BTK inhibitors

Abstract

JPEG2023510212000056.jpg9779A chemical entity of formula (I), or a pharmaceutically acceptable salt thereof, having BTK inhibitory activity and therefore useful in therapy and methods of treatment of the human or animal body. Also provided are processes for the preparation of said chemical entities, pharmaceutical compositions containing them, and their use in the manufacture of medicaments for use in a therapeutic effect in a warm-blooded animal, e.g., a human.

Description

[Technical field]

[0001] The present application is directed to inhibitors of Bruton's tyrosine kinase (BTK) kinase, including mutant BTK, that are oxane-substituted imidazopyrazines and imidazotriazines useful for the treatment of diseases or disorders associated with BTK. These compounds have potential utility in the treatment of immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction, and neurological disorders.

[0002] In particular, the present application is directed to compounds and compositions thereof that inhibit BTK, methods of treating diseases or disorders associated with BTK, and methods of synthesis of these compounds. [Background technology]

[0003] Bruton's tyrosine kinase (BTK), also known as tyrosine-protein kinase BTK, is a member of the Tec family of tyrosine kinases that plays a key role in the control of early B cell development and in the activation and survival of mature B cells (Hunter, Cell, 87, 50, 823-829). The BTK enzyme, encoded by the BTK gene, has been shown to initiate many cellular processes, including cell proliferation, survival, differentiation, motility, angiogenesis, cytokine production, and antigen presentation.

[0004] BTK-deficient mouse models have demonstrated that BTK plays a role in allergic and / or autoimmune and / or inflammatory disorders, and that BTK inhibition has potential utility in the treatment of diseases such as systemic lupus erythematosus (SLE), urticaria / Sjogren's syndrome, rheumatoid arthritis, vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, and asthma.

[0005] The role of BTK in apoptosis also demonstrates the utility of inhibiting BTK activity for the treatment of cancer, such as B cell lymphoma, leukemia, and other hematological malignancies. Additionally, because BTK plays a role in osteoclast function, inhibition of BTK activity has potential utility in the treatment of bone diseases, such as osteoporosis.

[0006] Approved compounds that inhibit BTK include ibrutinib (B-cell malignancies, e.g., mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenstrom'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's lymphoma and CLL), spebrutinib (relapsed or refractory B-cell non-Hodgkin's lymphoma, CLL, and Waldenstrom's macroglobulinemia), and HM71224 (autoimmune diseases).

[0007] Despite major therapeutic advances in the treatment of B-cell malignancies with BTK inhibitors, primary and secondary resistant cases emerge with poor prognosis and limited therapeutic options.

[0008] Covalent (irreversible) BTK inhibitors, such as ibrutinib and acalabrutinib, bind to the C481 site of BTK, rendering it kinase inactive. This binding is permanent until the BTK protein is degraded. The advantage of these irreversible inhibitors is that they are potent and usually effective even with short exposures. However, their clinical benefit is limited by off-target toxicity, high discontinuation rates, and acquired resistance due to BTK C481 mutations that disrupt the covalent binding to BTK, reducing the binding affinity of the compounds and attenuating their ability to inhibit BTK enzymatic activity (Leukaemia 2015, April;29(4):895-900). The majority (>50%) of CLL patients who undergo covalent BTK inhibitor therapy become resistant to treatment due to the development of the C481S mutation (N. Engl. J. Med. 370;24, 2014; JAMA Oncol. 2015;1(1):80-87; and J. Clin. Oncol. 35:1437-1443, 2017).

[0009] Primary central nervous system lymphoma (PCNSL) is a disease in which malignant (cancer) cells form in the lymphatic tissues of the brain and / or spinal cord; it accounts for approximately 1% of all lymphomas and 2%-5% of all primary brain tumors. The majority of PCNSL (approximately 95%) are diffuse large B-cell lymphomas (DLBCL). Mutations in the CD79B and MYD88 genes frequently (approximately 30-80%) occur together with PCNSL (Neuropathol. Appl. Neurobiol. 2016 April; 42(3):279-90). Currently, BTK inhibitors are not approved for the treatment of DLBCL, but data suggest that DLBCL with CD79B and MYD88 mutations may be more sensitive to BTK inhibition (Nat. Med. 2015 August; 21(8):922-6).

[0010] Secondary CNS lymphoma (SCNSL) refers to the spread of lymphoma originating elsewhere to the central nervous system (as opposed to primary CNS lymphoma). It is usually a non-Hodgkin's lymphoma and may be a single recurrence or part of a systemic disease at the time of presentation. Unlike primary CNS lymphoma, it more commonly involves the leptomeninges.

[0011] PRN2246 (SAR442168), a blood-brain barrier (BBB)-penetrating covalent BTK inhibitor, was well tolerated in a Phase I trial for multiple sclerosis (MS). Furthermore, several studies (Grommes C et al., Cancer Discov. 2017 Sep;7(9):1018-1029; Grommes C et al., Blood. 2019;133(5):436-445; Lionakis et al., 2017, Cancer Cell 31:833-843 and Soussain C et al., Eur J Cancer. 2019 Aug;117:121-130) suggest that high-dose ibrutinib (840 mg) should have efficacy in CNS lymphomas (both PCNSL and secondary nervous system lymphoma (SCNSL)), but currently no BTK inhibitors are approved that target BTK-C481 mutations or have activity in PCNSL. All of these remain unmet medical needs.

[0012] WO2009 / 143051 discloses several substituted imidazopyrazines and imidazotriazines, including several hexane-substituted imidazopyrazines and imidazotriazines, as active p21cdc42Hs-associated kinase (ACK1) inhibitors. However, the compounds of WO2009 / 143051 exhibit high human hepatocyte clearance, meaning that the compounds cannot reach sufficient sustained drug coverage even at maximum absorbed doses (potentially rendering the compounds ineffective), and / or require very high doses to inhibit the target, resulting in high maximum drug concentrations (potentially resulting in secondary pharmacological (i.e., adverse) effects and toxicity issues).

[0013] WO2017111787A1 discloses tetrahydropyranylamino-pyrrolopyrimidinones that modulate the activity of BTK, WO2018039310A1 discloses amino-pyrrolopyrimidinone compounds and methods of use thereof, WO2017103611A1 discloses compounds useful as inhibitors of BTK, and WO2011152351 discloses purinone derivatives with selective BTK inhibitory activity. However, none of these compounds possess the desired combination of properties possessed by the compounds of the present invention.

[0014] Disclosed herein are potent selective inhibitors of both wild-type BTK and BTK with C481 mutations (e.g., C481S, C481Y, C481R, or C481F mutations), several novel oxane-substituted imidazopyrazines and imidazotriazines that are non-covalent, reversible inhibitors that exhibit low human hepatocyte clearance and have blood-brain barrier (BBB) ​​permeability properties. Summary of the Invention

[0015] Disclosed herein is a compound of formula (I)

[0016] [ka]

[0017] and pharma- ceutically acceptable salts thereof, and their uses as BTK inhibitors, particularly in therapy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Many embodiments of the present invention are detailed throughout this specification and will be apparent to the reader of the art. The present invention is not to be construed as being limited to any of the enumerated embodiments, and the claims are embodiments. It is understood that some features of the present disclosure that are described in the context of separate embodiments for clarity can also be provided in combination in a single embodiment. Conversely, various features of the disclosure that are described in the context of a single embodiment for brevity can also be provided separately or in any suitable subcombination.

[0019] Disclosed herein is a compound of formula (I)

[0020] [ka]

[0021] [In the formula, R 1 is hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, N.C. 1~6 Alkylamino, N,N-(C 1~6 alkyl)2amino, carbocyclyl and heterocyclyl; R 1 is one or more R 5 and optionally replacing R 2 Halo, C 1~3 Alkyl, C 1~3 alkoxy, carbocyclyl and heterocyclyl, or two R on the same atom or on adjacent atoms; 2 can form a 3- to 7-membered ring together with the atoms to which they are attached, k is 0 to 4; R 3 Halo, C 1~3 Alkyl and C 1~3 alkoxy; n is 0 to 4; R 4 Halo, C 1~3 Alkyl and C1~3 alkoxy; m is 0 to 5; A is =N- or =C(R 6 )-and R 5 is halo, hydroxy, C 1~6 Alkoxy, amino, NC 1~6 Alkylamino, N,N-(C 1~6 alkyl)2amino, carbocyclyl and heterocyclyl; R 5 independently, optionally, one or more R 7 can be replaced by R 6 is selected from hydrogen and halo; R 7 are halo, hydroxy, amino, C 1~3 Alkyl and C 1~3 alkoxy] or a pharma- ceutically acceptable salt thereof.

[0022] In one embodiment, R 1 is hydrogen and C 1~6 alkyl; R 1 is one R 5 and R 5 is hydroxy, C 1~6 Alkoxy, N,N-(C 1~6 alkyl)2amino and heterocyclyl.

[0023] In one embodiment, R 1 is hydrogen and C 1~3 alkyl; R 1 is one R 5 and R 5 is hydroxy, C 1~3 Alkoxy, N,N-(C 1~2 alkyl)2amino and azetidinyl.

[0024] In one embodiment, R 1is selected from hydrogen, methyl, hydroxymethyl, methoxymethyl, N,N-dimethylaminomethyl, and azetidin-1-ylmethyl. In one embodiment, R 1 is hydroxymethyl.

[0025] In one embodiment, R 2 is halo or C 1~3 alkoxy. In one embodiment, R 2 is selected from fluoro or methoxy. In one embodiment, two R 2 can form a 3- to 7-membered ring together with the atom to which they are attached.

[0026] In one embodiment, two R 2 can form a 3- to 7-membered ring together with the atom to which they are attached. In one embodiment, two R on adjacent atoms 2 can form a 3- to 7-membered ring together with the atom to which they are attached.

[0027] In one embodiment, k is 0. In one embodiment, k is 1. In one embodiment, k is 2.

[0028] In one embodiment, k is 3. In one embodiment, k is 4. In one embodiment, R 3 is a halo.

[0029] In one embodiment, R 3 is fluoro. In one embodiment, n is 0-2. In one embodiment, n is 0.

[0030] In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3.

[0031] In one embodiment, n is 4. In one embodiment, R 4 is a halo. In one embodiment, R 4 is fluoro.

[0032] In one embodiment, m is 0-2. In one embodiment, m is 0. In one embodiment, m is 1.

[0033] In one embodiment, m is 2. In one embodiment, m is 3. In one embodiment, m is 4.

[0034] In one embodiment, m is 5. In one embodiment, A is =N- or =C(H)-. In one embodiment, A is =N-.

[0035] In one embodiment, A is ═C(R 6 )-. In one embodiment, A is =C(H)-. Compounds of formula (I) (when R1 ≠ hydrogen) contain two chiral centers (marked with "*").

