Leniolisib

CAS 1354690-24-6

WeightAverage: 450.466
Monoisotopic: 450.199108558

Chemical FormulaC₂₁H₂₅F₃N₆O₂

• 
  CDZ-173-NX
• CDZ173
• CDZ173-NX

1-[(3S)-3-({6-[6-methoxy-5-(trifluoromethyl)pyridin-3-yl]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}amino)pyrrolidin-1-yl]propan-1-one

FDA APPROVED Joenja, 3/24/2023, To treat activated phosphoinositide 3-kinase delta syndrome
Drug Trials Snapshot

Leniolisib (INN^[3][4]), sold under the brand name Joenja, is a medication used for the treatment of activated phosphoinositide 3-kinase delta syndrome (APDS).^[2][5] It is a kinase inhibitor^[2][6] that is taken by mouth.^[2]

The most common side effects include headache, sinusitis, and atopic dermatitis.^[5]

Leniolisib was approved for medical use in the United States in March 2023.^[5][7][8] It is the first approved medication for the treatment of activated PI3K delta syndrome.^[5] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[9]

PATENT

US8653092

https://patents.google.com/patent/US8653092B2/en

PATENT

• Example 67 (WO2012004299)

https://patentscope.wipo.int/search/en/WO2012004299

Example 67 was prepared according the general procedure described in scheme 4

Example 67: 1 -{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-one

To a solution of (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1 -carboxylic acid tert-butyl ester (intermediate 24) (13.4 g, 27.1 mmol) in CH₂CI₂ (100 mL), was added TFA (41 .8 mL) and the mixture stirred at rt for 1 h. Concentrated in vacuo and partitioned between 2M NaOH(aq) (300 mL) and CH₂CI₂ (200 mL). The organic phase was separated and the aqueous phase extracted with CH₂CI₂ (2 x 200 mL). The organic phases were combined, dried (MgS0₄) and

evaporated in vacuo to give a brown foam. The foam was dissolved in CH₂CI₂ (50 mL) and was added simultaneously portionwise with sat.NaHC0₃(aq) (50 mL) to a vigourously stirring solution of propionyl chloride (2.63 g, 28.5 mmol) in CH₂CI₂ (50 mL) at rt. The resulting biphasic mixture was stirred at rt for 1 h. Further propionyl chloride (0.566g, 6.12 mmol) was added and continued stirring vigorously for 20 min. The organic layer was separated and the aqueous layer extracted with CH₂CI₂ (100 mL). The organic layers were combined, dried (MgS0₄) and concentrated in vacuo to give a brown gum. The gum was stirred in EtOAc (100 mL) and the resulting solid filtered (9.4 g). The mother liquors were concentrated in vacuo and purified by column chromatography through a Biotage^® amino silica gel eluting with EtOAc / MeOH, 100/0 to 90/10 to give a yellow foam which was then stirred in EtOAc (20 mL) and the resulting solid filtered (870 mg). Both batches of solids were combined and stirred in refluxing EtOAc (50 mL) for 1 h. Filtered to give 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1 -yl}-propan-1 -one as a colourless solid (9.42 g, 76% yield). ¹ H NMR (400 MHz, DMSO-d6, 298K) δ ppm 0.95-1.05 (m, 3H) 1 .87-2.32 (m, 4H) 2.77-2.86 (m, 2H) 3.25-3.88 (m, 6H) 3.93 (s, 3H) 3.98 (s, 2H) 4.55-4.80 (m, 1 H) 6.70-6.80 (m, 1 H, N-H) 7.86-7.92 (m, 1 H) 8.27-8.33 (m, 1 H) 8.33-8.37 (m, 1 H) LCMS: [M+H]+=451.0, Rt ⁽⁶⁾= 1.49 min.

