WO2012078802A1 - Préparation de 4,5-dihydropyrrolo[4,3,2-de][2,6]naphtyridin-3(1h)-ones substituées - Google Patents

Préparation de 4,5-dihydropyrrolo[4,3,2-de][2,6]naphtyridin-3(1h)-ones substituées Download PDF

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WO2012078802A1
WO2012078802A1 PCT/US2011/063811 US2011063811W WO2012078802A1 WO 2012078802 A1 WO2012078802 A1 WO 2012078802A1 US 2011063811 W US2011063811 W US 2011063811W WO 2012078802 A1 WO2012078802 A1 WO 2012078802A1
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Prior art keywords
naphthyridin
formula
oxopyrrolo
methyl
compound
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PCT/US2011/063811
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English (en)
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Mark E. Adams
Young K. Chen
Qing Dong
Toufike Kanouni
Chunrong Ma
Wolfgang Reinhard Ludwig Notz
Michael B. Wallace
Yuxin Zhao
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Takeda Pharmaceutical Company Limited
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Publication of WO2012078802A1 publication Critical patent/WO2012078802A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems

Definitions

  • 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.
  • Janus Kinase 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 Signal Transducer and Activator of Transcription
  • 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.
  • 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.
  • allergic rhinitis allergic asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythemato
  • the present invention provides comparatively efficient and cost-effective methods for preparing compounds of formula 1 ,
  • R 1 is selected from optionally substituted C 3 _ 8 cycloalkyl, optionally substituted C 3 _ 6
  • heterocycloalkyl optionally substituted C 6-14 aryl, optionally substituted C 1-10 heteroaryl, and optionally substituted Ci_ 6 alkyl;
  • R 2 is selected from hydrogen, halo, and Ci_ 4 alkyl.
  • One aspect of the present invention provides a method for preparing compounds of formula 1 , the method comprising:
  • Another aspect of the present invention provides a method for preparing compounds of formula 1, the method comprising:
  • R 1 and R 2 in formula 11 are each as defined for formula 1 , R 3 is selected from hydrogen and an amine protective group, and X 2 in formula 11 is halo;
  • Another aspect of the invention provides intermediate compounds used in the methods for preparing the compounds of formula 1.
  • 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 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.
  • 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.
  • 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.
  • C 2 _ 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.
  • Ci_ 4 alkyl refers to a straight or branched alkyl chain having from one to four carbon atoms.
  • 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, C 2 _ 4 alkenyl, Ci_ 4 alkoxy, Ci_ 4 thioalkoxy, Ci_9 amide, Ci_ 5
  • Ci_ 6 alkyl refers to a straight or branched alkyl chain having from one to six carbon atoms.
  • 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, C 2 _ 4 alkenyl, Ci_ 4 alkoxy, Ci_ 4 thioalkoxy, C 1-14 amide, Ci_ 5
  • Ci_ 8 sulfonyl optionally substituted C 1-10 heteroaryl, optionally substituted C 3 _ 6 heterocycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Ci_g sulfonyl refers to a sulfonyl linked to a Ci_ 6 alkyl group
  • Ci_ 4 alkoxy refers to a Ci_ 4 alkyl attached through an oxygen atom.
  • Ci_ 4 alkoxy refers to a Ci_ 4 alkoxy optionally having from 1 to 6 substituents independently selected from the group consisting of C 2 _ 4 alkenyl, Ci_ 4 alkoxy, Ci_ 9 amide, Ci_ 5 oxycarbonyl, cyano, C 3 _ 8 cycloalkyl, halo, hydroxy, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Ci_9 amide refers to an amide having two groups independently selected from the group consisting of hydrogen and Ci_ 4 alkyl, e.g., -CONH 2 , -CONHCH 3 , and -CON(CH 3 ) 2 .
  • 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., -CONH 2 , -CONHCH 3 , and -CON(CH 3 ) 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 C 3 _g cycloalkyl, optionally substituted C 3 _ 6 heterocycloalkyl, optionally substituted C 6-14 aryl, and optionally substituted C 1-10 heteroaryl, e.g., -CONH- (cyclopentyl), -CONH-(aryl), -CONH-CH 2 -(phenyl), and so on.
  • Ci_ 4 alkyl e.g., -CONH 2 , -
  • Ci_ 7 amido refers to a -NHC(0)R group in which R is Ci_ 6 alkyl.
  • Ci_ 5 carbamoyl refers to an O- or N-linked carbamate having a terminal Ci_ 4 alkyl.
