at 50°C to form a clear solution. Activated carbon (Darco G60, -100 mesh) was added at 50°C. The mixture was stirred for 60 minutes while allowing it to cool to RT. The activated carbon was removed by filtration through a pad of Celite, which was rinsed with a mixture of THF (12 mL) and MeOH (3 mL), and then THF (10 mL). The combined filtrate was distilled at 42°C and 380 mbar to collect 50 mL solvent. Ethanol (30 mL) was added.

Distillation was resumed at 42°C with vacuum of 250 mbar to remove 20 mL of solvent. Ethanol (30 ml) was added. Distillation resumed at 45°C, 160 mbar to remove 40 mL of solvent. Solid gradually crystallized during this process. The slurry was stirred at 50°C for 30 minutes and then slowly cooled to RT over a 3 hour period. The solid was collected by filtration, washed with EtOH (20 mL) and dried at 60°C under high vacuum for 16 hours to afford the title compound (2.695 g, 57%).

[0170] Method B: 4-(Chloromethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylic acid (7.87 kg), (i?)-l-(2-amino-3-methylbutanoyl)azetidine-3 -carbonitrile hydrochloride (8.38 kg), water (1.57 L), acetonitrile (29.9 L), and N,N-diisopropylethylamine (15.9 L, 2.6 eq) were charged to a 30 gallon reactor. After heating the solution to 35-45°C for 18.5 hours, the batch was cooled to 10°C and held at 5-15°C for two hours before filtration. The reactor was rinsed with 5% water in acetonitrile (2 x 7.9 L) and the rinse was transferred onto the filter cake. The filter cake was conditioned for 19 hours and was subsequently transferred to an oven and dried under reduced pressure for 19.5 hours at 40°C until the material contained 0.4 wt % acetonitrile by 1H NMR and 4.8% water by Karl Fischer titration. This afforded (i?)-4-(((l -(3 -cyanoazetidin-l-yl)-3 -methyl- 1 -oxobutan-2- yl)amino)methyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carboxylic acid as a yellow crystalline solid (10.33 kg, 80%; 97.3% AUC purity by HPLC).

[0171] (R)-4-(((l -(3-Cyanoazetidin- 1 -yl)-3 -methyl- 1 -oxobutan-2-yl)amino)methyl)-5- methyl-lH-pyrrolo[2,3-£]pyridine-3-carboxylic acid (10.32 kg, 27.9 mol), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (6.95 L, 36.3 mol), and isopropyl alcohol (72.0 L) were charged to a 30 gallon reactor. The mixture was stirred at 15-25°C for 18 hours. The batch was cooled to -5°C and held for two hours before it was filtered. The filter cake was washed with isopropyl alcohol (10.3 L), conditioned for 22.5 hours under vacuum, and then transferred to an oven and dried under reduced pressure at 50°C until a constant weight was achieved. This afforded the crude title compound as a brown solid (9.34 kg, 95%; 98.3% AUC purity by HPLC; 0.67% water by Karl Fischer titration).

[0172] Crude (i?)-l-(3-methyl-2-(6-methyl-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin- 4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile was further purified as described below.

[0173] Purification Method 1: Into a 50 L reactor were charged crude (i?)-l-(3-methyl-2- (6-methyl-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)butanoyl)azetidine-3- carbonitrile (1.3 kg, 3.7 mol), ethanol (1.3 L), water (10.8 L), and concentrated HCl (0.88 L, 2.88 eq). The solution was heated to 40°C. The solution was held at 40°C for 4.2 hours, after which a 22% phosphate buffer solution (1.895 kg of K₂HP0₄ and 6.73 L of water) was slowly charged to the reaction mixture. After approximately 35-40% of the phosphate buffer solution had been added (about 3 kg of solution), seed crystals (1.3 g, 0.001 eq) were added to the solution. After the addition of more of the phosphate buffer solution

(approximately 5%) and stirring for 15 minutes, significant crystallization had occurred. The remaining portion of the buffer solution was then charged to the reactor over 35 minutes. The resulting suspension was stirred at 40°C for 25 minutes and cooled to 15- 25°C. After aging the suspension at 15-25°C for 30 minutes, the suspension was filtered, and the filter cake was washed with water (5 x 1.3 L). The pH of the final wash was only 5.5 so five additional washes were added. The pH of these washes did not increase, so the cake was conditioned under vacuum for 1.7 hours, and then transferred to an oven and dried under reduced pressure for four days at 40°C. This afforded (i?)-l-(3-methyl-2-(6-methyl-3- oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile as an off-white solid (1.13 kg, 87%; 98.5% AUC purity by HPLC; 0.12% water by Karl Fischer titration).