Alternative synthesis for example 67

A solution of (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 24) (29.04 g, 58.73 mmol) in 2-Me-THF (100 mL) was dropwise added into aqueous HCI solution (150 mL, 31 %) over 15 min. The reaction mixture was partitioned between water (300 mL) and isopropyl acetate (100 mL) and the upper organic phase was discarded. The aqueous phase was partitioned between 25% NaOH (aq) (200 g) and 2-Me-THF (200 mL), and the organic phase was collected and dried. Triethylamine (16.32 mL, 1 17.48 mmol) was added into the organic phase followed by dropwise addition of propionyl chloride (6.0 g, 64.6 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was washed with water (1 10 mL) and the resulting organic phase was concentrated in vacuo to give a brown gum.

The residue was recrystallized with isopropanol and methyl tert-butyl ether to give 1 -{(S)-3- [6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- ylamino]-pyrrolidin-1-yl}-propan-1 -one as a colourless solid (17.2 g, 65% yield).

Crystallization of Example 67 by heating in acetonitrile/water

2.0 g of Example 67 (4.440 mol) were dissolved in 10 mL of acetonitrile and 0.5 mL of water at 75°C. The solution was allowed to cool down to rt within 30 min resulting in a suspension. The mixture was stirred for 16 h at rt. The crystals were collected by filtration. The filter cake was washed 2 times with 1 mL of acetonitrile and afterwards dried for 16 h at 24°C and ca. 10 mbar vacuum. Elementary analysis of the material showed a waterless form.

PAPER

https://pubs.acs.org/doi/10.1021/acsmedchemlett.7b00293

ACS Medicinal Chemistry Letters

Cite this: ACS Med. Chem. Lett. 2017, 8, 9, 975–980

https://doi.org/10.1021/acsmedchemlett.7b00293

The predominant expression of phosphoinositide 3-kinase δ (PI3Kδ) in leukocytes and its critical role in B and T cell functions led to the hypothesis that selective inhibitors of this isoform would have potential as therapeutics for the treatment of allergic and inflammatory disease. Targeting specifically PI3Kδ should avoid potential side effects associated with the ubiquitously expressed PI3Kα and β isoforms. We disclose how morphing the heterocyclic core of previously discovered 4,6-diaryl quinazolines to a significantly less lipophilic 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, followed by replacement of one of the phenyl groups with a pyrrolidine-3-amine, led to a compound series with an optimal on-target profile and good ADME properties. A final lipophilicity adjustment led to the discovery of CDZ173 (leniolisib), a potent PI3Kδ selective inhibitor with suitable properties and efficacy for clinical development as an anti-inflammatory therapeutic. In vitro, CDZ173 inhibits a large spectrum of immune cell functions, as demonstrated in B and T cells, neutrophils, monocytes, basophils, plasmocytoid dendritic cells, and mast cells. In vivo, CDZ173 inhibits B cell activation in rats and monkeys in a concentration- and time-dependent manner. After prophylactic or therapeutic dosing, CDZ173 potently inhibited antigen-specific antibody production and reduced disease symptoms in a rat collagen-induced arthritis model. Structurally, CDZ173 differs significantly from the first generation of PI3Kδ and PI3Kγδ-selective clinical compounds. Therefore, CDZ173 could differentiate by a more favorable safety profile. CDZ173 is currently in clinical studies in patients suffering from primary Sjögren’s syndrome and in APDS/PASLI, a disease caused by gain-of-function mutations of PI3Kδ.

Synthesis and full characterization of (S)-1-(3-((6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)propan-1-one (3h, CDZ173,
leniolisib)

