BTK inhibitors

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which has BTK inhibitory activity and is therefore suitable for use in therapies and methods of treatment of the human or animal body. The present invention also relates to a method for manufacturing the compound, a pharmaceutical composition containing the compound, and its use in the manufacture of a medicament for the therapeutic effect of a warm-blooded animal such as a human.

Description

Field of the Invention

[0001] The present application relates to oxane-substituted imidazopyrazine and imidazotriazine inhibitors of Bruton's Tyrosine Kinase (BTK) (including mutant BTK), which are suitable for treating diseases or disorders associated with BTK kinase. These compounds have potential utility in treating immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolic / endocrine dysfunction and neurological disorders.

[0002] In particular, the present application relates to compounds and compositions thereof that inhibit BTK, methods for treating diseases or conditions associated with BTK, and methods for synthesizing these compounds. Background Art

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

[0004] BTK-deficient mouse models have shown that BTK plays a role in allergic disorders and / or autoimmune and / or inflammatory diseases; and BTK inhibition has potential utility in treating 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 cancers such as B-cell lymphoma, leukemia and other hematological malignancies. In addition, BTK plays a role in osteoclast function, so inhibiting BTK activity has potential utility in the treatment of bone disorders such as osteoporosis.

[0006] Approved compounds that inhibit BTK include ibrutinib (B-cell malignancies such as mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia ( macroglobulinemia); acalabrutinib (mantle cell lymphoma and CLL); and zanubrutinib (mantle cell lymphoma). In addition, there are several BTK inhibitors in clinical trials, including evobrutinib (multiple sclerosis); ABBV-105 (systemic lupus erythematosus (SLE)); ONO-4059 / GS-4059 (non-Hodgkin lymphoma and CLL); spebrutinib (relapsed or refractory B-cell non-Hodgkin lymphoma, CLL and Waldenstrom's macroglobulinemia); and HM71224 (autoimmune disease).

[0007] Despite significant therapeutic advances in the use of BTK inhibitors for the treatment of B-cell malignancies, cases of primary and secondary resistance have emerged with poor prognosis and limited treatment options.

[0008] Covalent (irreversible) BTK inhibitors (such as ibrutinib and acalabrutinib) bind to the C481 site of BTK, thereby inactivating its kinase. This binding is permanent until the BTK protein is degraded. The advantage of these irreversible inhibitors is that they are potent and usually only effective for a short period of exposure. However, its clinical benefits are limited by off-target toxicity, resulting in a high discontinuation rate, and due to the destruction of the BTK C481 mutation that covalently binds to BTK, drug resistance is acquired, thereby reducing the binding affinity of the compound and weakening its ability to inhibit BTK enzyme activity (Leukemia April 2015; 29 (4): 895-900). The majority (>50%) of CLL patients treated with covalent BTK inhibitor therapy develop resistance to treatment due to the development of the C481S mutation (N. Engl. J. Med. 370;24, 2014; JAMA Oncol. 2015;1(1):80-87; 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 lymphoid tissue of the brain and / or spinal cord, and it accounts for about 1% of all lymphomas and 2% to 5% of all primary brain tumors. The vast majority (about 95%) of PCNSL are diffuse large B-cell lymphomas (DLBCL). Mutations in the CD79B and MYD88 genes are usually (about 30-80%) consistent with PCNSL (Neuropathol. Appl. Neurobiol. April 2016; 42(3): 279-90). Although BTK inhibitors have not been approved for the treatment of DLBCL so far, data suggest that DLBCL with CD79B and MYD88 mutations is more sensitive to BTK inhibition (Nat. Med. August 2015; 21(8): 922-6).

[0010] Secondary CNS lymphoma (SCNSL) refers to the spread of the central nervous system from lymphomas that originated elsewhere (as opposed to primary CNS lymphoma). It is usually non-Hodgkin lymphoma and can be an isolated relapse or, when present, part of a systemic disease. Unlike primary CNS lymphoma, it more commonly involves the leptomeninges.

[0011] PRN2246 (SAR442168), a blood-brain barrier (BBB)-penetrable covalent BTK inhibitor, was well tolerated in a phase I trial in multiple sclerosis (MS). In addition, some trials (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) showed that high doses of ibrutinib (840 mg) were effective in CNS lymphomas (PCNSL and secondary nervous system lymphoma (SCNSL)), but so far, no BTK inhibitors targeting BTK-C481 mutations or active in PCNSL have been approved. These are unmet medical needs.

[0012] WO 2009 / 143051 discloses certain substituted imidazopyrazines and imidazotriazines, including certain hexane-substituted imidazopyrazines and imidazotriazines, as activated p21cdc42Hs-related kinase (ACK1) inhibitors. However, the compounds of WO 2009 / 143051 exhibit high human hepatocyte clearance, meaning that even at the maximum absorbable dose, the compounds may not achieve sufficient sustained drug coverage (making the compounds ineffective); and / or require extremely high doses to inhibit the target, thereby producing high maximum drug concentrations (which may produce secondary pharmacological (i.e., adverse) effects and toxicity issues).

[0013] WO2017111787A1 discloses tetrahydropyranylamino-pyrrolopyrimidones that modulate BTK activity; WO2018039310A1 discloses amino-pyrrolopyrimidone compounds and methods of use thereof; WO2017103611A1 discloses compounds used as BTK inhibitors; and WO2011152351 discloses purinone derivatives having BTK selective inhibitory activity. However, none of these compounds has the combination of desired properties possessed by the compounds of the present invention.

[0014] Disclosed herein are certain novel oxane-substituted imidazopyrazines and imidazotriazines that are potent, selective inhibitors of both BTK, wild-type BTK, and BTK with a C481 mutation (e.g., C481S, C481Y, C481R, or C481F mutation). These compounds 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 are compounds of formula (I):

[0016]

[0017]

[0018] and pharmaceutically acceptable salts thereof, and use thereof as BTK inhibitors, particularly in therapy. DETAILED DESCRIPTION

[0019] Many embodiments of the invention are described in detail throughout this specification and will be apparent to a skilled reader in the art. The invention should not be construed as limited to any one of the embodiments set forth, and the claims are embodiments. It should be understood that certain features of the disclosure described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the disclosure described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination.

[0020] Disclosed herein is a compound of formula (I):

[0021]

[0022] in:

[0023] R 1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, NC 1-6 Alkylamino, N,N-(C 1-6 alkyl)2amino, carbocyclic and heterocyclic groups; wherein R 1 Optionally, one or more R 5 replace;

[0024] R 2 Selected from halogen, C 1-3 Alkyl, C 1-3 Alkoxy, carbocyclyl and heterocyclyl; or two R on the same atom or adjacent atoms 2 Together with the atoms to which they are attached, they can form a 3-7 membered ring;

[0025] k is 0-4;

[0026] R 3 Selected from halogen, C 1-3 Alkyl and C 1-3 Alkoxy;

[0027] n is 0-4;

[0028] R 4 Selected from halogen, C 1-3 Alkyl and C 1-3 Alkoxy;

[0029] m is 0-5;

[0030] A is =N- or =C(R 6 )-;

[0031] R 5 Selected from halogen, hydroxyl, C 1-6 Alkoxy, amino, NC 1-6 Alkylamino, N,N-(C 1-6 alkyl)2amino, carbocyclic and heterocyclic groups; wherein R 5 Can be independently optionally composed of one or more R 7 replace;

[0032] R 6 is selected from hydrogen and halogen;

[0033] R 7 Selected from halogen, hydroxyl, amino, C1-3 Alkyl and C 1-3 Alkoxy;

[0034] or a pharmaceutically acceptable salt thereof.

[0035] In one embodiment, R 1 Selected from hydrogen and C 1-6 Alkyl; wherein R 1 Optionally, an R 5 Substitution; wherein R 5 Selected from hydroxyl, C 1-6 Alkoxy, N,N-(C 1-6 alkyl)2amino and heterocyclic.

[0036] In one embodiment, R 1 Selected from hydrogen and C 1-3 Alkyl; wherein R 1 Optionally, an R 5 Substitution; wherein R 5 Selected from hydroxyl, C 1-3 Alkoxy, N,N-(C 1-2 alkyl)2amino and azetidinyl.

[0037] In one embodiment, R 1 is selected from the group consisting of hydrogen, methyl, hydroxymethyl, methoxymethyl, N,N-dimethylaminomethyl and azetidin-1-ylmethyl.

[0038] In one embodiment, R 1 It is hydroxymethyl.

[0039] In one embodiment, R 2 Selected from halogen or C 1-3 Alkoxy.

[0040] In one embodiment, R 2 Selected from fluoro or methoxy.

[0041] In one embodiment, two R on the same atom or adjacent atoms are 2 Together with the atoms to which they are attached, they can form a 3-7 membered ring.

[0042] In one embodiment, or two R on the same atom 2 Together with the atoms to which they are attached, they can form a 3-7 membered ring.

[0043] In one embodiment, or two R on adjacent atoms 2 Together with the atoms to which they are attached, they can form a 3-7 membered ring.

[0044] In one embodiment, k is zero.

[0045] In one embodiment, k is 1.

[0046] In one embodiment, k is 2.

[0047] In one embodiment, k is 3.

[0048] In one embodiment, k is 4.

[0049] In one embodiment, R 3 It is a halogen group.

[0050] In one embodiment, R 3 It's fluorine.

[0051] In one embodiment, n is 0-2.

[0052] In one embodiment, n is zero.

[0053] In one embodiment, n is 1.

[0054] In one embodiment, n is 2.

[0055] In one embodiment, n is 3.

[0056] In one embodiment, n is 4.

[0057] In one embodiment, R 4 It is a halogen group.

[0058] In one embodiment, R 4 It's fluorine.

[0059] In one embodiment, m is 0-2.

[0060] In one embodiment, m is 0.

[0061] In one embodiment, m is 1.

[0062] In one embodiment, m is 2.

[0063] In one embodiment, m is 3.

[0064] In one embodiment, m is 4.

[0065] In one embodiment, m is 5.

[0066] In one embodiment, A is =N- or =C(H)-.

[0067] In one embodiment, A is =N-.

[0068] In one embodiment, A is =C(R 6 )-.

[0069] In one embodiment, A is =C(H)-.