[0174] Purification Method 2: Ethanol (6.0 L), water (25 L), and concentrated HC1 (2 L, 2.88 eq) were charged to a 45 L glass carboy. Crude (i?)-l-(3-methyl-2-(6-methyl-3- oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile (6.0 kg, 3.7 mol) was charged to a 100 L reactor and the HCl/FLO/ethanol solution was added to it. The mixture was stirred at 20-25°C until a black solution was obtained. The solution was circulated through a lenticular filter equipped with a carbon pad. After circulating for 45 minutes, the color had lightened to a dark brown solution. Additional activated carbon (Norit Darco G-60, 600 g) was charged to the filter and the solution was circulated for another 55 minutes. This provided an additional slight reduction in the color of the solution and more activated carbon was added (900 g). The solution was circulated through the filter for another 20 minutes. Then, a 22% phosphate buffer solution (8.75 kg of Κ₂ΗΡ0₄ and 31.0 L of water) was slowly charged to the reaction mixture. After

approximately 40% of the phosphate buffer solution had been added (approximately 15.8 kg of solution) over 1.1 hours, seed crystals (6.0 g, 0.001 eq) were added to the solution. The seed crystals did not dissolve. After stirring the mixture for approximately 12 minutes, crystallization had occurred, and the remainder of the buffer solution was charged to the reactor over 1.3 hours. The resulting suspension was stirred at 15-25°C for 50 minutes and then filtered. The filter cake was washed successively with water (6 x 6.0 L) and with i- PrOAc (6.0 L) and subsequently conditioned under vacuum for 14 hours. Following another wash with -PrOAc (6 L) and conditioning for an additional 5 hours, the filter cake was transferred to an oven and dried under reduced pressure at 40°C for six days. This afforded (i?) 3-methyl-2-(6-methyl-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)- yl)butanoyl)azetidine-3-carbonitrile as an off- white solid (4.85 kg, 81%; 99.8% AUC purity by HPLC; 0.2 wt % water by Karl Fischer titration).

[0175] EXAMPLE 13: 5-Methyl-lH-pyrrolo[2,3-¾]pyridine-4-carbaldehyde

[0176] A. (5-Methyl-lH-pyrrolo[2,3-¾]pyridin-4-yl)methanol

[0177] 4-(Hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-¾]pyridine-3-carbonitrile (1 g, 5.34 mmol) was dissolved in aq sulfuric acid (50%, 10 mL) to form a light yellow solution. The solution was heated to 70°C for 16 hours until the reaction was completed. The reaction mixture was cooled to RT and aq NaOH (20%>) was added to adjust the pH to 11, while the temperature was maintained below 33°C. During the pH-adjustment, a solid precipitate formed, and the mixture was stirred at RT for 30 minutes. The mixture was filtered to isolate the solids, which were washed with water (30 mL) and dried in a vacuum oven at 60°C for 16 hours to afford the title compound as a white solid (0.81 g, 93%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (s, 3H), 4.76 (s, 2H), 6.60 (m, 1H), 7.36 (m, 1H), 7.99 (s, 1H), 11.41 (s br, 1H); ¹³C NMR (400 MHz, DMSO-d₆) δ ppm 15.18, 58.69, 98.83, 118.96, 121.66, 125.32, 139.42, 143.76, 147.75.