  • Ci_ 5 ureido refers to a urea having a Ci_ 4 alkyl.
  • Ci_g alkylamino refers to an amino having one or two Ci_ 4 alkyl.
  • 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.
  • 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.
  • Ci_ 5 oxycarbonyl refers to an oxycarbonyl group (-C0 2 H) and Ci_ 4 alkyl ester thereof.
  • Ci_ 4 alkyl ester thereof refers to an alkyl ring having from three to eight carbon atoms, and includes cyclopropyl, 2-methyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 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, C 2 _ 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.
  • C3_8 cycloalkoxy refers to a C3_8 cycloalkyl attached through an oxygen atom.
  • halogen and halo refer to chloro, fluoro, bromo or iodo.
  • 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.
  • the term includes azetidine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran, hexahydropyrimidine, tetrahydropyrimidine, dihydroimidazole, and the like.
  • heterocycloalkyl optionally substituted on the ring carbons with 1 to 4 substituents independently selected from the group consisting of optionally substituted Ci_ 4 alkyl, C 2 _ 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, C 2 _ 4 alkenyl, C3-8 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C 1-10 heteroaryl, optionally substituted phenyl, and Ci_s sulfonyl.
  • 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.
  • 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.
  • 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 C 3 -6 heterocycloalkyl, and optionally substituted phenyl.
  • 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.
  • an acetyl radical (-C(0)CH 3 ) is contemplated as an oxo substituted alkyl group and a pryidone radical is contemplated as oxo substituted C 1-10 heteroaryl.
  • phenyl refers to a phenyl group optionally having 1 to 5 substituents independently selected from the group consisting of amino, C 2 _ 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.
  • Ci_ 6 sulfonylamido refers to a -NHS(0) 2 -R group wherein R is Ci_ 6 alkyl.
  • Co-6 sulfonylamino refers to a -S(0) 2 NH-R group wherein R is selected from the group consisting of hydrogen and Ci_ 6 alkyl.
  • Ci_ 4 thioalkoxy refers to a Ci_ 4 alkyl attached through a sulfur atom.
  • 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.
  • 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.
  • 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.
  • 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.
  • ZIE geometrical isomers
  • 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.
  • stereochemical configuration of a compound is not specified, then “stereoisomers" refers to possible stereochemical configurations of the compound.
  • substantially pure stereoisomer and variants thereof refer to a sample containing a stereoisomer which comprises at least about 95% of the sample.
  • pure stereoisomer and variants thereof refer to a sample containing a stereoisomer which comprises at least about 99.5% of the sample.
  • phrases "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.
  • 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.
  • THF trifluoroacetic acid
  • THF tetrahydrofuran
  • Ts tosyl
  • 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.
  • R 2 is selected from the group consisting of hydrogen, halo, and Ci_ 4 alkyl.
  • Another embodiment relates to compounds of formula 1 in which R 2 is halo.
  • Ci_ 4 alkyl Ci_ 4 alkyl
  • Another embodiment relates to compounds of formula 1 in which R 2 is methyl.
  • Another embodiment relates to compounds of formula 1 , and optionally any one of the above embodiments a, b, c, d, and e, in which R 1 in formula 1 is optionally substituted C3-8 cycloalkyl.
  • Another embodiment relates to compounds of formula 1, and optionally any one of the above embodiments a, b, c, d, and e, in which R 1 in formula 1 is optionally substituted C3-6 heterocycloalkyl.
  • Another embodiment relates to compounds of formula 1 , and optionally any one of the above embodiments a, b, c, d, and e, in which R 1 in formula 1 is a nitrogen containing C 3 _6 heterocycloalkyl substituted on a ring carbon with Ci_ 4 alkyl and substituted on a ring nitrogen with optionally substituted Ci_ 4 alkyl.
  • Another embodiment relates to compounds of formula 1 , and optionally any one of the above embodiments a, b, c, d, and e, in which R 1 in formula 1 is optionally substituted C 6-14 aryl.
  • Another embodiment relates to compounds of formula 1, and optionally any one of the above embodiments a, b, c, d, and e, in which R 1 in formula 1 is optionally substituted C 1-10 heteroaryl.
  • Another embodiment relates to compounds of formula 1 , and optionally any one of the above embodiments a, b, c, d, and e, in which R 1 in formula 1 is optionally substituted Ci_ 6 alkyl.
  • Another embodiment relates to compounds of formula 1, and optionally any one of the above embodiments a, b, c, d, and e, in which R 1 in formula 1 is Ci_ 6 alkyl having an oxo substituent and an optionally substituted C 3 _ 6 heterocycloalkyl.
