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US-20260125375-A1 - SUBSTITUTED 1H-PYRAZOLO-PYRIDINE AND -PYRIMIDINE COMPOUNDS

US20260125375A1US 20260125375 A1US20260125375 A1US 20260125375A1US-20260125375-A1

Abstract

This disclosure relates to compounds of Formula (I) (I), or a pharmaceutically acceptable salt thereof, in which R3, R4, L2, W, X, Y, and Z are as 5 defined herein, to pharmaceutical compositions comprising such compounds and salts; to processes for their preparation; to intermediates used in such process; and to methods of using such compounds, salts and compositions for the treatment of immunosuppression-associated disorders such as chronic viral infections and cancer.

Inventors

  • Sujin Cho-Schultz
  • Sajiv Krishnan Nair
  • Ryan Lloyd PATMAN
  • Khanh Tuan Tran
  • Hanna Maria Wisniewska
  • Ru Zhou
  • Judith Gail Deal
  • Joyann Susan DONALDSON
  • Kevin Daniel Freeman-Cook
  • Mehran JALAIE
  • Matthew Scott JEFFREYS
  • Stephen Elliott Kaiser
  • John Charles Kath
  • Timothy Patrick Montgomery

Assignees

  • PFIZER INC.

Dates

Publication Date
20260507
Application Date
20231002

Claims (20)

  1. 1 . A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: W is N or C-L 1 -R 1 ; X is N or C-L 1 -R 1 ; Y is N or CR 2 ; Z is N or CH; with the provisos that: one of W and X is N or CH and the other one of W and X is C-L 1 -R 1 ; when Z is N, X is N; and Y and Z are not both N; R 1 is selected from the group consisting of H, halogen, C 3 -C 10 cycloalkyl, 4-8 membered heterocycloalkyl, NR 5 R 6 , and OR 7 ; wherein said C 3 -C 10 cycloalkyl or said 4-8 membered heterocycloalkyl ring is optionally substituted by one or more R 9 which can be the same or different; R 2 is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 3 -C 10 cycloalkyl; wherein said C 1 -C 6 alkyl, said C 1 -C 6 alkoxy or said C 3 -C 10 cycloalkyl is optionally substituted by one or more halogen or oxo; R 3 and R 4 are independently selected from the group consisting of H, fluoro, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and 4-8 membered heterocycloalkyl, each of which is optionally substituted by one or more R 10 which can be the same or different; or R 3 and R 4 together with the carbon atom to which they are attached form a C 3 -C 8 cycloalkyl or 4-8 membered heterocycloalkyl ring, each of which is optionally substituted by one or more R 10 which can be the same or different; R 5 and R 6 are independently H, C(O)R 8 , C(O)OR 8 , C(O)NHR 8 , SOR 8 , SO 2 R 8 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or said 4-8 membered heterocycloalkyl is optionally substituted by one or more R 9 which can be the same or different; or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4-8 membered heterocycloalkyl ring optionally further containing one or more heteroatoms selected from oxygen, sulfur, and nitrogen, wherein said 4-8 membered heterocycloalkyl ring is optionally substituted by one or more R 9 which can be the same or different; R 7 is H, C 1 -C 6 alkyl or 4-8 membered heterocycloalkyl, wherein said C 1 -C 6 alkyl or said C 3 -C 10 heterocycloalkyl is optionally substituted by one or more R 9 which can be the same or different; R 8 is C 1 -C 6 alkyl optionally substituted by one or more R 9 which can be the same or different; R 9 is each independently halogen, C 1 -C 6 alkyl, OH, hydroxyalkyl, C 1 -C 3 alkoxy, NR 11 R 12 , NR 11 COR 12 , NR 11 SO 2 R 12 , NR 11 COOR 12 , NR 11 CONR 12 R 13 , SR 11 , SOR 11 , SO 2 R 11 , CONR 11 R 12 , CN or oxo; R 10 is each independently halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, fluoroalkyl, CN, oxo or OH; R 11 , R 12 and R 13 are each independently H or C 1 -C 3 alkyl; L 1 and L 2 are independently a bond or a C 1 -C 3 alkylene optionally substituted by one or more F, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, fluoroalkyl or OH, and wherein is selected from the group consisting of:
  2. 2 . (canceled)
  3. 3 . The compound or pharmaceutically acceptable salt of claim 1 , having the Formula (II):
  4. 4 . The compound or pharmaceutically acceptable salt of claim 1 , having the Formula (II-a), (II-b), (II-c), (II-d), (II-e), or (II-f):
  5. 5 . (canceled)
  6. 6 . The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is NR 5 R 6 , further wherein one of R 5 and R 6 is H and the other one of R 5 and R 6 is C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocycloalkyl, C(O)R 8 , C(O)OR 8 , C(O)NHR 8 , SOR 8 , or SO 2 R 8 , further wherein said C 1 -C 6 alkyl, said C 3 -C 10 cycloalkyl, or said 4-8 membered heterocycloalkyl is optionally substituted by one or more R 9 which can be the same or different.
  7. 7 . The compound or pharmaceutically acceptable salt of claim 6 , wherein one of R 5 and R 6 is selected from the group consisting of C 1 -C 3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, and azetidinyl, where each of which is optionally substituted by one or more R 9 which can be the same or different, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4-8 membered heterocycloalkyl ring selected from the group consisting of: optionally substituted by one or more R 9 which can be the same or different.
  8. 8 . (canceled)
  9. 9 . (canceled)
  10. 10 . The compound or pharmaceutically acceptable salt of claim 1 , wherein each R 9 is independently halogen, OH, NH 2 , C 1 -C 6 alkyl, or oxo.
  11. 11 . The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 is CF 3 .
  12. 12 . (canceled)
  13. 13 . The compound or pharmaceutically acceptable salt of claim 1 , wherein R 3 is cyclobutyl.
  14. 14 . The compound or pharmaceutically acceptable salt of claim 1 , wherein R 3 and R 4 together with the carbon atom to which they are attached to form a 4-8 membered heterocycloalkyl ring.
  15. 15 . The compound or pharmaceutically acceptable salt of claim 14 , wherein R 3 and R 4 together with the carbon atom to which they are attached to form an optionally substituted oxetane.
  16. 16 . (canceled)
  17. 17 . The compound or pharmaceutically acceptable salt of claim 1 , wherein L 1 is selected from —CH 2 — or —CHCH 3 —.
  18. 18 . The compound or pharmaceutically acceptable salt of claim 1 , wherein L 2 is selected from a bond, —CH 2 — or —CHCH 3 —.
  19. 19 . The compound or pharmaceutically acceptable salt of claim 1 , wherein L 2 is a bond; R 3 is cyclobutyl; and R 4 is H.
  20. 20 . The compound or pharmaceutically acceptable salt of claim 1 , wherein L 2 is CH 2 ; and R 3 and R 4 together with the carbon atom to which they are attached to form an oxetane.