[0070] The compound of formula (I) (when R1≠hydrogen) contains two chiral centers (marked with "*"):

[0071]

[0072] These chiral centers can exist in a "trans" configuration (meaning that the two substituents on the oxane ring point to opposite sides of the oxane ring); and in a "cis" configuration (meaning that the two substituents on the oxane ring point to the same side 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).

[0073] In one aspect of the invention, the compound of formula (I) is the trans compound of formula (I).

[0074] In one aspect of the invention, the compound of formula (I) is a cis compound of formula (I).

[0075] In one aspect of the invention, the compound of formula (I) is a compound of formula (IA):

[0076]

[0077] In one aspect of the invention, the compound of formula (I) is a compound of formula (IB):

[0078]

[0079] In one aspect of the invention, the compound of formula (I) is a compound of formula (IC):

[0080]

[0081] In one aspect of the invention, the compound of formula (I) is a compound of formula (ID):

[0082]

[0083] In one aspect of the present invention, the compound of formula (I) is selected from:

[0084] (5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0085] (5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0086] (5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0087] (5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0088] (5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0089] (5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0090] (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;

[0091] (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;

[0092] 3-(6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine;

[0093] 7-(6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0094] 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;

[0095] 5-(2-fluoro-4-phenoxyphenyl)-7-(6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0096] 5-(2-fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; and

[0097] 5-(2-Fluoro-4-phenoxyphenyl)-7-(6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine.

[0098] In one aspect of the present invention, the compound of formula (I) is selected from:

[0099] (5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0100] (5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0101] (5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0102] (5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0103] (5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0104] (5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0105] (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;

[0106] (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;

[0107] 3-(6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine;

[0108] 7-(6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0109] 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;

[0110] 5-(2-fluoro-4-phenoxyphenyl)-7-(6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0111] 5-(2-fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; and

[0112] 5-(2-fluoro-4-phenoxyphenyl)-7-(6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0113] or a pharmaceutically acceptable salt thereof.

[0114] In one aspect of the present invention, the compound of formula (I) is selected from:

[0115] ((2R,5R)-5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0116] ((2R,5R)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0117] ((2R,5R)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0118] ((2R,5R)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0119] ((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;

[0120] ((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;

[0121] ((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;

[0122] ((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;

[0123] 3-((3R,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine;

[0124] 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;

[0125] 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;

[0126] 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;

[0127] (R)-5-(2-fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; and

[0128] 5-(2-Fluoro-4-phenoxyphenyl)-7-((3R,6R)-6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0129] or a pharmaceutically acceptable salt thereof.

[0130] In one aspect of the present invention, the compound of formula (I) is selected from:

[0131] ((2S,5S)-5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0132] ((2S,5S)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0133] ((2S,5S)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0134] ((2S,5S)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0135] ((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;

[0136] ((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;

[0137] ((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;

[0138] ((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;

[0139] 3-((3S,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine;

[0140] 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;

[0141] 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;

[0142] 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;

[0143] (S)-5-(2-fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; and

[0144] 5-(2-Fluoro-4-phenoxyphenyl)-7-((3S,6S)-6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0145] or a pharmaceutically acceptable salt thereof.

[0146] In one aspect of the present invention, the compound of formula (I) is selected from:

[0147] ((2S,5R)-5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0148] ((2S,5R)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0149] ((2S,5R)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0150] ((2S,5R)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0151] ((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;

[0152] ((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;

[0153] ((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;

[0154] ((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;

[0155] 3-((3S,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine;

[0156] 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;

[0157] 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;

[0158] 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

[0159] 5-(2-Fluoro-4-phenoxyphenyl)-7-((3S,6R)-6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0160] or a pharmaceutically acceptable salt thereof.

[0161] In one aspect of the present invention, the compound of formula (I) is selected from:

[0162] ((2R,5S)-5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0163] ((2R,5S)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0164] ((2R,5S)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0165] ((2R,5S)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0166] ((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;

[0167] ((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;

[0168] ((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;

[0169] ((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;

[0170] 3-((3R,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine;

[0171] 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;

[0172] 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;

[0173] 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

[0174] 5-(2-Fluoro-4-phenoxyphenyl)-7-((3R,6S)-6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0175] or a pharmaceutically acceptable salt thereof.

[0176] In one aspect of the present invention, there is provided a compound of any of the formula (I) disclosed herein.

[0177] In one aspect of the present invention, there is provided any compound of formula (I) disclosed herein, or a pharmaceutically acceptable salt thereof.

[0178] In one aspect of the present invention, there are provided synthetic intermediates for the preparation of compounds of formula (I) as disclosed herein.

[0179] In one aspect of the present invention, there are provided synthetic intermediates for the preparation of compounds of formula (I) or pharmaceutically acceptable salts thereof as disclosed herein.

[0180] In various places of this disclosure, linking substituents are described. Where a structure clearly requires a linking group, the Markush variable listed for that group is to be understood as a linking group. For example, if a structure requires a linking group and the Markush group definition for that variable lists "alkyl," it is to be understood that the "alkyl" means a linking alkylene group.

[0181] As used herein, when referring to a chemical group, the term "substituted" means that the chemical group has one or more hydrogen atoms removed and replaced by a substituent. As used herein, the term "substituent" has the common meaning known in the art and refers to a chemical moiety covalently attached to a parent group or fused to the parent group when appropriate. As used herein, the term "optionally substituted" or "optionally substituted by..." means that a chemical group may have no substituents (i.e., unsubstituted) or may have one or more substituents (i.e., substituted). It should be understood that substitution at a given atom is limited by valence.

[0182] As used herein, the term “C i-j " represents a range of carbon atoms, wherein i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and every integer point therebetween, and wherein j is greater than i. For example, C 1-6 represents a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term “C 1-6 ” means 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3 or especially 1 to 2 carbon atoms.

[0183] As used herein, whether used as part of another term or independently, the term "alkyl" refers to a saturated hydrocarbon chain. The hydrocarbon chain mentioned above can be a straight chain or a branched chain. The term "C i-j "Alkyl" refers to an alkyl group having i to j carbon atoms.1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylbutyl, etc. 1-3 Examples of "alkyl" are methyl, ethyl, propyl and isopropyl.

[0184] As used herein, the terms "halo" and "halogen" refer to an atom selected from fluorine, chlorine, bromine and iodine.

[0185] As used herein, whether used as part of another term or by itself, the term "alkoxy" refers to a group 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 (eg, n-propoxy and isopropoxy), tert-butoxy, and the like. "C 1-6 Examples of "alkoxy" are methoxy, ethoxy and propoxy. 1-3 Examples of "alkoxy" are methoxy, ethoxy and propoxy.

[0186] "N-(C 1-6 Examples of "N,N-(C 1-6 Examples of the "alkyl)2amino" group are N,N-dimethylamino, N,N-diethylamino and N-ethyl-N-methylamino.

[0187] As used herein, whether used as part of another term or independently, the term "carbocyclyl" refers to a saturated monocyclic ring in which all ring atoms are carbon and which contains at least three ring-forming carbon atoms. In some embodiments, the carbocyclyl may contain 3 to 7 ring-forming carbon atoms or 3 to 6 ring-forming carbon atoms. In some embodiments, the ring-CH2-group may be replaced by a ring-C(O)-group. Examples of carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0188] 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 heteroatoms, including, but not limited to, oxygen, sulfur, nitrogen, phosphorus, and the like. In some embodiments, the ring-CH2-group may be replaced by a ring-C(O)-group. In some embodiments, the ring sulfur atom may be optionally oxidized to form an S-oxide. In some embodiments, the heterocyclyl group is carbon-connected. In some embodiments, the heterocyclyl group is nitrogen-connected. Exemplary heterocyclyl groups include, but are not limited to, azetidinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and the like.

[0189] In one embodiment, two R on the same atom 2 Together with the atoms to which they are attached, they form a 3-7 membered ring. 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 3-7 membered carbocyclyl ring or a 3-7 membered heterocyclic ring. Two R on the same atom 2 Examples of oxanes which, taken together with the atoms to which they are attached, form a 3-7 membered ring (depicted by oxane of formula (I)) include:

[0190]

[0191] (in Depict the connection to the rest of the molecule).

[0192] In one embodiment, two R on adjacent atoms 2 Together with the atoms to which they are attached, they form a 3-7 membered ring. The resulting "fused ring" has two rings (one of which is an oxane of formula (I)) sharing two adjacent atoms. The non-oxane ring can be a 3-7 membered carbocyclyl ring or a 3-7 membered heterocyclic ring. Or two R on adjacent atoms 2 Examples of oxanes that together form a 3-7 membered ring (depicted by the oxane of formula (I)) include:

[0193]

[0194] (in Depict the connection to the rest of the molecule).

[0195] Unless otherwise stated, "compounds" of the present disclosure are intended to encompass all stereoisomers, geometric isomers, and tautomers of the depicted structure.

[0196] 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 "asymmetric centers"). The disclosed compounds containing an asymmetric center can be separated in optically active (enantiomers or diastereomers) or optically inactive (racemic) forms. The term "enantiomer" encompasses pairs of stereoisomers that are not superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic mixture." The term "diastereomer" or "diastereoisomer" encompasses stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Certain compounds containing one or more asymmetric centers may give rise to enantiomers, diastereomers, or other stereoisomeric forms, which may be defined according to the Cahn-Ingold-Prelog RS system as (R)- or (S)- according to the absolute configuration at each asymmetric center. Resolved compounds whose absolute configuration is unknown may be designated using the term "or" at the asymmetric center. Methods on how to prepare optically active forms from racemic mixtures are known in the art, such as by HPLC resolution or stereoselective synthesis.

[0197] The term "geometric isomers" or "cis and trans isomers" refers to compounds that have identical formulas but whose functional groups are rotated into different orientations in three dimensional space.

[0198] The term "tautomer" includes proton transfer tautomers in isomeric protonation states of compounds with the same formula and total charge. Examples of proton transfer tautomers include, but are not limited to, keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomers can be in equilibrium or spatially locked into one form by appropriate substitution. Unless otherwise stated, compounds of the present disclosure identified as a particular tautomeric form by name or structure are intended to include other tautomeric forms.

[0199] The "compounds" of the present disclosure are also intended to encompass all isotopes of atoms in the compound. Isotopes of atoms include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine or iodine in the "compounds" of the present disclosure are intended to also include their isotopes, such as (but not limited to): 1 H. 2H. 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 131 I. In 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 with deuterium" or "deuterium substituted" refers to other isoforms (e.g., protium) that replace hydrogen in a chemical group with deuterium. In some embodiments, carbon includes 12 C and 13 C.