[0036] [ka]

[0037] These chiral centers can be in the "trans" configuration, meaning the two substituents on the oxane ring point to opposite faces of the oxane ring, and in the "cis" configuration, meaning the two substituents on the oxane ring point to the same face of the oxane ring. Structures (IA) and (IB) below show cis isomers of compounds of formula (I), and structures (IC) and (ID) below show trans isomers of compounds of formula (I).

[0038] In one aspect of the invention, the compound of formula (I) is a trans compound of formula (I). In one aspect of the invention, the compound of formula (I) is a cis compound of formula (I). In one aspect of the invention, the compound of formula (I) has the formula (IA)

[0039] [ka]

[0040] It is a compound of the formula: In one aspect of the invention, the compound of formula (I) has the formula (IB)

[0041] [ka]

[0042] It is a compound of the formula: In one aspect of the invention, the compound of formula (I) has the formula (IC)

[0043] [ka]

[0044] It is a compound of the formula: In one aspect of the invention, the compound of formula (I) has the formula (ID)

[0045] [ka]

[0046] It is a compound of the formula: In one aspect of the invention, the compound of formula (I) is (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-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 is selected from.

[0047] In one aspect of the invention, the compound of formula (I) is (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-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; or a pharma- ceutically acceptable salt thereof.

[0048] In one aspect of the invention, the compound of formula (I) is ((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-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; or a pharma- ceutically acceptable salt thereof.

[0049] In one aspect of the invention, the compound of formula (I) is ((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-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; or a pharma- ceutically acceptable salt thereof.

[0050] In one aspect of the invention, the compound of formula (I) is ((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-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; or a pharma- ceutically acceptable salt thereof.

[0051] In one aspect of the invention, the compound of formula (I) is ((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-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; or a pharma- ceutically acceptable salt thereof.

[0052] In one aspect of the invention, there is provided any compound of formula (I) disclosed herein. In one aspect of the invention, there is provided any compound of formula (I) disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0053] In one aspect of the present invention, there are provided synthetic intermediates that are used to prepare the compounds of formula (I) disclosed herein. In one aspect of the present invention, there are provided synthetic intermediates used to prepare the compounds of formula (I) disclosed herein, or pharma- ceutically acceptable salts thereof.

[0054] At various points in this disclosure, linking substituents are described. When a structure clearly requires a linking group, it is understood that the Markush variable recited for that group is the linking group. For example, when a structure requires a linking group and the Markush group definition for that variable recites "alkyl," it is understood that "alkyl" represents a linking alkylene group.

[0055] As used herein, the term "substituted" when referring to a chemical group means that the chemical group has one or more hydrogen atoms removed and replaced by a substituent. As used herein, the term "substituent" has its ordinary meaning known in the art and means a chemical moiety that is covalently attached to a parent group or optionally fused to a parent group. As used herein, the term "optionally substituted" or "optionally... substituted" means that a chemical group may have no substituents (i.e., unsubstituted) or may have one or more substituents (i.e., substituted). It is to be understood that substitution at a given atom is limited by the valence of the atom.

[0056] As used herein, the term "C i~j" denotes a range of carbon atoms, where i and j are integers, and the range of carbon atoms includes its endpoints (i.e., i and j) and every integer point in between, where j is greater than i. For example, C 1~6 represents a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, the term "C 1~6 " denotes 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3, or particularly 1 to 2 carbon atoms.

[0057] As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated hydrocarbon chain. Said hydrocarbon chain may be straight or branched. The term "C i~j "Alkyl" means an alkyl having i to j carbon atoms. 1~6 Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. 1~3 Examples of "alkyl" are methyl, ethyl, propyl and isopropyl.

[0058] As used herein, the terms "halo" and "halogen" refer to an atom selected from fluorine, chlorine, bromine, and iodine. As used herein, the term "alkoxy", whether used as part of another term or independently, refers to a radical of the formula -O-alkyl. i~j "Alkoxy" means that the alkyl portion of the alkoxy group has i to j carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. 1~6Examples of "alkoxyl" are methoxy, ethoxy and propoxy. 1~3 Examples of "alkoxyl" are methoxy, ethoxy and propoxy.

[0059] "N-(C 1~6 Examples of "N,N-(C alkyl)amino" are methylamino and ethylamino. 1~6 Examples of "alkyl)2amino" are N,N-dimethylamino, N,N-diethylamino and N-ethyl-N-methylamino.

[0060] As used herein, the term "carbocyclyl", whether used as part of another term or independently, refers to a saturated monocyclic ring in which all ring atoms are carbon and which contains at least three carbon atoms forming the ring. In some embodiments, a carbocyclyl can contain 3-7 carbon atoms forming the ring or 3-6 carbon atoms forming the ring. In some embodiments, the -CH2- ring group may be replaced by a -C(O)- ring group. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0061] As used herein, the term "heterocyclyl" refers to a monocyclic saturated carbocyclyl group in which one or more (e.g., 1, 2, or 3) ring atoms are replaced by a heteroatom, including, but not limited to, oxygen, sulfur, nitrogen, phosphorus, and the like. In some embodiments, the -CH- ring group may be replaced by a -C(O)- ring group. In some embodiments, the sulfate ring atom may be optionally oxidized to form an S-oxide. In some embodiments, the heterocyclyl is carbon-linked. In some embodiments, the heterocyclyl is nitrogen-linked. Representative heterocyclyl groups include, but are not limited to, azetidinyl, piperidyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, and the like.

[0062] In one embodiment, two R 2 form a 3- to 7-membered ring together with the atom to which they are attached. The resulting "spirocycle" has two rings (one of which is an oxane of formula (I)) connected by a single common atom. The non-oxane ring can be a 3- to 7-membered carbocyclyl ring or a 3- to 7-membered heterocyclic ring. Two R on the same atom that form a 3- to 7-membered ring together with the atom to which they are attached. 2 Examples of (shown together with the oxane of formula (I) include:

[0063] [ka]

[0064] (In the formula,

[0065] [ka]

[0066] indicates the bond to the rest of the molecule) Includes: In one embodiment, two R on adjacent atoms 2 form a 3- to 7-membered ring together with the atoms to which they are attached. The resulting "fused ring" has two rings (one of which is the oxane of formula (I)) that share two adjacent atoms. The non-oxane ring can be a 3- to 7-membered carbocyclyl ring or a 3- to 7-membered heterocyclic ring. Two R on adjacent atoms that together form a 3- to 7-membered ring 2 Examples of (shown together with the oxane of formula (I) include:

[0067] [ka]

[0068] (In the formula,

[0069] [ka]

[0070] indicates the bond to the rest of the molecule) Includes: "Compounds" of the present disclosure, unless otherwise specified, are intended to encompass all stereoisomers, geometric isomers, and tautomers of the structures depicted.

[0071] The term "stereoisomer" refers to any of the various stereoisomeric configurations (e.g., enantiomers, diastereomers, and racemates) of asymmetric compounds (e.g., those having one or more asymmetrically substituted carbon atoms or "chiral centers"). Compounds of the present disclosure that contain asymmetric centers can be isolated in optically active (enantiomers or diastereomers) or optically inactive (racemic) forms. The term "enantiomers" includes pairs of stereoisomers that are non-superimposable mirror images of one another. A 1:1 mixture of a pair of enantiomers is a "racemic mixture." The term "diastereomers" or "diastereoisomers" includes stereoisomers that have at least two asymmetric atoms but are not mirror images of one another. Some compounds that contain one or more asymmetric centers can give rise to enantiomers, diastereomers, or other stereoisomeric forms that can be defined with respect to the absolute configuration at each asymmetric center as (R)- or (S)- according to the Cahn-Ingold-Prelog RS system. Resolved compounds, where the absolute configuration is unknown, can be designated at the asymmetric center with the term "or." Methods on how to prepare optically active forms from racemic mixtures are known in the art, for example, by separation by HPLC or stereoselective synthesis.

[0072] The terms "geometric isomers" or "cis and trans isomers" refer to compounds that have the same formula but their functional groups are rotated in different directions in three-dimensional space. The term "tautomer" includes prototropic tautomers, which are isomeric protonation states of a compound having the same formula and total charge. Examples of prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position of a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomers can be in equilibrium or sterically fixed in one form by appropriate substitution. Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include the other tautomeric form unless otherwise specified.

[0073] The "compounds" of the present disclosure are also intended to include all isotopes of atoms in the compound. Isotopes of an atom include atoms having the same atomic number but different mass numbers. For example, but not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the "compounds" of the present disclosure, unless otherwise specified. 1 H, 2 H, 3 H, 11 C. 12 C. 13 C. 14 C. 14 N, 15 N, 16 O. 17 O. 18 O. 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 127 I and 131In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, hydrogen refers to protium. In some embodiments, hydrogen refers to deuterium. In some embodiments, hydrogen refers to tritium. In some embodiments, the term "substituted by deuterium" or "deuterium substitution" refers to the replacement of other isoforms of hydrogen (e.g., protium) with deuterium in a chemical group. In some embodiments, carbon is 12 C and 13 Contains C.

[0074] It is also to be understood that the "compounds" of the present disclosure can exist in solvated as well as unsolvated forms, such as hydrated forms, solid forms, etc., and that the present disclosure is intended to encompass all such solvated and unsolvated forms.

[0075] It is to be further understood that the "compounds" of the present disclosure can exist in the form of pharma- ceutically acceptable salts. As used herein, the term "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals, within the scope of sound medical judgment, without undue toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio. In some embodiments, pharma- ceutically acceptable compounds, materials, compositions, and / or dosage forms refer to those approved by a regulatory agency (such as the U.S. Food and Drug Administration, the China Food and Drug Administration, or the European Medicines Agency) or those listed in generally recognized pharmacopoeias (such as the United States Pharmacopoeia, the Chinese Pharmacopoeia, or the European Pharmacopoeia) for use in animals, and more particularly in humans.

[0076] As used herein, "pharmaceutical acceptable salts" refers to derivatives of the compounds of the present disclosure, where the parent compound is modified by converting an acidic moiety (e.g., carboxyl, etc.) or basic moiety (e.g., amine, alkali, etc.) present in the compound into its salt form. In many cases, the compounds of the present disclosure can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Also, pharmaceutical acceptable salts are acid and / or base salts that typically retain the biological effectiveness and properties of the parent compound, which are not biologically or otherwise undesirable. Suitable pharma- ceutically acceptable salts of the compounds of the present disclosure include, for example, acid addition salts which may be derived, for example, from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like) or organic acids (e.g., formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, trimesic acid, citric acid, lactic acid, phenylacetic acid, benzoic acid, mandelic acid, methanesulfonic acid, napadisylic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, salicylic acid, sulfosalicylic acid, and the like).