[0178] B.5-Methyl-lH-pyrrolo[2,3-¾]pyridine-4-carbaldehyde

[0179] (5-Methyl-lH-pyrrolo[2,3-¾]pyridin-4-yl)methanol (0.1 g, 0.617 mmol) was dissolved in DMSO (0.3 mL). DCM (0.8 mL) was added, followed by the addition of Et₃N (0.473 mL, 3.39 mmol), upon which solids began to precipitate. The mixture was cooled to -9°C under an inert atmosphere of N₂. Pyridinium sulfur trioxide complex (0.294 g, 1.850 mmol) was added in one portion and the reaction mixture turned into a clear solution. After 3 hours, the reaction was complete and H₂0 (1 mL) was added to the reaction solution. Solids precipitated out gradually. DCM was removed on a rotary evaporator and water (4 mL) was subsequently added. The mixture was stirred for 20 minutes and then filtered to isolate the solids, which were washed with water (2 mL) and dried in a high vacuum oven at 50°C overnight to afford the title compound (79 mg, 80%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 2.7 (s, 3H), 6.99 (m, 1H), 7.70 (m, 1H), 8.24 (s, 1H), 10.69 (s, 1H), 11.95 (s br, 1H); ¹³C NMR (100 MHz, DMSO- d₆) δ ppm 15.04, 99.37, 116.62, 126.18, 129.29, 130.09, 145.07, 149.26, 193.62. [0180] As used in this specification and the appended claims, singular articles such as "a," "an," and "the," may refer to a single object or to a plurality of objects unless the context clearly indicates otherwise. Thus, for example, reference to a composition containing "a compound" may include a single compound or two or more compounds. It is to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those of skill in the art upon reading the above description. Therefore, the scope of the invention should be determined with reference to the appended claims and includes the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patents, patent applications and publications, are herein incorporated by reference in their entirety and for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A method of making a compound of formula 1 ,

1

or a pharmaceutically acceptable salt thereof, wherein

R¹ is selected from optionally substituted C3-8 cycloalkyl, optionally substituted

C3-6 heterocycloalkyl, optionally substituted C_6-14 aryl, optionally substituted Ci_io heteroaryl, and optionally substituted Ci_₆ alkyl; and

R² is selected from hydrogen, halo, and Ci_₄ alkyl;

the method comprising:

(a) reacting a compound of form la 5

with a compound of formula 6,

R¹-NH₂

6

in the presence of a base to give a compound of formula 7,

wherein R¹ in formula 6 and formula 7, and R² in formula 5 and formula 7, are each as defined for formula 1, and X¹ in formula 5 is a leaving group;

(b) reacting the compound of formula 7 under amide bond-forming conditions; and

(c) optionally converting the compound of formula 1 to a pharmaceutically acceptable salt.

2. The method according to claim 1, further comprising converting a hydroxy moiety of formula 4,

to a leaving group, X¹, to give the compound of formula 5, wherein R² in formula 4 is as defined for formula 1.

3. The method according to claim 2, further comprising hydro lyzing a cyano moiety of a compound of formula 3,

to give the compound of formula 4, wherein R² in formula 3 is as defined for formula 1.

4. The method according to claim 3, further comprising reducing a carboxy moiety of a compound of formula 2,

to give the compound of formula 3, wherein R² in formula 2 is as defined for formula 1.

5. A method of making a compound of formula 1 ,

1

or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from optionally substituted C3-8 cycloalkyl, optionally substituted

C₃_6 heterocycloalkyl, optionally substituted C_6-14 aryl, optionally substituted Ci_io heteroaryl, and optionally substituted Ci_₆ alkyl; and

R² is selected from hydrogen, halo, and Ci_₄ alkyl;

the method comprising:

(a) reacting a compound of formula 1 1

1 1

with CO in the presence of a palladium catalyst and a base, wherein R¹ and R² in formula 1 1 are each as defined for formula 1 , R³ is selected from hydrogen and an amine protective group, and X² is halo;

(b) optionally removing the amine protective group; and

(c) optionally converting the compound of formula 1 to a pharmaceutically acceptable salt.

6. The method according to claim 5, further comprising reacting a compound of formula 10,

10

with a compound of formula 6,

R¹-NH₂

6

in the presence of a reducing agent to give a compound of formula 1 1 , wherein R¹ in

formula 6 and R² in formula 10 are each as defined for formula 1 , X² in formula 10 is as defined for formula 1 1 , and R³ is an amine protective group.

7. The method according to claim 6, further comprising halogenating a compound of formula 9,

wherein R² in formula 9 is as defined for formula 1.

