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US-12624029-B2 - JAK inhibitor compounds, method for synthesizing same and use thereof

US12624029B2US 12624029 B2US12624029 B2US 12624029B2US-12624029-B2

Abstract

Novel compounds having formula (I) and methods of using these compounds to treat diseases, conditions, and disorders are described.

Inventors

  • Gilles Ouvry
  • Branislav Musicki
  • Craig Harris
  • Claire Bouix-Peter
  • Marie-Hélène Fouchet
  • NICOLAS GEORGE

Assignees

  • Galderma Holding SA

Dates

Publication Date
20260512
Application Date
20230310

Claims (17)

  1. 1 . A compound of formula (I), a salt thereof, or an enantiomer thereof, wherein: R is —NO 2 , —SR a , —S(O)R b , —S(O) 2 R b , —S(O)NR c R d , —S(O) 2 NR c R d , —NR c R d , —NR c C(O)R b , —NR c C(O)NR c R d , —NR c C(O)OR a , —NR c S(O) 2 R b , —NR c S(O) 2 NR c R d , —NR c NR c R d , —NR c NR c C(O)R b , —NR c NR c C(O)NR c R d , —NR c NR c C(O)OR a , —OR a , or —OC(O)NR c R d ; R 2 is a hydrogen atom, an alkyl radical or a substituted alkyl radical, an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, a substituted alkynyl radical, an aryl radical, a substituted aryl radical, a heterocyclic radical, or a substituted heterocyclic radical; R 3 is a hydrogen atom, an alkyl radical, a substituted alkyl radical, an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, a substituted alkynyl radical, an alkoxy radical, a haloalkyl radical, a halogen, —CN, —NO 2 , —SR a , —S(O) 2 R b , —S(O)R b , —S(O)NR c R d , —CHO, —C(O)R b , —C(O)OR a , —C(O)NR c R d , —NR c R d , —NR c C(O)R b , —NR c C(O)OR a , —NR c C(O)NR c R d , —NR c S(O)R b , —NR c S(O) 2 R b , —NR c S(O) 2 NR c R d , —OC(O)R b , or —OC(O)NR c R d ; each of R a , R c and R d is independently selected from a hydrogen atom, an alkyl radical, a substituted alkyl radical, an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, a substituted alkynyl radical, ahaloalkyl radical, a cycloalkyl radical, a substituted cycloalkyl radical, a heterocyclic radical, a substituted heterocyclic radical, an aryl radical, a substituted aryl radical, a heteroaralkyl radical, or a substituted heteroaralkyl radical; or R c and R d taken together with the nitrogen to which they are attached forms a heterocyclic radical, a substituted heterocyclic radical, a heteroaryl radical or a substituted heteroaryl radical; each R b is independently selected from a halogen, an alkyl radical, a substituted alkyl radical, an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, a substituted alkynyl radical, and a haloalkyl radical; and n is an integer from 0 to 5.
  2. 2 . A compound as claimed in claim 1 , having the formula (II) a salt thereof, or an enantiomer thereof, wherein: R 1 is an alkyl radical, a substituted alkyl radical, an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, a substituted alkynyl radical, R 2 is a hydrogen atom, an alkyl radical or a substituted alkyl radical, an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, a substituted alkynyl radical, an aryl radical, a substituted aryl radical, a heterocyclic radical, or a substituted heterocyclic radical; R 3 is a hydrogen atom, an alkyl radical, a substituted alkyl radical, an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, a substituted alkynyl radical, an alkoxy radical, a haloalkyl radical, a halogen, —CN, —NO 2 , —SR a , —S(O)R b , —S(O) 2 R b , —S(O)NR c R d , —CHO, —C(O)R b , —C(O)OR a , —C(O)NR c R d , —NR c R d , —NR c C(O)R b , —NR c C(O)OR a , —NR c C(O)NR c R d , —NR c S(O)R b , —NR c S(O) 2 R b , —NR c S(O) 2 NR c R d , —OC(O)R b , or —OC(O)NR c R d ; each of R a , R c and R d is independently selected from a hydrogen atom, an alkyl radical, a substituted alkyl radical, an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, a substituted alkynyl radical, and a haloalkyl radical; or R c and R d taken together with the N in —NR c R d , form a heterocyclic radical or a substituted heterocyclic radical; each R b is independently selected from a halogen, an alkyl radical, a substituted alkyl radical, an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, a substituted alkynyl radical, and a haloalkyl radical; and n is an integer from 0 to 5.