TFA (41.8 mL) was added to a solution of (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-
tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (13.4 g,
27.1 mmol) in CH2Cl2 (100 mL), and the mixture was stirred at RT for 1 h. After that time, the mixture
was concentrated under reduced pressure, and the residue was partitioned between NaOH (aqu., 2M,
300 mL) and CH2Cl2 (200 mL). The organic phase was separated, and the aqueous phase was extracted
with CH2Cl2 (2 x 200 mL). The combined organic phases were dried (MgSO4) and concentrated under
reduced pressure. The resulting brown foam was dissolved in CH2Cl2 (50 mL) and added simultaneously with a NaHCO3 solution (aqu., saturated) (50 mL) to a vigorously stirring solution of propionyl chloride (2.63 g, 28.5 mmol) in CH2Cl2 (50 mL) at RT. The resulting biphasic mixture was stirred at RT for
1h. Additional propionyl chloride (0.566 g, 6.12 mmol) was added, and vigorous stirring was continued
for 20 min. The organic layer was separated and the aqueous layer extracted with CH2Cl2 (100 mL). The
combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting
brown gum was stirred in EtOAc (100 mL) and the resulting solid was filtered (9.4 g). The mother liquors were concentrated under reduced pressure and purified by column chromatography through a Biotage®
amino silica gel eluting with EtOAc / MeOH, 100/0 to 90/10. After concentration under reduced
pressure, the resulting yellow foam was stirred in EtOAc (20 mL) and the resulting solid was filtered
(870 mg). Both batches of solids were combined and stirred in refluxing EtOAc (50 mL) for 1h. The
resulting solid was filtered to give the title compound as a colorless solid (9.42 g, 76%). 1H NMR (400
MHz, DMSO-d6, 298K, ca. 1:1 mixture of rotamers) δ ppm 8.35 (m, 1H) 8.30 (m, 1H) 7.89 (m, 1H)
6.80-6.70 (m, 1H, N-H) 4.80-4.55 (m, 1H) 3.93 (s, 3H) 3.98 (s, 2H) 3.88-3.25 (m, 6H) 2.86-2.75 (m,
2H) 2.32-1.87 (m, 4H) 1.05-0.95 (m, 3H); 13C-NMR (150 MHz, DMSO-d6, 298K, ca. 1:1 mixture of
rotamers, data given for cis-isomer): δ ppm 171.3, 158.6, 158.1, 155.5, 153.6, 141.3, 138.0, 125.7,
123.3, 111.1, 109.7, 53.7, 50.8, 49.4, 45.8, 45.8, 44.3, 31.2, 29.7, 26.6, 8.97; LCMS method 1: Rt 1.49
min, calcd for C21H26F3N6O2 [M+H]+
451.2, found 451.0, HRMS (ESI+) calcd for C21H26F3N6O2
[M+H]+ 451.20693, found 451.20642

REF

https://www.researchgate.net/figure/Stereo-divergent-strategy-for-the-synthesis-of-key-intermediates-2-and-3-of-leniolisib_fig6_369490553

REF

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1337436/full

-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (compound 1) is coupled with (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (compound 2) in the presence of triethylamine at 120 °C for 42 h to give compound 3 a 93% yield. The benzyl group is deprotected with 20% palladium hydroxide on carbon and ammonium formate in methanol at 65 °C for 2 h to give compound 4 a 66% yield. Compound 4 is coupled with 5-bromo-2-methoxy-3-(trifluoromethyl)pyridine (compound 5) in the presence of sodium –tert-butoxide, tris(dibenzylideneacetone)dipalladium(0), 2-di-t-butylphosphino-2′-(N,N-dimethylamino)biphenyl in tert-butanol at 100 °C for 5 h to give compound 6 a 74% yield. Deprotection of the Boc group in DCM/TFA, followed by coupling with propionyl chloride in the presence of sodium bicarbonate in DCM at room temperature for 1 h gives the final compound 7 (leniolisib) a 76% yield.