[0077] Suitable pharma- ceutically acceptable salts of the compounds of the present disclosure also include, for example, base addition salts, which may be derived, for example, from inorganic bases (e.g., sodium, potassium, ammonium salts, and hydroxides, carbonates, bicarbonates of metals from columns I-XII of the periodic table of the elements, such as, for example, calcium, magnesium, iron, silver, zinc, copper, etc.), or organic bases (e.g., primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc.). Some organic amines include, but are not limited to, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. One skilled in the art should understand that it may also be possible to add acids or bases to form acid / base addition salts other than those shown in these examples. Lists of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing Company, Easton, Pa., (1985) and Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0078] The inventors have found that the compounds defined in the present invention, or pharma- ceutically acceptable salts thereof, are effective BTK inhibitors and can be used to produce a BTK inhibitory effect in a warm-blooded animal in need of such treatment. Accordingly, the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated solely or in part by BTK.

[0079] Thus, the compounds of the invention are expected to be useful in the treatment of immune disorders, cancer, heart disease, viral infections, metabolic / endocrine dysfunction, and neurological disorders, allergic disorders, autoimmune diseases, and inflammatory diseases, including urticaria / Sjogren's syndrome, rheumatoid arthritis, osteoporosis, vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, asthma, multiple sclerosis, and systemic lupus erythematosus.

[0080] As a result of their BTK inhibitor properties, the compounds of the present invention are expected to have a broad range of anti-cancer properties. BTK-mediated proliferation has been observed in human cancers, including but not limited to B-cell malignancies. In particular, such compounds of the present invention are expected to be useful in the treatment of lymphomas and leukemias. More particularly, such compounds of the present invention, or pharmacologic acceptable salts thereof, are expected to be useful in the treatment of small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia, non-Hodgkin's lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma, or diffuse large B-cell lymphoma. In particular, the compounds of the present invention are useful in the treatment of diffuse large B-cell lymphoma, primary central nervous system lymphoma, or secondary central nervous system lymphoma that has metastasized to the brain. In particular, the compounds of the present invention are useful in the treatment of chronic lymphocytic leukemia. In particular, the compounds of the present invention are useful in the second-line treatment of chronic lymphocytic leukemia. In particular, the compounds of the present invention are useful in the first-line treatment of chronic lymphocytic leukemia. In particular, the compounds of the present invention are useful in the treatment of diffuse large B-cell lymphoma. In particular, the compounds of the present invention are useful in the treatment of primary central nervous system lymphoma.

[0081] In some embodiments, the compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, have anti-cancer activity in early stage, aggressively progressing, metastatic and / or drug resistant cancer. In some cancer-related embodiments, the cancer is a locally advanced cancer. In some cancer-related embodiments, the cancer is a locally advanced and / or metastatic cancer. In some cancer-related embodiments, the cancer is a metastatic cancer. In some cancer-related embodiments, the cancer is an invasive cancer. In some cancer-related embodiments, the cancer is an ibrutinib-resistant cancer.

[0082] In one embodiment of the present invention, when BTK inhibition is mentioned, this refers to both wild-type BTK and BTK with a C481 mutation (e.g., a C481S, C481Y, C481R or C481F mutation).

[0083] In one embodiment of the present invention, when BTK inhibition is mentioned, this means wild-type BTK. In one embodiment of the present invention, when BTK inhibition is mentioned, this means BTK with a C481 mutation.

[0084] In one embodiment of the present invention, when BTK inhibition is mentioned, this means BTK with a C481S mutation. In one embodiment of the present invention, when BTK inhibition is mentioned, this means BTK with a C481Y mutation.

[0085] In one embodiment of the present invention, when BTK inhibition is mentioned, this means BTK with a C481R mutation. In one embodiment of the present invention, when BTK inhibition is mentioned, this means BTK with a C481F mutation. Pharmaceutical Compositions, Dosage and Administration The present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure or its pharmaceutically acceptable salt.In some embodiments, the pharmaceutical composition comprises two or more compounds of the present disclosure or its pharmaceutically acceptable salt.In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0086] Generally, the pharmaceutically acceptable carrier is a conventional pharmaceutical carrier in the art, which can be prepared in a manner well known in the pharmaceutical field. In some embodiments, the compound of the present disclosure or its pharmaceutically acceptable salt can be mixed with a pharmaceutically acceptable carrier for the preparation of a pharmaceutical composition.

[0087] The form of the pharmaceutical composition depends on many criteria, including but not limited to the route of administration, the extent of the disease, or the dose to be administered. The pharmaceutical composition can be formulated for oral, nasal, rectal, transdermal, intravenous, or intramuscular administration. According to the desired route of administration, the pharmaceutical composition can be formulated in the form of tablets, capsules, pills, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as solids or in the form of liquid media), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants, or suppositories.

[0088] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg, particularly 1 mg to about 200 mg, of the compound of the present disclosure, or a pharma- ceutically acceptable salt thereof. The pharmaceutical composition may also be administered once, twice, three times, or even four times a day. However, the daily dose will necessarily vary depending on the subject being treated, the particular route of administration, and the severity of the illness being treated. Thus, the optimum dosage can be determined by the physician treating any particular patient.

[0089] The therapeutically effective amount of the compounds provided herein or pharma- ceutically acceptable salts thereof will depend on a variety of factors known in the art, such as weight, age, past medical history, current medications, the subject's health status and potential for cross-reactivity, allergies, sensitivities and adverse side effects, as well as the route of administration and extent of disease onset, etc. Dosages may be proportionately reduced or increased by one skilled in the art (e.g., the attending physician or veterinarian) as indicated by these and other circumstances or requirements.

[0090] In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, in association with a pharma- ceutically acceptable diluent or carrier.

[0091] In a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable diluent or carrier for use in producing a BTK inhibitory effect in a warm-blooded animal, such as a human.

[0092] In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable diluent or carrier for use in producing an anti-cancer effect in a warm-blooded animal, such as a human.

[0093] In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutical acceptable salt thereof, together with a pharma- ceutical acceptable diluent or carrier for use in the treatment of small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia, non-Hodgkin's lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma in a warm-blooded animal, such as a human.

[0094] In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutical acceptable salt thereof, together with a pharma- ceutical acceptable diluent or carrier for use in the treatment of diffuse large B-cell lymphoma, primary central nervous system lymphoma or secondary central nervous system lymphoma which has metastasized to the brain. combination In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure, or a pharma- ceutically acceptable salt thereof, as a first active ingredient, and further comprises a second active ingredient, which can be any anti-tumor agent known in the art, such as a PI3K inhibitor, an anti-CD20 antibody, an anti-PD-1 / L1 antibody, and other approved drugs or drug combinations for non-Hodgkin's lymphoma. Representative examples of antitumor agents that are second active ingredients include, but are not limited to, idelalisib, duvelisib, obinutuzumab, ofatumumab, rituximab, alemtuzumab, bleomycin, brentuximab, vedotin, carmustine, cyclophosphamide, chlorambucil, dacarbazine, dexamethasone, doxorubicin, lomustine, mechlorethamine, procarbazine, prednisone, bendamustine, venetoclax, prednisone, CVP (combination treatment of C-cyclophosphamide (chemotherapeutic drug), V-vincristine (chemotherapeutic drug), and P-prednisolone (steroid)), midostaurin, and vinblastine.

[0095] When the term "combination" is used herein, it is understood to mean simultaneous, separate or sequential administration. In one aspect of the present disclosure, "combination" means simultaneous administration. In another aspect of the present disclosure, "combination" means separate administration. In a further aspect of the present disclosure, "combination" means sequential administration. When administration is sequential or separate, the delay in administering the second component should not, for example, cause the beneficial effect of the combination to be lost.

[0096] Thus, in a further aspect of the disclosure there is provided a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, in combination with an anti-tumour agent selected from those set out above.

[0097] Thus, in a further aspect of the disclosure, there is provided a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, in combination with an anti-tumour agent selected from those set out in the specification above, for use in producing an anti-cancer effect.

[0098] Thus, in a further aspect of the disclosure there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt thereof, in combination with an anti-tumor agent selected from those set out in the specification above, for use in treating small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia, non-Hodgkin's lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma.

[0099] Thus, in a further aspect of the disclosure there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined herein, in combination with an anti-tumour agent selected from those set out in the specification above, for use in treating diffuse large B-cell lymphoma, primary central nervous system lymphoma or secondary central nervous system lymphoma which has metastasized to the brain.

[0100] According to this aspect of the disclosure there is provided a combination suitable for use in the treatment of cancer comprising a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, and any one of the anti-tumour agents set out above.

[0101] According to a further aspect of the present disclosure there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt thereof, in combination with an anti-tumor agent selected from those set out above, together with a pharma- ceutically acceptable diluent or carrier.

[0102] According to a further aspect of the present disclosure there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt thereof, in combination with an anti-tumour agent selected from those set out in the specification above, together with a pharma- ceutically acceptable diluent or carrier, for use in producing an anti-cancer effect.

[0103] In a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutical acceptable salt thereof, in combination with an anti-tumour agent selected from those set out in the specification above, together with a pharma- ceutical acceptable diluent or carrier, for use in treating small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia, non-Hodgkin's lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma.

[0104] In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutical acceptable salt thereof, in combination with an anti-tumour agent selected from those set out in the specification above, together with a pharma- ceutical acceptable diluent or carrier, for use in treating diffuse large B-cell lymphoma, primary central nervous system lymphoma or secondary central nervous system lymphoma which has metastasized to the brain.

[0105] In a further aspect of the invention there is provided a kit comprising a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, in combination with an anti-tumour agent selected from those set out in the specification above.

[0106] According to a further aspect of the present disclosure, a) a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt thereof in a first unit dosage form; b) an antitumor agent selected from those set forth above, in a second unit dosage form; and c) A kit is provided, comprising container means for containing said first and second dosage forms. Pharmacological tools In addition to their use in therapeutic agents, the compounds of formula (I), or pharma- ceutically acceptable salts thereof, are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of BTK inhibition in laboratory animals, such as cats, dogs, rabbits, monkeys, rats and mice, as part of the investigation of new therapeutic agents. Treatment methods According to a further aspect of the invention there is provided a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

[0107] According to a further feature of this aspect of the invention, there is provided a method of producing a BTK inhibitory effect in a warm-blooded animal, such as a human, comprising the step of administering to said animal an effective amount of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof.

[0108] According to a further feature of this aspect of the invention there is provided a method of treating cancer in a warm-blooded animal, such as a human, comprising the step of administering to said animal an effective amount of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof.

[0109] According to an additional feature of this aspect of the invention, there is provided a method of treating small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia, non-Hodgkin's lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma in a warm-blooded animal, such as a human, comprising the step of administering to said animal an effective amount of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt thereof.

[0110] According to an additional feature of this aspect of the invention, there is provided a method of treating diffuse large B-cell lymphoma, primary central nervous system lymphoma or secondary central nervous system lymphoma metastasizing to the brain in a warm-blooded animal, such as a human, comprising the step of administering to said animal an effective amount of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt thereof.