  • 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 R 1 in formula 1 is Ci_ 6 alkyl having an oxo substituent and an optionally substituted C 3 _ 6 heterocycloalkyl attached to the same carbon atom of the Ci_ 6 alkyl group.
  • Another embodiment relates to compounds of formula 1 , and optionally any one of the above embodiments a, b, c, d, and e, in which R 1 in formula 1 is Ci_ 6 alkyl substituted with Ci_i4 amide.
  • 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.
  • reaction schemes may omit minor products resulting from chemical transformations (e.g., an alcohol from the hydrolysis of an ester, C0 2 from the decarboxylation of a diacid, etc.).
  • reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).
  • 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.
  • 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).
  • 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.
  • the chemical transformations may also employ one or more compatible solvents, which may influence the reaction rate and yield.
  • the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination.
  • 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
  • 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 X 1 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.
  • the compound of formula 1 may be optionally converted to a pharmaceutically acceptable salt.
  • Substituent R 1 in formula 6 and 7, and substituent R 2 in formula 2, 3, 4, 5, and 7, are each as defined for formula 1.
  • 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 NaBH 4 ; BH 3 -THF; 9-BBN; LiAlH(OCH 3 ) 3 in THF; LiAlH 4 in diethyl ether; A1H 3 in THF; (z ' -Bu) 2 AlH; and NaAlEt 2 H 2 .
  • 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 NaBH 4 in water (e.g., at about 0°C to RT) to give the primary alcohol in formula 3.
  • 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 NaBH 4 to give the primary alcohol in formula 3.
  • the pyrrolopyridine nitrile (formula 2) may be prepared using the method shown in Scheme IV.
  • the primary alcohol (formula 4) is converted to a leaving group (X 1 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
  • arylsulfonates e.g., tosylate, brosylate, closylate, and nosylate
  • the primary alcohol 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 X 1 is mesylate, tosylate, etc.
  • a base e.g., pyridine
  • 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.
  • 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.
  • a catalyst e.g., DCM
  • 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, Et 3 N, CS 2 CO 3 , etc.) to give an amino acid (formula 7),
  • a non- nucleophilic base e.g., DIPEA, Et 3 N, CS 2 CO 3 , etc.
  • 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 include those in which R 1 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.
  • 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 Et 3 N, 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.
  • the reaction may include an optional additive, such as DMAP,
  • HODhbt HODhbt, HOBt, and HOAt, which may accelerate the reaction and/or suppress side reactions (e.g., minimize racemization).
  • Scheme II shows another method for preparing compounds of formula 1.
  • the method includes halogenating the 3-position of an lH-pyrrolo[2,3-3 ⁇ 4]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.
  • a polar aprotic solvent such as ACN, THF or DMF.
  • Substituent R 1 in formula 11 and substituent R 2 in formula 8, 9, 10, and 11, are each as defined for formula 1.
  • Substituent X 2 in formula 9, 10, and 11 is halo, particularly iodo or bromo, and substituent R 3 in formula 10 and 11 is hydrogen or an amine protective group, such as Boc, Cbz or DMB.
  • 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.
  • the reaction is carried out in a solvent, such as THF or dichloromethane or mixtures thereof.
  • a solvent such as THF or dichloromethane or mixtures thereof.
  • 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.
  • 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.
  • Pd(0) or Pd(II) catalyst include (PPh 3 ) 2 PdCl 2 , Pd(OAc) 2 , and (Ph 3 P) 4 Pd, 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 Et 3 N, Na 2 C0 3 or K 3 P0 4 , which is often used at stoichiometric excess (e.g., 2 or 3 eq).
  • a base such as Et 3 N, Na 2 C0 3 or K 3 P0 4
  • 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.
  • 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 Et 3 N, DIPEA, etc.
  • 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 R 5 OH, for example, in the presence of an acid catalyst, such as H 2 S0 4 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 R 3 being H).
  • an acid catalyst such as H 2 S0 4 or HC1
  • an oxidizing agent such as Dess-Martin periodinane
  • the ester moiety (formula 15) may be hydro lyzed by treatment with an acid (e.g., HC1 or H 2 SO 4 ) and excess H 2 0 to give the acid (formula 12) or by treatment with an aqueous inorganic base (e.g., LiOH, KOH, NaOH, CsOH, Na 2 C0 3 , K 2 C0 3 , Cs 2 C0 3 ) 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 R 2 in formula 4, 14, and 15, are each as defined for formula 1, and substituent R 5 in formula 14 and formula 15 is Ci_ 4 alkyl, particularly methyl or ethyl.
