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WO-2026096385-A1 - HETEROARYL COMPOUNDS USEFUL AS TYK2 INHIBITORS

WO2026096385A1WO 2026096385 A1WO2026096385 A1WO 2026096385A1WO-2026096385-A1

Abstract

The present disclosure provides compounds useful as TYK2 inhibitors for treating autoimmune disorders.

Inventors

  • KIM, BYUNGCHAN
  • MONDAL, SAYAN
  • NOWAK, PAWEL
  • JIANG, CHUN

Assignees

  • NEUROLAMBDA THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20251027
Priority Date
20241028

Claims (20)

  1. CLAIMS
  2. 1. A compound of Formula I:
  3. I’
  4. or a pharmaceutically acceptable salt thereof, wherein:
  5. V 1 is N and V 2 is C, or V 2 is N and V 1 is C;
  6. X 1 is C-H orN;
  7. Ring A is a 6-membered heteroaryl ring having 0-2 nitrogen atoms in addition to V 1 or V 2 ; R 1 is -C(O)Y or an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  8. Y is -R a , -OR a , -NHR a , or -C(O)NHR a ;
  9. R 2 is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 2 is substituted with 0-3 instances of R b ;
  10. R 3 is halogen, -CN, -OR, -N(R)2, C 1-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 8-membered bridged bicyclic carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 3 is substituted with 0-3 instances of R c ;
  11. R a is hydrogen, Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6- membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 - to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R a is substituted with 0-2 instances of R al ;
  12. R al is Ci-6 aliphatic, halogen, or -OR; R x
  13. b ¥ y
  14. R is halogen, -CN, -OR",, - or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 6- to 8-membered bridged bicyclic carbocyclic ring, a 3- to 8-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 11 -membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:
  15. two instances of R b , together with the atoms to which they are attached, may cyclize to form a 5- to 6-membered saturated carbocyclic ring, a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two R b groups is substituted by 0-3 instances of R b *;
  16. R b * is halogen, -OR, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein two instances of R b * attached to the same carbon atom may cyclize to form a 3- to 6- membered saturated carbocyclic ring or a 3- to 6-membered heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur;
  17. R c is halogen, oxo, -CN, -OR, -N(R)2, Ci-6 aliphatic optionally substituted with 1-3 halogen, - C(O)R, -CO2R, or a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  18. R w is hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3- to 6- membered saturated carbocyclic ring, a 3 - to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9- membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 8-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  19. R x is hydrogen or Ci-6 aliphatic;
  20. R y is hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6- membered saturated carbocyclic ring, a 3 - to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9- membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 8-membered fused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 8- membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Description

HETEROARYL COMPOUNDS USEFUL AS TYK2 INHIBITORS BACKGROUND [0001] Tyrosine Kinase 2 (TYK2) is a non-receptor tyrosine kinase involved in both adaptive and innate immune responses. It is a member of the Janus kinase (JAK) family, which also includes JAK1, JAK2, and JAK3. These kinases are associated with cytokine receptors and mediate the tyrosine phosphorylation of these receptors. This process recruits and activates STAT transcription factors, regulating gene expression crucial for diverse cellular functions and human physiology. [0002] More than 50 cytokines, growth factors and hormones are known to utilize the JAK-STAT signaling pathway to perform their roles in cell differentiation, metabolism, survival, homeostasis, and immune response. TYK2, which is ubiquitously expressed and particularly active in immune cells, transduces signals downstream from various cytokine receptor families, including type I IFNAR, IL-6R, IL-10R, IL-12R, IL-13R, and IL-23R. Consequently, TYK2 coordinates a broad range of cellular responses, significantly impacting cytokine functions (Hu, X. (2021). The JAK/STAT signaling pathway: from bench to clinic. In Signal Transduction and Targeted Therapy (Vol. 6, Issue 1). Springer Nature, https://doi.org/10.1038/s41392-021-00791-1). SUMMARY [0003] The present disclosure provides the recognition that the modulation of TYK2 plays a role in many cellular responses. In some embodiments, the present disclosure provides a compound of formula I: I or a pharmaceutically acceptable salt thereof, wherein each of V1, V2, X1, R1, R2, R3, and n is as defined herein. [0004] In particular, the present disclosure provides compounds of formula I, or a pharmaceutically acceptable salt thereof, that are useful in inhibiting the TYK2 pathway. In some embodiments, the present disclosure provides methods of inhibiting TYK2, the method comprising contacting a biological sample or administering to a subject a compound of formula I, or a pharmaceutically acceptable salt thereof. [0005] In certain embodiments, the present disclosure provides a method of treating a TYK2 -mediated disease, disorder, or condition, the method comprising administering to a subject a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, a TYK2 -mediated disease, disorder, or condition is an autoimmune disorder that comprises neurological involvement such as, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis, and psoriatic arthritis, among others. DETAILED DESCRIPTION Definitions [0006] Compounds provided herein include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0007] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0008] As used herein, the term “carbocyclic” means a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring comprises a cyclic C3-C6 hydrocarbon. [0009] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2//-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in [0010] The term “halogen” means F, Cl, Br, or I. [0