8. The method according to any one of the preceding claims, wherein the compound of formula 1 is selected from:

(iS)-4-(l -oxo- 1 -(pyrrolidin- 1 -yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-

<ie][2,6]naphthyridin-3(lH)-one;

(i?)-4-( 1 -oxo- 1 -(pyrrolidin- 1 -yl)butan-2-yl)-4,5-dihydropyrrolo[4,3 ,2-

<ie][2,6]naphthyridin-3(lH)-one;

(i?)-4-(3-methyl-l-oxo-l-(pyrrolidin-l-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-

<ie][2,6]naphthyridin-3(lH)-one;

(i?)-4-(4-methyl- 1 -oxo- 1 -(pyrrolidin- 1 -yl)pentan-2-yl)-4,5-dihydropyrrolo[4,3 ,2-

<ie][2,6]naphthyridin-3(lH)-one;

(i?)-N-cyclopentyl-3-methyl-2-(3-oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-

4( lH,3H,5H)-yl)butanamide;

(2i?,3i?)-N-cyclopentyl-3-methyl-2-(3-oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-

4( lH,3H,5H)-yl)pentanamide;

(2i?,35)-N-cyclopentyl-3-methyl-2-(3-oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-

4( lH,3H,5H)-yl)pentanamide;

(i?)-N-cyclopentyl-2-cyclopropyl-2-(3-oxopyrrolo[4,3,2-<ie][2,6]naphthyridin-

4(lH,3H,5H)-yl)acetamide;

(i?)-N-cyclopentyl-3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-

4( lH,3H,5H)-yl)butanamide;

(i?)-N,2-dicyclopentyl-2-(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)- yl)acetamide;

(i?)-N-cyclopentyl-4,4,4-trifluoro-2-(3-oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-

4( lH,3H,5H)-yl)butanamide;

(i?)-N-cyclopentyl-3-hydroxy-3-methyl-2-(3-oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-

4( lH,3H,5H)-yl)butanamide; (i?)-2-(6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3-cyano-

N-cyclopentylpropanamide;

N-cyclopentyl -(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)- yl)cyclopentanecarboxamide;

(i?)-2 6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-N-

(cyanomethyl)-3-methylbutanamide;

l-((i?)-2-(6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3- methylbutanoyl)pyrrolidine-3-carbonitrile;

(i?) 2 6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3- methylbutanoyl)piperidine-4-carbonitrile;

(i?)-2 6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-N-(4- cyanophenyl)-3-methylbutanamide;

(i?)-2 6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-N-(3- cyanophenyl)-3-methylbutanamide;

(i?)-2 6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-N-((S)-l- cyanobutan-2-yl)-3-methylbutanamide;

(i?)-2 6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-N-((i?)-l- cyanobutan-2-yl)-3-methylbutanamide;

(i?) 2 6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3- methylbutanoyl)azetidine-3-carbonitrile;

(i?)-2 6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-N-(2- cyanoethyl)-3,3-dimethylbutanamide;

(i?) 2 6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3,3- dimethylbutanoyl)azetidine-3-carbonitrile;

(i?) 2 6-fluoro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3- methylbutanoyl)azetidine-3-carbonitrile;

(i?)-2 6-fluoro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3- methylbutanoic acid;

(2i?)-2 6-fluoro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3- methyl-N-(tetrahydrofuran-3-yl)butanamide;

(i?)-2 6-fluoro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3-methyl-

N-( 1 , 1 -dioxidotetrahydrothien-3 -yl)butanamide; (i?)-2 6-fluoro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3-methyl-

N-(2-(methylsulfonyl)ethyl)butanamide;

(i?)-N-(l , l-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(6-fluoro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3-methylbutanamide;

4- {(IR)-1 -[(1 , 1 -dioxidothiomorpholin-4-yl)carbonyl]-2-methylpropyl} -6-fluoro-4,5- dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-one;

(i?)-N-(cyclopropylmethoxy)-2-(6-fluoro-3-oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-

4(lH,3H,5H)-yl)-3-methylbutanamide;

(2i?)-N-(3,3-difluorocyclopentyl)-2-(6-fluoro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3-methylbutanamide;

(i?)-3-(fluoromethyl)-l-(3-methyl-2-(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-

4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;

(i?) 2 6-fluoro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3- methylbutanoyl)-3 -methylazetidine-3 -carbonitrile;

(i?)-3-methyl-l-(3-methyl-2-(3-oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-

4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;

(i?)-4-(l-morpholino-l-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2- de][2,6]naphthyridin-3(lH)-one;

(R)-4-( 1 -(4-methylpiperazin- 1 -yl)- 1 -oxobutan-2-yl)-4,5-dihydropyrrolo[4,3 ,2-

<ie][2,6]naphthyridin-3(lH)-one;

4-((2R)- 1 -(3-hydroxypyrrolidin-l -yl)- 1 -oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2- de][2,6]naphthyridin-3(lH)-one;

(i?)-N-cyclopentyl-2-(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)- yl)butanamide;

