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WO2025003177A1 - (3-(méthyl(7h-pyrrolo[2,3-d]pyrimidin-4yl)amino)cyclobutyl) carbamate de benzyle ou sel de celui-ci, son procédé de préparation et son utilisation dans la synthèse d'abrocitinib - Google Patents

(3-(méthyl(7h-pyrrolo[2,3-d]pyrimidin-4yl)amino)cyclobutyl) carbamate de benzyle ou sel de celui-ci, son procédé de préparation et son utilisation dans la synthèse d'abrocitinib Download PDF

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WO2025003177A1
WO2025003177A1 PCT/EP2024/067882 EP2024067882W WO2025003177A1 WO 2025003177 A1 WO2025003177 A1 WO 2025003177A1 EP 2024067882 W EP2024067882 W EP 2024067882W WO 2025003177 A1 WO2025003177 A1 WO 2025003177A1
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compound
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salt
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Celeste ARE
Oscar RAMÓN ÚBEDA
Roberto BALLETTE
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Moehs Iberica SL
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Moehs Iberica SL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a new intermediate useful in the synthesis of abrocitinib, to a method for obtaining same, to the use of said intermediate for preparing abrocitinib, and to a method for preparing abrocitinib using said intermediate.
  • Abrocitinib is a Janus kinase JAK1 -inhibiting pharmaceutical active ingredient indicated for the treatment of moderate to severe atopic dermatitis in adult candidates for systemic therapy.
  • Abrocitinib is a compound of formula (VIII)
  • Abrocitinib was approved for medical use in the United States in January 2022 and in Europe in December 2021.
  • benzyl cis-[3-(methylamino)cyclobutyl]carbamate is designated as the synthetic intermediate which reacts with 2,4-dichloro-7-H-pyrrolo-(2,3-d)pyrimidine through an aromatic nucleophilic substitution reaction.
  • formation of the desired sulfonamide takes place in the presence of trimethylsilane derivatives, which are used in superstoichiometric amounts.
  • the 98% yield of the aromatic nucleophilic substitution step is due to the presence of the chlorine atom in position 2 of the pyrimidine ring which activates the chlorine atom in position 4 of said ring as a leaving group.
  • the sulfonamide formation step takes place with yields of between 21 and 65% according to the sulfonyl chloride compound used in said step.
  • abrocitinib synthetic intermediate of the invention which is a compound of formula (I)
  • abrocitinib allows abrocitinib to be prepared with a high yield in two steps and with an overall yield of 78.6%, according to the following scheme
  • the overall yield of said synthesis is surprisingly higher compared to that described in the state of the art using benzyl (cis-3-((2-chloro-7/7-pyrrolo[2,3-d]pyrimidin-4- yl)(methyl)amino)cyclobutyl)carbamate as the starting product, for which a yield of 76% is described for the step of benzyl carbamate group deprotection, which is lower than the overall yield observed using the synthetic intermediate of the invention.
  • the compound of formula (I) can be prepared through aromatic nucleophilic substitution by means of the following reaction with a yield of 98.3%:
  • a first aspect of the invention relates to a compound of formula (I) or a salt thereof wherein the bonds represented by a wavy line are in the c/s configuration.
  • a third aspect of the invention relates to a method of preparing a compound of formula (I) according to the first aspect of the invention which comprises step (a) of reacting a compound of formula (II), wherein the bonds represented by a wavy line are in the c/s configuration, or a salt thereof, with a compound of formula (III) or a salt thereof,
  • the fourth aspect of the invention relates to a method for preparing /V-[c/s-3-(methyl-7/7- pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclobutyl]-1 -propanesulfonamide (abrocitinib), or a salt thereof, characterized in that it comprises:
  • step (g) reacting the compound resulting from step (f) to convert the amino group formed from the benzyl carbamate group of the compound of formula (I) or the salt thereof into a group of formula -NHSO2CH2CH2CH3.