[0200] It will also be understood that the "compounds" of the present disclosure may exist in solvated as well as unsolvated forms (eg, hydrated forms, solid forms), and the present disclosure is intended to encompass all such solvated and unsolvated forms.

[0201] It should be further understood that the "compounds" of the present disclosure may exist in the form of pharmaceutically acceptable salts.

[0202] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. In some embodiments, pharmaceutically acceptable compounds, materials, compositions and / or dosage forms refer to those compounds, materials, compositions and / or dosage forms listed in approved or recognized pharmacopeias (such as the US Pharmacopoeia, the China Pharmacopoeia or the European Pharmacopoeia) by regulatory agencies (such as the US Food and Drug Administration, the China Food and Drug Administration or the European Medicines Agency) for use in animals and particularly humans.

[0203] As used herein, "pharmaceutically acceptable salts" refer to derivatives of compounds of the present disclosure, wherein the parent compound is modified by converting an existing acidic moiety (e.g., carboxyl, etc.) or basic moiety (e.g., amine, alkali metal, etc.) into its salt form. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. And pharmaceutically acceptable salts are acid and / or base salts that retain the biological effectiveness and properties of the parent compound and are generally not biologically or otherwise undesirable. Suitable pharmaceutically acceptable salts of the compounds of the present disclosure include, for example, acid addition salts, which can be derived from, for example, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) 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, naphthalene disulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, salicylic acid, sulfosalicylic acid, etc.).

[0204] Suitable pharmaceutically acceptable salts of the disclosed compounds also include, for example, base addition salts, which can be derived from, for example, inorganic bases (e.g., sodium, potassium, ammonium and hydroxides, carbonates, bicarbonates of metals from columns I to XII of the periodic table (e.g., 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.). Certain organic amines include, but are not limited to, isopropylamine, benzathine, cholate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine. The skilled artisan will appreciate that, in addition to what is shown in the examples, it is also possible to add acids or bases for the formation of acid / base addition salts. Lists of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0205] We have found that the compounds defined in the present invention or their pharmaceutically acceptable salts are effective BTK inhibitors and can be used to produce BTK inhibition in warm-blooded animals in need of such treatment. Therefore, it is expected that the compounds of the present invention are useful for treating diseases or medical conditions mediated alone or in part by BTK.

[0206] Thus, the compounds of the invention are expected to be useful in the treatment of immune disorders, cancer, cardiovascular disease, viral infections, metabolic / endocrine dysfunction and neurological disorders, allergic disorders, autoimmune diseases and inflammatory diseases, including urticaria / Sjögren's syndrome, rheumatoid arthritis, osteoporosis, vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, asthma, multiple sclerosis and systemic lupus erythematosus.

[0207] Due to its BTK inhibitor properties, the compounds of the present invention are expected to have a wide range of anti-cancer properties, and BTK-mediated growth has been observed in human cancers (including, but not limited to, B-cell malignancies). Specifically, it is expected that this class of compounds of the present invention is suitable for the treatment of lymphomas and leukemias. More specifically, it is expected that this class of compounds of the present invention or a pharmaceutically acceptable salt thereof is suitable for 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. Specifically, the compounds of the present invention are suitable for 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. Specifically, the compounds of the present invention are suitable for the treatment of chronic lymphocytic leukemia. Specifically, the compounds of the present invention are suitable for second-line treatment of chronic lymphocytic leukemia. Specifically, the compounds of the present invention are suitable for first-line treatment of chronic lymphocytic leukemia. Specifically, the compounds of the present invention are suitable for treating diffuse large B-cell lymphoma. Specifically, the compounds of the present invention are suitable for treating primary central nervous system lymphoma.

[0208] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have anticancer activity in early stage, actively progressing, metastatic, and / or resistant cancers. In some embodiments where cancer is mentioned, the cancer is locally advanced cancer. In some embodiments where cancer is mentioned, the cancer is locally advanced and / or metastatic cancer. In some embodiments where cancer is mentioned, the cancer is metastatic cancer. In some embodiments where cancer is mentioned, the cancer is invasive cancer. In some embodiments where cancer is mentioned, the cancer is ibrutinib resistant cancer.

[0209] In one embodiment of the invention referring to BTK inhibition, this refers to wild-type BTK and BTK with a C481 mutation (e.g., a C481S, C481Y, C481R or C481F mutation).

[0210] In one embodiment of the invention referring to BTK inhibition, this refers to wild-type BTK.

[0211] In one embodiment of the invention referring to BTK inhibition, this refers to BTK having a C481 mutation.

[0212] In one embodiment of the invention referring to BTK inhibition, this refers to BTK having a C481S mutation.

[0213] In one embodiment of the invention referring to BTK inhibition, this refers to BTK having a C481Y mutation.

[0214] In one embodiment of the invention referring to BTK inhibition, this refers to BTK having a C481R mutation.

[0215] In one embodiment of the invention referring to BTK inhibition, this refers to BTK having a C481F mutation.

[0216] Pharmaceutical compositions, dosages and administration

[0217] The present disclosure provides pharmaceutical compositions comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises more than one compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0218] In general, a 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 compounds of the present disclosure or pharmaceutically acceptable salts thereof can be mixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical composition.

[0219] The form of the pharmaceutical composition depends on a variety of criteria, including, but not limited to, the route of administration, the extent of the disease, or the dose to be administered. The pharmaceutical composition may be formulated for oral, nasal, rectal, transdermal, intravenous, or intramuscular administration. Depending on the desired route of administration, the pharmaceutical composition may be formulated in the form of tablets, capsules, pills, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants, or suppositories.

[0220] In certain embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, specifically 1 mg to about 200 mg. The pharmaceutical composition may also be administered once a day, twice a day, three times a day, or even four times a day. However, the daily dose will necessarily vary depending on the host being treated, the particular route of administration, and the severity of the disease being treated. Therefore, the optimal dose may be determined by the physician treating any particular patient.

[0221] The therapeutically effective amount of a compound as provided herein or a pharmaceutically acceptable salt thereof will depend on various factors known in the art, such as body weight, age, past medical history, current medications, individual health status and the possibility of cross-reactions, allergies, sensitivities and adverse side effects, as well as the route of administration and the extent of disease progression. As indicated by these and other circumstances or requirements, a person of ordinary skill in the art (e.g., a physician or veterinarian) may proportionally reduce or increase the dosage.

[0222] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0223] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier for use in producing a BTK inhibitory effect in a warm-blooded animal such as a human.

[0224] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier for use in producing an anti-cancer effect in a warm-blooded animal such as a human.

[0225] In another aspect of the present invention, a pharmaceutical composition is provided which comprises a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically 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 warm-blooded animals such as humans.

[0226] In another aspect of the present invention, a pharmaceutical composition is provided which comprises a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier for use in the treatment of diffuse large B-cell lymphoma that has metastasized to the brain, primary central nervous system lymphoma or secondary central nervous system lymphoma.

[0227] combination

[0228] In some embodiments, the pharmaceutical composition includes one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof as a first active ingredient, and further includes a second active ingredient. The second active ingredient 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 the second active ingredient anti-tumor agent include, but are not limited to, idelalisib, duvelisib, obinutuzumab, ofatumumab, rituximab, alemtuzumab, bleomycin, brentuximab, vedotin, carmustine, cyclophosphamide, chlorambucil, dacarbazine, dexamethasone ... xamethasone), doxorubicin, lomustine, mechlorethamine, procarbazine, prednisone, bendamustine, venetoclax, prednisone, CVP (a combination of the C-chemotherapeutic drug cyclophosphamide, the V-chemotherapeutic drug vincristine, and the P-steroid prednisolone), midostaurin, and vinblastine.

[0229] Here, when the term "combination" is used, it should be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the present disclosure, "combination" refers to simultaneous administration. In another aspect of the present disclosure, "combination" refers to separate administration. In another aspect of the present disclosure, "combination" refers to sequential administration. When sequentially or separately administered, delaying the administration of the second component should not result in loss of the beneficial effects of the combination.

[0230] Therefore, in another aspect of the present disclosure, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an anti-tumor agent selected from the anti-tumor agents listed herein above.

[0231] Therefore, in another aspect of the present disclosure, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an anti-tumor agent selected from the anti-tumor agents listed herein above, for use in producing an anti-cancer effect.

[0232] Therefore, in another aspect of the present disclosure, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an anti-tumor agent selected from the anti-tumor agents listed herein above, 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.

[0233] Therefore, in another aspect of the present disclosure, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an anti-tumor agent selected from the anti-tumor agents listed herein above, for use in the treatment of diffuse large B-cell lymphoma that has metastasized to the brain, primary central nervous system lymphoma or secondary central nervous system lymphoma.

[0234] According to this aspect of the disclosure, there is provided a combination suitable for the treatment of cancer comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, and any one of the anti-tumor agents listed above.

[0235] According to another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an antitumor agent selected from the antitumor agents listed above herein, and a pharmaceutically acceptable diluent or carrier.

[0236] According to another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an antitumor agent selected from the antitumor agents listed above herein, and a pharmaceutically acceptable diluent or carrier, for producing an anticancer effect.

[0237] According to another aspect of the present disclosure, a pharmaceutical composition is provided, which includes a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an antitumor agent selected from the antitumor agents listed above herein, and a pharmaceutically acceptable diluent or carrier for 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.

[0238] According to another aspect of the present disclosure, a pharmaceutical composition is provided, which comprises a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an anti-tumor agent selected from the anti-tumor agents listed above herein, and a pharmaceutically acceptable diluent or carrier for use in treating diffuse large B-cell lymphoma that has metastasized to the brain, primary central nervous system lymphoma, or secondary central nervous system lymphoma.

[0239] According to another aspect of the present disclosure, there is provided a kit comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an anti-tumor agent selected from the anti-tumor agents listed herein above.

[0240] According to another aspect of the present disclosure, there is provided a kit comprising:

[0241] a) a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in a first unit dosage form;

[0242] b) an anti-neoplastic agent selected from the anti-neoplastic agents listed herein above; in a second unit dosage form; and

[0243] c) container means for containing said first and second dosage forms.