4-((2R)- 1 -(3-(4-fluorophenyl)pyrrolidin- 1 -yl)-l -oxobutan-2-yl)-4,5- dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-one;

4-((2R)- 1 -(3-(dimethylamino)pyrrolidin- 1 -yl)- 1 -oxobutan-2-yl)-4,5- dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-one;

4-((2R)- 1 -(3-(methoxymethyl)pyrrolidin- 1 -yl)-l -oxobutan-2-yl)-4,5- dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-one;

4-{(2R)- 1 -(3-methylpiperidin- 1 -yl)- 1 -oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2- de][2,6]naphthyridin-3(lH)-one; (R)-4-( 1 -(4-(2-hydroxypropan-2-yl)piperidin- 1 -yl)- 1 -oxobutan-2-yl)-4,5- dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-one;

(R)-4-( 1 -(4-(methylsulfonyl)piperazin- 1 -yl)- 1 -oxobutan-2-yl)-4,5 - dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-one;

(R)-4-( 1 -oxo- 1 -(4-(pyridin-2-yl)piperazin- 1 -yl)butan-2-yl)-4,5- dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-one;

(i?)-N-cyclopropyl-2-(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)- yl)butanamide;

(i?)-N-(cyclopropylmethyl)-2-(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-

4( lH,3H,5H)-yl)butanamide;

(i?)-N-isobutyl-2-(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)- yl)butanamide;

(i?)-N-isobutyl-N-methyl-2-(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)- yl)butanamide;

(2i?)-N-(l-hydroxypropan-2-yl)-2-(3-oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-

4( lH,3H,5H)-yl)butanamide;

(i?)-N-(2-hydroxy-2-methylpropyl)-2-(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-

4( lH,3H,5H)-yl)butanamide;

(i?)-N-((5)-2,3-dihydroxypropyl)-2-(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-

4( lH,3H,5H)-yl)butanamide;

(i?)-2-(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-N- phenylbutanamide;

(i?)-N-(l-(methylsulfonyl)piperidin-4-yl)-2-(3-oxopyrrolo[4,3,2- de] [2,6]naphthyridin-4( lH,3H,5H)-yl)butanamide;

(2i?)-2-(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-N-

((tetrahydrofuran-2-yl)methyl)butanamide;

(2i?)-N-(l-cyanoethyl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-

4(lH,3H,5H)-yl)-3-methylbutanamide;

(R)-4-(l -(3,3-difluoroazetidin- 1 -yl)-3 -methyl- 1 -oxobutan-2-yl)-6-fluoro-4,5- dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-one;

(R)-4-(l -(1 , 1 -dioxidothiazolidin-3-yl)-3-methyl- 1 -oxobutan-2-yl)-6-fluoro-4,5- dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-one; (i?)-2 6-fluoro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-N,3- dimethyl-N-(2-(methylsulfonyl)ethyl)butanamide;

(i?)-N-(cyanomethyl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-

4(lH,3H,5H)-yl)-N,3-dimethylbutanamide;

(i?)-4-(l-(3-(difluoromethyl)azetidin-l-yl)-3-methyl-l-oxobutan-2-yl)-6-fluoro-4,5- dihydropyrrolo[4,3,2-(ie][2,6]naphthyridin-3(lH)-one;

(i?) 3-methyl-2 3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)- yl)butanoyl)azetidine-3-carbonitrile;

(i?)-l-(3,3-dimethyl-2-(3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)- yl)butanoyl)azetidine-3-carbonitrile;

(i?)-N-(cyanomethyl)-3,3-dimethyl-2-^

4( lH,3H,5H)-yl)butanamide;

(5)-l-((i?)-2 6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3- methylbutanoyl)pyrrolidine-2-carbonitrile;

(i?) (i?)-2 6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)-yl)-3- methylbutanoyl)pyrrolidine-2-carbonitrile;

(2^,45)-l-((i?)-2-(6-chloro-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-4(lH,3H,5H)- yl)-3-methylbutanoyl)-4-fluoropyrrolidine-2-carbonitrile;

(i?)-l-(3,3-dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-

4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;

(i?)-l-(3-methyl-2-(6-methyl-3-oxopyrrolo[4,3,2- e][2,6]naphthyridin-

4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;

a stereoisomer of any one of the aforementioned compounds; and

a pharmaceutically acceptable salt of any one of the aforementioned stereoisomers or compounds.