  • Figure 1 shows the X-ray powder diffractogram (XRPD) obtained for the product of formula (I), i.e. , benzyl (3-(methyl(7/7-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate.
  • XRPD X-ray powder diffractogram
  • salt must be understood as an ionic compound formed by a cation of the amino group of the compound of formula (I) or (II), and a counterion (an anion) such as, for example, an anion of an inorganic acid (such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, among others) or an organic acid (such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate, among others).
  • the terms “approximate” and “about”, in reference to a value refer to any value which is comprised in the interval defined by the value ⁇ 5% of said value.
  • the term “acid” refers to a substance capable of donating a proton (to a base).
  • Said substance can be inorganic, as in the case of hydrochloric, nitric, sulfuric, phosphoric, hydrobromic, and boric acids, or organic as in the case of formic, acetic, trifluoroacetic, propionic, oxalic, malic, maleic, fumaric, succinic, citric, tartaric, mandelic, methanesulfonic, p-toluenesulfonic, and benzoic acids.
  • base refers to a substance capable of accepting a proton (from an acid).
  • Said substance can be inorganic, as in the case of hydroxide salts of alkaline metals and carbonate salts of alkaline metals and alkaline earth metals, or organic as in the case of pyridine, imidazole, and tertiary amines of formula NR1R2R3, wherein each R1 , R2, or R3 is an alkyl(Ci-Ce) group.
  • alkaline metal refers to a metal selected from the group consisting of lithium, sodium, potassium, rubidium, cesium, and francium.
  • the alkaline metal is selected from the group consisting of lithium, sodium, and potassium; more preferably, it is sodium or potassium, and even more preferably potassium.
  • the compound of formula (I) or the salt thereof is in a solid form.
  • the compound of formula (I) has an X-ray powder diffractogram measured with CuKa radiation comprising peaks at one or more of 12.0, 13.3, 14.4, 17.8, 19.8, and 23.9 20, all of them with a margin of error of ⁇ 0.2° 20.
  • the compound of formula (I) has an X-ray powder diffractogram measured with CuKa radiation comprising peaks at 12.0, 13.3, 14.4, 17.8, 19.8, and 23.9 20, all of them with a margin of error of ⁇ 0.2° 20.
  • the compound of formula (I) has an X-ray powder diffractogram measured with CuKa radiation essentially like the one of Figure 1.
  • X-ray diffractograms can be recorded using a powder diffraction system with a copper anode which emits CuKa radiation with a wavelength of 1.54 A, particularly following the method described in the examples.
  • the compound of formula (I) has a differential scanning calorimetry (DSC) diagram comprising an endothermic peak having a threshold temperature of about 180.5°C ⁇ 2°C.
  • DSC differential scanning calorimetry
  • the differential scanning calorimetry diagram can be obtained as described in the examples.
  • T onset refers to the temperature resulting from extrapolating the baseline before the start of transition and the baseline during the absorption of energy (tangent of the curve). It can be calculated as defined in the DIN ISO 11357-1 :2016(E) standard.
  • a second aspect of the invention relates to the use of the compound of formula (I) or a salt thereof in the preparation of abrocitinib.
  • the third aspect of the invention relates to a method of preparing a compound of formula (I) or a salt thereof which comprises step (a) of reacting a compound of formula (II), wherein the bonds represented by a wavy line are in the c/s configuration, or a salt thereof, with a compound of formula (III) or a salt thereof,
  • step (a) is carried out in the presence of a base.
  • Said base is preferably an alkaline salt of carbonate such as, for example, sodium carbonate or potassium carbonate. More preferably, the base is potassium carbonate.
  • the base is preferably present in an amount such that the molar ratio of the base with respect to the compound of formula (I) is between 2:1 and 3:1 , more preferably about 2.4:1.
  • step (a) is carried out in the presence of molar excess of the compound of formula (III) with respect to the compound of formula (II), said molar excess preferably being between 0.1% and 5% with respect to the amount of the compound of formula (II).