[0244] Pharmacological tools

[0245] In addition to their use in therapeutic medicine, the compounds of formula (I) or their pharmaceutically acceptable salts are also suitable as pharmacological tools for developing and standardizing in vitro and in vivo test systems for evaluating the effects of BTK inhibition in experimental animals such as cats, dogs, rabbits, monkeys, rats and mice as part of the search for new therapeutic agents.

[0246] Treatment

[0247] According to another aspect of the present invention there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

[0248] According to another 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 administering to the animal an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

[0249] According to another feature of this aspect of the invention, there is provided a method of treating cancer in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

[0250] According to additional features 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, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

[0251] According to additional features of this aspect of the invention, there is provided a method of treating diffuse large B-cell lymphoma that has metastasized to the brain, primary central nervous system lymphoma or secondary central nervous system lymphoma in a warm-blooded animal such as a human, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0252] As used herein, the term "treatment" or "treat" refers to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder as described herein or one or more symptoms thereof. In some embodiments, treatment may be performed after one or more symptoms have appeared. In other embodiments, treatment may be performed in the absence of symptoms. For example, susceptible individuals may be treated before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetics or other susceptibility factors). Treatment may also continue after symptoms have resolved, for example to prevent or delay their recurrence.

[0253] The present disclosure also provides a method for screening a patient suitable for treatment with a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof. The method comprises sequencing a tumor sample from the patient and detecting the accumulation of BTK or the presence of a BTK mutation.

[0254] According to another 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 (1) determining whether the warm-blooded animal has a cancer susceptible to BTK inhibition, and (2) if so, administering to the animal an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

[0255] Uses of Compounds

[0256] In certain embodiments, the present disclosure provides the use of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a BTK-mediated or dependent disease or condition.

[0257] Thus, according to this aspect of the invention there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0258] Thus, according to this aspect of the invention there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0259] Thus, according to this aspect of the invention there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0260] According to another aspect of the present invention there is provided the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for producing an inhibitory effect on BTK in a warm-blooded animal such as a human.

[0261] According to this aspect of the invention there is provided the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for producing an anti-cancer effect in a warm-blooded animal such as man.

[0262] According to another feature of the present invention, there is provided the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating the following diseases: 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.

[0263] According to another feature of the present invention, there is provided the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating diffuse large B-cell lymphoma that has metastasized to the brain, primary central nervous system lymphoma or secondary central nervous system lymphoma.

[0264] According to another aspect of the present invention there is provided the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for producing a BTK inhibitory effect in a warm-blooded animal such as a human.

[0265] According to this aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for producing an anti-cancer effect in a warm-blooded animal such as man.

[0266] According to another feature of the present invention, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, 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.

[0267] According to another feature of the present invention, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for use in treating diffuse large B-cell lymphoma, primary central nervous system lymphoma or secondary central nervous system lymphoma that has metastasized to the brain.

[0268] In the above pharmaceutical compositions, methods, uses and medicament manufacturing features, alternative and preferred embodiments of the disclosed compounds described herein also apply.

[0269] Examples

[0270] General Experiments

[0271] abbreviation

[0272]

[0273] The synthesis of the compound (including its pharmaceutically acceptable salt) provided herein is described in the synthesis process in the example. The compound provided herein can be prepared using any known organic synthesis technology and can be synthesized according to any of a variety of possible synthetic pathways, and therefore, these processes are only illustrative and are not intended to limit other possible methods that can be used to prepare the compound provided herein. In addition, the steps in the method are to better illustrate and can be changed when appropriate. For the purpose of research and possible submission to the management agency, the embodiment of the compound in the example is synthesized.

[0274] The reaction for preparing the disclosed compounds can be carried out in a suitable solvent, which can be easily selected by a technician in the field of organic synthesis. Suitable solvents can be at a temperature for reacting, for example, at a temperature ranging between the freezing temperature of the solvent and the boiling temperature of the solvent, substantially unreactive to the starting material (reactant), intermediate or product. The specified reaction can be carried out in a solvent or in a mixture of more than one solvent. Depending on the specific reaction step, the suitable solvent for the specific reaction step can be selected by a skilled person.

[0275] The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The demand for protection and deprotection, and the selection of appropriate protecting groups can be easily determined by those skilled in the art. The chemical properties of protecting groups can be found in, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0276] The reaction can be monitored according to any suitable method known in the art. For example, the reaction can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible light), mass spectrometry, or by chromatography, such as high pressure liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or thin layer chromatography (TLC) to monitor product formation. Those skilled in the art can purify compounds 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, "Journal of Combinatorial Chemistry (J. Combi. Chem.), 2004, 6 (6), 874-883, which is incorporated herein by reference in its entirety), supercritical fluid chromatography (SFC) and normal phase silica chromatography.

[0277] The structures of the compounds in the examples were characterized by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) were expressed in 10 -6The units are given in ppm. The values ​​were recorded 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 internal standard in dimethyl sulfoxide-d6 (DMSO-d6) or CDCl3 or CD3OD or D2O or acetone-d6 or CD3CN (from Aldrich or Cambridge Isotope Lab., Inc.) 1 H-NMR spectrum.

[0278] MS measurements were 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 range of instruments. The detailed methods used in the present invention include:

[0279] LC-MS method A: 10-80AB_7min_220&254_Shimadzu.lcm

[0280] Mobile phase: 1.5 mL / 4 L TFA / water (solvent A) and 0.75 mL / 4 L TFA / acetonitrile (solvent B), using a 10%-80% (solvent B) gradient over 6 minutes and holding at 80% for 0.5 minutes at a flow rate of 0.8 mL / min;

[0281] Column: Xtimate C18 2.1*30mm, 3μm;

[0282] Wavelength: UV 220nm, 254nm;

[0283] Column temperature: 50°C;

[0284] MS ionization: ESI

[0285] LC-MS method B: 10-80AB_4min_220&254_Shimadzu.lcm

[0286] Mobile phase: 1.5 mL / 4 L TFA / water (solvent A) and 0.75 mL / 4 L TFA / acetonitrile (solvent B), using a 10%-80% (solvent B) gradient over 3 minutes and holding at 80% for 0.5 minutes at a flow rate of 0.8 mL / min;

[0287] Column: Xtimate C18 2.1*30mm, 3μm;

[0288] Wavelength: UV 220nm, 254nm;

[0289] Column temperature: 50°C;

[0290] MS ionization: ESI

[0291] LC-MS method C: 10-80CD_7min_220&254_Agilent.lcm

[0292] Mobile phase: 0.2 mL / 1 L NH3.H2O / water (solvent A) and acetonitrile (solvent B), using a 10%-80% (solvent B) gradient over 6 minutes and holding at 80% for 0.5 minutes at a flow rate of 0.8 mL / min;

[0293] Column: Xbrige Shield RP-18, 5μm, 2.1*50mm;

[0294] Wavelength: UV 220nm and 254nm;

[0295] Column temperature: 30°C;

[0296] MS ionization: ESI

[0297] High performance liquid chromatography (HPLC) was performed on a Shimadzu LC-20A system or Shimadzu LC-2010HT series, or Agilent 1200LC or Agilent 1100 series using 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*30mm), or MERCKRP18 2.5-2mm, etc. The detailed method used in the present invention comprises:

[0298] HPLC method A: 10-80AB_8min.met

[0299] Mobile phase: 2.75 mL / 4 L TFA / water (solvent A) and 2.5 mL / 4 L TFA / acetonitrile (solvent B), using a 10%-80% (solvent B) gradient over 6 minutes and holding at 80% for 2 minutes at a flow rate of 1.2 mL / min;

[0300] Column: Ultimate C18 3.0*50mm, 3μm

[0301] Wavelength: UV220nm, 215nm, 254nm;

[0302] Column temperature: 40°C;

[0303] HPLC method B: 10-80CD_8min.met

[0304] Mobile phase: 2.0 mL / 4 L NH3H2O / water (solvent A) and acetonitrile (solvent B), using a 10%-80% (solvent B) gradient over 4 minutes and holding at 80% for 2 minutes at a flow rate of 1.2 mL / min;

[0305] Column: Xbrige Shield RP-18, 2.1*50mm, 5μm;

[0306] Wavelength: UV 220nm, 215nm, 254nm;

[0307] Column temperature: 40°C;

[0308] Supercritical fluid chromatography (SFC) measurement was performed on Agilent 1260 series or Waters UPCC series, or Shimadzu LC-20AB series, using ChiralPak AD-3 column (3 μm, 150×4.6 mm), or Chiralcel OJ-3 column (3 μm, 150×4.6 mm), or Chiralpak IG-3 column (3 μm, 50 mm*4.6 mm). The detailed method used in the present invention comprises:

[0309] SFC method A: Mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5.5 min and hold at 40% for 3 min, then 5% B for 1.5 min, flow rate: 2.5 mL / min;

[0310] Column: ChiralPak AD-3 150×4.6 mm ID, 3 μm;

[0311] Column temperature: 40°C;

[0312] Back pressure: 100 bar.

[0313] SFC method B: Mobile phase: A: CO2, B: methanol (0.05% DEA), gradient: 5% to 40% B in 5 min and 40% to 5% B in 0.5 min, hold 5% B for 1.5 min, flow rate: 2.5 mL / min

[0314] Column: Chiralcel OJ-3 150×4.6mm ID, 3μm;

[0315] Column temperature: 35 °C;

[0316] ABPR:1500psi.

[0317] SFC method C: Mobile phase: A: CO2, B: methanol (0.05% DEA), isocratic: 40% B, flow rate: 4 mL / min;

[0318] Column: Chiralpak IG-3 50 mm × 4.6 mm ID, 3 μm;

[0319] Column temperature: 35 °C;

[0320] ABPR:1500psi.

[0321] Thin layer chromatography was performed using Yantai Huanghai HSGF254 silica gel or Anhui Liang Chen Gui Yuan plates. The silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.2 mm. The silica gel plates used to separate and purify the products by TLC were 0.4 mm to 0.5 mm.

[0322] Purification chromatographic columns use silica gel as a carrier (100-200, 200-300 or 300-400 mesh, manufactured by Yantai Huanghai Co. or Anhui Liang Chen Gui Yuan Co., etc.), or a fast column (silica-CS fast column 40-60 μm, or reverse phase C18 column 20-35 μm, manufactured by Agela Technologies, etc.) or Agela Technologies' fast column silica-CS (40-60 μm) or C18 column (20-40 μm) in Teledyne ISCO combi-flash or Biotage fast system. The size of the column is adjusted according to the amount of the compound.