[0111] As used herein, the terms "treatment" and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment can be performed after one or more symptoms have developed. In other embodiments, treatment can be performed in the absence of symptoms. For example, treatment can be performed on a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of the symptoms and / or taking into account genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0112] The present disclosure also provides a method of screening a patient for treatment with a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined herein, comprising sequencing a tumor sample obtained from the patient and detecting the presence of BTK accumulation or a BTK mutation.

[0113] According to a further feature of this aspect of the disclosure, there is provided a method of treating cancer in a warm-blooded animal, such as a human, comprising the steps of: (1) determining whether the warm-blooded animal has a cancer amenable to BTK inhibition; and (2) if so, administering to the animal an effective amount of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, as defined herein. Use of the compound In some embodiments, the disclosure provides for the use of a compound, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the manufacture of a medicament for the treatment of a BTK-mediated or BTK-dependent disease or condition.

[0114] Thus, according to this aspect of the invention there is provided a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use as a medicament. Thus, according to this aspect of the invention there is provided the use of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, as a medicament.

[0115] Thus, according to this aspect of the invention there is provided a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use in therapy. According to a further aspect of the invention there is provided the use of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for producing a BTK inhibitory effect in a warm-blooded animal, such as a human.

[0116] According to this aspect of the disclosure there is provided the use of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for producing an anti-cancer effect in a warm-blooded animal, such as a human.

[0117] According to a further feature of the invention there is provided the use of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenström's macroglobulinemia, non-Hodgkin's lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma.

[0118] According to a further feature of the invention there is provided the use of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diffuse large B-cell lymphoma, primary central nervous system lymphoma or secondary central nervous system lymphoma which has metastasized to the brain.

[0119] According to a further aspect of the present invention there is provided the use of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use in producing a BTK inhibitory effect in a warm-blooded animal, such as a human.

[0120] According to this aspect of the invention there is provided the use of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use in producing an anti-cancer effect in a warm-blooded animal, such as a human.

[0121] According to a further feature of the invention there is provided a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment of small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia, non-Hodgkin's lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma.

[0122] According to a further feature of the invention there is provided a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment of diffuse large B-cell lymphoma, primary central nervous system lymphoma or secondary central nervous system lymphoma which has metastasized to the brain.

[0123] The alternative and preferred embodiments of the compounds of the present disclosure described herein also apply to the pharmaceutical compositions, methods, uses and medicinal product features described above. EXAMPLES

[0124] Common Laboratory Abbreviations

[0125] [Table 1]

[0126] The synthesis of the compounds provided herein, including their pharma-ceutically acceptable salts, is illustrated in the synthetic schemes in these examples.The compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of a number of possible synthetic routes, and therefore these schemes are merely illustrative and are not meant to limit other possible methods that can be used to prepare the compounds provided herein.In addition, the steps in the methods are for better illustration and can be modified as necessary.The compound embodiments in the examples are synthesized for the purpose of investigation and possible application to regulatory authorities.

[0127] The reaction for preparing the compounds of the present disclosure can be carried out in a suitable solvent, which can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range from the freezing temperature of the solvent to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on a particular reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0128] The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of suitable protecting groups, can be easily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in TW Greene and PG M Huts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0129] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), infrared spectroscopy, spectroscopic methods (e.g., UV-visible), mass spectrometry, or chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography mass spectrometry (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (Preparative LC-MS Purification: Improved Compound Specific Method Optimization, Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem. 2004, vol. 6(no. 6), pp. 874-883, which is incorporated herein by reference in its entirety), supercritical fluid chromatography (SFC), and normal phase silica chromatography.

[0130] The structures of the compounds in these examples are characterized by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shifts (δ) are within 10 -6 It is given in units of (ppm). 1 H-NMR spectra were recorded in dimethylsulfoxide-d6 (DMSO-d6) or CDCl3 or CD3OD or D2O or acetone-d6 or CD3CN (Aldrich or Cambridge Isotope Lab., Inc.) on a Bruker AVANCE NMR (400 MHz) spectrometer using ICON-NMR (under TopSpin program control) or on a Varian 400MR NMR or Varian VNMR400 NMR (400 MHz) spectrometer (under VnmrJ program control) using tetramethylsilane as an internal standard.

[0131] MS measurements are performed using a Shimadzu 2010 mass spectrometer or an Agilent 6110A MSD or 1969A TOF mass spectrometer using electrospray, chemical and electron impact ionization methods from a variety of instruments. Detailed methods used in the present invention include the following: LC-MS method A:10~80AB_7min_220&254_Shimadzu.lcm Mobile phase: 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solvent B). Use an elution gradient of 10% to 80% (solvent B) over 6 min, held at 80% for 0.5 min at a flow rate of 0.8 mL / min; Column: Xtimate C18 2.1 * 30 mm, 3 μm; Wavelength: UV220nm, 254nm; Column temperature: 50°C; MS ionization: ESI LC-MS method B:10~80AB_4min_220&254_Shimadzu.lcm Mobile phase: 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solvent B). Use an elution gradient of 10% to 80% (solvent B) over 3 min, held at 80% for 0.5 min at a flow rate of 0.8 mL / min; Column: Xtimate C18 2.1 * 30 mm, 3 μm; Wavelength: UV220nm, 254nm; Column temperature: 50°C; MS ionization: ESI LC-MS method C:10~80CD_7min_220&254_Agilent.lcm Mobile phase: 0.2 mL / 1 L NH3.H2O in water (solvent A) and acetonitrile (solvent B). Use an elution gradient of 10% to 80% (solvent B) over 6 min, held at 80% for 0.5 min at a flow rate of 0.8 mL / min; Column: Xbridge Shield RP-18, 5 μm, 2.1 * 50mm; Wavelength: UV220nm&254nm; Column temperature: 30°C; MS ionization: ESI High performance liquid chromatography (HPLC) measurements were performed using an Ultimate XB-C18 column (3.0 * 50mm, 3μm or 3.0 * 150mm, 3μm), or Xbridge shieldRP18 column (5μm, 50mm * 2.1mm), or Xtimate C18 column (3μm, 2.1 * 30 mm) or MERCK RP18 2.5-2 mm, etc., on a Shimadzu LC-20A system or Shimadzu LC-2010HT series, or Agilent 1200 LC or Agilent 1100 series. The detailed method used in the present invention includes the following. HPLC method A: 10~80AB_8 minutes.met Mobile phase: 2.75 mL / 4 L TFA in water (solvent A) and 2.5 mL / 4 L TFA in acetonitrile (solvent B). Use an elution gradient of 10% to 80% (solvent B) over 6 min, held at 80% for 2 min at a flow rate of 1.2 mL / min; Column: Ultimate C18 3.0 * 50mm, 3μm Wavelength: UV220nm, 215nm, 254nm; Column temperature: 40°C; HPLC method B:10~80CD_8min.met Mobile phase: 2.0 mL / 4 L NH3H2O ​​in water (solvent A) and acetonitrile (solvent B). Use an elution gradient of 10% to 80% (solvent B) over 4 min, held at 80% for 2 min at a flow rate of 1.2 mL / min; Column: Xbrige Shield RP-18, 2.1 * 50 mm, 5 μm; Wavelength: UV220nm, 215nm, 254nm; Column temperature: 40°C; Supercritical fluid chromatography (SFC) measurements were performed using a ChiralPak AD-3 column (3 μm, 150 × 4.6 mm), a Chiralcel OJ-3 column (3 μm, 150 × 4.6 mm), or a Chiralpak IG-3 column (3 μm, 50 mm * 4.6 mm) or the like, and performed on an Agilent 1260 series, Waters UPCC series, or Shimadzu LC-20AB series. The detailed method used in the present invention includes the following. SFC method A: Mobile phase: A:CO2 B:Ethanol (0.05% DEA), gradient: 5% to 40% B in 5.5 min, hold at 40% for 3 min, then 5% B for 1.5 min, flow rate: 2.5 mL / min; Column: ChiralPak AD-3 150×4.6mm ID, 3μm; Column temperature: 40°C; Back pressure: 100 bar. SFC method B: Mobile phase: A: CO2, B: Methanol (0.05% DEA), Gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold at 5% B for 1.5 min, Flow rate: 2.5 mL / min Column: Chiralcel OJ-3 150 × 4.6 mm ID, 3 μm; Column temperature: 35°C; ABPR: 1500 psi. SFC method C: Mobile phase: A: CO2 B: Methanol (0.05% DEA), isocratic: B 40%, flow rate: 4 mL / min; Column: Chiralpak IG-3 50mm * 4.6mm ID, 3μm; Column temperature: 35°C; ABPR: 1500 psi.

[0132] Thin layer chromatography is performed using Yantai Huanghai HSGF254 silica gel or Anhui Liang Chen Gui Yuan plates. The silica gel plates used for thin layer chromatography (TLC) are 0.15mm-0.2mm. The silica gel plates used for separating and purifying the products by TLC are 0.4mm-0.5mm.

[0133] The purification chromatography column uses silica gel as the carrier (100-200, 200-300 or 300-400 mesh, produced by Yantai Huanghai co., or Anhui Liang Chen Gui Yuan co., etc.), or flash column (silica-CS flash column 40-60 μm, or reversed phase C18 column 20-35 μm, produced by Agela Technologies, etc.) or flash column silica-CS (40-60 μm) or C18 column (20-40 μm) by Agela Technologies in Teledyne ISCO Combi Flash or Biotage Flash system. The size of the column is adjusted according to the amount of compound.

[0134] Known starting materials of the present disclosure can be synthesized using or following methods known in the art or can be purchased commercially from Alfa Aesar, TCI, Aldrich, Bepharm, and Scochem (or PharmaBlock, Bide, Amatek, Stru Chem, Firster Pharmaceutical, Titan (Adamas), etc.).

[0135] Unless otherwise specified, these reactions are all carried out under an argon or nitrogen atmosphere. By argon or nitrogen atmosphere, we mean that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L. Hydrogenations are usually carried out under pressure. Unless otherwise specified, the reaction temperature in these examples is ambient temperature, which is between 10°C and 30°C.

[0136] The reaction progress is monitored by TLC or / and LC-MS. The eluent system used for the reaction includes dichloromethane-methanol system and petroleum ether-ethyl acetate system. The volume ratio of the solvent is adjusted according to the different polarity of the compound.