  • step (a) is carried out in the presence of water as a solvent.
  • step (a) is carried out in the presence of a salt of the compound of formula (II).
  • Said salt is formed from the amino groups of the compound of formula (II) and an acid.
  • the acid used to form the salt of the compound of formula (II) can be organic or inorganic, as described above.
  • the salt of the compound of formula (II) is a hydrochloride salt.
  • step (a) is carried out at a temperature of at least 50°C, preferably between 50°C and 95°C, more preferably between 50°C and 70°C, and even more preferably about 60°C.
  • step (a) is carried out in the presence of an aqueous base solution, preferably an alkaline salt of carbonate, and/or at a temperature of between 50°C and 70°C, preferably about 60°C.
  • an aqueous base solution preferably an alkaline salt of carbonate
  • the aqueous solution of the alkaline salt of carbonate of the particular embodiments of step (a) of the third aspect of the invention preferably has a concentration of between 1 M and 2 M, preferably 1.45 M.
  • the method of preparing the compound of formula (I) or a salt thereof comprises the previous step (b) of preparing the compound of formula (II), wherein said step (b) comprises:
  • step (b-2) reacting the product of step (b-1) to convert the methylimine group or a salt thereof into a methylamine group.
  • steps (b-1) and (b-2) are carried out in the presence of a polar protic solvent, such as methanol, ethanol, or isopropanol.
  • a polar protic solvent such as methanol, ethanol, or isopropanol.
  • the solvent is methanol.
  • steps (b-1) and (b-2) are carried out without isolating the product of step (b-1).
  • step (b-1) is carried out in the presence of an acid.
  • Said acid is preferably an organic acid and more preferably acetic acid.
  • the function of the acid is to catalyze the formation of the methylimine group and facilitate the reduction of said group into a methylamine group in step (b-2), when it is carried out by means of catalytic hydrogenation.
  • step (b-2) is carried out by means of catalytic hydrogenation.
  • the catalyst is platinum, preferably Pt/C.
  • step (b-2) further comprises converting the product of step (b-2), i.e. , the compound of formula (II), into a hydrochloride salt.
  • the hydrochloride salt can be prepared by means of treatment using a base, for example using an aqueous solution of an alkaline carbonate such as potassium carbonate, followed by treatment with an aqueous hydrochloric acid solution.
  • a base for example using an aqueous solution of an alkaline carbonate such as potassium carbonate
  • Such deprotonation/protonation exchanges are known in the art and one skilled in the art will have no difficulty in reducing same to practice.
  • the method of preparing the compound of formula (I) or a salt thereof comprises the previous step (c) of preparing the compound of formula (IV), wherein said step (c) comprises reacting a compound of formula (V) to form a compound of formula (IV)
  • step (c) is carried out by means of the acid hydrolysis of the compound of formula (V).
  • the compound of formula (V) is treated with hydrochloric acid in a 1 :1 v/v mixture of tetrahydrofuran with water.
  • the method of preparing the compound of formula (I) or a salt thereof comprises the previous step (d) of preparing the compound of formula (V), wherein said step (d) comprises reacting a compound of formula (VI) to form a compound of formula (V)
  • step (d) comprises:
  • step (d-2) reacting the product of step (d-1) with benzyl alcohol.
  • said transformation preferably comprises step (d-1) of converting the compound of formula (VI) into a compound of formula (VI’) by means of reacting the compound of formula (VI) with phosgene or carbonyldiimidazole; preferably with carbonyldiimidazole.
  • Step (d) is preferably carried out in an apolar aprotic solvent such as, for example, hexane, cyclohexane, heptane, and toluene, preferably toluene.
  • an apolar aprotic solvent such as, for example, hexane, cyclohexane, heptane, and toluene, preferably toluene.
  • Step (d) is preferably carried out at a temperature of between 60°C and 110°C, preferably at a temperature of about 90°C.