[0323] The known starting materials of the present disclosure can be synthesized by using or according to methods known in the art, or can be purchased from Alfa Aesar, TCI, Aldrich, Bepharm, and Scochem (or PharmaBlock, Bide, Amatek, StruChem, Firster Pharmaceutical, Titan (Adamas), etc.).

[0324] Unless otherwise stated, the reactions were carried out under an argon or nitrogen atmosphere. Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L. Hydrogenation is usually carried out under pressure. Unless otherwise stated, the reaction temperature in the examples is ambient temperature, which is 10°C to 30°C.

[0325] The reaction progress was monitored by TLC or / and LC-MS. The eluent system used for the reaction included a dichloromethane-methanol system and a petroleum ether-ethyl acetate system. The volume ratio of the solvent was adjusted according to the different polarities of the compounds.

[0326] The elution system of column chromatography and the eluent system of TLC used for purifying compounds include a dichloromethane-methanol system and a petroleum ether-ethyl acetate system. The volume ratio of the solvent is adjusted according to the different polarities of the compounds. A small amount of alkaline or acidic agent (0.1% to 1%), such as formic acid, acetic acid, TFA or ammonia water, can be added for adjustment.

[0327] Compounds of the present invention

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336] Table 1: Compounds of the present invention

[0337] Synthesis method

[0338] The compounds of the present invention can be prepared according to the following two synthetic methods.

[0339] Method A

[0340]

[0341] Method B

[0342]

[0343] Method A

[0344] Compound 2A: 5-(((3-chloropyrazin-2-yl)methyl)carbamoyl)tetrahydro-2H-pyran-2-carboxylic acid ethyl ester

[0345]

[0346] HATU (16.64 g, 43.76 mmol) and DIEA (11.31 g, 87.51 mmol) were added 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). The mixture was stirred at room temperature (18-22 ° C) for 12 hours. The reactant was concentrated and diluted with water (100 mL) and extracted with ethyl acetate (200 mL * 3). The combined organic layers were washed with brine (200 mL * 4), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (2.5-3.5% methanol / dichloromethane) to give compound 2A (9.0 g, yield 94.0%) as a yellow oil.

[0347] LCMS: tR = 0.689 min in 5-95AB_1.5min_220&254_Shimadzu.lcm chromatograph (Agilent Pursult 5C18 20*2.0mm), MS (ESI) m / z = 328.2 [M+H] +

[0348] Compound 3A: 5-(8-chloroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-carboxylic acid ethyl ester

[0349]

[0350] POCl3 (21.05 g, 137.30 mmol) was added to a mixture of compound 2A (9.0 g, 27.46 mmol) and DMF (600 μL) in MeCN (150 mL). The mixture was stirred at 70 ° C for 1 hour. The reactant was concentrated and washed with water (50 mL) and saturated NaHCO3 (50 mL), extracted with ethyl acetate (100 mL * 3). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (52-62% ethyl acetate / petroleum ether) to give compound 3A (3.5 g, 41.2% yield) as a yellow oil.

[0351] LCMS:t R=0.742 min in 5-95AB_1.5min_220&254_Shimadzu.1cm chromatogram (Agilent Pursult 5C18 20*2.0 mm), MS (ESI) m / z=310.2 [M+H] +

[0352] 1 H NMR (400MHz, CDCl3): δ = 7.80 (d, J = 0.4Hz, 1H), 7.70-7.64 (m, 1H), 7.37 (d, J = 4.8Hz, 0.3H),7.35(d,J=4.8Hz,0.7H),4.44(t,J=4.4Hz,0.7H),4.30-4.25(m,2H),4.23-4 .14(m,1H),4.00(dd,J=3.2,12.0Hz,1H),3.79(t,J=11.2Hz,0.4H),3.42-3.19(m,1 H),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).

[0353] Compound 4A: (5-(8-chloroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0354]

[0355] To a mixture of LiAlH4 (860 mg, 22.60 mmol) in THF (20 mL) was added THF (20 mL) containing compound 3A (3.5 g, 11.30 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour. The reactant was quenched with water (860 μL), 15% NaOH (860 μL) and water (2580 μL). The mixture was dried over anhydrous sodium sulfate and stirred at room temperature for 0.5 hours, filtered and concentrated to give compound 4A (2.7 g, 89.4% yield) as a yellow solid.

[0356] LCMS:t R = 0.635 min in 5-95AB_1.5min_220&254_Shimadzu.1cm chromatograph (Agilent Pursult 5C18 20*2.0 mm), MS (ESI) m / z = 267.8 [M+H] +

[0357] Compound 5A: (5-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0358]

[0359] 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 hour. The reactants were concentrated to give a crude product, which was purified by silica gel column chromatography (2.2% methanol / dichloromethane) to give compound 5A (2.5 g, 71.63% yield) as a yellow solid.

[0360] LCMS:t R =0.717 min in 5-95AB_1.5min_220&254_Shimadzu.1cm chromatogram (Agilent Pursult 5C18 20*2.0 mm), MS (ESI) m / z=347.8 [M+H] +

[0361] Compound 6A: (5-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0362]

[0363] To a mixture of compound 5A (2.5 g, 7.21 mmol) in IPA (15 mL) was added NH 3 ·H 2 O (15 mL). The mixture was stirred at 100° C. for 12 hours in a 100 mL sealed tube. The reaction was concentrated to give compound 6A (2.4 g, purity 98.0%) as a yellow oil.

[0364] LCMS:t R =0.436min in 10-80AB_3min_220&254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30mm), MS (ESI) m / z=327.1[M+H] +

[0365] Compound 7A: (5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0366]

[0367] Under nitrogen, to a mixture of compound 6A (500 mg, 1.31 mmol, purity 97.99%) and (2-fluoro-4-phenoxyphenyl)boronic acid (450 mg, 1.95 mmol) in 1,4-dioxane (15 mL) / H2O (5 mL) was added Pd(dppf)Cl2.CH2Cl2 (32 mg, 0.04 mmol) and K2CO3 (375 mg, 2.62 mmol). The mixture was stirred at 100 ° C for 12 hours under nitrogen. The reactant was diluted with water (20 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (2.2% methanol / dichloromethane) to give Compound 7A (mixture of cis / trans racemates) (150 mg, yield 26.4%) as a yellow solid.

[0368] LCMS:t R = 0.723 min in 5-95AB_1.5min_220&254_Shimadzu.1cm chromatograph (Agilent Pursult 5C18 20*2.0 mm), MS (ESI) m / z = 435.1 [M+H] +

[0369] 2-Fluoro-4-phenoxyphenyl)boronic acid:

[0370]

[0371] At room temperature (25-30° C.), compound 1a (10 g, 52.35 mmol) was added to CH2Cl2 (480 mL), PhB(OH)2 (12.8 g, 104.71 mmol), Cu(OAc)2 (9.5 g, 52.35 mmol), NEt3 (21 mL, 151.05 mmol) and The mixture was stirred at room temperature (25-30 ° C) for 16 hours under air. The mixture was filtered through a celite pad. The filtrate was concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (petroleum ether) to obtain compound 2a (11.3 g, 80.8% yield) as a colorless oil.

[0372] 1H NMR (400MHz, CDCl3): δ=7.47(t,J=8.4Hz,1H),7.42-7.36(m,2H),7.19(t,J=8.4Hz,1 H), 7.05 (d, J = 8.0Hz, 2H), 6.78 (dd, J = 10.0, 2.8Hz, 1H), 6.71 (dd, J = 8.8, 2.0Hz, 1H).

[0373] At -65 ° C, 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. The mixture was stirred at -65 ° C for 0.5 hours. 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 hours. The mixture was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL * 3), and washed with brine (100 mL * 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was triturated with 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 silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to give 2-fluoro-4-phenoxyphenyl)boronic acid (3 g) as a yellow oil.

[0374] 1 H NMR (400MHz, DMSO-d6): δ = 8.10 (s, 2H), 7.58 (t, J = 8.0Hz, 1H), 7.47-7.41 (m, 2H), 7.22 (t, J = 7.6Hz, 1H), 7.09 (d, J = 7.6Hz, 2H), 6.78-6.68 (m, 2H).

[0375] 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

[0376] 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

[0377]

[0378] Mixture 7A (150 mg, 0.35 mmol) was purified by chiral SFC (column: DAICEL CHIRALPAK AD-H) (250 mm * 30 mm, 10 μm), condition: 0.1% NH .H O / EtOH, 40%, flow rate 80 mL / min. The fraction containing the desired compound was concentrated, diluted with H O (10 mL) and CH CN (10 mL), and freeze-dried to obtain compound 2 (34.8 mg, yield 23.2%) and compound 3 (29.4 mg, 19.6%) as a white solid. Two cis enantiomers were not collected.

[0379] Spectrum of compound 2:

[0380] LCMS R =2.037min in 10-80AB_7min_220&254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30mm), MS (ESI) m / z=435.3[M+H] + .

[0381] HPLC R =3.03 min in 10-80AB_8min.met (HPLC-BJ Ultimate 3.0*50mm 3μm).

[0382] SFC R =6.119 min, optical purity: 96.3%. Method notes: Column: ChiralPak AD-3 150×4.6 mm ID, 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5.5 min and 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.

[0383] 1HNMR (400MHz, CD3OD) δ = 7.63 (d, J = 5.2Hz, 1H), 7.54-7.36 (m, 3H), 7.27-7.18 (m ,1H),7.14(dd,J=8.8,0.8Hz,2H),7.02(d,J=4.8Hz,1H),6.98-6.82(m,2H),4.2 3-4.07(m,1H),3.75(t,J=11.2Hz,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=13.6Hz,1H),1.66-1.49(m,1H).

[0384] 19 FNMR (CD3OD) δ=-112.240

[0385] Spectrum of compound 3:

[0386] LCMS R =2.030 min in 10-80AB_7min_220&254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30 mm), MS (ESI) m / z=435.3 [M+H] + .

[0387] HPLC R =3.02 min in 10-80AB_8min.met (HPLC-BJ Ultimate 3.0*50mm 3μm).

[0388] SFC R =7.334, optical purity: 92.7%. Method notes: Column: ChiralPak AD-3 150×4.6 mm I.D., 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5.5 min and hold 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.