[0137] The eluent system of column chromatography and the eluent system of TLC used to purify the compounds include dichloromethane-methanol system and petroleum ether-ethyl acetate system. The volume ratio of the solvents is adjusted according to the different polarity of the compounds. A small amount of alkaline or acidic agent (0.1%-1%), such as formic acid, or acetic acid, or TFA, or ammonia, can be added for adjustment. Compounds of the Invention

[0138] [Table 2-1]

[0139] [Table 2-2]

[0140] [Table 2-3]

[0141] [Table 2-4]

[0142] [Table 2-5]

[0143] [Table 2-6]

[0144] [Table 2-7]

[0145] Synthesis method The compounds of the present invention can be prepared according to two synthetic methods. Method A

[0146] [ka]

[0147] Method B

[0148] [ka]

[0149] Method A Compound 2A: Ethyl 5-(((3-chloropyrazin-2-yl)methyl)carbamoyl)tetrahydro-2H-pyran-2-carboxylate

[0150] [ka]

[0151] To a mixture of 6-(ethoxycarbonyl)tetrahydro-2H-pyran-3-carboxylic acid (see WO2019001420A1) (5.90 g, 29.17 mmol) and compound 1A (5.25 g, 29.17 mmol) in dichloromethane (150 mL) was added HATU (16.64 g, 43.76 mmol) and DIEA (11.31 g, 87.51 mmol). The mixture was stirred at room temperature (18-22 °C) for 12 h. The reaction was concentrated, diluted with water (100 mL) and diluted with ethyl acetate (200 mL). * The combined organic layers were extracted with brine (200 mL * 4), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by column chromatography on silica gel (2.5-3.5% methanol in dichloromethane) to give compound 2A (9.0 g, 94.0% yield) as a yellow oil.

[0152] LCMS: tR = 0.689 min (5-95AB_1.5 min_220&254_Shimadzu. lcm chromatography (Agilent Pursult 5 C18 20 * 2.0mm)), MS(ESI)m / z=328.2[M+H] + Compound 3A: Ethyl 5-(8-chloroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-carboxylate

[0153] [ka]

[0154] To a mixture of compound 2A (9.0 g, 27.46 mmol) and DMF (600 μL) in MeCN (150 mL) was added POCl3 (21.05 g, 137.30 mmol). The mixture was stirred at 70 °C for 1 h. The reaction was concentrated, washed with water (50 mL) and saturated NaHCO3 (50 mL), and diluted with ethyl acetate (100 mL). *The crude product was purified by column chromatography on silica gel (52-62% ethyl acetate in petroleum ether) to give compound 3A (3.5 g, 41.2% yield) as a yellow oil. LCMS:t R =0.742 min (5-95AB_1.5 min_220&254_Shimadzu.lcm chromatography (Agilent Pursult 5 C18 20 * 2.0mm)), MS(ESI)m / z=310.2 [M+H] + 1 H NMR (400MHz, CDCl3): δ = 7.80 (d, J = 0.4 Hz, 1H), 7.70-7.64 (m, 1H), 7.37 (d, J = 4.8 Hz, 0.3H), 7.35 (d, J = 4.8 Hz, 0.7H), 4.44 (t, J = 4.4 Hz, 0.7H), 4.30-4.25 (m, 2H), 4.23-4.14 (m, 1H), 4.00 (dd, J = 3.2, 12.0 Hz, 1H), 3.79 (t, J = 11.2 Hz, 0.4H), 3.42-3.19 (m, 1H), 2.47-2.37 (m, 0.8H), 2.29-2.06 (m, 3H), 1.91-1.77 (m, 0.4H), 1.35-1.31 (m, 3H). Compound 4A: (5-(8-chloroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0155] [ka]

[0156] To a mixture of LiAlH4 (860 mg, 22.60 mmol) in THF (20 mL) was added compound 3A (3.5 g, 11.30 mmol) in THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction was quenched with water (860 μL), 15% NaOH (860 μL), and water (2580 μL). The mixture was dried over anhydrous sodium sulfate, stirred at room temperature for 0.5 h, filtered, and concentrated to give compound 4A (2.7 g, 89.4% yield) as a yellow solid. LCMS:t R =0.635 min (5-95AB_1.5 min_220&254_Shimadzu.lcm chromatography (Agilent Pursult 5 C18 20 * 2.0mm)), MS(ESI)m / z=267.8[M+H] + Compound 5A: (5-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0157] [ka]

[0158] To a mixture of compound 4A (2.7 g, 10.11 mmol) in MeCN (100 mL) was added NBS (2.34 g, 13.14 mmol). The mixture was stirred at room temperature (16-20 °C) for 1 h. The reaction was concentrated to give the crude product, which was purified by column chromatography on silica gel (2.2% methanol in dichloromethane) to give compound 5A (2.5 g, 71.63% yield) as a yellow solid. LCMS:t R =0.717 min (5-95AB_1.5 min_220&254_Shimadzu.lcm chromatography (Agilent Pursult 5 C18 20 * 2.0mm)), MS(ESI)m / z=347.8 [M+H] + Compound 6A: (5-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0159] [ka]

[0160] To a mixture of compound 5A (2.5 g, 7.21 mmol) in IPA (15 mL) was added NH3·H2O (15 mL). The mixture was stirred at 100 °C for 12 h in a 100 mL sealed tube. The reaction was concentrated to give compound 6A (2.4 g, 98.0% purity) as a yellow oil. LCMS:t R =0.436 min (10-80AB_3 min_220&254_Shimadzu.lcm Chromatography (Xtimate C18 2.1 * 30mm)), MS(ESI)m / z=327.1[M+H] + Compound 7A: (5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0161] [ka]

[0162] To a mixture of compound 6A (500 mg, 1.31 mmol, 97.99% purity) and (2-fluoro-4-phenoxyphenyl)boronic acid (450 mg, 1.95 mmol) in 1,4-dioxane (15 mL) / HO (5 mL) under nitrogen was added Pd(dppf)Cl.CHCl (32 mg, 0.04 mmol) and KCO (375 mg, 2.62 mmol). The mixture was stirred at 100 °C under nitrogen for 12 h. The reaction was diluted with water (20 mL) and ethyl acetate (50 mL). *3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (2.2% methanol in dichloromethane) to give compound 7A (mixture of cis / trans racemates) (150 mg, 26.4% yield) as a yellow solid. LCMS:t R =0.723 min (5-95AB_1.5 min_220&254_Shimadzu.lcm chromatography (Agilent Pursult 5 C18 20 * 2.0mm)), MS(ESI)m / z=435.1[M+H] + 2-Fluoro-4-phenoxyphenyl)boronic acid:

[0163] [ka]

[0164] A mixture of compound 1a (10 g, 52.35 mmol) in CHCl (480 mL), PhB(OH) (12.8 g, 104.71 mmol), Cu(OAc) (9.5 g, 52.35 mmol), NEt (21 mL, 151.05 mmol) and 4Å Ms (5 g) was added at room temperature (25-30 °C). The mixture was stirred at room temperature (25-30 °C) under air for 16 h. The mixture was filtered through a Celite pad. The filtrate was concentrated in vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether) to give compound 2a (11.3 g, 80.8% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ = 7.47 (t, J = 8.4 Hz, 1H), 7.42-7.36 (m, 2H), 7.19 (t, J = 8.4 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.78 (dd, J = 10.0, 2.8 Hz, 1H), 6.71 (dd, J = 8.8, 2.0 Hz, 1H). To a solution of compound 2a (11.3 g, 42.30 mmol) in THF (150 mL) at -65°C, n-BuLi (19 mL, 46.53 mmol, 2.5 N in n-hexane) was added at -65°C. The mixture was stirred at -65°C for 0.5 h. Then, B(Oi-Pr)3 (9.5 g, 50.76 mmol) was added at -65°C. The mixture was stirred at -65°C for 2 h. The mixture was quenched with saturated ammonium chloride solution (50 mL) and ethyl acetate (50 mL). * 3) and extract with brine (100 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was triturated from petroleum ether (100 mL), filtered and the filter cake was concentrated to give 2-fluoro-4-phenoxyphenyl)boronic acid (4.3 g) as a yellow oil. The filtrate was concentrated and purified by column chromatography on silica gel (0-20% ethyl acetate in petroleum ether) to give 2-fluoro-4-phenoxyphenyl)boronic acid (3 g) as a yellow oil. 1 H NMR (400MHz, DMSO-d6): δ = 8.10 (s, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.47-7.41 (m, 2H), 7.22 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 2H), 6.78-6.68 (m, 2H). Trans isomer 1, compound 2: trans-(5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol Trans isomer 2, compound 3: trans-(5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0165] [ka]

[0166] Mixture 7A (150 mg, 0.35 mmol) was subjected to chiral SFC (column: DAICEL CHIRALPAK AD-H) (250 mm * The mixture was purified by chromatography (30 mm, 10 μm), conditions: 0.1% NH3.HO in EtOH, 40%, flow rate 80 mL / min). The fractions containing the desired compound were concentrated, diluted with HO (10 mL) and CH3CN (10 mL), and lyophilized to give compound 2 (34.8 mg, 23.2% yield) as a white solid and compound 3 (29.4 mg, 19.6%) as a white solid. The two cis enantiomers were not collected. Spectrum of compound 2: LCMS R =2.037 min (10-80AB_7 min_220&254_Shimadzu.lcm Chromatography (Xtimate C18 2.1 * 30mm)), MS(ESI)m / z=435.3[M+H] + . HPLC R =3.03 min (10-80AB_8 min.met (HPLC-BJ Ultimate 3.0 * 50mm 3μm). SFC t R = 6.119 min, optical purity: 96.3%. Method description: Column: ChiralPak AD-3 150 x 4.6 mm ID, 3 μm, Mobile phase: A: CO2 B: Ethanol (0.05% DEA), Gradient: 5% to 40% B in 5.5 min, hold at 40% for 3 min, then 5% B for 1.5 min, Flow rate: 2.5 mL / min, Column temperature: 40 °C, Back pressure: 100 bar. 1HNMR (400MHz, CD3OD) δ = 7.63 (d, J = 5.2 Hz, 1H), 7.54-7.36 (m, 3H), 7.27-7.18 (m, 1H), 7.14 (dd, J = 8.8, 0.8 Hz, 2H), 7.02 (d, J = 4.8 Hz, 1H), 6.98-6.82 (m, 2H), 4.23-4.07 (m, 1H), 3.75 (t, J = 11.2 Hz, 1H), 3.62-3.51 (m, 3H), 3.46-3.36 (m, 1H), 2.25-2.15 (m, 1H), 2.13-1.96 (m, 1H), 1.79 (d, J = 13.6 Hz, 1H), 1.66-1.49 (m, 1H). 19 FNMR (CD3OD) δ = -112.240 Spectrum of compound 3: LCMS R =2.030 min (10-80AB_7 min_220&254_Shimadzu.lcm Chromatography (Xtimate C18 2.1 * 30mm)), MS(ESI)m / z=435.3[M+H] + . HPLC R =3.02 min (10-80AB_8 min.met (HPLC-BJ Ultimate 3.0 * 50mm 3μm). SFC t R = 7.334, Optical purity: 92.7%. Method description: Column: ChiralPak AD-3 150 x 4.6 mm ID, 3 μm, Mobile phase: A: CO2 B: Ethanol (0.05% DEA), Gradient: 5% to 40% B in 5.5 min, hold at 40% for 3 min, then 5% B for 1.5 min, Flow rate: 2.5 mL / min, Column temperature: 40 °C, Back pressure: 100 bar. 1H NMR (400MHz, CD3OD) δ =7.65 (d, J = 5.2 Hz, 1H), 7.52-7.37 (m, 3H), 7.29-7.21 (m, 1H), 7.20-7.11 (m, 2H), 7.04 (d, J = 4.8 Hz, 1H), 6.99-6.84 (m, 2H), 4.24-4.13 (m, 1H), 3.77 (t, J = 11.2 Hz, 1H), 3.62-3.51 (m, 3H), 3.48-3.77 (m, 1H), 2.31-2.17 (m, 1H), 2.15-2.01 (m, 1H), 1.91-1.74 (m, 1H), 1.69-1.51 (m, 1H). 19 F NMR (400MHz, CD3OD) δ = -112.258. The following compounds were synthesized according to Method A:

[0167] [Table 3]

[0168] [Table 4-1]

[0169] [Table 4-2]

[0170] Method B Compound 2B: Ethyl 5-(((3-amino-5-hydroxy-1,2,4-triazin-6-yl)methyl)carbamoyl)tetrahydro-2H-pyran-2-carboxylate

[0171] [ka]

[0172] To a mixture of 5-(2,5-dioxopyrrolidin-1-yl) 2-ethyl tetrahydro-2H-pyran-2,5-dicarboxylate (crude product 20 g, 60.88 mmol) in acetonitrile (30 mL) was added compound 1B (13 g, 60.88 mmol) and triethylamine (25 mL, 182.6 mmol). The mixture was stirred at 50° C. for 16 hours. The mixture was concentrated to produce compound 2B (crude product 35 g) as a brown solid. LCMS:t R =0.582 min (5-95AB_1.5 min_220&254_Shimadzu.lcm chromatography (Merck RP18 25-3mm)), MS(ESI) m / z=325.9 [M+H] + 5-(2,5-dioxopyrrolidin-1-yl)2-ethyltetrahydro-2H-pyran-2,5-dicarboxylate:

[0173] [ka]

[0174] To a solution of 6-(ethoxycarbonyl)tetrahydro-2H-pyran-3-carboxylic acid (1.4 g, 6.92 mmol) in CHCl (30 mL) was added 1-hydroxypyrrolidine-2,5-dione (877 mg, 7.61 mmol) and EDCl (1.6 g, 8.30 mmol). The mixture was stirred at 22-26 °C for 1.5 h. The mixture was diluted with dichloromethane (30 mL) and washed with brine (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 5-(2,5-dioxopyrrolidin-1-yl)2-ethyltetrahydro-2H-pyran-2,5-dicarboxylate as a colorless oil, which was used directly. Compound 3B: Ethyl 5-(2-amino-4-hydroxyimidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-carboxylate

[0175] [ka]

[0176] To a solution of compound 2B (crude product 35 g, 60.88 mmol) in acetonitrile (300 mL) was added phosphorus oxychloride (23 mL, 243.52 mmol). The mixture was then stirred at 70° C. for 16 h. The mixture was concentrated and the residue was diluted with dichloromethane (150 mL), poured into a cold saturated solution of sodium bicarbonate (300 mL) until pH=8, and diluted with dichloromethane / methanol (10:1, 200 mL). * 4) and then extract with IPA / CHCl3 (150 mL * 4) was extracted. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 3B (crude product 45 g) as a black oil. LCMS:t R =0.13 min (5-95AB_1.5 min_220&254_Shimadzu.lcm chromatography (Merck RP18 25-3mm)), MS(ESI) m / z=308.0[M+H] + Compound 4B: Ethyl 5-(2-amino-5-bromo-4-hydroxyimidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-carboxylate

[0177] [ka]

[0178] To a solution of compound 3B (crude product 45 g, 60.88 mmol) in N,N-dimethylformamide (200 mL) was added NBS (11.8 g, 66.96 mmol). The mixture was stirred at room temperature (16-21 °C) for 0.5 h. The mixture was poured into water (300 mL) and ethyl acetate (300 mL) was added. * 4) and extract with brine (500 mL * 4) The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give compound 4B (crude 19 g) as a black oil. LCMS:tR =0.602 min (5~95AB_1 min_220&254_Agilent Chromatography (Agilent Poroshell 120 EC-C18 2.7μm 3.0 * 30mm)), MS(ESI)m / z=388.0[M+H+2] + (Bromide isotopes). Compound 5B: Ethyl 5-(5-bromo-4-hydroxyimidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-carboxylate

[0179] [ka]

[0180] To a solution of compound 4B (19 g impure, 49.19 mmol) in tetrahydrofuran (300 mL) was added tert-butyl nitrite (12 mL, 98.39 mmol) at 0-5° C., and the mixture was stirred at room temperature (16-21° C.) for 16 h. The mixture was combined with another batch (7.2 g crude product of compound 4B) and concentrated to give the crude material, which was purified by column chromatography on silica gel (0-60% ethyl acetate in petroleum ether) to give compound 5B (14.3 g, 44% yield for 5 steps) as a yellow solid. LCMS:t R =0.753 min (5-95AB_1.5 min_220&254_Shimadzu.lcm chromatography (Agilent Pursult 5 C18 20 * 2.0mm)), MS(ESI)m / z=370.9 [M+H] + 1H NMR (400MHz, CD3OD): δ = 7.74 (s, 0.3H), 7.72 (s, 0.5H), 4.37 (t, J = 4.8 Hz, 0.7H), 4.29-4.16 (m, 3H), 4.12 (dd, J = 11.6, 2.0 Hz, 0.3H), 3.92 (dd, J = 11.6, 4.0 Hz, 0.7H), 3.70 (t, J = 11.2 Hz, 0.4H), 3.57-3.45 (m, 1H), 2.35-1.92 (m, 4H), , 1.33-1.27 (m, 3H). Compound 6B: Ethyl 5-(4-amino-5-bromoimidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-carboxylate

[0181] [ka]

[0182] To a solution of 1,2,4-triazole (28 g, 404.1 mmol) in acetonitrile (200 mL) was added POCl3 (12.5 mL, 134.7 mol) below 10° C., followed by trimethylamine (56 mL, 404.1 mmol). The mixture was stirred at 10° C. for 20 min, compound 5B (5 g, 13.47 mmol) was added, and the reaction mixture was stirred at 90° C. for 1.5 h. The mixture was cooled to 10° C., and ammonia (30 mL, 28%) was added while maintaining the temperature below 20° C., and stirred at 10° C. for 0.5 h. Another batch was carried out on the same scale. The mixture was combined, diluted with water (200 mL), and ethyl acetate (500 mL) was added. * 3) and extract with brine (500 mL * 3), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by column chromatography on silica gel (2-4% methanol in dichloromethane) to give compound 6B (9 g, 90% yield) as a yellow solid. LCMS:t R=0.614 min (\5~95AB_1 min_220&254_Agilent Chromatography (Agilent Poroshell 120 EC-C18 2.7μm 3.0 * 30mm)), MS(ESI)m / z=372.0[M+H+2] + (Bromide isotopes). 1 H NMR (400MHz, CD3OD): δ = 7.81 (s, 0.3H), 7.79 (s, 0.6H), 4.36 (t, J = 5.2 Hz, 0.6H), 4.29-4.19 (m, 3H), 4.12 (dd, J = 11.6, 2.0 Hz, 0.3H), 3.93 (dd, J = 11.6, 4.0 Hz, 0.7H), 3.71 (t, J = 11.2 Hz, 0.3H), 3.63-3.48 (m, 1H), 2.35-2.20 (m, 1H), 2.17-1.94 (m, 2.7H), 1.79-1.68 (m, 0.3H), 1.34-1.26 (m, 3H). Compound 7B: (5-(4-amino-5-bromoimidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol

[0183] [ka]

[0184] To a solution of compound 6B (6.1 g, 16.48 mmol) in tetrahydrofuran (120 mL) cooled at 0-5 °C, LiAlH4 (1.20 g, 32.95 mmol) was added while maintaining the temperature below 10 °C. The mixture was stirred at 0-10 °C for 1.5 h. To the mixture was added 5 g of Na2SO4·10H2O2 at 0-5 °C, stirred for 2 h, and filtered. The filter cake was suspended twice in dichloromethane / methanol (100 mL of a 10:1 mixture) and filtered. The combined filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica (0-10% methanol in dichloromethane) to produce compound 7B (3.9 g, 72% yield) as a white solid and 0.6 g of the debrominated by-product as a yellow solid. LCMS:t R =1.958 min and 2.016 min (\0~60AB_7min_220&254_Shimadzu.lcm Chromatography (Xtimate C18 2.1 * 30mm, 3μm)), MS(ESI)m / z=328.1[M+H] + . 1 H NMR (400MHz, methanol-d4): δ = 7.80 (s, 0.3H), 7.78 (s, 0.6H), 4.47 (dt, J = 10.0, 2.0 Hz, 0.6H), 4.20-4.13 (m, 0.3H), 3.84 (dd, J = 11.6, 3.2 Hz, 0.6H), 3.64 (t, J = 10.8 Hz, 0.4H), 3.60-3.38 (m, 4H), 2.45-2.36 (m, 0.6H), 2.22-2.13 (m, 0.3H), 2.09-1.96 (m, 1H), 1.93-1.73 (m, 1H), 1.62-1.45 (m, 1H). Compound 8B: (5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol

[0185] [ka]

[0186] Compound 7B (106 mg, 0.457 mmol), Pd(dppf)Cl2·CH2Cl2 (25 mg, 0.0304 mmol) and potassium carbonate (84 mg, 0.608 mmol) were placed in a reaction tube, purged with nitrogen three times, and (2-fluoro-4-phenoxyphenyl)boronic acid (100 mg, 0.304 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was added. The resulting mixture was stirred at 100 °C under nitrogen for 2 h. The mixture was concentrated to give the crude product, which was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to yield compound 8B (80 mg impure, mixture of trans / cis racemates) as a yellow oil. LCMS:t R =2.274 min and 2.340 min (10-80AB_7 min_220&254_Shimadzu.lcm Chromatography (Xtimate C18 2.1 * 30mm)), MS(ESI)m / z=436.2[M+H] + . SFC:t R = 4.171 min, 4.286 min, 4.454 min and 5.581 min. Method: Column: Chiralcel OJ-3 150 x 4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Methanol Gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold 5% B for 1.5 min Flow rate: 2.5 mL / min, Column temperature: 35 °C ABPR: 1500 psi. Cis isomer 1, compound 8: cis-(5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol Cis isomer 2, compound 9: cis-(5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol Trans isomer 1, compound 10: trans-(5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol Trans isomer 2, compound 11: trans-(5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol

[0187] [ka]