REF

https://www.sciencedirect.com/science/article/abs/pii/S0223523424000047

REF

J. Med. Chem. 2025, 68, 2147−2182

Leniolisib (Joenja). Leniolisib (5), is a twice-daily, orally available selective phosphoinositide 3-kinase-delta
(PI3Kδ) inhibitor developed by Novartis and in-licensed by Pharming Group NV for the treatment of activated phosphoinositide 3-kinase-delta syndrome (APDS). APDS is a primary immunodeficiency caused by mutations in PI3Kδ catalytic (PIK3CD) or regulatory (PIK3R1) subunits. The loss or gain of function of these subunits results in hyperactivity of the PI3Kδ pathway which can result in infections, lymphoprolif
eration, autoimmunity, increased risk of malignant lymphoma and early mortality. 44−46
Current treatment strategies include immunosuppressives such as corticosteroids, antiviral, and antibiotic therapies, stem cell transplantation, and immunoglobulin replacement therapy. However, none of these therapeutic strategies treats the underlying hyperactivity of the PI3Kδpathway. Thus, the approval of leniolisib by the USFDA in March 2023 provided a significant breakthrough therapy for patients 12 years and older.47 48
A concise synthetic route to leniolisib has been disclosed by Novartis,beginning with commercially available tetrahydropyridopyrimidine 5.1 (Scheme 9). An SNAr reaction with amine 5.2 furnished intermediate 5.3 in good yield. Transfer hydrogenation with Pd(OH)2 on carbon to remove the benzyl
group gave free amine 5.4, setting up the system for a Buchwald−Hartwig amination with bromide 5.5 to produce 5.6 in good yield. Protecting group removal and subsequent acylation with ethyl chloroformate provided leniolisib (5) in 76% yield over two steps.

(44) Hoegenauer, K.; Soldermann, N.; Stauffer, F.; Furet, P.;
Graveleau, N.; Smith, A. B.; Hebach, C.; Hollingworth, G. J.; Lewis,
I.; Gutmann, S.; et al. Discovery and pharmacological characterization
of novel quinazoline-based PI3K delta-selective inhibitors. ACS Med.
Chem. Lett. 2016, 7, 762−767.
(45) Hoegenauer, K.; Soldermann, N.; Zécri, F.; Strang, R. S.;
Graveleau, N.; Wolf, R. M.; Cooke, N. G.; Smith, A. B.; Hollingworth,
G. J.; Blanz, J.; et al. Discovery of CDZ173 (Leniolisib), representing a
structurally novel class of PI3K delta-selective inhibitors. ACS Med.
Chem. Lett. 2017, 8, 975−980.

(46) Duggan, S.; Al-Salama, Z. T. Leniolisib: first approval. Drugs
2023, 83, 943−948.
(47) Pharming announces US FDA approval of Joenja® (leniolisib) as
the first and only treatment indicated for APDS. Pharming, March 24, 2023 https://www.pharming.com/news/pharming-announces-us-fda
approval-joenja-leniolisib-first-and-only-treatment-indicated-apds (ac
cessed February 2024).
(48) Fernandes Gomes dos Santos, P. A.; Hogenauer, K.;
Hollingworth, G.; Soldermann, N.; Stowasser, F.; Tufilli, N.; Zecri, F.
Solid forms and salts of tetrahydro-pyrido-pyrimidine derivatives. WO
2013001445 A1, 2013

Ref

https://www.sciencedirect.com/science/article/abs/pii/S0223523424000047

Leniolisib developed by Novartis Pharma AG, was approved on March 24, 2023, making it the first treatment drug for APDS [3]. APDS is an immunodeficiency disorder that primarily occurs due to mutations in the gene responsible for encoding phosphotidylinsitol-3-kinase δ(PI3Kδ). These mutations enhance the function of PI3Kδ, resulting in impaired immune response and heightened vulnerability to infections.
Leniolisib is capable of inhibiting the hyperactive PI3Kδ enzyme by obstructing the active binding site within the p110δ subunit [54]. Inisolated enzyme assays conducted without cells, the selectivity of PI3K-δ
was found to be higher compared to PI3Kα(28-fold), PI3K-β (43-fold),and PI3K-γ (257-fold), as well as other enzymes in the kinome [54].Leniolisib demonstrated the ability to decrease phosphoinositide-3-kinase/protein kinase B (pAKT) pathway activity and suppress the growth and activation of B and T cell subsets in cell-based experiments. Leniolisib effectively blocks the signaling pathways responsible for the excessive production of phosphatidylinositol 3,4,5-trisphosphate (PIP3), overactivation of the downstream
mammalian target of rapamycin (mTOR)/protein kinase B (AKT) pathway, and the imbalanced functioning of B and T cells [55].
One representative approach of Leniolisib is depicted in Scheme 15 [55]. Pyrrolidine LENI-003 was obtained by nucleophilic substitution of aminopyrrolidine LENI-001 and the 4-Cl of LENI-002 under alkaline conditions, and LENI-004 was obtained by debenzylation of LENI-003 under palladium hydroxide/carbon. LENI-004 and 5-bromo-2-methox y-3-(trifluoromethyl)pyridine (LENI-005) were coupled to obtain LENI-006. LENI-006 was deprotected by TFA and further condensed with acyl chloride to obtain Leniolisib.