  • the amount of benzyl alcohol in step (d-2) is preferably between 1 and 3 equivalents with respect to the compound of formula (VI), preferably between 2 and 2.5 equivalents.
  • the method of preparing the compound of formula (I) or a salt thereof comprises the previous step (e) of preparing the compound of formula (VI), wherein said step (e) comprises:
  • step (e-2) reacting the compound of formula (VII) resulting from step (e-1) with hydroxylamine or a salt thereof to produce a compound of formula (VI).
  • Step (e-1) is preferably carried out in the presence of an acid catalyst, preferably a heterogenous acid catalyst, such as an ion exchange resin, for example Amberlyst 15®.
  • an acid catalyst preferably a heterogenous acid catalyst, such as an ion exchange resin, for example Amberlyst 15®.
  • Methanol is preferably used as a solvent in step (e-1).
  • step (e-1) is isolated before use thereof in step (e- 2). It is particularly preferred that the acid catalyst and/or trimethyl orthoformate are removed from the reaction medium during this isolation step.
  • step (e-2) comprises using a hydroxylamine salt, for example a hydrochloride salt.
  • the reaction medium must comprise enough media, for example a base, to provide the free form of hydroxylamine.
  • Said base can be an alkaline alkoxide (Ci-Ce) such as, for example, sodium methoxide.
  • step (e-2) is carried out in an alcohol-type solvent, preferably methanol.
  • the compound of formula (I) can be prepared according to the following synthetic scheme:
  • the compound of formula (VI) is useful in the preparation of a compound of formula (I) and abrocitinib.
  • Another aspect of the invention therefore relates to the use of the compound of formula (VI) in the preparation of a compound of formula (I) or in the preparation of abrocitinib.
  • a fourth aspect of the invention relates to a method of preparing abrocitinib from the compound of formula (I) or a salt thereof. Said method comprises:
  • step (g) reacting the compound resulting from step (f) to convert the amino group formed from the benzyl carbamate group of the compound of formula (I) or the salt thereof into a group of formula -NHSO2CH2CH2CH3.
  • step (f) is a catalytic hydrogenation step.
  • Said step comprises reacting the compound of formula (I) with hydrogen or a hydrogen precursor such as, for example, cyclohexene, in the presence of a catalyst.
  • Said catalyst is preferably Pd/C.
  • step (f) is carried out in the presence of a polar protic organic solvent such as, for example, methanol, ethanol, or isopropanol. It is preferable that step (f) is carried out in the presence of methanol.
  • step (g) comprises reacting the product of step (f) with a compound of formula C3H7-SO2X, wherein X represents a leaving group, preferably selected from chloride and triazolyl.
  • step (g) comprises reacting the product of step (f) with 1 -propanesulfonyl chloride.
  • step (g) is carried out in the presence of a solvent, wherein the reaction product, i.e. , /V-[c/s-3-(methyl- 7/7-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclobutyl]-1-propanesulfonamide, precipitates substantially.
  • the reaction product i.e. , /V-[c/s-3-(methyl- 7/7-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclobutyl]-1-propanesulfonamide.
  • step (g) is carried out in the presence of a solvent which is a mixture of acetonitrile with an aqueous solution of an alkaline salt of carbonate, preferably a mixture of acetonitrile with a 20% by weight aqueous solution of potassium carbonate, and the acetonitrile content of which is between 30% and 80% by volume.
  • a solvent which is a mixture of acetonitrile with an aqueous solution of an alkaline salt of carbonate, preferably a mixture of acetonitrile with a 20% by weight aqueous solution of potassium carbonate, and the acetonitrile content of which is between 30% and 80% by volume.
  • the inventors have found that the N atom comprised in the pyrrole ring can react with the compound of formula C3H7-SO2X, giving rise to unwanted byproducts.
  • the formation of this byproduct can be minimized by carrying out the first few hours of the reaction at a low temperature.