[0188] Compound 8B (80 mg) was subjected to preparative SFC (column: DAICEL CHIRALCEL OJ-H (250 mm * Further separation by preparative HPLC (column: Welch Xtimate C18 100 mm, 5 μm, conditions: 30% MeOH (0.1% NH3H2O) in CO2, flow rate: 60 mL / min) gave 116.8 mg of impure compound, which was purified by HPLC (column: Welch Xtimate C18 100 * 40mm * Further purification by HPLC using 3 μm column, conditions: 25-55% (A: water (0.225% FA), B: CH3CN), flow rate: 25 mL / min) afforded compound 11 (1.7 mg, 1% yield for two steps) as a white solid. After SFC, the mixture of the other three peaks (40 mg) was purified by chiral SFC (column: DAICEL CHIRALPAK IG (250 mm * Further purification by HPLC using a 30 mm, 10 μm column, conditions: 55% MeOH (0.1% NHHO) in CO, flow rate: 80 mL / min) afforded compound 8 (8.6 mg, 6.4% yield for two steps) as a white solid, compound 9 (6.7 mg, 5% yield for two steps) as a white solid, and compound 10 (5.4 mg, 4% yield for two steps) as a white solid. Spectrum of compound 8: LCMS:t R=2.356 min (10-80AB_7 min_220&254_Shimadzu.lcm Chromatography (Xtimate C18 2.1 * 30mm)), MS(ESI)m / z=436.2[M+H] + . HPLC: R =3.00 min (10-80CD_8 min.met. chromatography (XBridge Shield RP 18 2.1 * 50mm 5μm). 1 H NMR (400MHz, CD3OD): δ = 7.84 (s, 1H), 7.54 (t, J = 8.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.26-7.20 (m, 1H), 7.17-7.12 (m, 2H), 6.94 (dd, J = 8.0, 2.0 Hz, 1H), 6.88 (dd, J = 10.8, 2.4 Hz, 1H), 4.56-4.51 (m, 1H), 3.89 (dd, J = 11.6, 3.6 Hz, 1H), 3.65-3.48 (m, 4H), 2.51-2.42 (m, 1H), 2.12-2.02 (m, 1H), 1.99-1.85 (m, 1H), 1.64-1.55 (m, 1H). SFC:t R =4.059 min, optical purity 99.94%. Method: Column: Chiralcel OJ-3 150 x 4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Methanol (0.05% DEA), Gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold 5% B for 1.5 min, Flow rate: 2.5 mL / min Column temperature: 35 °C ABPR: 1500 psi. Spectrum of compound 9: LCMS:t R =2.340 min (10-80AB_7 min_220&254_Shimadzu.lcm Chromatography (Xtimate C18 2.1 * 30mm)), MS(ESI)m / z=436.3[M+H]+. HPLC: R=2.99 min (10-80CD_8 min.met. chromatography (XBridge Shield RP 18 2.1 * 50mm 5μm). 1 H NMR (400MHz, CD3OD): δ = 7.84 (s, 1H), 7.53 (t, J = 8.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.25-7.19 (m, 1H), 7.17-7.12 (m, 2H), 6.94 (dd, J = 8.4, 2.0 Hz, 1H), 6.87 (dd, J = 11.2, 2.4 Hz, 1H), 4.56-4.50 (m, 1H), 3.88 (dd, J = 12.0, 3.6 Hz, 1H), 3.65-3.48 (m, 4H), 2.50-2.41 (m, 1H), 2.12-2.02 (m, 1H), 1.97-1.86 (m, 1H), 1.64-1.55 (m, 1H). SFC:t R =4.161 min, optical purity 100%. Method: Column: Chiralcel OJ-3 150 x 4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Methanol (0.05% DEA) Gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold 5% B for 1.5 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C ABPR: 1500 psi. Spectrum of compound 10: LCMS:t R =2.410 min (10-80AB_7 min_220&254_Shimadzu.lcm Chromatography (Xtimate C18 2.1 * 30mm)), MS(ESI)m / z=436.3[M+H] + . HPLC: R =2.98 min (10-80CD_8 min.met. chromatography (XBridge Shield RP 18 2.1 * 50mm 5μm). 1H NMR (400MHz, CD3OD): δ = 7.86 (s, 1H), 7.50 (t, J = 8.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.26-7.20 (m, 1H), 7.17-7.12 (m, 2H), 6.94 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 (dd, J = 10.8, 2.4 Hz, 1H), 4.24-4.18 (m, 1H), 3.75 (t, J = 11.2 Hz, 1H), 3.68-3.48 (m, 4H), 2.27-2.19 (m, 1H), 2.16-2.04 (m, 1H), 1.84-1.76 (m, 1H), 1.59-1.47 (m, 1H). SFC:t R =4.405 min, optical purity 99.83%. Method: Column: Chiralcel OJ-3 150 x 4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Methanol (0.05% DEA), Gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold 5% B for 1.5 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C ABPR: 1500 psi. Spectrum of compound 11: LCMS:t R =2.365 min (10-80AB_7 min_220&254_Shimadzu.lcm Chromatography (Xtimate C18 2.1 * 30mm)), MS(ESI)m / z=436.2[M+H] + . HPLC: R =3.05 min (10-80CD_8 min.met. chromatography (XBridge Shield RP 18 2.1 * 50mm 5μm). 1H NMR (400MHz, CD3OD): δ = 7.86 (s, 1H), 7.50 (t, J = 8.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.26-7.21 (m, 1H), 7.17-7.12 (m, 2H), 6.94 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 (dd, J = 10.8, 2.4 Hz, 1H), 4.24-4.18 (m, 1H), 3.75 (t, J = 10.8 Hz, 1H), 3.68-3.47 (m, 4H), 2.26-2.18 (m, 1H), 2.16-2.04 (m, 1H), 1.84-1.76 (m, 1H), 1.59-1.47 (m, 1H). SFC:t R =5.802 min, optical purity 100%. Method: Column: Chiralcel OJ-3 150 x 4.6 mm ID, 3 μm Mobile phase: A: CO2 B: Methanol (0.05% DEA), Gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold 5% B for 1.5 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C, ABPR: 1500 psi. The following compounds were synthesized according to Method B:

[0189] [Table 5]

[0190] [Table 6-1]

[0191] [Table 6-2]

[0192] Biological Data: BTK WT and BTK C481S HTRF kinase assay Recombinant BTK wild type (BTK WT) was purchased from Thermo Fisher. Recombinant BTK (C481S) was purchased from SignalChem. The inhibitory potency of compounds against BTK and BTK (C481S) was evaluated using a homogenous time resolved fluorescence approach.

[0193] Briefly, recombinant kinases were pre-incubated for 30 min at room temperature in the presence or absence of compounds. The reaction was started by adding ATP and a substrate peptide that can be phosphorylated by the kinase in the reaction. After 120 min of incubation, the reaction was stopped by adding a detection reagent mix containing EDTA. Fluorescence was measured at 615 nm and 665 nm, respectively, with an excitation wavelength of 320 nm. The calculated signal ratio 665 nm / 615 nm is proportional to the kinase activity. The concentration of compound that results in 50% inhibition of each kinase (IC50) was calculated using a four-parameter logistic fit with XLfit.

[0194] [Table 7]

[0195] TMD8 cell line p-BTK Elisa assay TMD-8 cells were plated in 96-well plates at a density of 30000 cells / well in RPMI1640 medium containing 1.5% fetal bovine serum. Test compounds were added to the cells and the cells were incubated at 37°C with 5% CO2 for 0.5 hours. Pervanadate solution was then added to the cells to make a final concentration of 100 μM and the cells were incubated at 37°C with 5% CO2 for another hour. After compound treatment, the cells were lysed and p-BTK signal was detected using PathScan® Phospho-Btk (Tyr223) Sandwich ELISA kit (#23843) according to the exact procedure. The plate was read on a Multiscan Spectrum reader set at a wavelength of 450 nm. The data was processed with GraphPad Prism software.

[0196] [Table 8]

[0197] HEK293-BTK(WT) and HEK293-BTK(C481S) A full-length cDNA of BTK containing the C481S mutation was generated by mutagenesis using the QuikChange II XL Site-Directed Mutagenesis Kit. The mutated BTK cDNA was confirmed by sequencing. Then, the cDNA of BTK(WT), BTK-C481S, was cloned into the PLVX-Puro lentiviral vector. The lentivirus was packaged into 293T cells by transfecting with the lentiviral vector and packaging mix. BTK(WT), BTK-C481S lentivirus was transfected into HEK293 cells. The transfected cells were selected in puromycin 2μg / mL. The stable polyclonal cell line was confirmed by WB and used for further testing. HEK293-BTK(WT) and HEK293-BTK(C481S) cells were cultured in DMEM (Gibco; 12430) containing 10% FBS (Gibco; 10099) with 1 μg / mL puromycin. All cells were maintained in a humidified incubator at 37°C with 5% CO2.

[0198] HEK293-BTK(WT) and HEK293-BTK(C481S) cells were plated in 96-well plates at a density of 5000 cells / well in RPMI1640 medium containing 1.5% fetal bovine serum. Test compounds were added to the cells, and the cells were incubated at 37°C with 5% CO2 for 1.5 hours. After compound treatment, the cells were lysed and p-BTK signals were detected using the PathScan® Phospho-Btk(Tyr223)Sandwich ELISA kit (#23843) according to the exact procedure. The plates were read on a Multiscan Spectrum reader set at a wavelength of 450 nm. The data was processed with GraphPad Prism software.

[0199] [Table 9]

[0200] TMD-8 anti-proliferation assay TMD-8 cells were prepared in RPMI1640 medium containing 10% fetal bovine milk and plated at 1500 cells per well in 384-well plates. Cells were incubated overnight at 37°C and 5% CO2. After incubation, different concentrations of compounds were added to the assay plate and cells were incubated for an additional 72 hours at 37°C and 5% CO2. After 72 hours of incubation, 15 μL of CellTiter 96® AQueous One Solution Reagent was added to each well and the plate was incubated at room temperature for 30 minutes. Cell viability was determined using CellTiter-Glo (Promega, USA). The CellTiter-Glo assay was performed according to the manufacturer's instructions and luminescence was determined in a multi-label reader (Envision, PerkinElmer, USA). The data was processed with XLfit software.

[0201] [Table 10]

[0202] In Vitro Rat / Human Hepatocyte Clearance Assay Male rat hepatocytes and mixed-sex human hepatocytes were obtained from commercial suppliers (e.g., BioreclamationIVT) and stored at -150°C prior to use. 10 mM stock solutions of test compounds were prepared in DMSO. Thawing medium and supplemented incubation medium (serum-free) were placed in a 37°C water bath for at least 15 minutes prior to use. Stock solutions were diluted to 100 μM by combining 198 μL acetonitrile and 2 μL of 10 mM stock solution.

[0203] A vial of cryopreserved hepatocytes was removed from storage, ensuring that the vial was kept cold. The vial was thawed in a 37°C water bath with gentle agitation. The vial was kept in the water bath until all ice crystals had melted and were no longer visible. The vial was sprayed with 70% ethanol before being moved to a biosafety cabinet. The contents were then poured into a 50 mL thawing medium conical tube. The vial was centrifuged at 100 g for 10 minutes at room temperature. The thawing medium was aspirated and the hepatocytes were resuspended in serum-free incubation medium to approximately 1.5 x 10 6 Measured in cells / mL.