[0389] 1H NMR (400MHz, CD3OD) δ = 7.65 (d, J = 5.2Hz, 1H), 7.52-7.37 (m, 3H), 7.29-7.21 (m,1H),7.20-7.11(m,2H),7.04(d,J=4.8Hz,1H),6.99-6.84(m,2H),4.24- 4.13(m,1H),3.77(t,J=11.2Hz,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).

[0390] 19 F NMR (400MHz, CD3OD) δ=-112.258.

[0391] The following compounds were synthesized according to Method A:

[0392]

[0393]

[0394]

[0395] Method B

[0396] Compound 2B: 5-(((3-amino-5-hydroxy-1,2,4-triazin-6-yl)methyl)carbamoyl)tetrahydro-2H-pyran-2-carboxylic acid ethyl ester

[0397]

[0398] To a mixture of 5-(2,5-dioxopyrrolidin-1-yl)2-ethyltetrahydro-2H-pyran-2,5-dicarboxylate (20 g crude product, 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 give compound 2B (35 g crude product) as a brown solid.

[0399] LCMS:t R = 0.582 min in 5-95AB_1.5min_220&254_Shimadzu.1cm chromatograph (Merck RP18 25-3 mm), MS (ESI) m / z = 325.9 [M+H] +

[0400] 5-(2,5-dioxopyrrolidin-1-yl)2-ethyltetrahydro-2H-pyran-2,5-dicarboxylate:

[0401]

[0402] 1-Hydroxypyrrolidine-2,5-dione (877 mg, 7.61 mmol) and EDCI (1.6 g, 8.30 mmol) were added to a solution of 6-(ethoxycarbonyl)tetrahydro-2H-pyran-3-carboxylic acid (1.4 g, 6.92 mmol) in CH2Cl2 (30 mL). The mixture was stirred at 22-26 ° C for 1.5 hours. 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 give 5-(2,5-dioxopyrrolidin-1-yl) 2-ethyltetrahydro-2H-pyran-2,5-dicarboxylate as a colorless oil used directly.

[0403] Compound 3B: 5-(2-amino-4-hydroxyimidazo[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-carboxylic acid ethyl ester

[0404]

[0405] Phosphorus oxychloride (23 mL, 243.52 mmol) was added to a solution of compound 2B (35 g crude product, 60.88 mmol) in acetonitrile (300 mL). The mixture was then stirred at 70 ° C for 16 hours. The mixture was concentrated, the residue was diluted with dichloromethane (150 mL), poured into a cooled saturated sodium bicarbonate solution (300 mL) to pH = 8, extracted with dichloromethane / methanol (10: 1, 200 mL * 4), and then extracted with IPA / CHCl3 (150 mL * 4). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 3B (45 g crude product) as a black oil.

[0406] LCMS:t R = 0.13 min in 5-95AB_1.5min_220&254_Shimadzu.lcm chromatograph (Merck RP18 25-3 mm), MS (ESI) m / z = 308.0 [M+H] +

[0407] Compound 4B: 5-(2-amino-5-bromo-4-hydroxyimidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-carboxylic acid ethyl ester

[0408]

[0409] To a solution of compound 3B (45 g crude product, 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 hours. The mixture was poured into water (300 mL), extracted with ethyl acetate (300 mL * 4), and washed with brine (500 mL * 4). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 4B (19 g crude product) as a black oil.

[0410] LCMS:t R =0.602 min in 5-95AB_1min_220&254_Agilent chromatograph (Agilent Poroshell 120 EC-C18 2.7 μm 3.0*30 mm), MS (ESI) m / z=388.0 [M+H+2] + (Bromide isotopes).

[0411] Compound 5B: 5-(5-bromo-4-hydroxyimidazo[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-carboxylic acid ethyl ester

[0412]

[0413] 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 hours. The mixture was combined with another batch (7.2 g crude product of compound 4B) and concentrated to give a crude material, which was purified by silica gel column chromatography (0-60% ethyl acetate / petroleum ether) to give compound 5B (14.3 g, 44% yield for 5 steps) as a yellow solid.

[0414] LCMS:t R =0.753 min in 5-95AB_1.5min_220&254_Shimadzu.1cm chromatograph (Agilent Pursult 5C18 20*2.0 mm), MS (ESI) m / z=370.9 [M+H] +

[0415] 1H NMR (400MHz, CD3OD): δ = 7.74 (s, 0.3H), 7.72 (s, 0.5H), 4.37 (t, J = 4.8Hz, 0.7H), 4.29-4.16 (m, 3H), 4.12 (dd, J = 11.6, 2.0Hz, 0.3H), 3.92 (dd, J=11.6, 4.0Hz, 0.7H), 3.70 (t, J=11.2Hz, 0.4H), 3.57-3.45 (m, 1H), 2.35-1.92 (m, 4H),, 1.33-1.27 (m, 3H).

[0416] Compound 6B: 5-(4-amino-5-bromoimidazo[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-carboxylic acid ethyl ester

[0417]

[0418] 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) followed by trimethylamine (56 mL, 404.1 mmol) at below 10 °C. 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 hours. The mixture was cooled to 10 °C, ammonia (30 mL, 28%) was added, the temperature was kept below 20 °C, and stirred at 10 °C for 0.5 hours. Another batch of the same scale was performed. The mixture was combined and diluted with water (200 mL) and extracted with ethyl acetate (500 mL*3), washed with brine (500 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the mixture was purified by silica gel column chromatography (2-4% methanol / dichloromethane) to give compound 6B (9 g, yield 90%) as a yellow solid.

[0419] LCMS:t R =0.614 min in \5-95AB_1min_220&254_Agilent chromatograph (Agilent Poroshell 120 EC-C18 2.7μm 3.0*30mm), MS (ESI) m / z=372.0 [M+H+2] + (Bromide isotopes).

[0420] 1H NMR (400MHz, CD3OD): δ = 7.81 (s, 0.3H), 7.79 (s, 0.6H), 4.36 (t, J = 5.2Hz, 0.6H), 4.29-4.19 (m, 3H), 4.12 (dd, J = 11.6, 2.0Hz, 0.3H), 3.93 (dd, J = 1 1.6,4.0Hz,0.7H),3.71(t,J=11.2Hz,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).

[0421] Compound 7B: (5-(4-amino-5-bromoimidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol

[0422]

[0423] 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, keeping the temperature below 10 ° C. The mixture was stirred at 0-10 ° C for 1.5 hours. At 0-5 ° C, 25 g of Na2SO4·10H2O was added to the mixture and stirred for 2 hours and filtered. The filter cake was suspended twice and filtered with dichloromethane / methanol (100 mL of a 10: 1 mixture). The combined filtrate was concentrated in vacuo, and the residue was purified by silica column chromatography (0-10% methanol / dichloromethane) to obtain 0.6 g of debromination by-products as white solid compound 7B (3.9 g, 72% yield) and as a yellow solid.

[0424] LCMS:t R = 1.958 and 2.016 min in \0-60AB_7min_220&254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30mm, 3μm), MS (ESI) m / z = 328.1 [M+H] + .

[0425] 1H NMR (400MHz, methanol-d4): δ = 7.80 (s, 0.3H), 7.78 (s, 0.6H), 4.47 (dt, J = 10.0, 2.0Hz, 0.6H), 4.20-4.13 (m, 0.3H), 3.84 (dd, J = 11.6, 3.2Hz, 0.6H), 3. 64(t,J=10.8Hz,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).

[0426] Compound 8B: (5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol

[0427]

[0428] 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 and purged with nitrogen 3 times, and 1,4-dioxane (3 mL) and water (1 mL) containing (2-fluoro-4-phenoxyphenyl) boronic acid (100 mg, 0.304 mmol) were added. The resulting mixture was stirred at 100 ° C under nitrogen for 2 hours. The mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (0-100% ethyl acetate / petroleum ether) to obtain compound 8B (80 mg impure, a mixture of trans / cis racemates) as a yellow oil.

[0429] LCMS:t R =2.274min&2.340min in 10-80AB_7min_220&254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30mm), MS (ESI) m / z=436.2[M+H] + .

[0430] SFC:t R=4.171min, 4.286min, 4.454min and 5.581min. Method: Column: Chiralcel OJ-3150×4.6mm ID, 3μm Mobile phase: A: CO2, B: methanol, Gradient: 5% to 40% B in 5min and 40% to 5% B in 0.5min, keep 5% B for 1.5min, Flow rate: 2.5mL / min, Column temperature: 35℃, ABPR: 1500psi.

[0431] 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

[0432] 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

[0433] 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

[0434] 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

[0435]

[0436] Compound 8B (80 mg) was further separated by preparative SFC (column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm); condition: 30% MeOH (0.1% NH3H2O) / CO2; flow rate: 60 mL / min) to give 6.8 mg of impure compound 11, which was further purified by preparative HPLC (column: Welch Xtimate C18 100*40 mm*3 μm, condition: 25-55% (A: water (0.225% FA), B: CH3CN), flow rate: 25 mL / min) to give compound 11 (1.7 mg, yield of 1% for 2 steps) as a white solid. After SFC, the mixture of the other three peaks (40 mg) was further purified by chiral SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); conditions: 55% MeOH (0.1% NH3H2O) / CO2; flow rate: 80 mL / min) to obtain compound 8 as a white solid (8.6 mg, 6.4% yield for 2 steps), compound 9 as a white solid (6.7 mg, 5% yield for 2 steps) and compound 10 as a white solid (5.4 mg, 4% yield for 2 steps).

[0437] Spectrum of compound 8:

[0438] LCMS:t R =2.356 min in 10-80AB_7min_220&254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30 mm), MS (ESI) m / z=436.2 [M+H] + .

[0439] HPLC:t R = 3.00 min in 10-80 CD_8 min.met. chromatograph (XBridge Shield RP 18 2.1*50 mm 5 μm).

[0440] 1H NMR (400MHz, CD3OD): δ = 7.84 (s, 1H), 7.54 (t, J = 8.4Hz, 1H), 7.47-7.41 (m, 2H), 7 .26-7.20(m,1H),7.17-7.12(m,2H),6.94(dd,J=8.0,2.0Hz,1H),6.88(dd,J=10 .8,2.4Hz,1H),4.56-4.51(m,1H),3.89(dd,J=11.6,3.6Hz,1H),3.65-3.48(m,4 H),2.51-2.42(m,1H),2.12-2.02(m,1H),1.99-1.85(m,1H),1.64-1.55(m,1H).