  • 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 H 2 S0 4 (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
  • Scheme IV shows a method for preparing the compound of formula 2 in Scheme I.
  • a chloro-oxoacetate (formula 17) is reacted with an appropriately- substituted alkoxyethene (formula 18) in the presence of a non-nucleophilic base (e.g., Et 3 N) and solvent (e.g., dioxane) at a temperature of about 0°C to about 35°C.
  • a non-nucleophilic base e.g., Et 3 N
  • solvent e.g., dioxane
  • Substituent R 2 in formula 2, 18, 19, and 21 are each as defined for formula 1.
  • Substituent R 4 in formula 17, 19, and 21, and substituent R 5 in formula 18 and formula 19 are each independently Ci_ 4 alkyl, and more particularly, methyl or ethyl.
  • the compound of formula 1 can be converted to a
  • a compound of formula 1 may be reacted with an appropriate acid or base to give the desired salt.
  • 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.
  • 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.
  • Useful salts of the compound of formula 1 may include acid addition salts
  • 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.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acids
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and
  • 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,
  • 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.
  • suitable metal cations may include sodium, potassium, magnesium, calcium, zinc, and aluminum cations.
  • 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.
  • 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.
  • 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
  • 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).
  • Geometrical ⁇ cisl trans) isomers may be separated by conventional techniques such as chromatography and fractional crystallization.
  • 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.
  • 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.
  • 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).
  • a suitable solvent e.g., ACN
  • 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).
  • 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.
  • Ammonia refers to a concentrated solution of ammonia in water possessing a specific gravity of 0.88.
  • products of certain preparations and examples are purified by mass-triggered HPLC (e.g., Pump: WatersTM 2525; MS: ZQTM; Software: MassLynxTM), 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 NH 4 HCO 3 in water) and Solvent B (10 mM NH 4 HCO 3 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 VacTM), rotary evaporator, evacuated flask, lyophilizer, etc. Reactions in an inert (e.g., nitrogen) or reactive (e.g., H 2 , 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).
  • an inert e.g., nitrogen
  • reactive e.g., H 2 , CO
  • 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 N 2 for at least 20 minutes. Next, PdCl 2 (dppf) » CH 2 Ci 2 (22 g, 5 mol%>) was added and the reaction mixture was degassed by 3 pump/purge cycles prior to being heated to 90°C.
  • 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).
  • 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%>
  • 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.
  • 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).
  • 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%>).
  • 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.
  • 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%).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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%).
  • Method B In a 500 mL round bottom flask, tert-butyl 4-formyl-3-iodo-5-methyl- lH-pyrrolo[2,3-3 ⁇ 4]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 N 2 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.
  • 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), PdCl 2 (PPh 3 ) 2 (634 mg, 0.90 mmol), and DMF (70 mL), followed by Et 3 N (12.6 mL, 90.0 mmol). The reaction vessel was charged with N 2 (50 psi) and vacuum purged.
  • 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 NaHC0 3 and brine. The aqueous layer was back-extracted once with 5% MeOH/DCM.
  • Method B (R)-tert-Butyl 4-((l-(3-cyanoazetidin-l-yl)-3-methyl-l-oxobutan-2- ylamino)methyl)-3-iodo-5-methyl-lH-pyrrolo[2,3-3 ⁇ 4]pyridine-l-carboxylate (1.55 kg) and PdCl 2 (PPh 3 ) 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 Et 3 N (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%).
  • ammonium hydroxide (29% solution, 2.33 L) was added to the yellow reaction mixture.
  • 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 MgS0 4 (790 g) and charcoal (Darco G-60, 800 g).
  • 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.
  • Method B The jacket of a 300 gallon glass-lined reactor (reactor #1) was heated to approximately 40°C. 73 ⁇ 4rt-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.
  • 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.
  • acetic acid 77.0 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.
  • the contents of reactor #2 were cooled to 6°C, H 2 0 (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.
  • reactor #2 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 H 2 0 (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%).
  • 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.
  • H 2 0 (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 H 2 0 (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%).
  • 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).
  • H 2 0 (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 H 2 0 (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).
  • Method A A 5 L round bottom flask, equipped with an overhead stirrer, was dried with a heat gun under N 2 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.
  • 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%).
  • Method B To a 200 gallon glass-lined reactor were charged Et 3 N (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 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 H 2 0 (170 kg), followed by MTBE (125.9 kg), and the contents were agitated for about 20 minutes at approximately 25°C.