[0204] Cell viability and density were counted using trypan blue exclusion and cells were then cultured at a working cell density of 1 × 10 6 Dilute in serum-free incubation medium to 1 x 10 viable cells / mL. 6 A portion of viable cells / mL hepatocytes were boiled for 10 min to remove enzyme activity before being added to the plates as negative controls, since little or no substrate metabolic turnover should be observed. Negative samples were prepared using inactivated hepatocytes and were used to eliminate the misleading factor of instability of the chemicals themselves.

[0205] Aliquots of 247.5 μL of hepatocytes were distributed into each well of a 96-well uncoated plate. The plate was placed in an incubator on an orbital shaker for approximately 10 minutes. An aliquot of 2.5 μL of 100 μM test compound was added to each well of the uncoated 96-well plate to initiate the reaction. The assay was performed in duplicate. The plate was placed in an incubator on an orbital shaker for the designated time points. The reaction was terminated at 5, 15, 30, 45, 60, 80 and 100 minutes by transferring 20 μL of the contents and mixing with 6 volumes (120 μL) of cold acetonitrile with internal standard. The samples were centrifuged at 4000 g for 20 minutes and aliquots of 100 μL of the supernatant were used for LC-MS / MS analysis for the measurement of test compounds.

[0206] In vitro hepatocyte clearance was estimated based on the determination of the elimination half-life (T1 / 2) of the compounds' disappearance from their initial concentration. Peak area ratios for each compound (test or control) versus IS were calculated. Ln (% of control) versus incubation time (min) curves were plotted and the slope of the linear fitting line was calculated. The drug elimination rate constant k (min -1 ), T1 / 2 (min), and in vitro intrinsic clearance CLint (μL / min / E6) were calculated according to the following equations: k=-slope T1 / 2=0.693 / k CLint=k / Chep [In the formula, Chep(cells × μL -1 ) is the cell concentration in the incubation system]. Procedure for determining Log D Place 10 μL of standard solution from each cassette into each 96-well rack position (Log D plate) in sequence. Add 500 μL of saturated octanol to each vial of the uncapped Log D plate above, followed by 500 μL of saturated phosphate buffer. Seal with molded PTFE / SIL 96-well plate cover.

[0207] The Log D plate is transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 2,000 rpm at 25° C. for 2 hours. The phases are separated by centrifuging the samples at 4,000 rpm for 30 minutes at 25° C. Using a pipette and syringe, approximately 100 μL from the octanol and buffer phases, respectively, are transferred to a new 96-well plate.

[0208] Transfer 5 μL of the octanol samples to a new 96-well plate, then add 495 μL of a mixture of H2O and acetonitrile (1:1) containing the internal standard as the 100x octanol samples. Vortex at 1,000 rpm for 5 minutes.

[0209] Transfer 50 μL of the 100x samples to a new 96-well plate, then add 450 μL of a mixture of H2O and acetonitrile (1:1) containing the internal standard for the 1,000x octanol samples. Vortex at 1,000 rpm for 5 minutes.

[0210] The 1,000x octanol sample is serially diluted 10,000, 100,000 and 1,000,000 times in a mixture of H2O and acetonitrile (1:1) containing an internal standard.

[0211] Transfer 50 μL of buffer samples to a new 96-well plate, then add 450 μL of a mixture of H2O and acetonitrile (1:1) containing the internal standard as the 10x buffer samples. Vortex at 1,000 rpm for 5 minutes.

[0212] The 10x buffer samples are serially diluted 100, 1,000 and 10,000 fold with a mixture of H2O and acetonitrile (1:1) containing an internal standard. Samples are evaluated by LC / MS / MS analysis. All compounds are tested once.

[0213] All calculations are performed using Microsoft Excel. The concentration of the test compound in octanol / buffer is assessed by LC / MS / MS. The Log D value of the test compound is calculated as follows:

[0214]

number

[0215] DF means dilution factor. A procedure for measuring protein binding in human plasma by using equilibrium dialysis Add 597 μL of blank plasma to each vial in a new plastic plate or separate plastic tubes by adding 3 μL of standard solution from each cassette and vortex at 1,000 rpm for 5 minutes. The final volume percent of organic solvent is 0.5% and the final concentration for the test compound is 5 μM. Immediately transfer 50 μL of spiked plasma suspension to a 96-well plate to act as the T=0 control sample. The samples are treated the same as the post-incubation samples. Place all remaining spiked plasma in the incubator for the duration of the test.

[0216] The insert is placed open end up in the well of the bottom plate. 500 μL of phosphate buffer (pH 7.4) is added to the buffer chamber, indicated by a white ring. 300 μL of spiked plasma sample is added to the sample chamber, indicated by a red ring. The unit is covered with a gas permeable lid and incubated at 37° C., 300 rpm, 5% CO on an orbital shaker in a CO incubator for 18 hours. At the end of the incubation, the lid is removed and 50 μL of the dialyzed samples from the buffer and plasma chambers, respectively, are pipetted into separate 96-well plates for analysis.

[0217] Concurrently, the remaining spiked plasma samples in the plastic plate or separate plastic tubes are incubated for 18 hours in a CO2 incubator at 37° C. with 5% CO2. At T=18 hours, 50 μL of the original spiked plasma suspension is transferred to a 96-well plate for analysis.

[0218] Add 50 μL of human plasma to the buffer samples and an equal volume of PBS to the collected plasma samples. Vortex the plate at 1,000 rpm for 2 min and add 400 μL of acetonitrile containing the appropriate internal standard (IS) to precipitate proteins and release compounds. Vortex at 1,000 rpm for 10 min. Centrifuge at 4,000 rpm for 30 min. Transfer 250 μL of the supernatant to a new 96-well plate and centrifuge again (4,000 rpm, 30 min). Then transfer 100 μL of the supernatant to a new 96-well plate for analysis. Add 100 μL of distilled water to each sample and vortex at 1,000 rpm for 5 min for analysis by LC-MS / MS. All compounds are tested once at 5 μM in human plasma.

[0219] All calculations are performed using Microsoft Excel. The percent unbound, percent bound and percent recovery of test compound are calculated as follows:

[0220]

number

[0221] result

[0222] [Table 11-1]

[0223] [Table 11-2]

[0224] Short-term oral absorption (SOA) assay in rats The short-term oral absorption (SOA) model is an in-vivo screening model to identify the brain permeability of compounds. To evaluate the potential of compounds to cross the blood-brain barrier in rats, the total brain-to-plasma ratio (K p,brain ) and AUC brain / AUC plasma The CSF-to-plasma ratio (Kp,CSF ) at the available time points after oral administration, respectively, CSF / AUC plasma or the average CSF to plasma ratio. The free fraction in biological matrices was determined by in vitro plasma and brain binding assays in separate studies. p,uu,brain and K. p,uu,CSF was calculated by the following equation: (1)K p,uu,brain =K p,brain ×f u,brain / f u,plasma , (2) K p,uu,CSF =K p,CSF / f u,plasma .

[0225] [Table 12]

Claims

1. Compounds of formula (I): 【Chemistry 1】 [In the formula, R １ is 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; R １ is one or more R ５ and optionally replacing R ２ Ha, Haro, C １～３ Alkyl, C １～３ alkoxy, carbocyclyl and heterocyclyl, or two R on the same atom or on adjacent atoms; ２ can form a 3- to 7-membered ring together with the atoms to which they are attached; k is 0 to 4; R ３ Ha, Haro, C １～３ Alkyl and C １～３ alkoxy; n is 0 to 4; R ４ Ha, Haro, C １～３ Alkyl and C １～３ alkoxy; m is 0 to 5; A is ═N— or ═C(R ６ ) - and R ５ is halo, hydroxy, C １～６ Alkoxy, amino, N-C １～６ Alkylamino, N,N-(C １～６ Alkyl) ２ amino, carbocyclyl and heterocyclyl; R ５ independently, optionally, one or more R ７ can be replaced by R ６ is selected from hydrogen and halo; R ７ is halo, hydroxy, amino, C １～３ Alkyl and C １～３ alkoxy] or a pharma- ceutically acceptable salt thereof.

2. R １ 2. The compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein is selected from hydrogen, methyl, hydroxymethyl, methoxymethyl, N,N-dimethylaminomethyl and azetidin-1-ylmethyl.

3. 3. A compound of formula (I) according to claim 1 or claim 2, wherein k is 0; or a pharma- ceutically acceptable salt thereof.

4. R ３ 4. A compound of formula (I) according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

5. A compound of formula (I) according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein n is 0 to 2.

6. R ４ 6. A compound of formula (I) according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

7. 7. A compound of formula (I) according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein m is 0 to 2.

8. 8. A compound of formula (I) according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein A is =N- or =C(H)-.

9. (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 9. A compound of formula (I) according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, selected from:

10. ((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; 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; 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; 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, 9. A compound of formula (I) according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, selected from:

11. 11. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable diluent or carrier.

12. 13. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable diluent or carrier, for use in producing a BTK inhibitory effect in a warm-blooded animal.

13. The pharmaceutical composition of claim 12, wherein the warm-blooded animal is a human.

14. 11. A compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of claims 1 to 10 for use as a medicament.

15. 13. A pharmaceutical composition for treating a disease or disorder in a warm-blooded animal, comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of claims 1 to 10, wherein the disease or disorder is selected from immune disorders, cancer, cardiovascular diseases, viral infections, metabolic / endocrine dysfunction, neurological disorders, allergic disorders, autoimmune diseases, and inflammatory diseases.

16. The pharmaceutical composition of claim 15, wherein the warm-blooded animal is a human.

17. 13. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of a disease or disorder, wherein the disease or disorder is selected from immune disorders, cancer, cardiovascular diseases, viral infections, metabolic / endocrine dysfunction, neurological disorders, allergic disorders, autoimmune diseases, and inflammatory diseases.

18. 16. The pharmaceutical composition of claim 15, wherein the cancer is selected from small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia, non-Hodgkin's lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma, or diffuse large B-cell lymphoma.

19. 16. The pharmaceutical composition of claim 15, wherein the disease or disorder is selected from urticaria / Sjogren's syndrome, rheumatoid arthritis, osteoporosis, vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, asthma, multiple sclerosis and systemic lupus erythematosus.

20. 20. The pharmaceutical composition of claim 19, wherein the disease or disorder is multiple sclerosis.

21. 11. A pharmaceutical composition for inhibiting BTK comprising a compound of formula (I) according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof.

22. 22. The pharmaceutical composition of claim 21, wherein the BTK is wild-type BTK or BTK having a C481 mutation.

23. 23. The pharmaceutical composition of claim 22, wherein the BTK having a C481 mutation is selected from the group consisting of a BTK having a C481S mutation, a BTK having a C481Y mutation, a BTK having a C481R mutation, and a C481F mutation.

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