[0441] SFC:t R =4.059min, optical purity 99.94%.

[0442] Method: Column: Chiralcel OJ-3 150×4.6 mm ID, 3 μm Mobile phase: A: CO2, B: methanol (0.05% DEA), Gradient: 5% to 40% B in 5 min and 40% to 5% B in 0.5 min, maintain 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35°C, ABPR: 1500 psi.

[0443] Spectrum of compound 9:

[0444] LCMS:t R =2.340 min in 10-80AB_7min_220&254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30 mm), MS (ESI) m / z=436.3 [M+H]+.

[0445] HPLC:t R =2.99 min in 10-80 CD_8 min.met. chromatograph (XBridge Shield RP 18 2.1*50 mm 5 μm).

[0446] 1H NMR (400MHz, CD3OD): δ = 7.84 (s, 1H), 7.53 (t, J = 8.4Hz, 1H), 7.47-7.41 (m, 2H), 7 .25-7.19(m,1H),7.17-7.12(m,2H),6.94(dd,J=8.4,2.0Hz,1H),6.87(dd,J=11 .2,2.4Hz,1H),4.56-4.50(m,1H),3.88(dd,J=12.0,3.6Hz,1H),3.65-3.48(m,4 H),2.50-2.41(m,1H),2.12-2.02(m,1H),1.97-1.86(m,1H),1.64-1.55(m,1H).

[0447] SFC:t R =4.161min, optical purity 100%.

[0448] Method: Column: Chiralcel OJ-3 150×4.6 mm ID, 3 μm Mobile phase: A: CO2, B: methanol (0.05% DEA), Gradient: 5% to 40% B in 5 min and 40% to 5% B in 0.5 min, maintain 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35°C, ABPR: 1500 psi.

[0449] Spectrum of compound 10:

[0450] LCMS:t R =2.410 min in 10-80AB_7min_220&254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30 mm), MS (ESI) m / z=436.3 [M+H] + .

[0451] HPLC:t R =2.98 min in 10-80 CD_8 min.met. chromatograph (XBridge Shield RP 18 2.1*50 mm 5 μm).

[0452] 1H NMR (400MHz, CD3OD): δ = 7.86 (s, 1H), 7.50 (t, J = 8.4Hz, 1H), 7.47-7.41 (m, 2H) ,7.26-7.20(m,1H),7.17-7.12(m,2H),6.94(dd,J=8.4,2.4Hz,1H),6.88(dd,J =10.8,2.4Hz,1H),4.24-4.18(m,1H),3.75(t,J=11.2Hz,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).

[0453] SFC:t R =4.405min, optical purity 99.83%.

[0454] Method: Column: Chiralcel OJ-3 150×4.6 mm ID, 3 μm Mobile phase: A: CO2, B: methanol (0.05% DEA), Gradient: 5% to 40% B in 5 min and 40% to 5% B in 0.5 min, maintain 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35°C, ABPR: 1500 psi.

[0455] Spectrum of compound 11:

[0456] LCMS:t R =2.365min in 10-80AB_7min_220&254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30mm), MS (ESI) m / z=436.2[M+H] + .

[0457] HPLC:t R = 3.05 min in 10-80 CD_8 min.met. chromatograph (XBridge Shield RP 18 2.1*50 mm 5 μm).

[0458] 1H NMR (400MHz, CD3OD): δ = 7.86 (s, 1H), 7.50 (t, J = 8.4Hz, 1H), 7.47-7.41 (m, 2H) ,7.26-7.21(m,1H),7.17-7.12(m,2H),6.94(dd,J=8.4,2.4Hz,1H),6.88(dd,J =10.8,2.4Hz,1H),4.24-4.18(m,1H),3.75(t,J=10.8Hz,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).

[0459] SFC:t R =5.802min, optical purity 100%.

[0460] Method: Column: Chiralcel OJ-3 150×4.6 mm ID, 3 μm Mobile phase: A: CO2, B: methanol (0.05% DEA), Gradient: 5% to 40% B in 5 min and 40% to 5% B in 0.5 min, maintain 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35°C, ABPR: 1500 psi.

[0461] The following compounds were synthesized according to Method B:

[0462]

[0463]

[0464]

[0465]

[0466] Biological data

[0467] BTK WT and BTK C481S HTRF kinase assays

[0468] Recombinant BTK wild type (BTK WT) was purchased from Thermo Fisher. Recombinant BTK (C481S) was purchased from SignalChem. The inhibitory potency of the compounds on BTK and BTK (C481S) was assessed using a homogenous time resolved fluorescence approach.

[0469] Briefly, the recombinant kinase was pre-incubated for 30 minutes at room temperature in the presence or absence of the compound. The reaction was initiated by adding ATP and a substrate peptide, which can be phosphorylated by the kinase. After 120 minutes of incubation, the reaction was stopped by adding a detector mixture containing EDTA. Fluorescence was measured at 615nm and 665nm, respectively, with an excitation wavelength of 320nm. The calculated signal ratio of 665nm / 615nm is proportional to the kinase activity. The concentration of the compound that produces 50% inhibition of the corresponding kinase (IC50) was calculated using a four-parameter logistic fit using XL-fit.

[0470] Compound No. <![CDATA[BTK WT IC 50 (nM)]]> <![CDATA[BTK C481S IC 50 (nM)]]> Ibrutinib 0.22 9.26 1 1.16 1.06 2 0.60 0.66 3 6.29 6.59 4 0.49 0.61 5 4.92 5.42 6 0.62 0.42 7 1.59 1.53 8 3.45 2.80 9 8.64 6.42 10 0.90 0.95 11 4.51 5.03 12 0.27 0.27 13 3.29 3.81 14 0.70 0.86 15 6.72 6.11

[0471] p-BTK Elisa analysis of TMD8 cell line

[0472] TMD-8 cells were seeded at a density of 30,000 cells / well in 96-well plates with RPMI1640 medium containing 1.5% fetal bovine serum. Test compounds were added to the cells and the cells were incubated at 37°C, 5% CO2 for 0.5 hours. Pervanadate solution was then added to the cells to a final concentration of 100 μM, and the cells were incubated at 37°C, 5% CO2 for another hour. After compound treatment, cells were lysed and the cells were incubated as described in detail below. The p-BTK signal was detected using the protocol of the Phospho-Btk (Tyr223) Sandwich ELISA Kit (#23843). The plate was read on a Multiscan spectral reader set at a wavelength of 450 nm. The data were processed in GraphPad Prism software.

[0473] Compound No. <![CDATA[p-BTK IC 50 (nM)]]> Maximum inhibition level (%) Ibrutinib 3.0 100 1 18.9 97.9 2 29.1 98.4 3 78.4 96.2 4 30.7 97.4 5 48.7 95.8 6 26.2 98.8 7 137.5 97.9 8 42.1 100.9 9 123.5 107.7 10 29.0 98.5 11 34.7 99.3 12 23.2 97.0 14 24.3 98.0

[0474] HEK293-BTK(WT) and HEK293-BTK(C481S)

[0475] The full-length cDNA of BTK containing C481S mutation was generated by mutation induction using QuikChange II XL site-directed mutagenesis kit. The mutated BTK cDNA was confirmed by sequencing. Then the cDNA of BTK (WT) and BTK-C481S was cloned into PLVX-Puro lentiviral vector. The lentivirus was encapsulated in 293T cells by transfection and packaging mixture with lentiviral vector. BTK (WT) and BTK-C481S lentivirus were transfected into HEK293 cells. Transfected cells were selected in 2 μg / mL of puromycin. Stable polyclonal cell lines were confirmed by WB and used for further study. HEK293-BTK (WT) and HEK293-BTK (C481S) cells were cultured in DMEM (Gibco; 12430) with 10% FBS (Gibco; 10099) and 1 μg / mL puromycin. All cells were maintained at 37°C in a humidified incubator with 5% CO2.

[0476] HEK293-BTK (WT) and HEK293-BTK (C481S) cells were seeded at a density of 5000 cells / well in 96-well plates with RPMI1640 medium containing 1.5% fetal bovine serum. Test compounds were added to the cells and the cells were incubated at 37°C, 5% CO2 for 1.5 hours. After compound treatment, cells were lysed and the cells were cultured as described in detail below. The p-BTK signal was detected using the procedure of the Phospho-Btk (Tyr223) Sandwich ELISA Kit (#23843). The plate was read on a Multiscan spectral reader set at a wavelength of 450 nm. The data were processed in GraphPad Prism software.

[0477] Compound No. <![CDATA[HEK293 WT IC 50 (nM)]]> <![CDATA[HEK293 C481S IC 50 (nM)]]> Ibrutinib 18.1 770.4 2 27.3 70.6 4 18.8 84.2 6 33.4 75.4 10 60.0 170.0 12 17.6 46.8 14 16.0 36.3

[0478] TMD-8 antiproliferation assay

[0479] TMD-8 cells were prepared in RPMI1640 medium containing 10% fetal bovine serum and seeded in 384-well plates at 1500 cells per well. The cells were incubated overnight at 37°C, 5% CO2. After incubation, compounds with different concentrations were added to the assay plate and the cells were incubated for another 72 hours at 37°C, 5% CO2. After 72 hours of incubation, 15 μL of CellTiter AQueous single solution reagent was added to each well and the plate was incubated at room temperature for 30 min. Cell viability was determined using CellTiter-Glo (Promega, USA). CellTiter-Glo analysis was performed according to the manufacturer's instructions and fluorescence was determined in a multi-label reader (Envision, PerkinElmer, USA). Data were processed in XLfit software.

[0480] Compound No. Antiproliferation IC50(nM) Ibrutinib 1.9 1 24.2 2 22.7 3 106.4 4 16.2 5 102.0 6 27.4 7 219.1 8 77.0 9 160.5 10 32.2 11 70.9

[0481] In vitro rat / human hepatocyte clearance assay

[0482] Male rat hepatocytes and mixed sex human hepatocytes were obtained from commercial suppliers (e.g., Bioreclamation IVT) and stored at -150°C before use. A 10 mM stock solution of the test compound was prepared in DMSO. Thawed medium and supplemented incubation medium (serum-free) were placed in a 37°C water bath for at least 15 minutes before use. The stock solution was diluted to 100 μM by combining 198 μL of acetonitrile and 2 μL of the 10 mM stock solution.

