Search

US-12624039-B2 - BTK inhibitors

US12624039B2US 12624039 B2US12624039 B2US 12624039B2US-12624039-B2

Abstract

The invention relates to chemical compounds, or pharmaceutically acceptable salts thereof, of the formula (I) which possess BTK inhibitory activity and are accordingly useful in therapy and in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them, and to their use in the manufacture of medicaments for use in a therapeutic effect in a warm-blooded animal such as man.

Inventors

  • Quan Zhou
  • Changmao Shen
  • Xiang Chen
  • Wengeng LIU
  • Rumin WANG
  • Qingbei Zeng
  • HONCHUNG TSUI
  • Zhenfan YANG
  • Xiaolin Zhang

Assignees

  • DIZAL (JIANGSU) PHARMACEUTICAL CO., LTD.

Dates

Publication Date
20260512
Application Date
20201229
Priority Date
20200102

Claims (20)

  1. 1 . A compound of formula (I): wherein: R 1 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, N—C 1-6 alkylamino, N,N—(C 1-6 alkyl) 2 amino, carbocyclyl and heterocyclyl; wherein R 1 may be optionally substituted by one or more R 5 ; R 2 is selected from halo, C 1-3 alkyl, C 1-3 alkoxy, carbocyclyl and heterocyclyl; or two R 2 , either on the same atom or on adjoining atoms, may together with the atoms to which they are attached form a 3-7 membered ring; k is 0-4; R 3 is selected from halo, C 1-3 alkyl and C 1-3 alkoxy; n is 0-4; R 4 is selected from halo, C 1-3 alkyl and C 1-3 alkoxy; m is 0-5; A is ═N— or ═C(R 6 )—; R 5 is selected from halo, hydroxy, C 1-6 alkoxy, amino, N—C 1-6 alkylamino, N,N—(C 1-6 alkyl) 2 amino, carbocyclyl and heterocyclyl; wherein R 5 may be independently optionally substituted by one or more R 7 ; R 6 is selected from hydrogen and halo; R 7 is selected from halo, hydroxy, amino, C 1-3 alkyl and C 1-3 alkoxy; or a pharmaceutically acceptable salt thereof.
  2. 2 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 1 is selected from hydrogen, methyl, hydroxymethyl, methoxymethyl, N,N-dimethylaminomethyl and azetidin-1-ylmethyl.
  3. 3 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein k is 0.
  4. 4 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 3 is fluoro.
  5. 5 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein n is 0-2.
  6. 6 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 4 is fluoro.
  7. 7 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein m is 0-2.
  8. 8 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein A is ═N— or ═C(H)—.
  9. 9 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 selected from: (5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; 3-(6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine; 7-(6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 7-(6-(azetidin-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-(6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; and 5-(2-fluoro-4-phenoxyphenyl)-7-(6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine.
  10. 10 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 selected from: ((2R,5R)-5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; 3-((3R,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine; 7-((3R,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 7-((3R,6R)-6-(azetidin-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6R)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; (R)-5-(2-fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; and 5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6R)-6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; ((2S,5S)-5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5S)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5S)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5S)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5S)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5S)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5S)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; 3-((3S,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine; 7-((3S,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 7-((3S,6S)-6-(azetidin-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-((3S,6S)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; (S)-5-(2-fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; and 5-(2-fluoro-4-phenoxyphenyl)-7-((3S,6S)-6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; ((2S,5R)-5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5R)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5R)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5R)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5R)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5R)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5R)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; 3-((3S,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine; 7-((3S,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 7-((3S,6R)-6-(azetidin-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-((3S,6R)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; AND 5-(2-fluoro-4-phenoxyphenyl)-7-((3S,6R)-6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; ((2R,5S)-5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5S)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5S)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5S)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5S)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5S)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5S)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; 3-((3R,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine; 7-((3R,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 7-((3R,6S)-6-(azetidin-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6S)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; and 5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6S)-6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine.
  11. 11 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein the compound is ((2S,5S)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol.
  12. 12 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein the compound is ((2S,5S)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol.