  • 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.
  • 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 H 2 0/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 H 2 0/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%).
  • 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 H 2 0 (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 H 2 0 (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.
  • 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).
  • 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
  • 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[2,3-3 ⁇ 4]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.
  • an aqueous solution of potassium hydroxide (66 kg) in H 2 0 (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.
  • Celite (23.0 kg) was charged to reactor #2.
  • a stainless steel Nutsche filter was conditioned with Celite (3.0 kg) and H 2 0 (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 H 2 0 (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.
  • reactor #2 was washed with H 2 0 (100 kg) and the aqueous wash was discarded as well.
  • the contents of reactor #1 were cooled to about 15°C.
  • a solution of citric acid monohydrate (76 kg) in H 2 0 (150 kg) was prepared.
  • the maximum internal temperature recorded was 15.5°C.
  • the solids in reactor #1 were collected by filtration using a stainless steel Nutsche filter. Reactor #1 was rinsed with H 2 0 (12.5 kg) and the rinse was transferred onto the filter cake.
  • 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 H 2 0 (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.
  • solutions of KOH (40 kg) in H 2 0 (160 kg) and of citric acid monohydrate (51 kg) in H 2 0 (102 kg) were prepared.
  • 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.
  • Method A 3-Cyano-5-methyl-lH-pyrrolo[2,3-3 ⁇ 4]pyridine-4-carboxylic acid (49 g, 244 mmol) and ⁇ , ⁇ -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.
  • the isolated wet cake was dispersed in H 2 0 (100 mL), filtered, rinsed with H 2 0 (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).
  • Method B To a 200 gallon glass-lined reactor (reactor #1) were charged 3-cyano- 5-methyl-lH-pyrrolo[2,3-3 ⁇ 4]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 NaBH 4 (10.3 kg).
  • a solution of NaOH (0.64 kg) in H 2 0 (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.
  • the internal temperature of reactor #2 was adjusted to about 25°C.
  • the contents of reactor #2 were slowly pressure-transferred to reactor #1 over about 1 hour period, keeping reactor #1 under a nitrogen purge.
  • a solution of NaBH 4 (1.54 kg) in H 2 0 (12.6 kg) was charged to reactor #1, and the contents were stirred at 20-25°C for an additional 2-3 hours.
  • 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 H 2 0 (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%).
  • Method A To a 250-mL 3-neck flask equipped with overhead stirrer, condenser, and thermocouple was added 4-(hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-3 ⁇ 4]pyridine-3- carbonitrile (18.99 g; contains 22 wt% H 2 0) 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.
  • Method B 4-(Hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-3 ⁇ 4]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).
  • 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
  • Method A 4-(Hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-3 ⁇ 4]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.
  • Method B 4-(Hydroxymethyl)-5-methyl-lH-pyrrolo[2,3-3 ⁇ 4]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.
  • 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).
  • 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.
  • Method B 4-(Chloromethyl)-5-methyl-lH-pyrrolo[2,3-3 ⁇ 4]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.
  • 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).
  • 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 ⁇ 2 ⁇ 0 4 and 31.0 L of water) was slowly charged to the reaction mixture. After
  • 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.

Abstract

La présente invention concerne des matériaux et des procédés pour préparer des 4,5-dihydropyrrolo[4,3,2-de][2,6]naphtyridin-3(1H)-ones substituées de formule (1). Les composés de formule (1) inhibent un ou plusieurs membres de la famille de la kinase Janus (JAK) de protéine tyrosine kinases cytoplasmiques, et sont utiles pour traiter des troubles, des maladies, et des affections associés au système immunitaire, l'inflammation, et une croissance cellulaire anormale.
PCT/US2011/063811 2010-12-08 2011-12-07 Préparation de 4,5-dihydropyrrolo[4,3,2-de][2,6]naphtyridin-3(1h)-ones substituées WO2012078802A1 (fr)

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CN102780000A (zh) * 2012-07-10 2012-11-14 长安大学 锂离子电池负极材料的制备方法
CN103333096A (zh) * 2013-06-25 2013-10-02 苏州大学 一种化学选择性制备多功能吡咯衍生物的新方法
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102780000A (zh) * 2012-07-10 2012-11-14 长安大学 锂离子电池负极材料的制备方法
CN103333096A (zh) * 2013-06-25 2013-10-02 苏州大学 一种化学选择性制备多功能吡咯衍生物的新方法
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors

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