  • step (g) comprises maintaining the reaction temperature between -5°C and 5°C for the first few hours of said step and for a time of between 2 and 4 hours. More particularly, step (g) comprises maintaining the reaction temperature at about 0°C for the first three hours of said step.
  • step (g) preferably further comprises maintaining the reaction temperature at a temperature of between 20°C and 25°C.
  • abrocitinib can be prepared according to the following synthetic scheme:
  • Example 5 The purity of the product obtained in Example 5 was analyzed by means of ultra-high performance liquid chromatography (LIHPLC) using the Waters Acquity apparatus provided with a photodiode detector, a mass detector, and a thermostated oven for the column.
  • a Premier BEH C18 column (1.8 pm, 2.1x100 mm) and mobile phases A (ammonium bicarbonate 30 mM, pH 8.5) and B (acetonitrile) were used with the following analysis conditions:
  • DSC Differential scanning calorimetry
  • DSC analysis was performed in a Mettler Toledo 822e apparatus with STARe SW15 software using the following parameters: heating interval of 30 to 300°C with a 10°C/min ramp and a 50 ml/min N2 flow. Measurement was taken with a closed perforated capsule.
  • XRPD analysis was performed using a BRLIKER D2 PHASER X-ray powder diffractometer with a copper anode.
  • the radiation used is CuKa with a wavelength of 1 .54060 A.
  • the following scan parameters were used: 3-50° 20, continuous scan, ratio: 5.6 degrees/minute.
  • the present invention contemplates that the compound of the invention is prepared and used in the preparation of abrocitinib following the following synthetic scheme: Example 1. Synthesis of methyl 3,3-dimethoxy-cyclobutanecarboxylate (VII)
  • the resulting reaction mass was cooled to a temperature of about 20°C and filtered to remove the Amberlyst 15® resin.
  • the filtrate was washed with two fractions of 100 mL each of methanol and the solvent was removed by means of vacuum distillation. 200 mL of methanol were added to the obtained residue and the solvent was again removed by means of vacuum distillation to obtain 305.5 g (99.2% purity by means of UHPLC) of a slightly yellowish oil corresponding to methyl 3,3-dimethoxy-cyclobutanecarboxylate which were dissolved in 760 mL of MeOH and used in the subsequent reaction step without further treatment.
  • reaction mixture was then cooled to a temperature of between 25 and 30°C and 394 g (3.83 mol, 2.3 eq) of benzyl alcohol were added.
  • the reaction mixture was heated to a temperature of about 80°C and kept under stirring at said temperature for 24 hours.
  • reaction mass was washed with two 1500 mL fractions of a 20% by weight aqueous ammonium chloride solution each and with an additional 1500 mL fraction of water.
  • the combined aqueous phases were washed with a 900 mL fraction of toluene.
  • the solvent was removed from the resulting organic phase by means of vacuum distillation to obtain 689.6 g of an oily residue comprising 58.9% by weight (406.2 g), by means of UHPLC, of the compound benzyl N-(3,3-dimethoxycyclobutyl)carbamate, which was used in the subsequent reaction step without further treatment.
  • reaction mixture was cooled to a temperature of about 20°C and a 20% by weight aqueous K2CO3 solution was added up to a pH value of between 8 and 9. 2435 mL of ethyl acetate were added and the phases were separated. The organic phase was washed with a 2000 mL fraction of a 20% by weight aqueous K2CO3 solution and with a 2030 mL fraction of a 10% by weight aqueous NaCI solution.
  • the overall yield of the hydrochloric acid salt of benzyl cis-[3- (methylamino)cyclobutyl]carbamate obtained from benzyl N-(3-oxocyclobutyl)carbamate is 59.6%.
  • the purity of the obtained solid can be increased by means of recrystallization in a suitable solvent.