54] V.K. Rao, S. Webster, V. Dalm, A. ˇ Sediv´ a, P.M. van Hagen, S. Holland, S.
D. Rosenzweig, A.D. Christ, B. Sloth, M. Cabanski, A.D. Joshi, S. de Buck,
J. Doucet, D. Guerini, C. Kalis, I. Pylvaenaeinen, N. Soldermann, A. Kashyap,
G. Uzel, M.J. Lenardo, D.D. Patel, C.L. Lucas, C. Burkhart, Effective “activated
PI3Kδ syndrome”-targeted therapy with the PI3Kδ inhibitor leniolisib, Blood 130
(2017) 2307–2316.

[55] K. Hoegenauer, N. Soldermann, F. Z´ ecri, R.S. Strang, N. Graveleau, R.M. Wolf, N.
G. Cooke, A.B. Smith, G.J. Hollingworth, J. Blanz, S. Gutmann, G. Rummel,
A. Littlewood-Evans, C. Burkhart, Discovery of CDZ173 (Leniolisib), representing
a structurally novel class of PI3K delta-selective inhibitors, ACS Med. Chem. Lett.
8 (2017) 975–980.[55] K. Hoegenauer, N. Soldermann, F. Z´ ecri, R.S. Strang, N. Graveleau, R.M. Wolf, N.
G. Cooke, A.B. Smith, G.J. Hollingworth, J. Blanz, S. Gutmann, G. Rummel,
A. Littlewood-Evans, C. Burkhart, Discovery of CDZ173 (Leniolisib), representing
a structurally novel class of PI3K delta-selective inhibitors, ACS Med. Chem. Lett.
8 (2017) 975–980.

,

References

1. ^ “Joenja (Ballia Holdings Pty Ltd)”. Therapeutic Goods Administration (TGA). 16 April 2025. Retrieved 3 May 2025.
2. ^ Jump up to:^{a b c d e f} “Joenja- leniolisib tablet, film coated”. DailyMed. 29 March 2023. Retrieved 20 June 2023.
3. ^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 76”. WHO Drug Information. 30 (3). hdl:10665/331020.
4. ^ World Health Organization (2017). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 77”. WHO Drug Information. 31 (1). hdl:10665/330984.
5. ^ Jump up to:^{a b c d e f g h i j} “FDA approves first treatment for activated phosphoinositide 3-kinase delta syndrome”. U.S. Food and Drug Administration (FDA) (Press release). 24 March 2023. Retrieved 24 March 2023.  This article incorporates text from this source, which is in the public domain.
6. ^ Duggan S, Al-Salama ZT (July 2023). “Leniolisib: First Approval”. Drugs. 83 (10): 943–948. doi:10.1007/s40265-023-01895-4. PMID 37256490. S2CID 258989663.
7. ^ Jump up to:^a b “US FDA approves Pharming’s immune disorder drug”. Reuters. Archived from the original on 24 March 2023. Retrieved 24 March 2023.
8. ^ “Pharming announces US FDA approval of Joenja (leniolisib) as the first and only treatment indicated for APDS” (PDF). Pharming Group N.V. (Press release). 24 March 2023. Retrieved 25 March 2023.
9. ^ New Drug Therapy Approvals 2023 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original on 10 January 2024. Retrieved 9 January 2024.

 This article incorporates text from this source, which is in the public domain: Bing Chat output modified to create the initial revision of this article. 25 March 2023. – via Microsoft

External links

Clinical trial number NCT02435173 for “Study of Efficacy of CDZ173 in Patients With APDS/PASLI” at ClinicalTrials.gov

//////////leniolisib, Joenja, FDA 2023, APPROVALS 2023, CDZ-173-NX, CDZ173, CDZ173-NX

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