  3. 3 . The compound as claimed in claim 2 , a salt thereof, or an enantiomer thereof, wherein: R 1 is an alkyl radical, a substituted alkyl radical, or —NR c R d ; R 2 is a hydrogen atom, a lower alkyl radical or a lower alkyl radical substituted with a flourine atom; R 3 is —CN or NO 2 ; each of R c and R d is independently selected from a hydrogen atom, an alkyl radical, a substituted alkyl radical, an alkenyl radical, or a substituted alkenyl radical; and n is 1 or 2.
  4. 4 . The compound as claimed in claim 2 , a salt thereof, or an enantiomer thereof, wherein R 1 is —NR c R d , and wherein one of R c and R d is an alkyl radical and the other is an alkenyl radical or a substituted alkyl radical.
  5. 5 . The compound as claimed in claim 2 , a salt thereof, or an enantiomer thereof, wherein R 1 is NR c R d , and wherein one of Rand R d is a methyl radical and the other is a butenyl radical.
  6. 6 . The compound as claimed in claim 1 , a salt thereof, or an enantiomer thereof, wherein R 2 is a hydrogen atom, a lower alkyl radical or a lower alkyl radical substituted with a flourine atom.
  7. 7 . The compound as claimed in as claimed in claim 1 , a salt thereof, or an enantiomer thereof, wherein R 2 is a hydrogen atom.
  8. 8 . The compound as claimed in as claimed in claim 1 , a salt thereof, or an enantiomer thereof, wherein R 3 is —CN.
  9. 9 . The compound as claimed in as claimed in claim 1 , a salt thereof, or an enantiomer thereof, wherein n is 1.
  10. 10 . The compound as claimed in claim 2 , having formula (IIa)
  11. 11 . The compound as claimed in claim 2 , having formula (IIb)
  12. 12 . The compound as claimed in claim 1 , a salt thereof, or an enantiomer thereof, wherein the compound is selected from: (a) N-(But-3-en-1-yl)-1-((cis)-3-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclobutyl)-N-methylmethanesulfonamide, and (b) N-(Cyclobutylmethyl)-1-((cis)-3-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclobutyl)-N-methylmethanesulfonamide.
  13. 13 . The compound as claimed in claim 1 , having the formula:
  14. 14 . A pharmaceutical composition comprising the compound as claimed in claim 1 , and a pharmaceutically acceptable carrier.
  15. 15 . A method of treating a disease, disorder, or condition involving JAK production, wherein the method comprises administering to a subject in need thereof, the pharmaceutical composition as claimed in claim 14 , wherein the disease, disorder, or condition is selected from the group consisting of rheumatoid arthritis, atopic dermatitis, alopecia areata, vitiligo, chronic hand eczema, psoriatic arthritis, ulcerative colitis, myelofibrosis, polycythemia vera, graft-versus-host disease, psoriasis, sarcoidosis, scleroderma, morphea/eosinophilic fascitis, Crohn's disease, ilic fasciitis, granuloma annulare, chronic itch, dermatomyositis, psoriasis vulgaris, hidradenitis suppurativa, and inflammatory bowel disease.
  16. 16 . The method as claimed in claim 15 , wherein the disease is selected from the group consisting of atopic dermatitis, vitiligo, chronic hand eczema and alopecia areata.
  17. 17 . The method as claimed in claim 15 , wherein the disease is atopic dermatitis.