  • recrystallization using 5 volumes (in mL) of isopropanol per gram of initial product allows obtaining the hydrochloric acid salt of benzyl cis-[3- (methylamino)cyclobutyl]carbamate with a yield of 90.0% and a purity by means of UHPLC of 99.96%.
  • reaction mixture was cooled to a temperature of about 20°C, kept under stirring at said temperature for 2 hours, the resulting solid was filtered and washed with two fractions of 50 mL each of water. Finally, the solid was dried in an air oven at a temperature of 50°C to obtain 33.85 g (98.3% yield, 99.58% purity by means of LIHPLC) of a practically white solid corresponding to benzyl cis-N-[3-(methyl(7/7-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclobutyl]carbamate.
  • the differential scanning calorimetry (DSC) diagram has an endothermic peak having a threshold temperature of about 180.5°C.
  • the solid obtained by means of the reaction step described in Example 7 was mixed at a temperature of about 20°C with 95 mL of acetonitrile and 60 mL of a 20% by weight K2CO3 solution.
  • the reaction mixture was cooled to a temperature of about 0°C, 6.7 g (47.0 mmol, 1.1 eq) of propanesulfony chloride were slowly added at said temperature, and the resulting reaction mixture was kept under stirring at said temperature for 3 hours and then at a temperature of between 20 and 25°C for 16 hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne du (3-(méthyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl) carbamate de benzyle ou un sel de celui-ci, son procédé de préparation et son utilisation dans la synthèse d'abrocitinib. La présente invention concerne un nouvel intermédiaire utile dans la synthèse d'abrocitinib, son procédé d'obtention, l'utilisation dudit intermédiaire pour la préparation d'abrocitinib, et un procédé de préparation d'abrocitinib à l'aide dudit intermédiaire.
PCT/EP2024/067882 2023-06-27 2024-06-26 (3-(méthyl(7h-pyrrolo[2,3-d]pyrimidin-4yl)amino)cyclobutyl) carbamate de benzyle ou sel de celui-ci, son procédé de préparation et son utilisation dans la synthèse d'abrocitinib Pending WO2025003177A1 (fr)

Applications Claiming Priority (2)

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ES202330534A ES2993658B2 (es) 2023-06-27 2023-06-27 (3-(metil(7h-pirrolo[2,3-d]pirimidin-4-il)amino)ciclobutilo)carbamato de bencilo o una sal del mismo, procedimiento para su preparacion y su uso en la sintesis de abrocitinib
ESP202330534 2023-06-27

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WO2025003177A1 true WO2025003177A1 (fr) 2025-01-02

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2958921B1 (fr) 2013-02-22 2017-09-20 Pfizer Inc Dérivés de pyrrolo-[2,3-d]pyrimidine en tant qu'inhibiteurs des janus kinases (jak)
WO2020008391A1 (fr) 2018-07-06 2020-01-09 Pfizer Inc. Processus de fabrication et intermédiaires pour un composé de pyrrolo[2,3-d]pyrimidine et utilisation associée

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
CN113637018A (zh) * 2020-04-27 2021-11-12 苏州晶云药物科技股份有限公司 磺酰胺类化合物的晶型及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2958921B1 (fr) 2013-02-22 2017-09-20 Pfizer Inc Dérivés de pyrrolo-[2,3-d]pyrimidine en tant qu'inhibiteurs des janus kinases (jak)
WO2020008391A1 (fr) 2018-07-06 2020-01-09 Pfizer Inc. Processus de fabrication et intermédiaires pour un composé de pyrrolo[2,3-d]pyrimidine et utilisation associée

Non-Patent Citations (3)

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Title
CONNOR ET AL., ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 25, 2021, pages 608 - 615
MICHAEL L. VAZQUEZ ET AL: "Identification of N -{ cis -3-[Methyl(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 3, 23 January 2018 (2018-01-23), US, pages 1130 - 1152, XP055629803, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b01598 *
VAZQUEZ ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, 2018, pages 1130 - 1152

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