[0483] Remove the vial of cryopreserved hepatocytes from storage, ensuring that the vial remains at cryogenic temperature. Thaw the vial in a 37°C water bath with gentle shaking. Keep the vial in a water bath until all ice crystals have dissolved and are no longer visible. Spray the vial with 70% ethanol and then transfer it to a biosafety cabinet. And then pour the contents into a 50mL thawing medium conical tube. Centrifuge the vial at room temperature at 100g for 10 minutes. Aspirate the thawing medium and resuspend the hepatocytes in serum-free culture medium to obtain approximately 1.5×10 6 cells / ml.

[0484] The cell viability and density were counted using the Trypan Blue exclusion method, and the cells were then diluted to 1×10 6 The working cell density is 1×10 viable cells / mL. 6 A portion of the hepatocytes at 10 viable cells / ml was boiled for 10 min and then added to the plate as a negative control to eliminate enzyme activity so that little or no substrate conversion should be observed. Inactivated hepatocytes were used to prepare negative samples, which were used to exclude misleading factors caused by the instability of the chemical itself.

[0485] Aliquots of 247.5 μ L hepatocytes are distributed in each hole of 96 well uncoated plates. Plate is placed in the incubator on the orbital oscillator for about 10 minutes. Aliquots of 100 μ M test compounds of 2.5 μ L are added to the corresponding holes of uncoated 96 well plates to initiate the reaction. This analysis is carried out in duplicate. Plates are cultivated in the incubator on the orbital oscillator for the time point of the design. At the time point of 5, 15, 30, 45, 60, 80 and 100 minutes, the contents of 20 μ L are transferred and mixed with the cold acetonitrile containing internal standard of 6 volumes (120 μ L) to terminate the reaction. Sample is centrifuged for 20 minutes at 4000 g and the aliquots of the supernatant of 100 μ L are used for LC-MS / MS analysis to measure the test compound.

[0486] In vitro hepatocyte clearance was estimated based on the elimination half-life (T1 / 2) of the compound disappearing from its initial concentration. The peak area ratio of each compound (test or control) to the IS was calculated. Ln (% of control) was plotted against incubation time (min) and the slope of the linear fit line was calculated. Drug elimination rate constant k (min -1 ), T1 / 2 (min) and in vitro intrinsic clearance CL int (μL / min / E6) is calculated according to the following equation:

[0487] k=-slope

[0488] T 1 / 2 =0.693 / k

[0489] CL int =k / Chep

[0490] Where Chep (cell × μL -1 ) is the cell concentration in the culture system.

[0491] Procedure for Log D determination

[0492] Place 10 μL of each cassette's working solution sequentially into the corresponding 96-well rack position (Log D plate). Add 500 μL of saturated octanol to each vial of the above uncovered Log D plate, followed by 500 μL of saturated phosphate buffer. Seal with a molded PTFE / SIL 96-well plate cover.

[0493] The Log D plate was transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 25°C, 2,000 rpm for 2 hours.

[0494] The samples were centrifuged at 4,000 rpm for 30 minutes at 25°C to separate the phases. A pipette and syringe were used to draw approximately 100 μL from the octanol and buffer phases, respectively, into a new 96-well plate.

[0495] 5 μL of the octanol sample was transferred to a new 96-well plate, followed by the addition of 495 μL of a mixture of H2O and acetonitrile containing an internal standard (1:1) as a 100-fold octanol sample. Vortex at 1,000 rpm for 5 minutes.

[0496] 50 μL of the 100-fold sample was transferred to a new 96-well plate, followed by the addition of 450 μL of a mixture of H2O and acetonitrile containing an internal standard (1:1) as a 1,000-fold octanol sample. Vortex at 1,000 rpm for 5 minutes.

[0497] The 1,000-fold octanol sample was serially diluted to 10,000, 100,000, and 1,000,000-fold with a mixture of H2O and acetonitrile containing the internal standard (1:1).

[0498] 50 μL of the buffer sample was transferred to a new 96-well plate, followed by the addition of 450 μL of a mixture of H2O and acetonitrile containing an internal standard (1:1) as a 10x buffer sample. Vortex at 1,000 rpm for 5 minutes.

[0499] The 10-fold buffer samples were serially diluted 100, 1,000, and 10,000-fold with a mixture of H2O and acetonitrile containing an internal standard (1:1). The samples were evaluated by LC / MS / MS analysis. All compounds were tested in duplicate.

[0500] All calculations were performed using Microsoft Excel. The concentration of the test compound in octanol / buffer solution was assessed by LC / MS / MS. The Log D value of the test compound was calculated as follows:

[0501]

[0502] DF means dilution factor.

[0503] Procedure for protein binding measurements in human plasma by using equilibrium dialysis

[0504] 597 μL of blank plasma was added to each vial of a new plastic plate or separate plastic tube by adding 3 μL of working solution of each box, vortexed at 1,000 rpm for 5 minutes. The final volume % of organic solvent was 0.5% and the final concentration of the test compound was 5 μM. 50 μL of the spiked plasma suspension was then transferred to a 96-well plate to serve as a T=0 control sample. The sample was treated identically to the sample after incubation. All remaining spiked plasma was placed in an incubator for the duration of the study.

[0505] The insert was placed in the well of the bottom plate with the open end facing upward. 500 μL of phosphate buffer (pH 7.4) was added to the buffer chamber, which is indicated by the white circle. 300 μL of spiked plasma sample was added to the sample chamber, which is indicated by the red circle. The unit was covered with a breathable cover and incubated at 37°C on an orbital shaker in a CO2 incubator at 300 rpm with 5% CO2 for 18 hours. At the end of the incubation, the cover was removed and 50 μL of the dialyzed sample was drawn from the buffer chamber and the plasma chamber into separate 96-well plates for analysis.

[0506] Meanwhile, the remaining spiked plasma samples in plastic plates or separate plastic tubes were incubated at 37°C in a CO2 incubator with 5% CO2 for 18 hours. At T = 18 hours, 50 μL of the original spiked plasma suspension was transferred to a 96-well plate for analysis.

[0507] 50 μL of human plasma was added to the buffer sample, and an equal volume of PBS was added to the collected plasma sample. The plate was vortexed at 1,000 rpm for 2 minutes and 400 μL of acetonitrile containing an appropriate internal standard (IS) was added to precipitate the protein and release the compound. Vortexed at 1,000 rpm for 10 minutes. Centrifuged at 4,000 rpm for 30 minutes. 250 μL of supernatant was transferred to a new 96-well plate and centrifuged again (4,000 rpm, 30 minutes). Then 100 μL of supernatant was transferred to a new 96-well plate for analysis. 100 μL of distilled water was added to each sample and vortexed at 1,000 rpm for 5 minutes to be analyzed by LC-MS / MS. All compounds were tested in duplicate at 5 μM in human plasma.

[0508] All calculations were performed using Microsoft Excel.

[0509] The percent unbound, percent bound, and percent recovered of the test compound were calculated as follows:

[0510] Unbound % = (Conc. 缓冲液室 / Conc. 血浆室 )×100%

[0511] Bound % = 100% - Free %

[0512] Recovery % = (500 × Conc. 缓冲液室 +300×Conc. 血浆室 ) / (300×Conc. 总样本 )×100

[0513]

[0514] Remaining % = Conc. 18hr / Conc. 0hr ×100%

[0515] result

[0516]

[0517] Short-term oral absorption (SOA) analysis in rats.

[0518] The short oral absorption (SOA) model is an in vivo screening model for identifying compounds with brain penetration. To assess the potential of compounds to cross the blood-brain barrier in rats, the AUC 大脑 / AUC 血浆 Measurement of total brain to plasma ratio (K p,大脑 ). The AUC at the available time points after oral administration were respectively CSF / AUC 血浆 or the average of the CSF to plasma ratio to determine the CSF to plasma ratio (K p,CSF ). In separate studies, the free fraction in biological matrices was determined by in vitro plasma and brain binding assays. K p,uu,大脑 and K p,uu,CSF Calculate by the following equation: (1) K p,uu,大脑 =K p,大脑 ×f u , 大脑 / f u,血浆 ; (2) K p,uu,CSF =K p,CSF / f u,血浆 .

[0519] Compound No. <![CDATA[Rat f u,br (%) / f u,pl (%)]]> <![CDATA[K p,大脑 ]]> <![CDATA[K p,uu Brain]]> <![CDATA[K p,uu CSF ]]> 2 3.3 / 3.8 1.35 1.19 0.86 10 2.2 / 3.7 0.38 0.23 0.56 14 1.5 / 2.0 0.32 0.23 0.59

Claims

1. A compound of formula (I): in: R 1 Selected from hydrogen and C 1-6 Alkyl; wherein R 1 Optionally, one or more R 5 replace; R 2 Selected from halogen, C 1-3 Alkyl, C 1-3 Alkoxy; k is 0; R 3 is selected from halogen; n is 0-4; R 4 is selected from halogen; m is 0-5; A is =N- or =C(R 6 )-; R 5 Selected from halogen, hydroxyl, C 1-6 Alkoxy, amino, NC 1-6 Alkylamino, N,N-(C 1-6 Alkyl)2amino, C 3-6 Carbocyclyl and azetidinyl groups; R 6 is selected from hydrogen and halogen; or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is hydrogen or methyl, R 5 is selected from hydroxy, methoxy, N,N-dimethylamino and azetidinyl.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 It's fluorine.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is 0-2.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 It's fluorine.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein m is 0-2.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is =N- or =C(H)-.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from: (5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; 3-(6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine; 7-(6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 7-(6-(azetidin-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-(6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; and 5-(2-Fluoro-4-phenoxyphenyl)-7-(6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from: ((2R,5R)-5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol; 3-((3R,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine; 7-((3R,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 7-((3R,6R)-6-(azetidin-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6R)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; (R)-5-(2-fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; 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.

10. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, and a pharmaceutically acceptable diluent or carrier.

11. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, or a pharmaceutical composition according to claim 10, in the preparation of a medicament for treating a disease or condition of a warm-blooded animal, the disease or condition being selected from: small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia ( macroglobulinemia, non-Hodgkin lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma, urticaria / Sjögren's syndrome, rheumatoid arthritis, osteoporosis, vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, asthma, multiple sclerosis, and systemic lupus erythematosus.

12. The use according to claim 11, wherein the warm-blooded animal is a human.

13. The use according to claim 11, wherein the disease or disorder is multiple sclerosis.

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