Description

RELATED APPLICATIONS This application is a continuation application of PCT Application No. PCT/IB2021/058267 filed Sep. 10, 2021, which application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63/077,542 filed Sep. 11, 2020, the entire contents of all of which are incorporated herein by reference. TECHNICAL FIELD The present disclosure relates to novel compounds of formula (I) below: to the process for synthesizing the compounds of formula (I), and to the use of the compounds of formula (I) in pharmaceutical compositions for the treatment of diseases, conditions, and disorders. The compounds of the present disclosure act as inhibitors of Janus kinase (JAK), particularly JAK1. They are consequently of use in the treatment of JAK1 mediated diseases, conditions, or disorders. BACKGROUND Protein kinases (PKs) regulate diverse biological processes including tissue repair, cell growth, survival, organ formation, neovascularization, differentiation, morphogenesis, and regeneration, among others. Protein kinases also play specialized roles in a host of human diseases including cancer. Cytokines encompasses many structurally unrelated proteins that are grouped based on their binding to distinct receptor superfamilies. Cytokines influence cell differentiation, proliferation and activation, and can modulate both pro-inflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens. Type I and Type II cytokine receptors is a family of receptors which employ Janus Kinases (JAKs) for intracellular signaling [Schwartz, Daniella M et al. Nature reviews. Drug discovery, vol. 17, 1 (2017): 78]. The JAKs are intracellular cytoplasmic tyrosine kinases, which signal in pairs and transduce cytokine signaling from membrane receptors via the signal-transducer and activator of transcription (STAT) factors to the cell nucleus. The JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first (pseudokinase). Four different types of JAKs are known: JAK1, JAK2, JAK3 (also known as Janus kinase, leukocyte; JAKL; and L-JAK), and TYK2 (protein-tyrosine kinase 2). [Namour, F., et al., Clin Pharmacokinet, 54, 859-874 (2015)]. Each JAK has a primary role in mediating signaling by a subset of factors, although there may be some overlapping role for the different JAKs. For example, JAK1 is a novel target for inflammatory diseases, transducing cytokine-driven proinflammatory signaling, and for other diseases driven by JAK-mediated signal transduction. JAK2 signals for a range of cytokines, but is used primarily by receptors for hematopoietic growth factors, such as erythropoietin and thrombopoietin (TPO). JAK3 has been studied for its primary role in mediating immune function, whereas Tyk2 functions in association with JAK2 or JAK3 to transduce signaling of cytokines, such as interleukin-12 and -23 (IL-12 and IL-23) [Pesu, Marko et al., Immunological reviews, vol. 223 (2008): 132-42]. While JAK1, JAK2, and Tyk2 are expressed in many cell types and tissues, JAK-3 expression is skewed to hematopoietic and lymphoid precursor cells. Inhibition of JAK1 has been associated with reductions in proinflammatory cytokines, such as interleukin-6 (IL-6) and interferons (IFN) α, β, and γ, and thereby with control of inflammation. JAK inhibitors such as Abrocitinib, Upadacitinib, Baricitinib, Tofacitinib, Ruxolitinib, Delgocitinib, Brepocitinib, Oclacitinib, Peficitinib and Fedratinib, are already known. However, a large number of these inhibitors do not act selectively on the JAK1 enzyme compared with other enzymes of the family. Selective inhibition of JAK1 may translate in to enhanced efficacy and reduced undesirable effects associated with inhibition of JAK2, JAK3, and Tyk2. For example, oral dosage forms of Upadacitinib and Baricitinib have been approved for treatment of Rheumatoid Arthritis with a black box warning regarding serious side effects such as thrombosis, malignancy (Lymphoma) and serious infections leading to hospitalization or death. While some of these oral drugs are being repositioned and repurposed for other forms of administration, the systemic undesired effects of these drugs is still an impediment to their successful development. The JAK-STAT pathway has been found to play a fundamental role in human health and disease, from rare monogenic disorders to more common complex diseases. Agents that selectively inhibit or reduce JAK1 production and activity, while eliminating the systemic side effects, are of great interest as therapeutic targets for the treatment of various diseases involving expression of JAK1, including autoimmune, inflammatory and oncological diseases. SUMMARY The present disclosure provides novel compounds having formula (I) a salt thereof, or an enantiomer thereof,wherein: R is —NO2, —S(O)Rb, —S(O)2Rb, —S(O)NRcRd, —S(O)2NRcRd, —NRcRd, —