  13. 13 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein the compound is ((2S,5S)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol.
  14. 14 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein the compound is ((2S,5S)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol.
  15. 15 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein the compound is ((2S,5S)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol.
  16. 16 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein the compound is ((2S,5S)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol.
  17. 17 . A pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , in association with a pharmaceutically-acceptable diluent or carrier.
  18. 18 . A method of inhibiting BTK by using one or more compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 .
  19. 19 . A method of inhibiting BTK, as claimed in claim 18 , wherein the BTK is wild-type BTK or BTK with a C481 mutation.
  20. 20 . A method of inhibiting BTK, as claimed in claim 19 , wherein the BTK with a C481 mutation is selected from the group consisting of: BTK with a C481S mutation, BTK with a C481Y mutation, BTK with a C481R mutation and BTK with a C481F mutation.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a national phase application, filed pursuant to 35 U.S.C § 371 of PCT Application No. PCT/CN2020/140517 filed on Dec. 29, 2020, which claims foreign priorities of PCT Application No. PCT/CN2020/070034 filed on Jan. 2, 2020 and PCT Application No. PCT/CN2020/134601 filed on Dec. 8, 2020, both are now abandoned. Each of these applications is hereby incorporated by reference herein in its entirety. FIELD The present application is directed towards oxane substituted imidazopyrazine and imidazotriazine inhibitors of Bruton's Tyrosine Kinase (BTK), including mutant BTK, useful in the treatment of diseases or disorders associated with BTK kinase. These compounds have potential utility in the treatment of immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders, and neurological disorders. Specifically, the application is directed towards compounds and compositions thereof which inhibit BTK, methods of treating diseases or disorders associated with BTK, and methods of synthesis of these compounds. BACKGROUND Bruton's Tyrosine Kinase (BTK), also known as tyrosine-protein kinase BTK, is a member of the Tec family of tyrosine kinases and plays an important role in the regulation of early B-cell development and mature B-cell activation and survival (Hunter, Cell, 87, 50, 823-829). The BTK enzyme is encoded by the BTK gene, and has been shown to initiate a number of cellular processes including cell proliferation, survival, differentiation, motility, angiogenesis, cytokine production, and antigen presentation. BTK-deficient mouse models have shown that BTK plays a role in allergic disorders and/or autoimmune disease and/or inflammatory disease; and BTK inhibition has potential utility in the treatment of such diseases as systemic lupus erythematosus (SLE), Urticaria/Sjogren's syndrome, rheumatoid arthritis, vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, and asthma. BTK's role in apoptosis also demonstrates the utility of inhibition of BTK activity for the treatment of cancers, for example B-cell lymphoma, leukaemia, and other haematological malignancies. In addition, BTK has a role in osteoclast function, so inhibition of BTK activity has potential utility in the treatment of bone disorders, such as osteoporosis. Approved compounds that inhibit BTK include ibrutinib (B cell malignancies e.g. mantle cell lymphoma, chronic lymphocytic leukaemia (CLL), Waldenström's macroglobulinemia); acalabrutinib (mantle cell lymphoma and CLL); and zanubrutinib (mantle cell lymphoma). In addition there are several BTK inhibitors in clinical trials including evobrutinib (multiple sclerosis); ABBV-105 (systemic lupus erythematosus (SLE)); ONO-4059/GS-4059 (non-Hodgkin lymphoma and CLL); spebrutinib (relapsed or refractory B Cell Non-Hodgkin Lymphoma, CLL and Waldenström's Macroglobulinemia); and HM71224 (autoimmune diseases). Despite major therapeutic advances in the treatment of B-cell malignancies using BTK inhibitors, cases of primary and secondary resistance have emerged with poor outcomes and limited treatment options. Covalent (irreversible) BTK inhibitors such as ibrutinib and acalabrutinib bind with the C481 site of BTK rendering it kinase-inactive. This binding is permanent until the BTK protein degrades. The advantages of these irreversible inhibitors are that they are potent and usually only a short period of exposure will be efficacious. However, their clinical benefit is limited by off-target toxicity, leading to high rates of discontinuation, and acquired resistance due to BTK C481 mutations that disrupt covalent binding to BTK, reducing the compounds' binding affinity, and diminishing their ability to inhibit BTK enzymatic activity (Leukaemia 2015, April; 29(4):895-900). The majority (>50%) of CLL patients who progress on covalent BTK inhibitor therapy become resistant to treatment due to the development of a C481S mutation (N. Engl. J. Med. 370; 24, 2014; JAMA Oncol. 2015; 1(1):80-87; and J. Clin. Oncol. 35:1437-1443, 2017). Primary central nervous system lymphoma (PCNSL) is a disease in which malignant (cancer) cells is form in the lymph tissue of the brain and/or spinal cord, and it accounts for approximately 1% of all lymphomas and 2% to 5% of all primary brain tumours. The vast majority (approximately 95%) of PCNSLs are diffuse large B-cell lymphomas (DLBCL). Mutation in the CD79B and MYD88 genes are frequently (˜30-80%) coincident with PCNSL (Neuropathol. Appl. Neurobiol. 2016 April; 42(3):279-90). Although to date BTK inhibitors have not been approved for the treatment of DLBCL, data suggests that DLBCL with CD79B and MYD88 mutations are more sensitive to BTK inhibition (Nat. Med. 2015 August; 21(8):922-6). Secondary CNS lymphoma (SCNSL) refers to central nervous system spread of a lymphoma that originated elsewhere (in contrast to primary CNS lymp