Description

FIELD The present disclosure relates to novel 1H-pyrazolo-pyridine and -pyrimidine compounds. The disclosure also relates to the preparation of the compounds and intermediates used in the preparation, compositions containing the compounds, and uses of the compounds as inhibitors of the E3 ubiquitin ligase enzyme, casitas B-lineage lymphoma proto-oncogene-b (CBL-B), in the treatment of immunosuppression-associated disorders such as chronic viral infections and cancer. BACKGROUND CBL-B is an E3 ubiquitin ligase and a key negative feedback regulator of TCR and costimulatory receptor signal transduction, which directly binds to and ubiquitinates multiple substrates including zeta-chain-associated protein kinase 70 (Zap70) (Zhang et al., Current Biology, 1999, 9(4):203-206, PMID 10074432) and p85 (Fang et al., Nature Immunology, 2001, PMID 11526404). Genetic loss of CBL-B catalytic function (CD3+ T cells that lacked CBL-B E3 ubiquitin ligase activity, C373A KI/KI cells) overcomes the requirement for co-stimulation provided by antigen presenting cells, decreases the T cell activation threshold and renders T cells resistant to repeat stimulation induced anergy. Consequently, loss of CBL-B activity leads to spontaneous tumor clearance in syngeneic tumor models in a CD8 T cell-dependent manner. (Paolino et al., J. Immunol. 2011, 186(4): 2138-2147, PMID 21248250). CBL-B is thus a compelling target for modulating an immune response to cancer. One such opportunity is to promote signaling via the T cell receptor (TCR) (Hwang et al., Exp. Mol. Med. 2020, 52(5):750-761, PMID 32439954) to enhance T cell activation. Following engagement of the TCR by major histocompatibility (MHC)-antigen complexes, a well described signal transduction cascade ensues, leading to the phosphorylation of substrates including Lck and Zap70 ultimately leading to the production of inflammatory cytokines (IL-2, IFNg and TNFa) and the acquisition of cytotoxic effector function. While CBL-B inhibition is a compelling therapeutic strategy, there are possible adverse autoimmune risks associated with simultaneous inhibition of the closely related molecule casitas B lineage lymphoma (C-CBL). The ubiquitously expressed protein C-CBL plays an important role in the internalization and negative regulation of signaling from receptor tyrosine kinases including epidermal growth factor receptor (EGFR) (Yokouchi et al., J Biol. Chem. 1999, 274(44):31707-12, PMID 10531381). Mice containing T-cells that are deficient for both CBL-B and C-CBL demonstrate a hypersensitive immune activation phenotype and succumb to lethal autoimmunity 12-14 weeks after birth, and mice with global loss of both CBL-B and C-CBL succumb to a systemic myeloproliferative disorder within a similar timeframe. (Naramura et al., Proc. Natl. Acad. Sci. 2010, 107(37):16274-9, PMID 20805496). These findings highlight the potential therapeutic benefit of inhibitors that display selectivity for CBL-B over C-CBL with broad application in cancer immunotherapy. Accordingly, there remains a need for improved therapeutic strategies to enhance anti-tumor immunity in patients. SUMMARY OF THE DISCLOSURE The present disclosure provides, in part, compounds of Formulae (I) to (V), including sub-Formulae (II-a to II-f), and pharmaceutically acceptable salts thereof. The compounds of the present disclosure may inhibit the activity of CBL-B and may be useful in the treatment, prevention, suppression and amelioration of cancer (see, for example, Chiang et al., J. Clin. Invest. 2007,117(4):1029-36, PMID 17364027), chronic viral infection (Ou et al., J. Virol. 2008, 82(7):3353-68, PMID 18199651) or diseases, disorders and conditions mediated by CBL-B. In particular, such compounds show affinity/activity for CBL-B which is greater than their affinity/activity against C-CBL. Also provided are pharmaceutical compositions, comprising the compounds or salts of the disclosure, alone or in combination with additional anticancer therapeutic agents. The present disclosure also provides, in part, methods for preparing such compounds, pharmaceutically acceptable salts and compositions of the disclosure, and methods of using the foregoing. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter. According to an embodiment of the disclosure there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof,wherein: W is N or C-L1-R1;X is N or C-L1-R1;Y is N or CR2;Z is N or CH;with the provisos that: one of W and X is N or CH and the other one of W and X is C-L1-R1;when Z is N, X is N; andY and Z are not both N; R1 is selected from the group consisting of H, halogen, C3-C1 cy