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EP-4166557-B1 - INTERMEDIATES OF N-(3-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PHENYL)BENZAMIDE DERIVATIVES

EP4166557B1EP 4166557 B1EP4166557 B1EP 4166557B1EP-4166557-B1

Inventors

  • ARISTA, LUCA
  • ZOLLER, THOMAS
  • HEBACH, CHRISTINA
  • HOLLINGWORTH, GREGORY JOHN
  • HOLZER, PHILIPP
  • IMBACH-WEESE, Patricia
  • LORBER, Julien
  • MACHAUER, RAINER
  • SCHMIEDEBERG, NIKO
  • VULPETTI, ANNA

Dates

Publication Date
20260506
Application Date
20190322

Claims (5)

  1. A compound of Formula (III) or (IIIa) or a salt thereof, wherein: R 6 is H or F; and R 7 is selected from -CH 3 , -OCH 3 , and -OCH 2 CH 3 .
  2. The compound of claim 1, or a salt thereof, wherein R 6 is H.
  3. The compound of claim 1 or 2, or a salt thereof, wherein R 7 is -OCH 3 .
  4. The compound of claim 1, or a salt thereof, having Formula (III): wherein R 6 is selected from H and F; and R 7 is selected from -CH 3 , -OCH 3 , and -OCH 2 CH 3 .
  5. The compound of claim 1, or a salt thereof, having Formula (IIIa): wherein R 6 is selected from H and F; and R 7 is selected from, -CH 3 , -OCH 3 , and -OCH 2 CH 3 .

Description

FIELD OF THE INVENTION The present invention relates to intermediates useful in the preparation of N-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)benzamide derivatives, which are useful in the treatment of conditions, diseases and disorders mediated by Bruton's Tyrosine Kinase. BACKGROUND OF THE INVENTION Bruton's Tyrosine Kinase (BTK) is a critical node for B-cell receptor (BCR) signaling, and an important target in cancer. Many cancers and lymphomas express BTK and are dependent on BTK function, and BCR signaling in tumor infiltrating B-cells has also been implicated in the tumor-promoting microenvironment of solid cancers (J.A. Burger and A. Wiestner, Nat Rev Cancer 2018, 18, 148). Pharmacological blockade of BTK using inhibitors, particularly inhibitors which irreversibly bind BTK through cysteine-481 is an established strategy, BTK being a primary target of the molecule ibrutinib (J.A. Burger and J.J. Buggy, Leukemia and Lymphoma 2013, 54, 2385) which is indicated for the treatment of several cancers (C-S Lee et al., J. Oncol. Pharm. Practice 2016, 22, 92-104. V. Kaur & A. Swami, Ann. Hematol. 2017, 96, 1175), as well as for acalabrutinib which is indicated for the treatment of patients with mantle cell lymphoma who have received at least one prior treatment (Wang M et al, Lancet 2018, 391, Issue 10121, 659-667). BTK also plays an essential role in autoimmune disease. BTK-deficient mice are protected in standard preclinical models for rheumatoid arthritis (L. Jansson and R. Holmdahl, Clinical and experimental immunology 1993, 94, 459; L.E. Nyhoff et al, Arthritis Rheumatol. 2016, 68, 1856), systemic lupus erythematosus (Steinberg, B. J. et al., J. Clin. Invest. 1982, 70, 587-597), as well as allergic disease and anaphylaxis (Hata, D. et al., J. Exp. Med. 1998, 187, 1235-1247), thus pharmacological blockade of BTK may be useful in the treatment of immune disorders. In view of the above, modulators of BTK may be useful in the treatment of proliferative disorders such as cancer and of immune (e.g. autoimmune) disorders. There remains a need for new medications to treat BTK-dependent diseases, particularly those resistant to or poorly responding to currently available medications. A molecule designed to reduce or remove BTK protein by inducing its degradation (hereinafter referred to as a 'BTK degrader') may be efficacious in treating a range of BTK mediated diseases such as proliferative disorders (such as cancers) and immune disorders. Furthermore, BTK degraders may be effective in settings of resistance to irreversible BTK inhibitors (which bind covalently to BTK). Resistance may arise through, for example mutation of cysteine-481 to serine (or other amino acid substitutions). Potential indications for a BTK degrader include, but are not limited to, cancers of hematopoietic origin such as Hodgkin lymphoma, non-Hodgkin lymphoma, post-transplant lymphoproliferative disorder, hairy cell leukemia, histiocytic and dendritic neoplasms and B-cell neoplasms such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, Marginal Zone Lymphoma, immunoblastic large cell lymphoma, Richter Syndrome, and precursor B-lymphoblastic lymphoma, primary and secondary multiple myeloma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, and acute lymphoblastic leukemia. Potential indications for a BTK degrader also include, but are not limited to, autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, allergic diseases, anaphylaxis and inflammatory conditions. Furthermore, potential indications for a BTK degrader include chronic graft-versus-host disease (cGvHD) and immunoglobulin Light Chain Amyloidosis (AL). The principle of induced degradation of protein targets as a potential therapeutic approach has been described in, for example, C.M. Crews, 2018, J. Med.Chem., 61(2), 403-404 and references cited therein. A BTK degrader molecule which incorporates an ibrutinib substructure as the BTK binding moiety is described in WO 2016/169989 at page 12 and incorporates an E3 ligase IAP binding moiety for recruitment of the target protein to the E3 ubiquitin ligase IAP for degradation. Two further BTK degrader molecules are described in Huang et. al., 2018, Cell Chemical Biology 25, 88-99 which incorporate two structurally different moieties as the BTK binding components. The molecules described in that publication incorporate an immunomodulatory imide drug (IMiD) moiety (pomalidomide) for recruitment of BTK to the E3 ligase complex comprising cereblon (CRBN) for ubiquiti